Fight Aging!

There are two ways to provide evidence for a specific cellular mechanism to cause a specific age-related disease. The first, the better method, is to remove, block, or work around the mechanism, while changing as few other variables as possible. This is better because it can lead immediately to the development of a therapy if it turns out that the mechanism in question is important. The worse option is to make the mechanism more active, while changing as few other variables as possible, and see if problems happen more rapidly because of that alteration. This is worse because there is always the risk that greater activity in any biological process does cause greater harm, but is nonetheless not actually relevant to aging and age-related disease because that greater activity never happens in the normal course of matters. DNA repair deficiency is a great example of the type. Significant impairment of DNA repair produces damage, dysfunction, and accelerated disease and mortality, but really isn't all that relevant to normal aging. All that this tells us is that it is important that DNA repair functions correctly, in the same way that it is important to breathe, or important that hearts beat and blood flows. There are many ways to cause damage by breaking the operation of our biochemistry - you can hit living organisms with a hammer, for example - but very few of them tell us much about aging and age-related disease.

With that preamble out of the way, today I'll point you to an interesting open access study in which the authors uses the worse of the two methods noted above to provide evidence for senescent cells to contribute to the development of osteoarthritis, a degenerative condition in which joint tissues become inflamed and break down. This is accomplished by transplanting a sizable number of senescent cells into the joints of mice and observing the outcome over a number of months following the transplant. Senescent cells accumulate in our tissues with age, and their presence is certainly a form of damage, with plenty of evidence to link it to the development of age-related disease. Researchers have produced benefits in laboratory animals by selectively destroying senescent cells, and a variety of these approaches are under development as clinical therapies. Given that, the more conditions linked to cellular senescence, the better off we all are. For this particular study, however, the question is whether or not transplanting senescent cells into tissue is a good enough replication of the processes of aging to tell us something, or whether it is just another sophisticated way of causing damage that isn't particularly relevant to aging. The devil is in the details, but having read the details, I'm leaning towards the former position.

Senescent cells cause harm through signaling. A cell becomes senescent and ceases replication in response to reaching the Hayflick limit, or suffering damage, or finding itself in a toxic environment. Most destroy themselves or are destroyed by the immune system, but some linger. Growing numbers of these cells eventually cause serious harm. A senescent cell secretes a mix of inflammatory and other signals that cause harm to surrounding tissue structures and change the behavior of normal cells for the worse. Perhaps a few percent of all cells in our tissues are senescent by the time we are old, but that is more than enough to cause major dysfunction. Since this is largely a signaling problem, it seems fairly reasonable to suggest that researchers could reproduce the effects of senescent cells on aging via transplantation. This would be something like the reverse of the goal of a stem cell transplant, in which the transplanted cells produce benefits largely through signaling. So long as the number of transplanted senescent cells falls within the bounds of what would be expected over the course of normal aging, one can argue that this type of study can be a good, rapid test of the outcomes that cellular senescence produces. In any case, read the paper and see what you think:

Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice

Osteoarthritis (OA) is one of the leading causes of pain and disability worldwide. It can greatly increase health care costs and reduce quality of life. The key characteristics of age-related OA in humans include damage of articular cartilage with joint space narrowing and degeneration of soft tissues. Age is the leading predictor for developing OA. However, modeling age- or senescence-associated OA, which may be distinct from injury-related OA, in mice has been challenging. So far, no disease-modifying drug has been approved to treat OA other than pain reducers, partly because etiological mechanisms of age-related OA have been poorly understood to date. Potential cellular mechanisms contributing to the development of OA include low-grade inflammation, chondrocyte alteration, mitochondrial dysfunction, loss of glycosaminoglycans, and dysregulated energy metabolism. In addition, a potential contribution by senescent cells has been suggested. Cellular senescence refers to a state of stable arrest of cell proliferation in replication-competent but apoptosis-resistant cells. Senescent cells accumulate with aging in various tissues, including the articular cartilage. One key feature of senescent cells is secretion of an array of pro-inflammatory cytokines, chemokines, and growth factors, termed the senescence-associated secretory phenotype (SASP). The SASP is observed across a number of senescent cell types, including fibroblasts and mesenchymal stem cells. Although mounting evidence suggests that cellular senescence is associated with OA, whether this link is causal remains to be determined.

To test if senescent cells cause an OA-like arthropathy, we injected either senescent or control nonsenescent fibroblasts into the knee joint region of mice. We transplanted seven mice with control cells and seven with senescent cells. Three months after cell injection, senescent and nonsenescent cell-injected knees were evaluated histologically and radiologically to assess articular cartilage and overall joint structure. We found that the senescent cells induced a phenotype with features resembling OA, including articular cartilage erosion, increased pain, and impaired function. We found that Rotarod performance was significantly decreased in the mice injected with senescent cells compared with animals injected with control nonsenescent cells or those that were not injected. In addition, we found that mice injected with senescent cells moved less and traveled shorter distances than mice injected with control nonsenescent cells. To our knowledge, this is the first evidence suggesting that cellular senescence can actually cause OA. Our findings also imply that targeting senescent cells is a promising approach for preventing or treating OA.

This both provides a new model of OA and implies that clearing senescent cells with senolytics or interfering with their pro-inflammatory SASP could be a disease-modifying therapeutic option. A next step will be to test such interventions in our senescent cell-transplanted model. One of the potential mechanisms by which senescent cells could induce an OA-like phenotype is through the SASP. OA is linked to inflammation and immune cells have been found in early stage OA. IL-6, one of the key SASP components, is highly associated with OA progression. We found that the senescent cells we transplanted secreted 20 times more IL-6 than nonsenescent cells. In addition, senescent cells can directly impair progenitor function through the SASP and spread senescence to nearby cells, both of which might contribute to dysfunction of chondrocytes and therefore to OA.

The finding that cellular senescence can drive development of an OA-like state is consistent with the geroscience hypothesis - that fundamental aging mechanisms, of which cellular senescence is one, predispose to age-related disabilities and chronic diseases, such as OA. If correct, this would imply that senescent cell accumulation may not only predispose to OA, but to multiple other age-related conditions, as is increasingly appearing to be the case. We predict that senolytics or SASP inhibitors such as ruxolitinib, which decreases IL-6 secretion and effects by senescent cells and also alleviates the senescent cell-induced stem cell dysfunction caused by TGFβ-related SASP factors, will delay, prevent, or alleviate OA. Consistent with this possibility, we found that senolytics attenuate age-related loss of glycosaminoglycans, a contributor to developing OA, from the intervertebral discs of progeroid mice. Moreover, senolytics are effective when administered periodically, likely because senescent cells do not of course divide and may be slow to re-accumulate once cleared in the absence of a strong continuing insult. We predict that senolytics may have fewer side effects than the anti-inflammatory agents currently used for controlling pain.

A recent commentary celebrates the granting of an International Classification of Disease (ICD) code to sarcopenia, an important step in the lengthy formal definition of a disease. Sarcopenia is the characteristic age-related decline of muscle mass and strength - though many would say that it only counts as sarcopenia if that decline is significantly greater than normal, and that "normal aging" should not be treated. Hopefully those voices will decline in the years ahead. The carving up of degenerative aging into named conditions is a long, slow, and messy process. It is driven by regulation rather than any sort of common sense goal, as regulators refuse to approve treatments for aspects of aging that are not formally defined as a disease. Thus there is far less funding and interest in those fields, and consequently slow progress. Turning reality into a regulatory definition requires lobbying, extensive debate, and a great deal of money that would be better spent on other things. In the case of sarcopenia, it has taken more than decade of work to get to the point at which the formal definitions of disease start to crystallize into bureaucratic acceptance. So much wasted time.

Sarcopenia has come a long way since Irwin Rosenberg first suggested the term to apply to age-related muscle mass. In 2010, the European Working Group on Sarcopenia defined sarcopenia as low muscle mass together with low muscle function (strength or performance). Subsequently, other international groups developed similar definitions for sarcopenia focusing on walking speed or distance walked in 6 min or grip strength in persons with lean muscle mass. A number of studies have confirmed the validity of these definitions. Based on the available literature, it would appear that sarcopenia is present in 5 to 10% of persons 65 years of age or older. This high quality research approach to sarcopenia has led to the recognition of sarcopenia as a disease entity with the awarding of an ICD-10-CM (M62.84) code in September, 2016. This is an important step similar to the much earlier recognition of osteoporosis as a disease state. This will lead to an accelerated interest in physicians making the diagnosis of sarcopenia and for pharmaceutical companies to accelerate the interest in developing drugs to treat sarcopenia. This research will be helped by there already being a number of biomarkers available for sarcopenia. This should also drive an increase in diagnostic tool availability for recognizing sarcopenia.

Sarcopenia is the most important cause of frailty in older persons. In addition, there is a close association between sarcopenia and bone loss and hip fracture - osteosarcopenia. Sarcopenia has also been found to be a major reason for poor outcomes in persons with diabetes mellitus. SARC-F is a simple screening test for sarcopenia. It prospectively identifies decreased walking speed, activities of daily living disability, hospitalization, and mortality. It has been shown to correlate well with the available international definitions for sarcopenia. There are numerous causes of sarcopenia including anorexia, inflammation, hypogonadism, lack of activity, hypovitaminosis D, motoneuron loss, insulin resistance, poor blood flow to muscle, mitochondrial dysfunction, and genetic causes. The established treatment for sarcopenia is resistance exercise. It appears that sarcopenia is always responsive to resistance exercise. Supplementation with leucine enriched, essential amino acid can also enhance muscle rejuvenation. Vitamin D declines with ageing, and supplementation enhances muscle function when deficient. Testosterone is the drug with the strongest record for increasing muscle mass and improving function. Anamorelin improves muscle mass but not strength. A number of other drugs are under development focusing mainly on myostatin and activin-2 receptor inhibitors. Selective androgen receptor molecules (SARMs) have also shown positive effects. Overall, the availability of an ICD-10 code for those of us who work in the area of muscle wasting disease is a very exciting time. Over the next few years, we can expect major advances in the treatment of older persons with sarcopenia.

Link: http://onlinelibrary.wiley.com/doi/10.1002/jcsm.12147/full

Back in 2015, Elizabeth Parrish underwent telomerase and follistatin gene therapy as a part of forming the startup BioViva: a human safety trial of one person, made public as a way to push the bounds of the current debate over when we should get started on human testing of these technologies. Personally, I agree that there is too much talk, too much unnecessary caution and hand-wringing, and not enough action. Sooner rather than later is better, especially given the large amount of animal data showing safety. Parrish is to be congratulated for forging ahead.

The latter of these two gene therapies is more interesting to me, as there is much more evidence in animal studies of the safety and effectiveness of either directly suppressing myostatin or enhancing follistatin to suppress myostatin. This has the effect of increasing muscle mass and reducing fat tissue, along the way tuning the operation of metabolism into a healthier mode of operation. It seems to me to be an enhancement that everyone should undergo, based on the evidence to date: a way to improve health and slow the age-related loss of muscle mass and strength. BioViva has now released some more data on the long term effects of the gene therapies, which show increased muscle mass, reduced fat, and improved aspects of metabolism. In a study of one, this should be taken as an anecdote, especially given that these items can all be changed over the longer term to some degree by lifestyle adjustments. The important thing is that safety has been proven, and that there appear to be benefits is just an added incentive to move to the next step of larger studies and availability of therapy via medical tourism. Hopefully the company will find the funding to achieve both of these goals.

In April 2016 BioViva stated that Elizabeth Parrish, CEO, had experienced telomere lengthening in her leukocytes, as a result of an injection of two experimental therapies. These consisted of a myostatin inhibitor to protect against loss of muscle mass with age, and a telomerase inducer to battle stem cell depletion responsible for diverse age-related diseases and infirmities. While the test was designed to establish the first human safety data regarding telomerase induction, in tests conducted by SpectraCell Laboratories, data indicated that her leukocyte telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. Further data will be released later this year. Upon further examination and testing, comparison of Parrish's data prior to the therapy and following the therapy has revealed additional positive changes. MRI scans taken before and after depict a slight increase in muscle size in conjunction with a noticeable reduction in muscle fat content. An over-accumulation of intramuscular fat, also known as 'marbling', is associated with increased insulin resistance, and as such an appropriate reduction may be linked to beneficial metabolic changes, in addition to the improved musculature. The aforementioned patient's total body weight has also not decreased during this period, and as such weight loss is not a confounding variable. The muscle growth achieved post-therapy corresponds with observed improvements in patients with Becker's Muscular Dystrophy, after receipt of myostatin inhibition gene therapy.

Researchers have noted that a significant reduction in fasting glucose was apparent in mice following telomerase gene therapy. The subject's fasting glucose has declined from previous measurements of 94 mg/dL and 86 mg/dL, to a fasting glucose level of 71 mg/dL by August 2016, as measured by Quest Diagnostics. Repeated testing will confirm the implied increase in insulin sensitivity. Previous research has also indicated that telomerase deficiency impairs glucose metabolism and insulin secretion in telomerase deficient mice, which may explain an apparent improvement in metabolic markers. In accordance with an improvement in metabolic health, triglyceride levels have also declined from 140 mg/dL in 2015 prior to the therapy, to 36 mg/dL in February 2016, subsequently rising to 80 and 84 mg/dL in August 2016. While there has been an increase in blood triglyceride content following the February reading, it is still measurably lower than before treatment. Both decreases in fasting glucose and triglycerides can be potentially explained by prior studies, of both telomerase and myostatin. Raised myostatin mRNA seen in type 2 diabetes patients is associated with impaired insulin sensitivity, raising triglyceride levels and low-grade chronic inflammation. Myostatin inhibition in mice has also been shown to reduce triglyceride levels and improve insulin sensitivity.

No negative effects have been reported, and there are no visible detrimental effects in blood analysis thus far; providing tentative evidence of safety in the first human test of BioViva's dual gene therapy strategy.

Link: http://bioviva-science.com/blog/dual-gene-therapy-has-beneficial-effects-on-blood-biomarkers-and-muscle-composition

Following the commercial shopping days of Black Friday and Cyber Monday is the day for non-profits and charitable donation, Giving Tuesday. It is a young idea, first announced in 2012, but a great idea, and one that has seen considerable adoption. Of this cluster of marked days, I expect Giving Tuesday to be the cultural phenomenon that will produce the greatest long-term change for the better. Just focusing on support for medical research, it is clear that very few people put any thought into where therapies come from and how progress in medicine happens. Every opportunity to explain to the public at large that the most important early stages of medical research are largely funded by philanthropy is an opportunity to increase that funding and speed progress. Yes, most people will ignore the request for help, but every year the communities focused on research for specific diseases grow. Every year more people realize that we live in the midst of a revolution in biotechnology, and medicine can and will make enormous progress in the decades ahead. In our case the disease is aging: addressing the root causes of aging will, to the extent that it is comprehensive and effective, halt and turn back all of the hundreds of named forms of age-related disease, as well as the frailty and degeneration that is currently thought of as normal.

For Giving Tuesday 2016 I ask you to make a donation to the SENS Research Foundation or Methuselah Foundation, organizations that have done more than any other over the past fifteen years to advance the state of rejuvenation research. They have pushed the scientific community towards developing much more of the basis for therapies capable of repairing the cell and tissue damage that causes aging, and funded many of these programs. They have removed roadblocks and enabled other groups to make significant progress. Indeed, the entire culture of the scientific community has changed over that time, from one in which it was career-threatening to talk about extending human life spans to one in which many researchers talk openly and publish papers on this topic. Now the biggest argument is over how to proceed. That, again, has a lot to do with the years of advocacy carried out by the SENS Research Foundation, Methuselah Foundation, and their allies. Fifteen years ago, next to no work on repair of the causes of aging was taking place. Now there is at least some funded research in every important line of work, and some are well funded indeed. This has come to pass because over this time a great many people have made charitable donations to the SENS Research Foundation and Methuselah Foundation, and those organizations made very good use of that money.

Until the end of 2016, all single donations made to the SENS Research Foundation will be matched, dollar for dollar, by the generosity of Michael Greve, who has put up a $150,000 challenge fund. Similarly, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put up another $36,000 challenge fund that will match the next year of donations for anyone who signs up as a SENS Patron to make monthly donations to the SENS Research Foundation. What are you waiting for?

This is a great time for progress in rejuvenation research and development, and a great time to reinforce that progress. The first class of therapies based on the SENS vision for rejuvenation, clearance of senescent cells, is in active development by a number of startup companies, including Oisin Biotechnologies, seed funded by the Methuselah Foundation and SENS Research Foundation, and UNITY Biotechnology, where the principals have raised more than $100 million to date to bring this therapy to the clinic. Other types of rejuvenation therapy that address other forms of cell and tissue damage are within a few years of that tipping point, given sufficient funding for continued research. Researchers focused on breaking down the cross-links that cause arterial stiffness and loss of elasticity in other tissues have made great strides in building the necessary tools thanks to SENS Research Foundation funding, and are presently engaged in the search for drug candidates. Removal of the amyloids that build up in old tissues is showing progress also in recent years, with a successful trial of clearance of transthyretin amyloid and the first trial in which amyloid-β was cleared in Alzheimer's disease patients. There is much more to tell, but you get the picture. Things are moving, the wheel is turning, and this is in large part due to our support for the SENS Research Foundation and Methuselah Foundation in past years.

We, the everyday philanthropists who dare to dream big, have helped to make these successes possible. We have pushing things past the first, hardest part of the bootstrapping process, and brought the end to frailty and disease in aging that much closer. We light the way, by our participation and advocacy attracting those who are more wealthy and conservative in their donations, and who were waiting for signs of support before stepping in. By donating today to the SENS Research Foundation and Methuselah Foundation, you help to set the foundation for the successes of the 2020s, for the widespread clinical availability rejuvenation therapies that, given the funding, will come to pass in that decade.

Rates of obesity and high blood pressure, or hypertension, follow the increases in wealth and comfort that have spread through much of the world over the past 60 years. Regions that are in the process of transitioning from predominantly poor agricultural populations to a level of wealth and mix of occupations that looks much more like Europe or the US, with South Korea as a good example of the full span of such a transition, see rising life expectancy as well as a rising level of lifestyle conditions. High blood pressure drives the development of cardiovascular disease, and is made worse by excess fat tissue and lack of exercise. Though at present we can't do much about the root cause of age-related increases in blood pressure, which is loss of elasticity in blood vessels, other than fund the most promising research that offers a path to meaningful therapies, we can adopt lifestyle choices that avoid making the problem larger than it has to be. Further, the past 20 years have seen some surprisingly effective advances in controlling high blood pressure through medication, surprising since these results have been achieved without doing much to address the underlying causes, but the very widespread use of these therapies has yet to spread to some of the regions that are now seeing increased incidence of hypertension.

In the past 40 years, there has been a large increase in the number of people living with high blood pressure worldwide because of population growth and ageing - rising from 594 million in 1975 to over 1.1 billion in 2015. The largest rise in the prevalence of adults with high blood pressure has been in low- and middle-income countries (LMICs) in south Asia (eg, Bangladesh and Nepal) and sub-Saharan Africa (eg, Ethiopia and Malawi). But high-income countries (eg, Australia, Canada, Germany, Sweden, and Japan) have made impressive reductions in the prevalence of adults with high blood pressure, according to the most comprehensive analysis of worldwide trends in blood pressure to date.

Both elevated systolic (higher than 140 mmHg; first number in blood pressure reading) and diastolic (higher than 90mmHg) blood pressure can be used to make a diagnosis of high blood pressure. Recent research suggests that the risk of death from ischemic heart disease and stroke doubles with every 20 mmHg systolic or 10 mmHg diastolic increase in middle and older ages. Over the past four decades, the highest average blood pressure levels have shifted from high-income western countries (eg, Norway, Germany, Belgium, France) and Asia-Pacific countries (eg, Japan) to LMICs in sub-Saharan Africa, South Asia, and some Pacific island countries. High blood pressure remains a serious health problem in central and eastern Europe (eg, Slovenia, Lithuania). The findings come from a comprehensive new analysis of global, regional, and national trends in adult (aged 18 and older) blood pressure between 1975 and 2015. This includes trends in average systolic (the maximum pressure the heart exerts while beating) and diastolic blood pressure (amount of pressure in the arteries between beats), as well as prevalence of high blood pressure. The Non-Communicable Disease (NCD) Risk Factor Collaboration pooled data from 1479 population-based studies totalling 19.1 million men and women aged 18 years or older from 200 countries (covering more than 97% of the world's adult population in 2015).

"High blood pressure is the leading risk factor for stroke and heart disease, and kills around 7.5 million people worldwide every year. Most of these deaths are experienced in the developing world. Taken globally, high blood pressure is no longer a problem of the Western world or wealthy countries. It is a problem of the world's poorest countries and people. Our results show that substantial reductions in blood pressure and prevalence are possible, as seen in high-income countries over the past 40 years. They also reveal that WHO's target of reducing the prevalence of high blood pressure by 25% by 2025 is unlikely to be achieved without effective policies that allow the poorest countries and people to have healthier diets - particularly reducing salt intake and making fruit and vegetables affordable - as well as improving detection and treatment with blood pressure lowering drugs."

Link: https://www.eurekalert.org/pub_releases/2016-11/tl-tln111416.php

Researchers here investigate a class of drug that blocks interleukin-1 receptor activity, something that has been found to reduce cell death and improve regeneration following stroke. This form of interference in cellular metabolism lowers the level of inflammation, but that may or may not be the most important mechanism in the outcome for stroke patients; it is plausible, but the details remain to be determined conclusively at this point.

The pro-inflammatory cytokine interleukin-1 (IL-1) is a major driver of inflammation, with well documented detrimental effects in multiple preclinical models of systemic inflammatory disease as well as in cerebral ischemia. To this end, the selective, naturally occurring competitive inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra) has shown potential as a new treatment for stroke. More specifically, in a number of experimental stroke paradigms IL-1Ra reduces infarct volume and improves long term functional outcome, including in co-morbid animals. However, exact mechanisms by which IL-1Ra is neuroprotective are yet to be fully established.

While much research has focused on limiting ischemic damage in the initial stages of acute reperfusion, it is also important to understand mechanisms that underpin brain repair following injury and develop strategies that enhance reparative endogenous processes, including adult neurogenesis. Ischemic injury elicits a robust neurogenic response by stimulating production of neuronal progenitor cells (NPCs) in distinct neurogenic regions, which include the subventricular zone (SVZ) and the subgranular zone (SGZ), to generate new functional neurons. Though mechanisms underlying post-stroke neurogenesis and the influence of inflammation on these processes are still poorly understood, it has been observed in young and aged animals that inflammation impairs both basal levels of neurogenesis and attenuates the neurogenic response triggered by central nervous system (CNS) injury via induction of the pro-inflammatory cytokines. IL-1, for example, reduces the proliferation and differentiation of NPCs to neurons in pathologies such as stress and depression, effects reversed by administration of IL-1Ra.

Here, we explored how inhibition of IL-1 actions by clinically relevant, delayed administration of subcutaneous IL-1Ra affects stroke outcome and neurogenesis up to 28 days after experimental ischemia, in aged/co-morbid and young rats. All experiments were performed using 13-month-old male, lean and corpulent (Cp) rats and 2-month-old Wistar rats. Cp rats are homozygous for the autosomal recessive cp gene (cp/cp), and spontaneously develop obesity, hyperlipidemia, insulin resistance, glomerular sclerosis, and atherosclerosis. Delayed IL-1Ra administration at 3 and 6 hours reperfusion in aged lean, aged Cp and young Wistar rats induced a significant reduction in infarct volume at 24 hours and 7 days of reperfusion, and a significant reduction in cortex loss at 28d in young Wistar rats. Reductions in infarct volume at 24 hours of reperfusion were 37%, 42% and 40% in aged lean, aged Cp and young Wistar rats respectively. IgG staining at 7 days reperfusion revealed a reduction of 40%, 48% and 46% in blood-brain barrier (BBB) damage in IL-1Ra treated aged lean, aged Cp and young Wistar animals respectively, versus their placebo-treated counterparts. A reduction of 26% was also observed at 14d reperfusion in young Wistar rats treated with IL-1Ra versus their placebo counterparts.

Our findings demonstrate that subcutaneous administration of IL-1Ra is neuroprotective in young and aged animals with multiple risk factors for stroke and increases post-stroke neurogenesis. It has previously been observed that delayed administration of IL-1Ra exerts neuroprotective effects at acute time points following experimental ischemia. Here we extend these findings to show that the early beneficial effects of IL-1Ra persist for at least 7 days in aged/co-morbid animals and for 28 days in young/healthy animals. Our data show that although 13-month-old corpulent rats had a plethora of stroke associated co-morbidities, infarct volumes were of a similar size to aged leans, suggesting that the extent of ischemic damage was close to maximal and that no further increase was possible. Conversely, younger rats were more resistant. This suggests that age is the primary variable that increases the brain susceptibility to infarction following an ischemic stroke. However, despite reaching maximal levels of infarction, tissue is still salvageable under these circumstances if IL-1Ra is administered within a therapeutic window.

Furthermore, our results indicate that although the delayed administration of IL-1Ra (3 and 6 hours from reperfusion onset) reduces infarct volume, it produces an increase on cellular proliferation and migration of immature neurons versus placebo counterparts in the SVZ following stroke in young and aged/co-morbid rats, suggesting that a reduced inflammation of the tissue fosters a more efficient repair of the damaged tissue. We also show that IL-1Ra increases the number of new integrated neurons in areas surrounding the infarct lesion in young animals compared to placebo groups a result that correlates with improvements in motor and behavioral sub-acute outcomes. The benefits of IL-1Ra are therefore not limited to inducing neuroprotection, but also favor and promote neurorepair mechanisms. We conclude that further studies are required to fully elucidate the mechanisms through which IL-1Ra may be mediating its beneficial, neurogenic effects.

Link: http://dx.doi.org/10.1016/j.bbi.2016.11.013

In the paper I'll point out today, researchers map an efficient form of protein quality control from stem cells and recreate it in somatic cells, producing extended life in nematode worms as a result. Proteins are large, complex molecules, and their correct function depends on the assumption of a precise three-dimensional arrangement after creation, a process known as protein folding. Proteins can and do misfold, however, and in doing so many become actively harmful rather than merely unwanted clutter. A baroque system of chaperone proteins assists in correct folding, as well as identification and removal of misfolded molecules. The presence of misfolded proteins is effectively a form of damage: some of the molecular waste that accumulates with age and contributes to the development of age-related disease consists of misfolded proteins, such as the various forms of amyloid, for example. The gradual failure of cellular recycling systems, such as declining lysosomal function caused by the presence of metabolic waste that is hard for the body to break down, or similar failures in the proteasome, also contribute to rising levels of damaged and dysfunctional proteins. Since aging is nothing more than the accumulation of damage and the reactions to that damage, more efficient operation of chaperone and other quality control systems in cells should slow aging: the less damage there is at any one time, the less of an opportunity that damage has to spread and cause secondary issues. It is probably not a coincidence that increased quality control activity is observed in many of the methods shown to modestly slow aging in laboratory animals, and that some forms of slowing aging cannot work without that quality control boost.

As for any study that extends life in short-lived species in this way, it is worth noting that the life span of short-lived species is far more plastic than that of longer-lived species such as we humans. Where the research community can directly compare methods, such as calorie restriction, exercise, or growth hormone receptor mutation, it is clear that doubling worm life spans or a 40-60% increase in mouse life spans certainly doesn't map to that much of a change in human life span - or even more than just a few years. If it did, we've have noticed by now, as it would leap out of the data on human health and mortality. That researchers don't see that in the data constrains the effects to be fairly small, a handful of years at most. So for my part I believe we should look at this and other similar studies as indicators of importance, not a literal guide to building human therapies. These studies help to point out which forms of age-related molecular damage have the biggest impact, and thus are the highest priority for repair via the methods outlined in the SENS rejuvenation research proposals. It isn't a suggestion to attempt to adopt modified chaperone systems in humans, as that would be a highly inefficient way to proceed. It would likely produce results on a par with exercise or calorie restriction: improved health, modestly slowed aging. That is far less useful than methods of repairing the damage, clearing out all of the misfolded proteins every now and again before they rise to the level of causing real issues. Periodic repair can create rejuvenation if comprehensive enough. In the near term of decades, adjusting biology to run in a different way can only modestly slow aging; it will be a long time indeed before the research community is capable of safely creating a new biology that doesn't age in this way. That is time far better spent on the faster path to working rejuvenation treatments.

Defining immortality of stem cells to identify novel anti-aging mechanisms

With age, somatic cells such as neurons lose their ability to maintain the quality of their protein content. Pluripotent stem cells, on the contrary, do not age and have increased mechanism to maintain the integrity of their proteins. The survival of an organism is linked to its ability to maintain the quality of the cellular proteins. A group of proteins called chaperones facilitate the folding of proteins and are essential to regulating the quality of the cellular protein content. This ability declines during the aging process, inducing the accumulation of damaged and misfolded proteins that can lead to cell death or malfunction. Several neurodegenerative age-related disorders such as Alzheimer's, Parkinson's or Huntington's disease are linked to a decline in protein quality control.

Human pluripotent stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity necessarily demands avoidance of any imbalance in the integrity of their protein content. "There is one chaperone system, the TRiC/CCT-complex that is responsible for folding about 10% of all the cellular proteins. By studying how pluripotent stem cells maintain the quality of their proteome, we found that this complex is regulated by the subunit CCT8. Then, we discovered a way to increase the assembly and activity of the TRiC/CCT complex in somatic tissues by modulating this single subunit, CCT8. The increase resulted in prolonged lifespan and delay of age-related diseases of the model organism Caenorhabditis elegans. For this study we combined the results from human pluripotent stem cells and C. elegans, to have both in vitro and in vivo models, providing a more convincing approach. Our results show that expressing CCT8 as the key subunit of the complex is sufficient to boost the assembly of the whole system. It is very interesting that expressing this single subunit is enough to enhance protein quality and extend longevity, even in older animals. One of our next steps will be to test our findings in mice."

Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan

Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.

The comparative biology of aging and longevity, comparing the biochemistry of similar species with different life spans, is a good way to improve understanding of which aspects of our biology are important determinants of degeneration and age-related disease. In the open access paper linked here, researchers undertake an examination of gene expression profiles in cell cultures for a range of mammalian species, for example. Despite the usefulness, as an investigative method this will, I expect, be overtaken by prototype rejuvenation therapies based on damage repair in the years ahead. Aging is an accumulation of cell and tissue damage, and the best way to determine the contribution of any one particular type of damage is to remove it. Researchers are beginning that process for cellular senescence, now that senescent cells can be selectively destroyed in an efficient manner, and other items from the SENS portfolio of rejuvenation biotechnologies will be added as they reach the stage of practical demonstration in animal studies.

The maximum lifespan of mammalian species differs by more than 100-fold, ranging from ~2 years in shrews to more than 200 years in bowhead whales. While it has long been observed that maximum lifespan tends to correlate positively with body mass and time to maturity, but negatively with growth rate, mass-specific metabolic rate, and number of offspring, the underlying molecular basis is only starting to be understood. One way to study the control of longevity is to identify the genes, pathways, and interventions capable of extending lifespan or delaying aging phenotypes in experimental animals. Studies using model organisms have uncovered several important conditions, such as knockout of insulin-like growth factor 1 (IGF-1) receptor, inhibition of mechanistic target of rapamycin (mTOR), mutation in growth hormone (GH) receptor, ablation of anterior pituitary (e.g. Snell dwarf mice), augmentation of proteins of the sirtuin family, and restriction of dietary intake. While many of these genes and pathways have been verified in yeast, flies, worms, and mice, the comparisons largely involve treatment and control groups of the same species, and the extent to which they explain the longevity variations across different species is unclear. For example, do the long-lived species have metabolic profiles resembling calorie restriction? Do they suppress IGF-1 or growth hormone signaling compared with the shorter-lived species? More generally, how do the evolutionary strategies of longevity relate to the experimental strategies that extend lifespan in model organisms?

To address these questions, a popular approach has been to compare exceptionally long-lived species with closely related species of common lifespan and identify the features associated with exceptional longevity. Examples include the amino acid changes in Uncoupling Protein 1 (UCP1) and production of high-molecular-mass hyaluronan in the naked mole rat; unique sequence changes in IGF1 and GH receptors in Brandt's bat; gene gain and loss associated with DNA repair, cell-cycle regulation, and cancer, as well as alteration in insulin signaling in the bowhead whale; and duplication of the p53 gene in elephants. Again, it is important to ascertain whether these mechanisms are unique characteristics of specific exceptionally long-lived species, or whether they can also help account for the general lifespan variation.

An extension of this approach has been cross-species analyses in a larger scale. For example, several biochemical studies across multiple mammalian and bird species identified some features correlating with species lifespan. Longevity of fibroblasts and erythrocytes in vitro, poly (ADP-ribose) polymerase activity, and rate of DNA repair were found to be positively correlated with longevity, whereas mitochondrial membrane and liver fatty acid peroxidizability index, rate of telomere shortening, and oxidative damage to DNA and mitochondrial DNA showed negative correlation. The advent of high throughput RNA sequencing (RNAseq) and mass spectrometry technologies has enabled the quantification of whole transcriptomes, metabolomes, and ionomes, across multiple species and organs. These studies revealed the complex transcriptomic and metabolic landscape across different organs and species, as well as some overlaps with the changes observed in the long-lived mutants created in laboratory.

While molecular profiling of mammals at the level of tissues may better represent the underlying biology, profiling in cell culture represents more defined experimental conditions and allows further manipulation to alter the identified molecular phenotypes. In this study, we examined the transcriptomes and metabolomes of primary skin fibroblasts across 16 species of mammals, to identify the molecular patterns associated with species longevity. We report that the genes involved in DNA repair and glucose metabolism were up-regulated in the longer-lived species, whereas proteolysis and protein translocation activities were suppressed. The longer-lived species also had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine and higher levels of amino acids; and the latter finding was validated in an independent dataset of bird and primate fibroblasts.

Link: http://dx.doi.org/10.7554/eLife.19130

To what degree does regular exercise beyond the recommended minimum of 30 minutes a day improve long-term health and life expectancy? This and related questions on the shape of the dose-response curve for aerobic exercise remain open for debate. It is clear that being sedentary has a cost in terms of health and life expectancy, and the balance of evidence to date suggests that the 80/20 point for benefits due to exercise is found somewhere higher than the generally recommended level. Yet it is unclear as to whether professional athletes, who tend to live longer than the general population, live longer because of the high levels of exercise or because they also tend to be more robust individuals who would have enjoyed greater longevity regardless of profession. While it remains to put good numbers to much of the dose-response curve for exercise, this study of the Hadza people adds to the evidence for additional benefits to accrue to those who go beyond 30 minutes a day:

The Hadza live a very different kind of lifestyle - and a very active one, engaging in significantly more physical activity than what is recommended by U.S. government standards. They also have extremely low risk of cardiovascular disease. Researchers have spent several years studying the lifestyle of the Hadza. "Our overall research program is trying to understand why physical activity and exercise improve health today, and one arm of that research program aims to reconstruct what physical activity patterns were like during the evolution of our physiology. The overarching hypothesis is that our bodies evolved within a highly active context, and that explains why physical activity seems to improve physiological health today."

The U.S. Department of Health and Human Services recommends that people engage in 150 minutes per week of moderate intensity activity - about 30 minutes a day, five times a week - or about 75 minutes per week of vigorous intensity activity, or an equivalent combination of the two. However, few Americans achieve those levels. The Hadza, on the other hand, meet those weekly recommendations in a mere two days, engaging in about 75 minutes per day of moderate-to-vigorous physical activity, or MVPA. Furthermore, and consistent with the literature identifying aerobic activity as a key element necessary to a healthy lifestyle, researchers' health screenings of Hadza people have shown that the population has extremely low risk for heart disease. "They have very low levels of hypertension. In the U.S., the majority of our population over the age of 60 has hypertension. In the Hadza, it's 20 to 25 percent, and in terms of blood lipid levels, there's virtually no evidence that the Hadza people have any kind of blood lipid levels that would put them at risk for cardiovascular disease."

While physical activity may not be entirely responsible for the low risk levels - diet and other factors may also play a role - exercise does seem to be important, which is significant because humans' physical activity levels have drastically declined as we have transitioned from hunting and gathering to farming to the Industrial Revolution to where we are today. "Over the last couple of centuries, we've become more and more sedentary, and the big shift seems to have occurred in the middle of the last century, when people's work lives became more sedentary. In the U.S., we tend to see big drop-offs in physical activity levels when people age. In the Hadza, we don't see that. We see pretty static physical activity levels with age. This gives us a window into what physical activity levels were we like for quite a while during our evolutionary history, and, not surprisingly, it's more than we do now. Perhaps surprisingly, it's a whole lot more than we do now. Going forward, this helps us model the types of physical activity we want to be looking at when we explore our physiological evolution. When we ask what kinds of physical activity levels would have driven the evolution of our cardiovascular system and the evolution of our neurobiology and our musculoskeletal system, the answer is not likely 30 minutes a day of walking on a treadmill. It's more like 75-plus minutes a day."

Link: https://uanews.arizona.edu/story/modern-huntergatherers-show-value-exercise

Cellular senescence is one of the root causes of aging, and there are at present serious, well-funded efforts underway to produce rejuvenation therapies based on the selective destruction of senescent cells in old tissues. This progress is welcome, but it could have started a long time ago. It has taken many years of advocacy and the shoestring production of technology demonstrations to finally convince the broader community of scientists and funding institutions that the evidence has long merited serious investment in treatments to clear senescent cells. This is what it is, and now we must look to the future, for all that it has been a long, uphill battle. Cellular senescence is today having its time in the sun. Many research groups are linking the mechanisms of senescence to other aspects of aging; senescent cells are showing up in many more research papers than in past years, now that there is more of a scientific and financial incentive to search carefully for their influence. I think that declaring cellular senescence to be the causal nexus of aging, as one research group did, is going overboard a little, as there are, after all, other independent causes of aging, forms of metabolic waste and damage that would cause death and disease even if cellular senescence did not exist. Nonetheless, it is gratify to watch the spreading realization that cellular senescence plays a role in many areas of health and biology associated with aging. The advent of therapies that can remove senescent cells promises to produce sweeping beneficial effects on aging and disease.

There is a set of fairly well established threads of research that link aging with visceral fat tissue and immune dysfunction in the form of chronic inflammation. Visceral fat produces an accelerated pace of aging by generating greater chronic inflammation, producing an hostile tissue environment of inappropriate signals that attract immune cells and then cause those cells to become dysfunctional. The more fat there is the more inflammation it creates. This is thought to be the primary mechanism by which obesity increases the risk and severity of age-related disease. All of the common age-related diseases are accelerated in their progression by higher levels of chronic inflammation. The material difference between a lot of fat and a normal amount of fat is well demonstrated by a study in which researchers produced life extension in mice through surgical removal of visceral fat, but there is a mountain of data on human health to show that people who are overweight will suffer a shorter life expectancy and more age-related illness, and that this effect scales by the amount of excess fat tissue. How do senescent cells fit into this picture? One of the characteristic features of senescent cells is that they produce greater levels of chronic inflammation via the secretion of signal molecules such as cytokines. Of late, researchers have shown that senescent cells are found in the immune system, as in other cell populations. Given this, it should not be a surprise to find that cellular senescence can be implicated in the way in which visceral fat accelerates aging: their presence in visceral fat tissue and the immune cells interacting with that tissue fits right in with the broader picture of inflammation and bad cellular behavior.

Obesity accelerates T cell senescence in murine visceral adipose tissue

Visceral obesity is associated with chronic low-grade inflammation in visceral adipose tissue (VAT) and a sustained whole-body proinflammatory state, which may underlie metabolic and cardiovascular diseases. VAT inflammation associated with obesity involves a complex network of responses of immune cell components, including acquired immune cells such as various subsets of T cells and B cells and innate immune cells such as macrophages. Among these cells, CD4+ T cells have been recognized as a central regulator of chronic VAT inflammation. The number of CD4+ T cells in VAT increases as the tissue expands in obesity. Factors that drive CD4+ T cell expansion and into proinflammatory effectors in VAT during the development of high-fat diet-induced (HFD-induced) obesity may include MHC class II-associated antigens, possibly self-peptides, because the T cell receptor (TCR) repertoire of CD4+ T cells in VAT is limited, and deficiency of MHC class II protects mice from high fat diet (HFD)-induced VAT inflammation and insulin resistance. However, the obesity-associated immune background underlying chronic inflammation in VAT remains elusive.

Significant changes occur in the overall T cell populations with age. In CD4+ T cells, proportions of naive (CD44loCD62Lhi) cells sharply decline in ontogeny, with an age-dependent increase in cells of the memory phenotype (CD44hiCD62Llo). Among CD44hiCD4+ T cells, a unique population expressing programmed cell death 1 (PD-1) and CD153 actually increases with age in mice. The CD153+PD-1+CD44hiCD4+ T cell population shows compromised proliferation and regular T cell cytokine production on T cell receptor (TCR) stimulation but secretes large amounts of proinflammatory cytokines, such as osteopontin. These CD4+ T cells also show signatures of cell senescence, including a marked increase in senescence-related gene expression and nuclear heterochromatin foci, and are termed senescence-associated T cells (SA-T cells). Notably, the age-dependent development of SA-T cells, which may include autoreactive cells, is dependent on B cells. As such, the increase in SA-T cells is suggested to be involved in part in immune aging phenotypes such as impaired acquired immune capacity, increased proinflammatory traits, and high risk for autoimmunity.

In the present study, we demonstrate that CD153+PD-1+CD44hiCD4+ T cells are remarkably increased and preferentially accumulated in the VAT of HFD-fed mice in a B cell-dependent manner and that these CD4+ T cells show functional and genetic features strongly resembling SA-T cells that increase in secondary lymphoid tissues with age. We also indicate that the CD153+PD-1+CD44hiCD4+ T cells play a crucial role in inducing chronic VAT inflammation and metabolic disorder via secretion of large amounts of osteopontin. We demonstrated that adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells, but not other CD4+ T cells, from HFD-fed spleens into VAT of ND-fed mice recapitulates the features of VAT inflammation, including a striking increase in CD11chiCD206lo macrophages and expression of proinflammatory cytokine genes. It is noteworthy that CD153+PD-1+CD4+ T cells in VAT of HFD-fed mice show features indistinguishable from those of CD153+ SA-T cells, which gradually increase systemically with age. The age-dependent increase in CD153+ SA-T cells may partly underlie the immune aging, including a reduction in acquired immunity and an increase in the inflammatory trait and autoimmunity risk. Obesity is also associated with diminished resistance against infection, chronic low-grade inflammation, and a greater susceptibility to autoimmunity. It has been suggested that the increase in CD153+ SA-T cells in chronological aging and systemic autoimmunity is attributable to a robust, homeostatic T cell proliferation, but the precise mechanism underlying the accumulation of these T cells in VAT of HFD-fed mice remains to be investigated. Nonetheless, it is an intriguing possibility that the predisposition often associated with obesity may partly be a systemic manifestation of the premature increase in CD153+ SA-T cells in VAT, since adipose tissues can constitute up to 50% to 60% of total BW in severe obesity.

Both birds and bats have great longevity for their size in comparison to mammalian species that do not fly, which has led researchers to theorize that the metabolic demands of flight lead to the evolution of cell structures that are more resistant to the damage of aging. Energy metabolism revolves around the mitochondria, the power plants of the cells, and so this in turn points to an important role for mitochondrial function and damage to mitochondria in determining aging and longevity, both across species and in individuals. There are good correlations between mitochondrial composition, the degree to which mitochondrial structures can resist oxidative damage, and mammalian life span, for example. Researchers here take a more reductionist approach to the question of why bats are exceptionally long-lived, and begin by mapping the RNA of a bat species:

Of all mammals, bats possess some of the most unique and peculiar adaptations that render them as excellent models to investigate the mechanisms of extended longevity and potentially halted senescence. They are considered the 'Methusalehs' among mammals due to their exceptional and surprising longevity given their body size and metabolic rate. Typically mammals that are small have a high metabolic rate (e.g. shrews) and do not live for a long time. However, despite their small size and high metabolic rate bats can live for an exceptionally long time, with the oldest recorded Brandt's bat (wild caught as an adult) ever recaptured being more than 41 years old with a body weight of 7 grams. Indeed, to get a positive correlation between longevity and body size in mammals, bats must be removed from the analyses. By comparing the ratio of expected longevity to that predicted from the 'non-bat placental mammal' regression line (longevity quotient - LQ) only 19 species of mammals are longer lived than man, one of these species being the naked mole rat and the other 18 are bats. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity.

MicroRNA (miRNA) are a subset of short endogenous non-coding RNA that play a significant role in post-transcriptional regulation, via repression of translation. Since the first miRNA was discovered in 1993, a multitude of miRNA have subsequently been identified, and implicated in the regulation of the vast majority of biological pathways including cell cycle regulation, metabolism, tumorigenesis, as well as immune response. However, the role of miRNA regulation in mammalian ageing and the onset of age-related diseases has only recently been established. In mammals, various miRNA have been shown to be differentially expressed during ageing, most of which appear to be generally tissue-specific. In addition to tissue-specific ageing, it is increasingly evident that many miRNA regulate gene expressions in well-known ageing pathways, most notably in the p53 tumor suppressor pathway and insulin-like growth factor signaling pathway.

Despite being the second largest order of mammals (~1200 species), there is a scarcity of genomic and transcriptomic bat resources. To date, only five well-annotated bat genomes are publically available. Phylogenomic studies of bat genomes and other mammalian species reveal that a number of genes are under positive selection in bats. These genic adaptations have been correlated with traits such as echolocation, powered flight, hibernation, immunity and longevity. For example, specific non-synonymous mutations in GHR and IGF1R, key ageing-related genes, were detected in several long-lived vespertilionid bats (M. brandtii, M. lucifugus and Eptesicus fuscus), while a large proportion of genes involved in DNA repair (RAD50, KU80, MDM2, etc.) and the NF-кB pathway (c-REL and ATM2, etc.) were reported to be under positive or divergent selection in M. davidii and P. alecto. These results suggest bats may better detect and repair DNA damage. Intriguingly, positive selection was also detected in mitochondrial-encoded and nuclear-encoded oxidative phosphorylation genes in bats, which may explain their efficient energy metabolism necessary for flight. Apart from comparative genome analysis, only a small number of transcriptomic studies on bats using have been carried out, focused primarily on the characteristics of hibernation, immunity, echolocation and phylogeny. However, the molecular mechanisms of adaptations affecting longevity are still far from understood, especially with respect to gene regulation.

In the present study, we sequenced six small RNA libraries from whole blood sampled from wild-caught greater mouse-eared bats (Myotis myotis) and for the first time made genome-wide comparisons of both miRNomes and mRNA transcriptomes between bat and non-bat mammalian species (human, pig and cow). The profiling of the M. myotis blood miRNome showed a large number of bat-specific miRNA involved in regulating important pathways related to immunity, tumorigenesis and ageing. Comparative analyses of both miRNomes and transcriptomes also revealed distinctive longevity mechanisms in bats. Several up-regulated miRNA possibly act as tumor suppressors. Gene Ontology (GO) enrichment analysis of differentially expressed protein-coding genes showed that up-regulated genes in bats compared to other mammals were mainly involved in mitotic cell cycle and DNA damage repair pathways while a high number of down-regulated genes were enriched in mitochondrial metabolism. The results and data presented here show unique regulatory mechanisms for protection against tumorigenesis, reduced oxidative stress, and robust DNA repair systems, likely contribute to the extraordinary longevity of bats.

Link: http://dx.doi.org/10.1186/s12864-016-3227-8

Very few genetic variants robustly correlate with longevity across different study populations, and those that do, such as variants of APOE and FOXO3A, have small effects, only visible in the mortality statistics of large numbers of people. This indicates that the genetics of longevity, the way in which variations in metabolism and the response to high levels of age-related cell and tissue damage in later life can produce modestly different mortality rates, is a matter of many thousands of tiny, interacting contributions, very sensitive to environmental factors. It appears ever less likely that there will be any easy, small number of genetic changes that can be made to humans in order to produce significant lengthening of life. Thus the study of genetics and longevity isn't the place to be looking for cost-effective ways to produce radical life extension of decades and more. This paper is one of many recent illustrations of this point; none of the described problems would be anywhere near as much of a challenge if there was a large genetic effect on aging and longevity with simple, narrow origins there to be found. That would stand out from the data much more readily.

The results of many genome-wide association studies (GWAS) of complex traits suffer from a lack of replication. Differences in population genetic structures among study populations are considered to be possible contributors to this problem. One aspect of population structure - the differences in genetic frequencies among subgroups of individuals comprising the population - was traditionally linked with the effects of population stratification. Another one - the presence of linkage disequilibrium (LD) in many parts of the human genome including those that contain causal single-nucleotide polymorphisms (SNPs) - was actively exploited in GWAS of complex traits. Methods of fine mapping following the "discovery" phase are used for evaluating causal SNPs. One could expect that the non-replication problem due to differences in LD patterns among study populations in GWAS would disappear if the detected marker SNP is a causal one, i.e., if it contributes to the variability of a trait. It turns out that the differences in LD levels around a functional SNP may still contribute to the non-replication problem.

The estimated associations in this case depend on whether the detected functional SNP is in LD with another functional SNP, the effects of these SNPs on the trait in the absence of LD (pure effects), and on the level of LD between corresponding SNP loci. This property has important consequences for interpretation of the results of genetic analyses of complex traits. In the presence of LD the estimated effects of a causal SNP may be spurious and may incorrectly characterize the biological relationships between the SNP and the trait. In contrast the pure effect of a given causal SNP estimated in the absence of LD with other such SNPs may correctly characterize the biological connections between the SNP and the trait. Therefore, for example, performing genetic analyses of African populations (that have lower levels of LD patterns for many SNP pairs than populations of European origin) has the potential to reduce bias in the estimated effects of functional SNPs on a trait caused by the presence of LD between functional loci. This condition is, however, not sufficient because of the possible presence of hidden gene/gene interaction effects, gene/environment correlations, and gene/environment interaction effects.

Human lifespan and many other aging, health and longevity related traits are multifactorial phenotypes, that is, they are affected by many genetic and non-genetic factors. The relationships between genes and these phenotypes have special features that distinguish them from other complex traits, influence methods of their genetic analyses, and affect the interpretation of the research results. The genetic variants that influence aging, health, and longevity related traits generate age dependent changes in the population genetic structure, i.e., changes in the frequencies of genetic variants and in the levels of linkage disequilibrium (LD) among them. This feature has important implications for studies focused on the replication of GWAS research findings: independent populations involved in such studies often have different genetic structures, due in part to the differences in the population age distribution at the time of biospecimen collection. As a result, the frequencies of the genetic variants associated with these traits and their LD patterns may differ even if the genetic structures in the corresponding population cohorts were the same at birth.

Detecting statistically significant associations of genetic variants with complex traits is not the end of the genetic analyses. One reason is that the relationship between a detected marker SNP and the complex trait of interest is not, necessarily, a causal one. More often these relationships serve as proxies for the real effect of some unobserved causal SNPs (due to linkage disequilibrium (LD) between the marker and causal SNPs), and, hence, do not have a direct biological effect on the phenotype. To generate insights about the biological mechanisms responsible for the trait's variability one has to identify the causal SNPs responsible for the association signal. To identify such SNPs a number of efficient fine-mapping procedures have been recommended. The main limitation of existing methods is that they seek to identify a single causal variant which is independent of (not in LD with) other causal variants. Since this is not sufficiently realistic, a new approach that allows for efficient detection of multiple causal variants has been proposed. The case where two or more causal SNPs are in LD creates additional problems for interpretation of the results of genetic association studies.

In this paper we show that the estimates of the effects of a causal SNP on lifespan depend on the genetic structure of the population under study (e.g., the level of LD of the SNP with other causal SNPs). Genetic association studies of this trait using data from populations with different LD levels are likely to produce different results. We show that differences in population genetic structures can explain why genetic variants favorable for longevity in one population appear as harmful risk factors in another population. Population structure may also be responsible for the age-specific effects of genetic variants on mortality risk. Differences in genetic structures in distinct populations may be responsible for the low level of replicability of GWAS of human aging, health, and longevity related traits.

Link: http://dx.doi.org/10.3389/fgene.2016.00188

I stumbled upon an interesting open access paper a few days ago, linked below, in which the authors present their view of immunosenescence, the age-related failure of the immune system, as being in part a process wherein some cells of the adaptive immune system change their characteristics and function to become more like innate immune system cells. It makes for interesting reading, though it is worth bearing in mind that the immune system as a whole is fantastically complex, and in many ways still a dark and unmapped forest. It is easy to theorize unopposed when there is such a lot of empty space remaining on the map, making it hard to argue concretely about the relative importance of various mechanisms and observations. This poor understanding of the intricacies of the immune system is why autoimmune diseases and immune aging are largely lacking in effective treatments, and why the best of the prospective cures are those that sidestep the entire question of specific causes and mechanisms in face of the Gordian strategy of destroying the entire immune system in order to start over with new stem cells and immune cells.

As you might know, the immune system of most higher animals is two-layered. The layer that evolved first, and which remains the entirety of the immune system in lower animals such as insects, is known as the innate immune system. It reacts quickly, generates inflammation, and reacts in the same, predictable way to every threat. It has no memory and does not reconfigure its operations in response to circumstances and history. Later in evolutionary history, a second layer known as the adaptive immune system came into being, a more sophisticated set of functions resting on top of the existing innate mechanisms. The innate immune system reacts to intruders, and then the adaptive immune system records the nature of the threat and responds in its own manner, augmenting the attack. As the name suggests, the adaptive immune system maintains a memory and adjusts its operations in order to more aggressively destroy pathogens that it has encountered in the past. As anyone in the field will tell you, however, this high level picture of cleanly divided dualism is overly simplistic, however. There are numerous grey areas and incompletely understood complexities at the border between the two sides of the immune system.

Given that the adaptive immune system can adapt, its failure with aging is in large part a matter of acquired misconfiguration. There is only a small influx of new immune cells in adults, and this puts an effective limit on the number of immune cells that is supported at any one time. The inevitable problem in a space-limited system that keeps a continual record of history is that it runs out of space: evolutionary pressures produced the trade-off of a system that works very well out of the gate in young people, but fails sometime in later life. An old adaptive immune system is burdened with too many cells devoted to memory and too few cells devoted to attacking new threats. That is on top of the progressive failures that occur due to the the growing burden of the molecular damage that accompanies aging: persistent metabolic waste products such as cross-links and lipofuscin, mitochondrial damage, diminished stem cell activity, and so forth. The innate immune system has its own problems that arise from this damage, but is less prone of the issue of misconfiguration.

Understanding exactly how aging progressively harms the intricate choreography of the immune response is a massive project, and nowhere near completion. It is possible to judge how far along researchers are in this work by the side effect of the quality of therapies for autoimmune disease, which are malfunctions in immune configuration, and largely incurable at the present time. From a practical point of view, and as mentioned above, the best prospects for effective treatments in the near future involve destroying and recreating the immune system. That works around our comparative ignorance by removing all of the problems that researchers don't understand in addition to ones that they do. Destroying the immune system can only be done with chemotherapy at the moment, which no-one would undergo unless there was no choice in the matter given that it has significant negative effects on long-term health, but once new methods of selective immune cell destruction are developed, lacking side-effects, then we can start to talk about treating immune aging by rebooting the immune system.

Convergence of Innate and Adaptive Immunity during Human Aging

Aging is associated with a general decline in immune function, contributing to a higher risk of infection, cancer, and autoimmune diseases in the elderly. Such faulty immune responses are the result of a profound remodeling of the immune system that occurs with age, generally termed as immunosenescence. While the number of naïve T cells emerging from the thymus progressively decreases with age as a result of thymic involution, the memory T cell pool expands and exhibits significant changes in the phenotype and function of antigen-experienced T cells, particularly evident in the CD8+ T cell compartment. Chronic immune activation due to persistent viral infections, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), is one of the main drivers contributing to the accumulation of highly differentiated antigen-specific CD8+ T lymphocytes that have characteristics of replicative senescence. In combination with the depletion of the peripheral pool of naïve T cells, the accumulation of these terminally differentiated T cells with age skews the immune repertoire and has been implicated in the impaired immune responses to new antigens and vaccination in the elderly

Natural killer cells and αβCD8+ T lymphocytes are the two major cell lineages with constitutive cytotoxic activity and have a crucial role in the recognition and killing of abnormal cells. However, the paradigm for the recognition of target cells is fundamentally different between these two cell types: conventional αβCD8+ T cells rely on the T cell receptor (TCR) to recognize specific peptides presented by major histocompatibility complex class-I (MHC-I) molecules, whereas NK cells use a repertoire of germ line-encoded receptors to detect "missing self" or "altered-self" antigens and directly kill abnormal cells, without prior sensitization. Besides antigen specificity, the development of immunological memory is conventionally another distinctive feature between NK and T cells, categorizing them into distinct arms of the immune system and the innate and adaptive immune system, respectively.

Nevertheless, accumulating evidence supports the existence of NK cell memory, as well as evidence for TCR-independent responses mediated by αβCD8+ T lymphocytes, suggesting that the conventional limits between the innate and adaptive arms of the immune system may be not as distinct as first thought. NK and T lymphocytes have a common origin from a lymphoid progenitor cell in the bone marrow, and recent comparative proteomic and transcriptomic studies have demonstrated a remarkably close proximity between effector αβCD8+ T lymphocytes and NK cells, reiterating an evolutionary ancestry and shared biology between the two cell lineages.

An increasing body of literature reveals the existence of subsets of T cells with features that bridge innate and adaptive immunity. These cells typically co-express a TCR and NK cell lineage markers, distinguishing them from NK cells and other innate lymphoid cells, which lack the expression of a TCR or somatically rearranged receptors. Functionally, innate-like T cells respond to TCR ligation but are also able to respond rapidly to danger signals and pro-inflammatory cytokines, independently of TCR stimulation, resembling innate cells. Recently, subsets of conventional αβCD8+ T cells expressing NK cell markers and intraepithelial T cells have been included in this vaguely defined group of innate-like T cells. Despite the similarities in phenotype and function, there are clear differences in ontogeny and tissue distribution between them.

In this review, we will discuss recent evidence that aging is associated with the expansion of a subset of conventional αβCD8+ T cells with phenotypic, functional, and transcriptomic features that resemble NK cells. Such innate-like αβCD8+ T cells have the characteristics of terminally differentiated T cells, and the acquisition of functional NK receptors is most likely part of a general reprograming of the CD8+ T cell compartment during human aging, to ensure broad and rapid effector functions. We propose that innate-like αβCD8+ T cells share important features with other innate-like T cells; however, fundamental differences in origin and development separate them from truly innate cells. Interestingly, these cells are also differentially affected by aging, suggesting distinct roles in immune responses at different times of life. Evidence indicates that chronological aging is associated with accumulation of cells combining features of both the innate and adaptive arms of the immune system, most likely to compensate for functional defects of conventional NK and CD8+ T cells with age. We propose that senescent CD8+ T cells should not be seen as a dysfunctional population but instead a functionally distinct subset, which uses recently acquired NK cell machinery to maintain rapid effector functions throughout life. Contrary to the classic paradigm that peripheral TCR ligation is essential for T cell activation, this subset of highly differentiated T cells has impaired TCR responsiveness and may be non-specifically activated by inflammatory cytokines or after ligation of innate receptors. The switch to an innate mode of function may shed light on the mechanisms that allow highly differentiated CD8+ T cells to maintain functionality, despite the loss of TCR signal functions.

Our understanding of the physiological significance of the expression of NKRs on T cells is still incomplete, and the identification of the molecular mechanisms and the transcriptional regulators underpinning the development of innate features in T cells is essential. Most importantly, it will be important to understand how the intersection between innate and adaptive immune features may be manipulated to enhance immune function and to use this information to develop new approaches to improve immunity in the elderly.

There are many possible answers to the question of why women have a longer life expectancy than men, but no real consensus on which of the candidate mechanisms are the important ones. It is interesting to note that, in an age in which rejuvenation therapies are starting to arrive, the research community has a better idea of how to bring aging under medical control, and thus make natural variations in longevity irrelevant, than of how to definitively determine the mechanisms causing those natural variations between groups of humans. Fully understanding our biochemistry is a massive undertaking, far greater in scope than merely wrestling degenerative aging into submission by addressing its root causes. Biology is enormously complex, and working with statistical demographic data or evolutionary theory doesn't tend to produce firm answers, only helping to narrow down the directions for further inquiry.

People worldwide are living longer, healthier lives. A new study of mortality patterns in humans, monkeys and apes suggests that the last few generations of humans have enjoyed the biggest life expectancy boost in primate history. The gains are partly due to advances in medicine and public health that have increased the odds of survival for human infants and reduced the death toll from childhood illness. Yet males still lag behind females - not just in humans but across the primate family tree, the researchers find. "The male disadvantage has deep evolutionary roots."

An international team compiled records of births and deaths for more than a million people worldwide, from the 18th century to the present. The data included people in post-industrial societies such as Sweden and Japan, people born in pre-industrial times, and modern hunter-gatherers, who provide a baseline for how long people might have lived before supermarkets and modern medicine. The researchers combined these measurements with similar data for six species of wild primates that have been studied continuously for three to five decades, including sifaka lemurs, muriqui monkeys, capuchins, baboons, chimpanzees and gorillas. The data confirm a growing body of research suggesting that humans are making more rapid and dramatic gains than ever before seen in the primate family tree. For example, in the last 200 years life expectancy in Sweden has jumped from the mid-30s to over 80, meaning that a baby born today can hope to live more than twice as long as one born in the early 19th century. The data show that today's longest-lived human populations have a similar 40- to 50-year advantage over people who live traditional lifestyles, such as the Hadza hunter-gatherers of Tanzania and the Aché people of Paraguay.

In contrast, these modern hunter-gatherers - the best lens we have into the lives of early humans - live on average just 10 to 20 years longer than wild primates such as muriquis or chimpanzees, from which human ancestors diverged millions of years ago. "We've made a bigger journey in lengthening our lifespan over the last few hundred years than we did over millions of years of evolutionary history." One indicator of healthcare improvement is infant mortality, which strikes fewer than 3 in 1000 babies born in Sweden or Japan today. But it was more than 40 times higher for those born two centuries ago, and is still high among hunter-gatherers and wild primates.

The researchers also studied lifespan equality, a measure similar to income equality that indicates whether longevity is distributed evenly across society, or only enjoyed by a few. They found that, for both humans and wild primates, every gain in average lifespan is accompanied by a gain in lifespan equality. That is, for a population to be very long-lived, everyone must benefit more or less equally, with fewer individuals left behind. The researchers were surprised to find that the longevity of human males has yet to catch up with females, and the improvements in males aren't spread as evenly. A girl born in Sweden in the early 1800s could expect to outlive her male counterparts by an average of three to four years. Two hundred years later, despite Swedes adding 45 years to their average lifespan, the gulf that separates the sexes has barely budged. The life expectancy gender gap isn't just true for humans. Females outlived males in almost every wild primate population they looked at.

Link: https://today.duke.edu/2016/11/life-expectancy-grows-men-still-lagging

In the field of tissue engineering, this is the era of organoids. Researchers are limited in the size of tissue they can produce because of the lack of a robust method of generating the blood vessel networks needed to support large tissue sections, but are otherwise making significant progress in the generation of functional organ tissue. Initially this is producing the greatest benefit for further research and development, allowing tests to be conducted in living tissue at a much faster pace and lower cost. For many tissue types, however, organoids also offer the possibility of benefits realized through transplantation, as in many cases they are capable of integrating with existing organ tissue to improve its function.

Scientists report using human pluripotent stem cells to grow human intestinal tissues that have functioning nerves in a laboratory. The paper puts medical science a step closer to using human pluripotent stem cells (which can become any cell type in the body) for regenerative medicine and growing patient-specific human intestine for transplant. "One day this technology will allow us to grow a section of healthy intestine for transplant into a patient, but the ability to use it now to test and ask countless new questions will help human health to the greatest extent." This ability starts with being able to model and study intestinal disorders in functioning, three-dimensional human organ tissue with genetically-specific patient cells. The technology will also allow researchers to test new therapeutics in functioning lab-engineered human intestine before clinical trials in patients.

Researchers started out by subjecting human pluripotent stem cells to a biochemical bath that triggers their formation into human intestinal tissue in a petri dish. The process was essentially the same as that used in a 2010 study, which reported the first-ever generation of three-dimensional human intestinal organoids in a laboratory. Intestinal tissues from the initial study lacked an enteric nervous system, which is critical to the movement of waste through the digestive tract and the absorption of nutrients. The gastrointestinal tract contains the second largest number of nerves in the human body. When these nerves fail to work properly it hinders the contraction of intestinal muscles. To engineer a nervous system for the intestinal organoids already growing in one petri dish, researchers generated embryonic-stage nerve cells called neural crest cells in a separate dish. The neural crest cells were manipulated to form precursor cells for enteric nerves. The challenge at this stage was identifying how and when to incorporate the neural crest cells into the developing intestine. "We tried a few different approaches largely based on the hypothesis that, if you put the right cells together at the right time in the petri dish, they'll know what do to. It was a long shot, but it worked." The appropriate mix caused enteric nerve precursor cells and intestines to grow together in a manner resembling developing fetal intestine.

A key test for the engineered intestines and nerves was transplanting them into a living organism - in this case laboratory mice with suppressed immune systems. This allowed researchers to see how well the tissues grow and function. Study data show the tissues work and are structured in a manner remarkably similar to natural human intestine. They grow robustly, process nutrients and demonstrate peristalsis - series of wave-like muscle contractions that in the body move food through the digestive tract.

Link: https://www.cincinnatichildrens.org/news/release/2016/hirschsprungs-intestinal-nerve-disorder

The first rejuvenation therapies to work well enough to merit the name will be based on the SENS vision: that aging is at root caused by a few classes of accumulated cell and tissue damage, and biotechnologies that either repair that damage or render it irrelevant will as a result produce rejuvenation. Until very recently, no medical technology could achieve this goal, and few research groups were even aiming for that outcome. We are in the midst of a grand transition, however, in which the research and development community is finally turning its attention to the causes of aging, understanding that this is the only way to effectively treat and cure age-related disease.

Age-related diseases are age-related precisely because they are caused by the same processes of damage that cause aging: the only distinctions between aging and disease are the names given to various collections of symptoms. All of frailty, disease, weakness, pain, and suffering in aging is the result of accumulated damage at the level of cells and protein machinery inside those cells. Once the medical community becomes firmly set on the goal of repairing that damage, we'll be well on the way to controlling and managing aging as a chronic condition - preventing it from causing harm to the patient by periodically repairing and removing its causes before they rise to the level of producing symptoms and dysfunction. The therapies of the future will be very different from the therapies of the past.

The full rejuvenation toolkit of the next few decades will consist of a range of different treatments, each targeting a different type of molecular damage in cells and tissues. In this post, I'll take a look at the likely order of arrival of some of these therapies, based on what is presently going on in research, funding, and for-profit development. This is an update to a similar post written four years ago, now become somewhat dated given recent advances in the field. Circumstances change, and considerable progress has been made in some lines of research and development.

1) Clearance of Senescent Cells

It didn't take much of a crystal ball four years ago to put senescent cell clearance in first place, the most likely therapy to arrive first. All of the pieces of the puzzle were largely in place at that time: the demonstration of benefits in mice; potential means of clearance; interested research groups. Only comparatively minor details needed filling in. Four years later no crystal ball is required at all, given that Everon Biosciences, Oisin Biotechnologies, SIWA Therapeutics, and UNITY Biotechnology are all forging ahead with various different approaches to the selective destruction of senescent cells. No doubt many groups within established Big Pharma entities are also taking a stab at this, more quietly, and with less press attention. UNITY Biotechnology has raised more than $100 million to date, demonstrating that there is broad enthusiasm for this approach to the treatment of aging and age-related disease.

With the additional attention and funding for this field, more methods of selective cell destruction have been established, and there is now a greater and more detailed understanding of the ways in which senescent cells cause harm, contributing to the aging process. Senolytic drugs that induce apoptosis have been discovered; senescent cells are primed to enter the programmed cell death process of apoptosis, and so a small nudge to all cells via a drug treatment kills many senescent cells but very few normal cells.

Researchers have established that senescent cells exist in the immune system, and may be important in immune aging. Similarly, the immune cells involved in the progression of atherosclerosis are also senescent, and removing them slows the progression of that condition. Other research has shown that removing senescent cells from the lungs restores lost tissue elasticity and improves lung function. Beyond these specific details, senescent cells clearly contribute to chronic inflammation in aging, and that drives the progression of near all common age-related conditions. The less inflammation the better. These effects are caused by the signals secreted by senescent cells: that their harm is based on signaling explains how a small number of these cells, perhaps 1% by number in an aged organ, can cause such widespread havoc.

2) Immune System Destruction and Restoration

At the present time it is a challenge to pick second place. A number of fields are all equally close to realization, and happenstance in funding decisions, regulatory matters, or technical details yet to be uncovered will make the difference. The destruction and recreation of the immune system wins out because it is already possible, already demonstrated to be successful, and just missing one component part that would enable it to be used by ordinary, healthy, older people. At present researchers and clinicians use chemotherapy to destroy immune cells and the stem cells that create them. Repopulation of the immune system is carried out via cell transplants that are by now a safe and proven application of stem cell medicine, little different from the many varieties of first generation stem cell therapy. This approach has been used to cure people with multiple sclerosis, and has been attempted with varying degrees of success for a number of other autoimmune conditions for going on fifteen years now: there are researchers with a lot of experience in this type of therapy.

The catch here is that chemotherapy is a damaging experience. The cost of undergoing it is high, both immediately, and in terms of negative impact on later health and life expectancy, similar to that resulting from a life spent smoking. It only makes sense for people who are otherwise on their way to an early death or disability, as is the case for multiple sclerosis patients. However, there are a number of approaches very close to practical realization that will make chemotherapy obsolete for the selective destruction of immune cells and stem cells - approaches with minimal or no side-effects. A combined approach targeting c-kit and CD47 was demonstrated earlier this year, for example. Sophisticated cell targeting systems such as the gene therapy approach developed for senescent cell clearance by Oisin Biotechnologies could also be turned to stem cell or immune cell destruction, given suitable markers of cell chemistry. There are quite a few of these, any one of which would be good enough.

Replacing the chemotherapy with a safe, side-effect-free treatment would mean that the established programs for immune system restoration could immediately expand to become a useful, effective treatment for immunosenescence, the age-related failure of the immune system. This is in part a problem of configuration: a lifetime of exposure to persistent pathogens such as herpesviruses leaves too much of the immune system uselessly devoted to specific targets that it cannot effectively clear from the body, and too little left ready to fight new threats and destroy malfunctioning cells. Then there are various forms of autoimmunity that become prevalent in older people, not all of which are in any way fully understood - consider just how recently type 4 diabetes was discovered, for example. Clearing out the entire immune system, all of its memory and quirks, and restarting it fresh with a new supply of stem cells is a good approach to many of the issues in the aged immune system. Not all of them, but many of them, and considering the broad influence immune function has over many other aspects of health and tissue function, it seems a worthwhile goal.

3) Clearance of the First Few Types of Amyloid

There are about twenty different types of amyloid, misfolded proteins that form solid deposits. Not all are robustly associated with age-related dysfunction, but of those that are, some progress has been made towards effective therapies based on clearance. Last year, a clinical trial of transthyretin amyloid clearance produced good results. This type of amyloid is associated with heart disease, and is thought to be the primary cause of death in supercentenarians. This year researchers finally demonstrated clearance of amyloid-β in humans, after a long series of failures. Amyloid-β is one of the forms of metabolic waste that accumulates in Alzheimer's disease.

So these types of rejuvenation therapy already exist in the sense of prototypes and trial treatments. To the degree that they are effective and safe, everyone much over the age of 40 should be undergoing a course of treatment every few years. In practice, since both of the above mentioned therapies are tied up in the slow-moving edifice of Big Pharma regulatory capture, it will be a long time before they make it to the clinic in any way that is accessible to an ordinary individual. The most likely path to that goal is for other groups outside that system to reverse engineer the basic technology from the scientific publications, implement their own methodologies, and market it in other regulatory regions, making it available via medical tourism. This is how stem cell medicine progressed, and seems likely to be the way that any other very significant field will also move forward.

4) Clearance of Glucosepane Cross-Links

Clearance of cross-links in the extracellular matrix of tissues is, like senescent cell destruction, one of the most exciting of early rejuvenation therapies. It is a single target that influences a great many aspects of aging: if we look at just the cross-link-induced loss of elasticity in blood vessels alone, that has a major influence on mortality through hypertension and consequent impact on cardiovascular health. It is also a single target in the sense that near all persistent cross-links important to aging in humans so far appear to be based on one compound, glucosepane. Thus all that is needed is one drug candidate.

Four years ago, the situation for glucosepane clearance looked pretty bleak. The funding was minimal, and the tools for working with glucosepane in living tissues didn't exist. Researchers avoided the whole topic, as making any progress would require a lot of funding and effort to even get to the point of starting in earnest. The SENS Research Foundation and their allies have since made major inroads into this challenge, however. Last year, a method of cheaply and reliably synthesizing glucosepane was established, and now the road is open to anyone who wants to try their hand at drug discovery. That is now underway in the Spiegel Lab, among others, and I'd hope to see the first potential drug candidates emerge at some point in the next couple of years.

5) Thymic Rejuvenation to Increase the Supply of Immune Cells

Another possible approach to partially restore lost function in the aging immune system is to increase the pace at which new immune cells are created. This is a very slow pace indeed in older people, due in large part to the age-related decline of the thymus. The thymus acts as a nursery for the maturation of T cells, and its atrophy thus restricts the rate at which new cells enter circulation. There has been some progress towards engineering of replacement active thymus tissue, as well as methods of providing signal proteins that instruct the old thymus to regenerate and begin to act in a more youthful manner. Transplants of young thymus organs into old mice has demonstrated that this class of approach can produce a meaningful improvement in immune function, and thereby extend healthy life. This is one of a number of regenerative approaches that is on the verge, just waiting for someone to start a company or join the final two dots together and get moving.

6) Mitochondrial Repair

Mitochondria, the power plants of the cell, are herds of bacteria-like organelles that bear their own DNA. This DNA becomes damaged in the course of normal cellular processes, and certain forms of mitochondrial DNA damage - to the thirteen genes needed for oxidative phosphorylation - produce malfunctioning mitochondria that can overtake their cells, either by replicating more readily or being more resistant to quality control mechanisms. Such cells become dysfunctional exporters of harmful signals and oxidized proteins, something that contributes to the progression of atherosclerosis via increased amounts of oxidized lipids in the bloodstream, to pick one example. If we're lucky, a substantial proportion of these cells will become senescent as a result of their mutant mitochondria, and will thus be destroyed by senescent cell clearance therapies. Regardless of whether or not that is true, a method of either repairing or working around this type of damage is needed.

Most of the possible approaches may or may not work well, because of the replication advantage that damaged mitochondria have over normal mitochondria, and are still to be tested in practice rather than theory or demonstration: upregulation of existing repair mechanisms; delivery of extra functional mitochondrial DNA or whole mitochondria; and so forth. The SENS approach is somewhat more radical, involving gene therapy to introduce copies of the thirteen genes into the cell nucleus, altered to ensure that the proteins produced can migrate back to the mitochondria where they are needed. Mitochondria will thus have the necessary protein machinery for correct function regardless of the state of their DNA. This has been demonstrated for three of the thirteen genes of interest, numbers two and three just this year, and getting that far has taken the better part of ten years at a low level of funding. It is likely that things will go faster in the future, now that there is a for-profit company, Gensight Biologics working on the problem in addition to non-profit groups, but it is still the case that the bulk of the work remains to be done.

Will it be useful to have therapies that fix half the problem, moving six or seven genes to the cell nucleus? Will that reduce the impact on aging by half? Hard to say until it is done and demonstrated in mice. Halfway there is probably a target reached by 2020 or so at the present pace. Mitochondrial function appears from all the evidence to be an important aspect of aging, so it is to my eyes worth trying at the halfway point to see what the outcome is.

7) A Robust Cure for Cancer

Some might find it counterintuitive that a universal cure for cancer is not last in this list. We've all been educated to think of cancer as the greatest challenge for medical science, the problem to be solved last of all. Nonetheless, a more rapid arrival of a generally applicable cure for cancer looks to be the likely course of events, as the basis for a treatment that can in principle put a halt to all cancer at all stages of development is currently in the earliest stages of development. All cancers depend absolutely on the ability to continually lengthen telomeres, and so avoid the Hayflick limit on cell replication. Telomere lengthening occurs through the activity of telomerase or the less well understood alternative lengthening of telomeres (ALT) mechanisms: these two are a small set of targets for modern medicine, and researchers are working on the challenge. If telomerase and ALT can both be blocked, temporarily and either globally throughout the body or selectively in cancerous tissue, then cancer will wither and become controllable. This is too fundamental a part of cellular biochemistry for the rapid mutational evolution of cancer cells to work around, as they can for many of the standard approaches to cancer treatment at the present time. Stem cell populations will suffer while telomerase activity is blocked, as they require telomere lengthening for self-renewal, but that is a lesser problem when compared to cancer and one that the stem cell research community will become increasingly able to address in the years ahead.

8) Reversing Stem Cell Aging

The stem cell industry is massively funded, and is on a collision course with stem cell aging. Most of the conditions that one would want to use stem cell therapies to treat are age-related conditions. Researchers must thus ensure that the altered cellular environment, the damage of aging, doesn't prevent the treatments from working - that pristine cells can integrate and work well, not immediately die or decline in response to an age-damaged stem cell niche. On the whole, the research community isn't engaging aggressively with this goal, however. Possible reasons for this include the fact that most stem cell treatments, even without addressing issues of the aged tissue environment, represent a considerable improvement in the scope of what is possible to achieve through modern medicine. So the incentive to go further is perhaps not as strong as it might otherwise be.

Stem cell populations become damaged by age, falling into quiescence or declining in overall numbers. They should be replaced with new populations, but while simple in concept, and even achieved for some cell types, such as the blood stem cells that produce immune cells, this is easier said than done for the body as a whole. Every tissue type is its own special case. There are hundreds of types of cell in the body. Each supporting stem cell population has so far required specific methodologies to be developed, and specific behaviors and biochemistry to be laboriously mapped. It isn't even entirely clear that researchers have found all of the stem cell or stem-like cell populations of interest. There is an enormous amount of work to be done here, and at the moment the field is still largely in the phase of getting the basics, the maps, and the reliable therapeutic methods sorted out for a few of the better understood tissue types, bone marrow and muscles in particular. So this seems at the present time like a long-term prospect, despite the high levels of funding for this line of medical research and development.

9) Clearance of Other Amyloids, Aggregates, and Sundry Lysosomal Garbage

A good portion of aging is driven by the accumulation of waste products, either because they are hard for our biochemistry to break down, is the case for glucosepane cross-links and many of the components of lipofuscin that degrade lysosomal function in long-lived cells, or because clearance systems fail over time, as appears likely to be the case for the amyloid-β involved in Alzheimer's disease. There are a lot of these compounds: a score of amyloids, any number of lipofuscin constituents, the altered tau that shows up in tauopathies, and so on and so forth. In many cases there isn't even a good defensible link between a specific waste compound and specific age-related diseases: the waste is one contribution buried in many contributions, and the research community won't start putting numbers to relative importance until it is possible to clear out these contributions one by one and observe the results.

A range of research groups are picking away at individual forms of waste, some with large amounts of funding, some with very little funding, but this is a similar situation to that I outlined above for stem cell aging. There is a huge amount of work to accomplish because there are many targets to address, and with few exceptions, such as amyloid-β, it is unclear which of the targets are the most important. They will all have to be addressed, in some order, but there are only so many researchers and only so much funding. We can hope that as the first effective therapies make it into the clinic, most likely for the clearance of forms of amyloid, there will be a growing enthusiasm for work on ways to remove other types of metabolic waste.

The big question in the study of the comparative biology of regeneration is the degree to which mammals retain the mechanisms needed for the exceptional regeneration found in species such as zebrafish and salamanders. The individuals of these highly regenerative species are capable of regrowing fins, limbs, and major portions of internal organs. Has evolution removed this machinery from mammals, or only buried it, leaving it dormant and awaiting activation? This experiment, in which the molecular signals provided via transplanted extracellular matrix material from zebrafish are shown to enhance heart regeneration in mice, argues for the latter theory. The heart in mammals is among the least regenerative of tissues, and does not recover well from damage, but there is considerable room for improvement in the healing processes for all mammalian tissues. Zebrafish and other highly regenerative species heal without scars and without loss of function, something that cannot be said for mammals.

Many lower forms of life on earth exhibit an extraordinary ability to regenerate tissue, limbs, and even organs - a skill that is lost among humans and other mammals. Now, researchers have used the components of the cellular "scaffolding" of a zebrafish to regenerate heart tissues in mammals, specifically mice, as well as exhibiting promising results in human heart cells in vitro. The researchers found that a single administration of extracellular matrix (ECM) material from zebrafish hearts restored the function of the heart and regenerated adult mouse heart tissues after acute myocardial infarction. The study also found that the zebrafish ECM protected human cardiac myocytes - specialized cells that form heart muscle - from stresses.

ECM are the architectural foundations of tissues and organs; not only do they provide a "scaffolding" on which cells can grow and migrate, they assist in the signaling necessary for the organ to develop, grow, or regenerate. In mammals, the heart quickly loses the ability to regenerate after the organism is born, except for a brief period after birth. In lower animals, such as zebrafish, the heart retains that ability throughout their lives: up to 20 percent of a zebrafish's heart can be damaged or removed, and within days the heart's capacity has been fully restored. The researchers first separated the ECM from the cells so that the recipient heart would not reject the treatment. They did this by freezing the zebrafish cardiac tissue, causing the cell membranes to burst and allowing the researchers to retrieve the ECM, a process called decellularization. They then injected the ECM into the hearts of mice with damaged heart muscles and watched the hearts repair themselves. It is difficult to inject foreign cells into a body because the body will recognize them as foreign and reject them. That's not the case with ECM because it is composed of collagen, elastin, carbohydrates and signaling molecules and has no cell surface markers, DNA or RNA from the donor, and so the recipient is less likely to reject the treatment.

Restored function starts almost immediately, and healing is noticeable as early as five days after treatment; within a week, his team could see the heart beating more strongly than the hearts of the untreated animals. The researchers tested the effectiveness of ECM from normal zebrafish and from zebrafish with damaged hearts, in which the ECM had already begun the healing process. They found that while both types of ECM were effective in repairing damage to the mice hearts, the ECM obtained from the zebrafish hearts that were healing were even more potent in restoring heart function in the mice. The researchers are now working on a process to regenerate nerves in mammals using the same process and hope to expand the heart treatments to larger animals in a future study.

Link: http://www.news.pitt.edu/news/how-do-you-mend-broken-heart

Heterochronic parabiosis involves joining the circulatory systems of an old and a young mouse. This produces harmful effects on the young mouse and beneficial effects on the old mouse. There is considerable interest in the research community in identifying the molecular signals involved. So far theory has focused on delivery of beneficial signals from young blood to the old individual, but here researchers present evidence to suggest it may be more a matter of diluting detrimental signals present in the old blood. This has implications for efforts to build therapies based on transfusions of young blood: if dilution is the primary mechanism, those efforts will have little to no effect.

A new study found that tissue health and repair dramatically decline in young mice when half of their blood is replaced with blood from old mice. The study argues against the rejuvenating properties of young blood and points to old blood, or molecules within, as driving the aging process. "Our study suggests that young blood by itself will not work as effective medicine. It's more accurate to say that there are inhibitors in old blood that we need to target to reverse aging." In 2005, researchers found evidence for tissue rejuvenation in older mice when they are surgically joined to younger mice so that blood is exchanged between the two. Despite remaining questions about the mechanism underlying this rejuvenation, media coverage of the study fixated on the potential of young blood to reverse the aging process, and on comparisons to vampires, which was not the takeaway from the study. In the years since the 2005 study, scientists have spent millions to investigate the potential medical properties of youthful blood with enterprises emerging to infuse old people with young blood. "What we showed in 2005 was evidence that aging is reversible and is not set in stone. Under no circumstances were we saying that infusions of young blood into elderly is medicine."

While the experimental model used in the 2005 study found evidence that some aspects of aging may be reversed, the techniques used in the study do not allow scientists to precisely control the exchange of blood, which is necessary to dig deeper into blood's effect on aging. When two mice are sutured together, a technique called parabiosis, blood is not the only thing that is exchanged in this setup; organs are also shared, so old mice get access to younger lungs, thymus-immune system, heart, liver and kidneys. In surgical suturing it takes weeks to a month for the effects of blood to take place and the precise timing is not actually known. Nor is the precise amount of the exchanged blood. In the new study, researchers developed an experimental technique to exchange blood between mice without joining them so that scientists can control blood circulation and conduct precise measurements on how old mice respond to young blood, and vice versa. In the new system, mice are connected and disconnected at will, removing the influence of shared organs or of any adaptation to being joined. One of the more surprising discoveries of this study was the very quick onset of the effects of blood on the health and repair of multiple tissues, including muscle, liver and brain. The effects were seen around 24 hours after exchange.

With the new experimental setup, the research team repeated the experiments from 2005. In each test, blood was exchanged between an old mouse and a young mouse until each mouse had half its blood from the other. The researchers then tested various indicators of aging in each mouse, such as liver cell growth as well as liver fibrosis and adiposity (fat), brain cell development in the region that is needed for learning and memory, muscle strength and muscle tissue repair. In many of these experiments, older mice that received younger blood saw either slight or no significant improvements compared to old mice with old blood. Young mice that received older blood, however, saw large declines in most of these tissues or organs. The most telling data was found when researchers tested blood's impact on new neuron production in the area of the brain where memory and learning are formed. In these experiments, older mice showed no significant improvement in brain neuron stem cells after receiving younger blood, but younger mice that received older blood saw a more than twofold drop in brain cell development compared to normal young mice. The researchers think that many benefits seen in old mice after receiving young blood might be due to the young blood diluting the concentration of inhibitors in the old blood.

Link: http://news.berkeley.edu/2016/11/22/young-blood-does-not-reverse-aging-in-old-mice-uc-berkeley-study-finds/

Cryonics is the low-temperature preservation of at least the brain following death, leaving open the possibility of restoration to life in a future in which molecular nanotechnology and total control of cellular biochemistry are mature industries. As individuals, each of us is the data of the mind, no more, no less, and that data is stored in the form of fine physical structures, most likely those of the synapses connecting neurons. If that structure is preserved sufficiently well, then the individual is not yet gone - only ceased for the moment. Early cryopreservations involved straight freezing to liquid nitrogen temperatures, and this likely caused great damage to the structures of the brain due to ice crystal formation. Modern cryopreservations use cryoprotectants and staged cooling to achieve vitrification of tissues with minimal ice crystal formation. There the degree of damage is much reduced, contingent on sufficient perfusion of cryoprotectant and the quality of the other aspects of the process. These technologies are also under development by groups in the organ transplantation and tissue engineering communities: reversible vitrification of organs would solve a great many logistical problems. From the present state of the science, that goal isn't very far distant. Proof of concept vitrification, thawing, and transplantation of mammalian organs has taken place in the laboratory. Even without present reversibility, however, the merits of cryonics stand: people who are preserved are not dead and gone, just dead, with a chance to return. A chance of unknown size, yes, but that is a big improvement over the grave and certain oblivion.

Cryonics suffers from being a small industry. People encountering the concept for the first time tend look at it askance because it is a small community and thus not the usual end of life choice. Then they make up reasons in their own minds as to why it won't work, or is stupid, or illogical, or otherwise wrong, simply because it is not the norm. It takes multiple exposures to a topic for most people to come around and actually engage with what is known rather than with their own knee-jerk reaction to the topic. In the normal run of things, however, few people actually encounter the ideas of cryonics; it doesn't get all that much press, and since it is such a small industry and surrounding community, few people encounter those involved as they make their way through life. Thus public awareness and understanding of the long-standing cryonics industry seems to advance by a series of infrequent great leaps rather than ongoing incremental gains, each such leap driven by the high-profile cryopreservation of a sympathetic or noted individual that attracts a short-lived mob of press attention. First there is a flood of commentary from those who know next to nothing of cryonics and are quick to condemn it for being different, then a following wave of more thoughtful commentary, for and against, and finally some few of the many people who read the coverage choose to dig further, peruse some of the mountain of literature written on cryonics over the past 40 years, and conclude that cryonics does make sense and is a good idea. So the community of supporters and those signed up as members of a cryonics organization grows a little.

The latest leap forward was spurred by the cryopreservation of a terminally ill young lady in the UK, unusual for its surrounding legal case regarding consent and self-determination. The UK has a cryonics support organization, as is the case for many countries, but like most parts of the world lacks a cryonics provider. This may be why so much of the initial commentary has been from those fairly new to the idea, and has been unusually hostile in tone when compared to the media attention of the past five years or so. Being the UK, there is also a considerable focus on regulation, since the bias over there, in the media at least, is very much towards the idea that nothing must ever happen without government involvement - all that is not explicitly allowed is forbidden, any new endeavor must be quickly regulated by a new government office, and so forth. Sadly the US has been heading in that direction quite energetically since the turn of the century; it has been a sad thing to watch taking place. Cultural differences aside, many cryopreservations are carried out under difficult circumstances, and this was one of them. The ideal preservation takes place at the cryonics provider location, or very close by, within a known window of time, and cooldown is rapid following death so as to minimize damage. Departures from that ideal have a cost, both monetary and in the quality of the preservation, but the people involved here by all accounts did the best possible under the circumstances, hampered by the existing regulatory environment that prevents near every possible approach that could make things easier, cheaper, and more reliable.

Below find a very small selection of the recent attention given to this case. There is a lot more out there, if you are interested enough to go looking, ranging from ignorant and hostile to thoughtful and considered. The incorrect term "cryogenics" is bandied around, as is the mistaken idea that cryopreservation involves freezing: the press is ever haphazard when it comes to accuracy, and it doesn't become much better if you glance at what the wisdom of the crowds produced at social news sites in this case. Ultimately this matter, just as any cryopreservation, boils down to issues of self-determination and responsibility for the self. Sadly this is a topic that many members of our society, and especially those in the media and positions of power, seem to find offensive and undesirable: the idea that people can make decisions for themselves, and that those decisions should be respected. But we live in a world in which there is no choice so personal that it will not be interfered with by regulators and lawmakers, and that seems true whether or not the individual is young enough to be considered by those with power effectively the property of his or her parents. (Which is an entirely different iniquity in and of itself). As adults with a lifetime of experience people have just as much trouble in matters of self-determination at the end of life. Witness the political and legal battles over euthanasia, for example, in which childhood is extended indefinitely and the uncaring minions of the state take on the role of distant and forbidding parents. How free are we, really, when it is declared illegal to decide on matters of our own bodies and our own lives, and those who help will be jailed for the crime of compassionate if they are found out?

14-year-old girl who died of cancer wins right to be cryogenically frozen

A 14-year-old girl who said before dying of cancer that she wanted a chance to live longer has been allowed by the high court to have her body cryogenically frozen in the hope that she can be brought back to life at a later time. The court ruled that the teenager's mother, who supported the girl's wish to be cryogenically preserved, should be the only person allowed to make decisions about the disposal of her body. Her estranged father had initially opposed her wishes. During the last months of her life, the teenager, who had a rare form of cancer, used the internet to investigate cryonics. She sent a letter to the court: "I have been asked to explain why I want this unusual thing done. I'm only 14 years old and I don't want to die, but I know I am going to. I think being cryo-preserved gives me a chance to be cured and woken up, even in hundreds of years' time. I don't want to be buried underground. I want to live and live longer and I think that in the future they might find a cure for my cancer and wake me up. I want to have this chance. This is my wish."

The judge wrote: "I was moved by the valiant way in which she was facing her predicament. The scientific theory underlying cryonics is speculative and controversial, and there is considerable debate about its ethical implications. On the other hand, cryopreservation, the preservation of cells and tissues by freezing, is now a well-known process in certain branches of medicine, for example the preservation of sperm and embryos as part of fertility treatment. Cryonics is cryopreservation taken to its extreme." The judge said the girl's family was not well off but that her mother's parents had raised the money. A voluntary UK group of cryonics enthusiasts, who were not medically trained, had offered to help make arrangements. Co-operation of a hospital was required. The hospital trust in the case was willing to help although it stressed it was not endorsing cryonics. "On the contrary, all the professionals feel deep unease about it," the judge said.

The Human Tissue Authority (HTA), which regulates organisations which remove, store and use human tissue, had been consulted but said it had no remit to intervene in such a case. "The HTA would be likely to make representations that activities of the present kind should be brought within the regulatory framework if they showed signs of increasing," the judge said. The HTA said: "We are gathering information about cryopreservation to determine how widespread it is currently, or could become in the future, and any risks it may pose to the individual, or public confidence more broadly. We are in discussion with key stakeholders on the possible need for regulatory oversight." The government may need to intervene in future, the judge said: "It may be that events in this case suggest the need for proper regulation of cryonic preservation in this country if it is to happen in future."

Cryonics debate: 'Many scientists are afraid to hurt their careers'

Vital interrogation of the science behind cryogenically freezing humans is being stifled because scientists fear being ostracised and ridiculed, according to a leading researcher in the field. The cryobiologist Ramon Risco said scientists risked damaging their careers and being excluded from scientific societies if they worked on cryonics, the controversial science used last month to freeze the body of a 14-year-old cancer victim. "There is an enormous 'stigma bias' to the conversation about cryonics among scientists. For scientists who would like to discuss it open-mindedly it tends to significantly hurt their career - in fact can potentially even get them kicked out of their scientific societies."

Prof Anders Sandberg, a research fellow at the Future of Humanity Institute at Oxford University, said scientists reliant on grants and looking for tenures might exercise self-censorship. "Many young scientists are afraid to hurt their careers. Talking about the future can be very career-limiting. Being seen to be eccentric in the wrong way is frowned upon." Cryonics enthusiasts argue that the stigma surrounding the area could leave people vulnerable to unscrupulous companies ready to fill the void left by science. Tim Gibson of the non-profit group Cryonics UK, which prepared the 14-year-old's body for transportation to the freezing facility in Michigan, said the group, all of whose staff are volunteers, would welcome regulation. "The danger for us is that as the idea gets more publicity, companies wanting to make a profit could spring up and damage us by [taking advantage of clients]."

Those interested in the area who were hopeful that scientific developments could see the reanimation of humans who had been cryogenically frozen would continue to work under the radar, said Risco. He added that "unconventional concepts" such as in vitro fertilisation, space travel and organ transplantation had all suffered "initial bias". "We don't need to start making a big polemic. We will keep on working on organ cryopreservation, no one will call us crazy and eventually we will end up with a solution for the whole body."

Court cryonics ruling is just common sense

Honestly, these cryonics stories are driving me mad. As someone with terminal cancer (and ignoring the fact that I find the description in your articles of people like myself as "cancer victims" to be teeth-grindingly irritating) I feel everyone is ignoring the fact that a young woman looked into her future and saw the denial of everything she was promised. She was denied boyfriends, university, a job, marriage, children, life... and she was not ready to give up on those promises. She didn't want to die. None of us does. I'm grateful that the judge had the good sense to realise this was not about whether cryonics worked, but her own hopes for the future. Reading some pieces lately it seems that while we'll arrange bungee-jumping days out for the terminally ill, how one disposes of one's own corpse is a step too far in giving the dying what they're asking for.

The risk of suffering dementia has fallen in recent years. The researchers involved in the paper here are reporting on epidemiological data, so the underlying reasons for this decline remain to be established conclusively. If I had to guess, it would be the increasing focus on control of blood pressure and other preventative cardiovascular treatment in medical practice. Dementia is driven in large part by the age-related failures of the vascular system. Stiffening of blood vessels leads to hypertension, which in turn damages sensitive tissues either through nothing more than greater pressure, or through greater rates of structural failure in small blood vessels, killing tissue one tiny volume at a time. There are other, less immediately physical mechanisms by which higher blood pressure degrades the normal operation of the brain as well, such as disruption of immune cell behavior. So it is entirely plausible to think that the approaches that have successfully reduced the risk of cardiovascular disease over the past few decades are also having an impact on dementia. Interestingly, the data in the paper suggests that the more recent improvements are not due to that cause, but you always have to weigh the details of any one paper against the bigger picture that emerges from all recent work on the topic.

Dementia, a decline in memory and other cognitive functions that leads to a loss of independent function, is a common and feared geriatric syndrome that affects an estimated 4 to 5 million older adults in the United States and has a large social and economic impact on patients, families, and government programs. Although the number of older adults with dementia in the United States and around the world is expected to grow up to 3-fold by 2050 owing to the large increase in the size of the elderly population, recent studies suggest that the age-specific risk of dementia may have actually declined in some high-income countries over the past 25 years, perhaps owing to increasing levels of education and better control of key cardiovascular risk factors, such as hypertension, diabetes, and hypercholesterolemia. For instance, the incidence of dementia among older participants in the Framingham Heart Study declined by about 20% per decade between 1977 and 2008, and the decline in risk was seen only among those with at least a high school education. If confirmed in representative populations, a decline in age-specific risk for dementia would have important implications for public health and public policy. For instance, a recent population-based study of dementia in England found a 24% decline in the expected number of cases of dementia between 1991 and 2011 (a 6.5% prevalence among older adults in 2011, compared with 8.3% in 1991), which translates to more than 200,000 fewer cases of dementia.

There have been changes over the past 2 to 3 decades in both the prevalence and treatment of cardiovascular risk factors that also influence the risk for dementia. For instance, 23% of US adults were obese in 1990 compared with 35% in 2012; among adults 65 years or older, the prevalence of diabetes increased from 9% to 21%. However, intensity of treatment for diabetes, hypertension, and high cholesterol level has increased with more patients achieving treatment goals, and a significant decline in the vascular complications of diabetes such as heart attack, stroke, and lower-extremity amputations, suggesting that there could be a "spill-over" benefit of a decline in the vascular-related risk for dementia. Rising levels of education among US adults over the past 25 years may also have contributed to decreased dementia risk. The proportion of adults 65 years or older with a high school diploma increased from 55% in 1990 to 80% in 2010, while the proportion with a college degree increased from 12% to 23%. More years of formal education is associated with a reduced risk of dementia, likely through multiple causal pathways, including a direct effect on brain development and function (i.e., the building of "cognitive reserve"), health behaviors, as well as the general health advantages of having more wealth and opportunities.

In a large nationally representative survey of older Americans we found that, among those 65 years or older, the prevalence of dementia decreased from 11.6% to 8.8% between 2000 and 2012, representing an absolute decrease of 2.8 percentage points, and a relative decrease of about 24%. Educational attainment increased significantly, with those 65 years or older in 2012 having nearly 1 additional year of education compared with the 2000 cohort. After controlling for the socioeconomic factors of education, wealth, and race/ethnicity, controlling for changes in the prevalence of cardiovascular risk factors did not explain much of the additional difference in dementia risk across the two cohorts. Our findings are consistent with those of a number of recent studies that also found declines in dementia incidence or prevalence in high-income countries around the world and also suggest that the trend toward a declining prevalence of cognitive impairment or dementia in the United States that we found between 1993 and 2002 using earlier data has continued through 2012, even with significant increases in the prevalence of cardiovascular risk factors that may increase dementia risk.

Link: http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2587084

The SENS view of mitochondrial damage in aging starts with the fact that deletions accrue to mitochondrial DNA. When those deletions remove one or more of the thirteen genes necessary to the primary processes of energy generation, the mutant becomes either more able to replicate or more able to resist destruction by quality control processes. In some cases, the mutant strain takes over the cell and turns it into a dysfunctional exporter of harmful, reactive molecules. There are even mechanisms by which such broken mitochondria can be exported to surrounding cells, spreading the rot. We accumulate a small but significant population of these malfunctioning cells over the years, and this is one of the root causes of aging and age-related disease. It is a step on the way to the production of oxidized lipids, to pick one example of the downstream consequences, and that contributes to the progression of atherosclerosis.

The SENS approach to remediation involves gene therapy to produce backup copies of the necessary mitochondrial genes, ensuring that the supply of vital protein machinery isn't interrupted by genetic damage in mitochondria. Is it possible, however, to manipulate the existing machinery of mitochondrial quality control to ensure that mutants are reliably destroyed rather than slipping past the net? This is an open question, and good arguments can be made either way: one the one hand, the existing system is pretty comprehensive but still fails catastrophically, allowing mutant mitochondria to very quickly overtake their cells. It isn't clear that simply dialing up quality control activity is going to help at all. On the other hand, cells that are reprogrammed for pluripotency quite clearly rejuvenate their mitochondria. Answering this question is better achieved through action rather than debate: in this open access paper researchers demonstrate clearance of mutant mitochondria with large deletions from fly tissues via manipulation of existing quality control systems as a proof of principle. It isn't at all clear to me from reading the paper that the authors have created a mutant strain that deletes the important genes relevant to aging, however, and therein lies the vital detail. They have, however, created the basis for model organisms that could be used for further exploration of this topic, in a more efficient manner than has been possible in the past.

Mitochondria are membrane-bound organelles present in many copies in most eukaryotic cells. The circular mitochondrial genome (mtDNA) encodes proteins necessary for oxidative phosphorylation, which generates the bulk of ATP in most cells. Individual mitochondria contain multiple copies of mtDNA, each of which is packaged into a structure known as a nucleoid, with primarily a single mtDNA per nucleoid. This multiplicity of genomes per cell, in conjunction with mtDNA's high mutation rate and limited repair capacity, often results in cells carrying mtDNA of different genotypes, a condition known as heteroplasmy. Recent studies suggest that 90% of individuals have some level of heteroplasmy, with 20% harbouring heteroplasmies that are implicated in disease. If the frequency of such a mutation reaches a threshold, pathology results. Heteroplasmy for deleterious mtDNA can also arise in somatic tissues during development and in adulthood. It accumulates throughout life, and is thought to contribute to diseases of aging. These observations emphasize the importance of devising ways to reduce heteroplasmy in vivo.

Mitochondria-targeted site-specific nucleases provide one way to decrease the levels of heteroplasmy. In this approach, a site-specific nuclease is engineered so as to bind and cleave a specific mutant version of the mtDNA genome, promoting its selective degradation. This approach has recently been used to decrease the levels of heteroplasmy in patient-derived cell lines, in oocytes and in single cell embryos. However, these methods are likely to be challenging to implement in the adult, as the nuclease being expressed is a non-self protein; many cells must be targeted without off target cleavage effects; and individuals may be heteroplasmic for multiple deleterious mutations. Here we seek to promote cell biological processes that normally regulate mtDNA quality as an alternative approach to decreasing heteroplasmy in adults.

Mitophagy serves as a form of quality control that promotes the selective removal of damaged mitochondria. In one important pathway, dysfunctional mitochondria are eliminated through a process dependent on PTEN-induced putative kinase 1 (PINK1) and Parkin, loss of which lead to familial forms of Parkinson's disease. Regardless, the fact that mutant mtDNA accumulates in individuals wild type for PINK1 and parkin during aging indicates that if PINK1- and Parkin-dependent mitophagy and/or other pathways promote mtDNA quality control, they are often not active or effective. To identify ways of reducing the mutant mtDNA load in somatic tissues, systems are needed in which a specific deleterious heteroplasmy can be induced in vivo and followed over time, ideally in post-mitotic cells so as to eliminate potential confounding effects associated with stochastic segregation during cell division, and differential cell proliferation and/or cell death. Current in vivo models are cumbersome and limited, but we describe the generation and use of a transgene-based system of heteroplasmy in post-mitotic muscle to identify conditions that result in the selective removal of mutant mtDNA.

We demonstrate that the load of deleterious mtDNA can be decreased through several different interventions. Genetic and chemical screens using such a model should prove useful in identifying molecules that can cleanse tissues of a deleterious genome, via known and unknown mitochondrial quality control pathways. The many tools for regulated spatial and temporal control of gene expression in Drosophila will allow such screens to be carried out in a variety of tissues and environmental contexts, including aging. Our results show that adult muscle has a significant but limited ability to remove mutant mtDNA utilizing genes required for autophagy, and that mutant mtDNA removal can be greatly stimulated in several ways: by limiting the ability of mitochondrial fragments to re-fuse with the network (decreasing Mfn levels), by limiting their ability to undergo repolarization through ATP synthase reversal (ATPIF1 expression), by increasing the tagging of mtDNA-bearing fragments (increasing PINK1 or Parkin levels), and by increasing the frequency with which these tagged fragments are degraded (activation of autophagy). These observations have important implications for new therapies for mitochondrial disease and diseases of aging.

Link: http://dx.doi.org/10.1038/ncomms13100

The end of year fundraiser for SENS rejuvenation research progresses apace. We are helping to fund the work needed to produce actual, working rejuvenation therapies soon enough to matter, treatments that can target and repair the fundamental causes of aging. Aging is caused by a few forms of molecular damage that accrue in cells and tissues, a sort of slow biological wear and tear that results from the normal operation of metabolism. Given the right lines of research, that damage can be repaired, and thus the clock turned back, age-related disease prevented or effectively treated. Those research programs are outlined in the SENS vision, and have been underway for some years now, making steady progress with the support of everyday philanthropists like you and I.

At the start of November, Josh Triplett and Fight Aging! put up a $24,000 challenge fund for new SENS Patrons: everyone who signs up before the end of the year to make a regular monthly donation to the SENS Research Foundation will have the next year of donations matched dollar for dollar. I'm pleased to announce that this past weekend, Christophe and Dominique Cornuejols stepped up to contribute another $12,000 to the fund. You might recall that they also provided a matching fund to help in the last days of the universal cancer therapy crowdfunding effort earlier this year. It is a privilege to have had the support of these folk over the past few years of Fight Aging! fundraisers.

The SENS Patron challenge fund was $24,000, and is now $36,000. That means we're looking for more SENS Patrons to take the plunge and help to extend and broaden the research success produced by the SENS Research Foundation and their allies in past years. We live in exciting times when it comes to medicine for human rejuvenation, with senescent cell clearance therapies now in well-funded clinical development and other lines of research threatening to follow in the years ahead. The transition is underway from the medicine of the past, that did not in any meaningful way address the molecular damage that causes aging and age-related disease, to the medicine of the future, in which that damage is targeted for repair. We will have longer, healthier lives thanks to the efforts of SENS advocates and researchers, and thanks to the many people whose charitable donations have allowed this work to take place at all.

It has been a tough job to bootstrap a new field of medicine from scratch, in the face of all of those who said it couldn't be done or shouldn't be done. There are certainly fewer naysayers now that the wheel is beginning to turn, however, and now that the first rejuvenation research startup companies are working on bringing therapies to the clinic. Researchers talk openly about targeting the processes of aging, and there is enthusiasm for progress in many parts of the research and development communities. This is the time for advocates and donors to push harder, to build atop present success, to lay the foundations for the next set of treatments to emerge in the years ahead. There are seven classes of cell and tissue damage involved in aging, and only two or three of those could be said to be proceeding at a productive pace today: senescent cell clearance, stem cell research, and some forms of amyloid clearance. The others are just as important, but still languishing, with comparatively little funding, and yet to reach the tipping point that senescent cell clearance reached in the past few years. When that point arrives for a specific line of research it becomes a pretty fast ride from a few groups in the laboratory to multiple venture funded companies working on clinical applications of longevity science, but getting there is up to us.

To a first approximation no-one cares about funding fundamental medical research, and the most important work is near always heavily funded by visionaries and philanthropists, rather the established funding institutions. It is really, really hard to raise funding for radical new approaches in medicine - until the researchers can prove that they work. See what David Spiegel of the noted Spiegel Laboratory at Yale had to say on that topic, for example:

The SENS Research Foundation funding has been critical to our work studying and developing methods to reverse the effects of advanced glycation end-products (AGEs) in aging. AGEs are non-enzymatic modifications that build up on proteins as people age, leading to inflammation and tissue damage. Early on, our lab focused significant effort on developing the first total synthesis of glucosepane - a major AGE cross-link found in human tissues - but we were unable to find funding from any of the traditional sources. The SENS Research Foundation came to our aid, and supported this research for over 5 years. In 2015, our glucosepane synthesis efforts were published in Science, and lay a foundation for developing drugs capable of detecting and reversing tissue damage in aging. We are deeply grateful to the SENS Research Foundation and Fight Aging! for all of their support and look forward to exciting, life-extending work to come!

The work of the Spiegel Laboratory will form the foundation of an approach to treat aging that will be just as important as senescent cell clearance. But like so many vital lines of research related to the future of rejuvenation therapies, and like so many vital lines of research in the broader field of medicine, funding just can't be found through the existing establishment. That is why our fundraisers and our acts of advocacy are so very important. The future is in our hands: we are the ones who raise up the lantern and shine a light on the research and development that must happen; who call for assistance and vote with our wallets; who raise the profile of this work; who provide the funding needed for prototypes and further evidence; and who start the ball rolling. When high net worth individuals join in, when the institutions finally pay attention, when the venture capitalists fund companies, it is because we took action, and because we did our part to show the way. So join in!

The mitochondrially targeted antioxidant SkQ1 and other compounds in its family have moved into commercial development in Europe. Over the past decade these plastoquinone derivatives have been shown to modestly slow aging in flies and mice, but the greatest and most reliable effects involve reduction of inflammation and effective treatment of inflammatory eye conditions. Thus clinical development has focused on diseases such as dry eye syndrome, an unpleasant condition caused by age-related dysfunction of the lacrimal gland responsible for tear secretion. Aging eventually causes problems in every bodily system, including those that we tend to take for granted, not realizing that we will be greatly pained and inconvenienced by their failure.

Dry eye syndrome (DES) is a frequent eye disorder affecting many people worldwide, especially at an old age. DES is a multifactorial disorder of the ocular surface unit and results in eye discomfort, visual disturbances, and tear film instability with potential damage to the ocular surface and often poor quality of life. Current therapies for DES are only palliative, focusing on replacement of tear fluid to reduce the symptoms. Thus, there is a need for drugs that directly address the causes of DES. Clinical and basic studies have shown that the age-related decline of lacrimal-gland functions decreases the ability to synthesize and secrete proteins. These alterations may cause aqueous tear deficiency in DES. Approximately 80% of the lacrimal gland is acinar cells: highly differentiated epithelial cells specialized for the synthesis, storage, and secretion of tear fluid components, such as water, proteins, glycoproteins, and electrolytes. During aging, the synthesis and secretion of proteins decrease in lacrimal glands, and acinar cells start to produce and secrete a mucous product. The latter causes aberrations in the tear film of the eyes.

Researchers have compared ultrastructure of mitochondria in acinar cells of 6- and 12-month-old ad libitum fed Fischer 344 rats and uncovered occasional mitochondrial swelling, disorientation, shortening, and disorganization of cristae in the 12-month-old animals. Mitochondria, when dysregulated, are a major source and target of oxidative stress. Mitochondrial dysfunction strongly promotes aging and the pathogenesis of age-related diseases including eye diseases. Some authors demonstrated a connection of age-related alterations in the lacrimal gland with oxidative stress. Other authors showed the possibility of interventions (e.g., calorie restriction) aimed at reducing excessive production of reactive oxygen species (ROS) to prevent disturbances in the mitochondrial ultrastructure of acinar cells in the lacrimal gland. Changes in signaling pathways associated with age-related upregulation of oxidative stress have been detected in the aging lacrimal gland. Increased oxidative stress can result from reductions in insulin secretion and parasympathetic signaling accompanied by an increase in hormone resistance and by accumulation of advanced glycation end products in the aging lacrimal gland.

Thus, an increasing body of evidence suggests that prevention of upregulation of mitochondrial ROS is important for possible therapeutic strategies to delay age-associated alterations and to prevent age-related disorders in humans. Despite the disappointing effects of antioxidants in clinical trials, there is growing evidence of beneficial effects of mitochondria-targeted antioxidants during aging and in age-related diseases. Previously, we showed that mitochondria-targeted antioxidant 10-(6′-plastoquinonyl) decyltriphenyl phosphonium cation (SkQ1) ameliorates the signs of aging and inhibits the development of such age-related diseases as cataract, age-related macular degeneration, and glaucoma in rats. SkQ1 (under the brand name Visomitin) in the form of eye drops is already manufactured and has been successfully used since 2012 for treatment of DES in Russia. Nevertheless, the link between SkQ1's effects and its suppression of age-related aberrations in the lacrimal gland has not been explored. The aim of this study was to examine the effects of long-term dietary supplementation with SkQ1 on age-related deterioration of lacrimal-gland ultrastructure Wistar rats.

Here we demonstrated that dietary supplementation with SkQ1 (250 nmol/[kg body weight] daily) starting at age 1.5 months significantly alleviated the pathological changes in lacrimal glands of Wistar rats by age 24 months. By this age, lacrimal glands underwent dramatic deterioration of the ultrastructure that was indicative of irreversible disturbances in these glands' functioning. In contrast, in SkQ1-treated rats, the ultrastructure of the lacrimal gland was similar to that in much younger rats. Morphometric analysis of electron-microscopic specimens of lacrimal glands revealed the presence of numerous secretory granules in acinar cells and a significant increase in the number of operating intercalary ducts. Our results confirm that dietary supplementation with SkQ1 is a promising approach to healthy ageing and to prevention of aberrations in the lacrimal gland that underlie dry eye syndrome.

Link: http://dx.doi.org/10.18632/oncotarget.13303

Perhaps the greatest challenge in the field of tissue engineering is the production of integrated networks of small blood vessels sufficient to support larger tissue sections. Without a reliable way to do this, researchers are limited to producing the tiny functional tissue masses known as organoids. When it comes to making larger blood vessels, however, good progress is being made. This article takes a look at the efforts of one alliance of research groups, aiming for the widespread, cost-effective availability of engineered arteries:

The prospect of creating artery "banks" available for cardiovascular surgery, bypassing the need to harvest vessels from the patient, could transform treatment of many common heart and vascular ailments. But it's a big leap from concept to reality. Patients needing bypass surgeries would benefit from a better source for arteries. Replacement tissue currently comes from another part of the patient's body, and suitable tissue can't be found for many patients. Current synthetic alternatives also fail at a high rate. Diseases of blood vessels - including coronary artery disease - kill more people worldwide than any other single cause.

"Tissue engineering for blood vessels is a pretty mature field. But there are still two major problems: One is the time it takes to make the vessels, and the other is the source of the cells to grow them." For example, taking induced pluripotent (iPS) stem cells from an individual patient, growing the relevant cells and assembling them into an artery would overcome the problem of transplant rejection. However, it would be cost-prohibitive and take months to complete - too long to be clinically useful to a patient. The promising alternative is to create tissue with cells banked from a unique population of people who are genetically compatible donors, based on rare alleles that circumvent rejection. It has been estimated that about 100 different cell lines from this rare population would be enough to cover a majority of the U.S. population.

A new effort covers four phases and addresses key questions about the feasibility of this approach. The model for the project is designed around treating critical limb ischemia, a debilitating condition that restricts blood flow to limbs and often leads to amputation or death. Researchers are working to create the optimal cellular building blocks of the artery - endothelial and smooth muscle cells - that will be most suitable for transplantation and continue to grow and remodel in the patient. In tandem, a different team will develop scaffolds from natural and synthetic materials to provide structure and shape for the artery. Other researchers will build a bioreactor that provides an environment in which the arterial cells can grow around the scaffolding. The transplant surgery and resulting immune response will then be tested using a monkey limb ischemia model. Having a primate model is important to produce results more relevant to human health than those from mice or other short-lived animals. Finally, there is the production of arterial cells that meet FDA standards for human clinical trials, paving the way for potential treatments for limb ischemia in humans. If the entire process works, researchers estimate that potential human therapies remain about 10 years away.

Link: http://news.wisc.edu/morgridge-uw-project-investigates-tissue-engineered-arteries-for-transplant/

Here I'll point out a varied collection of recent papers and research results linked by the theme of regeneration. I found them interesting enough to note in passing for one reason or another, but a great deal of similar research is passing by these days, far too much for any one individual to read in detail. Regenerative medicine is much more than just the production of effective stem cell treatments. In its broadest definition it also encompasses the sort of rejuvenation therapies outlined in the materials and scientific programs of the SENS Research Foundation. It is a matter of finding the breakage, the abnormality, the injury, and then taking the path of augmenting, altering, or steering cellular activity in order to induce regeneration sufficient to restore normal function. There are countless ways to achieve that goal: tissue engineering for transplantation; cell therapies and small molecule therapies that aim to adjust the behavior of local tissues; augmentations such as gene therapies that introduce entirely new capabilities to cells. Aging is a collection of breakages and damage at the level of cells and proteins that leads to lost functionality. Repairing that damage in order to allow the normal operation of organs and tissues is exactly a facet of regeneration.

Transplantation with induced neural stem cells improves stroke recovery in mice

In a study to determine whether induced neural stem cells (iNSCs), a type of somatic cell directly differentiated into neural stem cells, could exert therapeutic effects when transplanted into mice modeled with ischemic stroke, researchers found that the cells promoted survival and functional recovery. Additionally, they discovered that when administered during the acute phase of stroke, iNSCs protected the brain from ischemia-related damage. In contrast to other studies that have induced somatic cells to become pluripotent stem cells (iPSCs), which can then be differentiated into neural cells, this study directly converted somatic cells into neural stem cells. Researchers concluded that in addition to iNSC transplantation improving survival rate, results also demonstrated reduced infarct volume in the brain and enhanced sensorimotor function in the mice modeled with stroke. "The iNSCs did not produce any adverse responses in the animals, including tumor formation, which may suggest they are safer than regular iPSCs. Further studies are needed to confirm this cell type as a candidate for cell replacement therapy for stroke."

Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration

The skeletal muscle stem cell niche provides an environment that maintains quiescent satellite cells, required for skeletal muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite cells, supports communication with the niche, providing cell interactions and signals to maintain quiescent satellite cells. Syndecan-3 ablation unexpectedly improves regeneration in repeatedly injured muscle and in dystrophic mice, accompanied by the persistence of sublaminar and interstitial, proliferating myoblasts. Additionally, muscle aging is improved in syndecan-3 null mice. Since syndecan-3 null myofiber-associated satellite cells downregulate Pax7 and migrate away from the niche more readily than wild type cells, syxndecan-3 appears to regulate satellite cell homeostasis and satellite cell homing to the niche. Manipulating syndecan-3 provides a promising target for development of therapies to enhance muscle regeneration in muscular dystrophies and in aged muscle.

Bursting the unfolded protein response accelerates axonal regeneration

The endoplasmic reticulum (ER) is a dynamic interconnected network involved in quality control processes that maintain a functional proteome in the cell. Accumulating evidence indicates that central nervous system and peripheral nervous system injury alters ER proteostasis engaging a stress reaction in neurons and glial cells. ER stress activates an adaptive mechanism to cope with protein folding alterations, known as the unfolded protein response (UPR). We recently investigated the impact of the UPR to peripheral nerve regeneration. Using genetic manipulation, we studied the consequences of targeting XBP1 to assess the impact of the UPR to Wallerian degeneration after sciatic nerve damage. Deletion of Xbp1 in the nervous system led to decreased myelin clearance, axonal regeneration and macrophage infiltration after mechanical damage. Importantly, locomotor recovery in Xbp1 deficient mice was significantly delayed. Furthermore, overexpression of XBP1s in neurons using a transgenic mice increased axonal regeneration and locomotor recovery after injury. We moved forward and developed a therapeutic strategy to artificially engage XBP1-dependent gene expression programs to enhance axonal repair. We validated a gene transfer approach to deliver XBP1s into sensory axons using adeno-associated viruses (AAVs). AAV-XBP1s transduced neurons showed an enhancement in the axonal regeneration process. Altogether, these results demonstrated a differential contribution of the IRE1α/XBP1 signaling branch of the UPR in the injured peripheral nervous system.

We speculate that the local activation of UPR stress sensors in the axonal compartment after damage may trigger the retrograde transport of active XBP1s to engage transcriptional programs that contribute to alleviate proteostasis alterations. The next step in the field is to determine if the UPR has therapeutic potential. Overall, modulation of axonal regeneration programs by the UPR incorporates novel players in the process of nerve repair after mechanical damage. Since several small molecules and gene therapy strategies are available to target the UPR, manipulation of the ER proteostasis network might emerge as a new avenue to develop interventions that improve axonal regeneration in different degenerative conditions of the nervous system.

Rejuvenating Muscle Stem Cell Function: Restoring Quiescence and Overcoming Senescence

Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle satellite (or stem) cells (SMSCs) and progenitor cells. Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a presenescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion. Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the presenescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the presenescent state results from loss of autophagy, leading to increased reactive oxygen species and epigenetic modification at the CDKN2A locus, upregulating cell senescence biomarker p16ink4a. However, the presenescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells. Other work suggests that in humans, loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus downregulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to presenescence in the very old.

Researchers amplify regeneration of spinal nerve cells

Researchers successfully boosted the regeneration of mature nerve cells in the spinal cords of adult mammals - an achievement that could one day translate into improved therapies for patients with spinal cord injuries. "This research lays the groundwork for regenerative medicine for spinal cord injuries. We have uncovered critical molecular and cellular checkpoints in a pathway involved in the regeneration process that may be manipulated to boost nerve cell regeneration after a spinal injury." The researchers focused on glial cells, the most abundant non-neuronal type of cells in the central nervous system. Glial cells support nerve cells in the spinal cord and form scar tissue in response to injury. In 2013 and 2014, researchers created new nerve cells in the brains and spinal cords of mice by introducing transcription factors that promoted the transition of adult glial cells into more primitive, stem cell-like states, and then coaxed them to mature into adult nerve cells. The number of new spinal nerve cells generated by this process was low, however, leading researchers to focus on ways to amplify adult neuron production.

In a two-step process, researchers first silenced parts of the p53-p21 protein pathway that acts as a roadblock to the reprogramming of glial cells into the more primitive, stem-like types of cells with potential to become nerve cells. Although the blockade was successfully lifted, many cells failed to advance past the stem cell-like stage. In the second step, mice were screened for factors that could boost the number of stem-like cells that matured into adult neurons. They identified two growth factors - BDNF and Noggin - that accomplished this goal. Using this approach, researchers increased the number of newly matured neurons by tenfold. "Our ability to successfully produce a large population of long-lived and diverse subtypes of new neurons in the adult spinal cord provides a cellular basis for regeneration-based therapy for spinal cord injuries. If borne out by future studies, this strategy would pave the way for using a patient's own glial cells, thereby avoiding transplants and the need for immunosuppressive therapy."

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

The average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Impaired wound healing and disordered ischemia-mediated angiogenesis are key contributors to age-impaired vascular complications that can lead to amputation. High-density lipoproteins (HDL) have vasculo-protective properties and augment ischemia-driven angiogenesis in young animals. We aimed to determine the effect of reconstituted HDL (rHDL) on aged mice in a murine wound healing model and the hindlimb ischemia (HLI) model.

Daily topical application of rHDL increased the rate of wound closure by Day 7 post-wounding (25%). Wound blood perfusion, a marker of angiogenesis, was elevated in rHDL treated wounds (Days 4-10 by 22-25%). In addition, rHDL increased wound capillary density by 52.6%. In the HLI model, rHDL infusions augmented blood flow recovery in ischemic limbs (Day 18 by 50% and Day 21 by 88%) and prevented tissue necrosis and toe loss. Assessment of capillary density in ischemic hindlimb sections found a 90% increase in rHDL infused animals. In vitro studies in fibroblasts isolated from aged mice found that incubation with rHDL was able to significantly increase the key pro-angiogenic mediator vascular endothelial growth factor (VEGF) protein (25%). In conclusion, rHDL can promote wound healing and wound angiogenesis, and blood flow recovery in response to ischemia in aged mice. Mechanistically, this is likely to be via an increase in VEGF. This highlights a potential role for HDL in the therapeutic modulation of age-impaired vascular complications.

Researchers have been making progress in understanding exactly why skin healing falters with age. Changes in the behavior of sweat glands and surrounding structures built out of keratinocyte cells appear to be important, for example. Skin normally heals through construction of keratinocytes spreading outwards from the sweat glands, but that becomes disrupted in later life. Researchers here fill in more details in the signaling changes involved in that disruption, as well as the role of the immune system, and suggest that it should be possible to nudge the balance of signals back in the right direction. That wouldn't address the root causes of these changes, of course, such as the presence of senescent cells and cross-links in skin tissue, and the age-related decline of the immune system, but might produce enough of a benefit in wound healing to be worth the effort.

Older bodies need longer to mend. Yet until now, researchers have not been able to tease out what age-related changes hinder the body's ability to repair itself. Recent experiments explored this physiological puzzle by examining molecular changes in aging mouse skin. The results delineate a new aspect of how the body heals wounds. "Within days of an injury, skin cells migrate in and close the wound, a process that requires coordination with nearby immune cells. Our experiments have shown that, with aging, disruptions to communication between skin cells and their immune cells slow down this step. Wound healing is one of the most complex processes to occur in the human body. Numerous types of cells, molecular pathways, and signaling systems go to work over timescales that vary from seconds to months. Changes related to aging have been observed in every step of this process."

Both skin cells and immune cells contribute to this elaborate process, which begins with the formation of a scab. New skin cells known as keratinocytes later travel in as a sheet to fill in the wound under the scab. The team focused on this latter step in healing in two-month-old versus 24-month-old mice - roughly equivalent to 20- and 70-year-old humans. They found that among the older mice, keratinocytes were much slower to migrate into the skin gap under the scab, and, as a result, wounds often took days longer to close. Wound healing is known to require specialized immune cells that reside in the skin. The researchers' new experiments showed that following an injury, the keratinocytes at the wound edge talk to these immune cells by producing proteins known as Skints that appear to tell the immune cells to stay around and assist in filling the gap. In older mice, the keratinocytes failed to produce these immune signals.

To see if they could enhance Skint signaling in older skin, the researchers turned to the protein IL-6 that resident immune cells normally release after injury, activating STAT3. When they applied this protein to young and old mouse skin tissue in a petri dish, they saw an increase in keratinocyte migration, which was most pronounced in the older skin. In effect, the old keratinocytes behaved more youthfully. The scientists hope the same principle could be applied to developing treatments for age-related delays in healing. "Our work suggests it may be possible to develop drugs to activate pathways that help aging skin cells to communicate better with their immune cell neighbors, and so boost the signals that normally decline with age."

Link: http://newswire.rockefeller.edu/2016/11/17/new-research-clarifies-why-wounds-heal-more-slowly-with-age/

To me at least, it seems that links between low-level radiation exposure and Alzheimer's disease are tenuous at best. You can look at the painkiller theory of Alzheimer's for an example of finding correlations with rising levels of dementia that are unlikely to involve causation, but where one can dig up biochemistry that looks somewhat supportive to the idea. Yet in comparison to the standard view, that has very little weight of evidence. Suggestions that greater exposure to low levels of ionizing radiation, via medical scanning procedures and air travel, contributes meaningfully to dementia seems like another example of the type. If anything, the weight of evidence on low-level radiation exposure indicates that it produces beneficial hormetic effects that should modestly slow the progression of aging. But again, it is possible to produce results that look somewhat supportive of the thesis, as here. I am skeptical on the whole, and would want to see a lot more evidence before abandoning the more mainstream view that rising Alzheimer's incidence is a consequence of demographic aging and rising rates of obesity in the population at large.

Alzheimer's disease is the leading cause for dementia in the elderly, and its global prevalence is supposed to increase dramatically in the following decade - up to 80 million patients by 2040. In a new study, researchers show that low doses of ionising radiation induce molecular changes in the brain that resemble the pathologies of Alzheimer's. Large numbers of people of all age groups are increasingly exposed to ionizing radiation from various sources. Many receive chronic occupational exposure from nuclear technologies or airline travel. The use of medical diagnostics and therapeutic radiology has increased rapidly - for example more than 62 million CT scans per year are currently carried out in USA. Approximately one third of all diagnostic CT examinations are scans of the head region. "All these kinds of exposures are low dose and as long as we talk about one or a few exposures in a lifetime I do not see cause for concern. What concerns me is that modern people may be exposed several times in their lifetime and that we don't know enough about the consequences of accumulated doses."

Recent data suggest that even relatively low radiation doses, similar to those received from a few CT scans, could trigger molecular changes associated with cognitive dysfunction. In their new study, the researchers have elucidated molecular alterations in the hippocampus of mice. The hippocampus is an important brain region responsible for learning and memory formation and it is known to be negatively affected in Alzheimer´s. The authors induced changes in the hippocampus by two kinds of chronic low-dose-rate ionizing radiation treatments. The mice were exposed to cumulative doses of 0.3 Gy or 6.0 Gy given at low dose rates of 1 mGy over 24 hours or 20 mGy over 24 hours for 300 days. "Both dose rates are capable of inducing molecular features that are reminiscent of those found in the Alzheimer's disease neuropathology. When you compare these figures you will find that we exposed the mice to a more than 1000 times smaller cumulative dose than what a patient gets from a single CT scan in the same time interval. And even then we could see changes in the synapses within the hippocampus that resemble Alzheimer´s pathology." According to the researchers, the data indicate that chronic low-dose-rate radiation targets the integration of newborn neurons in existing synaptic wires.

Link: http://www.sdu.dk/en/om_sdu/fakulteterne/naturvidenskab/aktuelt/2016_10_27_radiationconcern

There have been a number of life science discoveries of late that might lead to therapies capable of reducing the level of tissue damage caused by structural failures in important blood vessels, the basis for a range of age-related conditions. News of another possible approach arrived recently, and you will find links to the publicity materials and open access paper below. Blood vessel failures cause an interruption of oxygenated blood flow to tissues, and depending on the location in the body and size of the failed vessel, can produce the dramatic symptoms of stroke, heart attack, and so forth. While methods of prevention are far preferable to methods the produce greater than normal resilience, if the resilience is on offer it would be foolish to turn it down.

In ischemic injuries where blood flow is lost for a period of time, the real damage is done not after blood supply ceases, but after it is restored. With renewed oxygenation, cells fall into a self-sabotaging state of intense activity and die in large numbers. Of course if blood supply is never restored, the same end result occurs and the tissue dies, but reperfusion injury is perhaps the biggest threat in stroke, heart attack, and the like. Thus there is great interest in the research community in finding ways to reduce this damage, and many different methodologies have been tried, sadly to little success. Now that researchers are getting a better handle on the cellular biochemistry of ischemia and reperfusion, however, targets are emerging. For example, suppressing the oxygen sensor PHD1 greatly reduces reperfusion damage, as fewer cells react inappropriately to the return of oxygenated blood. Similarly, temporary sabotage of the cell death process might achieve a similar outcome, while letting the cells otherwise react normally, and MIF is one target there. Another possible approach is to spur greater growth of alternative vasculature via Rabep2, so as to reduce the impact of any one path for blood failing. As you can see, there are many possible points at which to intervene.

Still, prevention seems a whole lot better. When the problem is failing aged blood vessels, the solution has to be something like the SENS approach to rejuvenation research. Taking the proximate causes of blood vessel failure, that include hypertension, loss of elasticity in blood vessels, and atherosclerosis, for example, we can the look at the root causes of these issues. These include cross-linking in the extracellular matrix of blood vessel walls, rising numbers of senescent cells, and the oxidized lipids produced as a result of cells taken over by malfunctioning mitochondria. Each of these root cause classes of cell and tissue damage has an associated path to therapies that will repair or work around this type of damage to remove its effects. The programs are as clearly mapped out as anything can be in the world of research and development. If we want to see an end to strokes and heart attacks, a world in which older people have great cardiovascular health with little to no decline beyond their earlier years, then this is the type of research we need to support.

BAG3 Protein Plays Critical Role in Protecting Heart From Reperfusion Injury, Temple Researchers Show

The inability of cells to eliminate damaged proteins and organelles following the blockage of a coronary artery and its subsequent re-opening with angioplasty or medications - a sequence known as ischemia/reperfusion - often results in irreparable damage to the heart muscle. To date, attempts to prevent this damage in humans have been unsuccessful. According to a new study, however, it may be possible to substantially limit reperfusion injury by increasing the expression of a protein known as Bcl-2-associated athanogene 3 (BAG3).

Ischemia impairs the function of cellular organelles including mitochondria, the cell's energy-producers, resulting in harmful effects that set the stage for a sudden burst in the generation of toxic oxidizing substances when oxygenated blood reenters the heart. The toxins lead to fundamental changes in the biology of the heart. Notably, they activate cell death pathways and decrease autophagy - the process by which cells remove malfunctioning proteins and organelles. Autophagy plays a critical role in removing damaged myocardial cells (the muscular tissue of the heart) and misfolded heart muscle fibers. The new work shows that BAG3 expression both inactivates cell death pathways, helping prevent the loss of heart cells triggered by ischemia, and activates autophagy, thereby enabling cells to clear out impaired components of the heart cell before they inflict extensive damage.

In initial work, the research group found that BAG3 promotes autophagy and inhibits programmed cell death (apoptosis) in cultured cardiac myocytes. Subsequently, they found that when heart cells were exposed to the stress of hypoxia/reoxygenation or when living mice were stressed with ischemia/reperfusion, they suffered dramatic reductions in BAG3 expression. Those paradoxical changes in BAG3 levels turned out to be directly associated with increases in biomarkers of autophagy and with decreases in biomarkers of apoptosis. By artificially knocking down BAG3 in mouse heart cells, the researchers were able to produce an apoptosis-autophagy biomarker phenotype nearly identical to that produced by hypoxia/reoxygenation. By contrast, BAG3 overexpression normalized apoptosis and autophagy. In a key experiment, the team further showed that tissue damage sustained following ischemia/reperfusion could be substantially reduced by treating mice with BAG3 prior to vessel re-opening. BAG3 overexpression before the onset of ischemia/reperfusion also resulted in normalization in apoptosis and autophagy biomarkers.

Bcl-2-associated athanogene 3 protects the heart from ischemia/reperfusion injury

BAG3 has come to the attention of investigators focused on the heart due to the observation that mutations in BAG3 lead to familial dilated cardiomyopathy, the finding that BAG3 modulates excitation-contraction coupling in the heart, and our recent observation that BAG3 promoted mitochondrial degradation through the autophagy-lysosome pathway and through direct interactions with mitochondria. Because disruption of the normal removal of damaged and dysfunctional mitochondria plays a pivotal role in reperfusion injury following ischemia, we hypothesized that alterations in the expression or function of BAG3 might play a role in reperfusion injury.

The role of autophagy and apoptosis in the development of cardiovascular disease and in particular in the development of heart failure has been well recognized. In fact, modest overexpression of active caspase leads to the development of heart failure. However, a pivotal role for BAG3 in regulating cardiac protection and its associated effects on autophagy and apoptosis have not been previously recognized. Importantly, while restitution of diminished levels of BAG3 after hypoxia/reoxygenation or ischemia/reperfusion lead to salutary effects in cells or tissues that have been stressed, BAG3 appears to have no untoward effects on either autophagy or apoptosis when BAG3 levels are increased in cells or hearts that have not been exposed to stress, suggesting that attempts to increase BAG3 levels could provide a unique and important therapeutic approach to cardiac protection.

Despite successful efforts to limit the time between the onset of coronary obstruction and coronary intervention in patients with an acute myocardial infarction, myocardial damage due to reperfusion injury remains a major clinical problem that has failed to be influenced by multiple pharmacologic approaches. The findings that BAG3 levels are reduced during the stress of hypoxia/reoxygenation in vitro or ischemia/reperfusion in vivo and that overexpression of BAG3 reduces infarct size and improves left ventricle function after ischemia/reperfusion in mice suggest that BAG3 could provide a therapeutic target for cardiac protection. We recognize that biological differences exist between mice and humans, and it will be important to demonstrate that similar salutary benefits of enhancing BAG3 levels can be seen in a large animal model of ischemia/reperfusion injury. Nonetheless, our results suggest that moving from evaluations in mice to studies in large animals with ischemia and reperfusion, the next step in translational science paradigm, would be warranted.

Increased levels of the neurotransmitter GABA have in the past been shown to produce greater neural plasticity. Here researchers link higher GABA levels in one part of the brain with a greater capacity of working memory. This preliminary finding is a very long way from being the basis for some form of therapy for age-related loss of memory function or enhancement technology to improve memory at all ages, but that is where investigations of the biochemistry of memory will eventually lead.

Working memory is the brain function that lets you carry on a phone conversation while adding three numbers in your head and remembering that you need to steer the car onto the freeway exit in about two minutes - all this time not forgetting who you're talking to. Working memory serves as a buffer where information, derived from the senses or retrieved from long-term memory, can be temporarily placed so the conscious brain can process it. It's tied to assessments of cognitive capacity such as IQ, and to real-world outcomes such as academic performance. As most people eventually find out, working memory declines with age.

A new study teases apart three key components of working memory and shows that one component, but not the other two, is tied to the amount of a chemical called GABA in a brain area known as the dorsolateral prefrontal cortex, or DLPFC. This component, referred to as load, is a measure of the number of separate bits of information a person's working memory can store at the same time. A second component, maintenance, denotes how long information can be stored in working memory before it's lost. A third, distraction resistance, gauges how well an individual's working memory holds onto information in the face of interfering stimuli. The DLPFC, a broad swath of neural tissue on the forebrain surface, has been shown in animal studies and in observations of brain-damaged patients to be integral to high-level executive functions in the brain, such as planning, prioritizing and avoiding distractions. It has likewise been strongly implicated in working memory. The DLPFC orchestrates activity in numerous distant centers throughout the brain, including the visual cortex, which is located near the brain's surface but in the hindbrain.

In the study, 23 healthy participants ages 19-32 were subjected to batteries of tests of working memory. The researchers reasoned that different components of working memory would involve different neurotransmitter inputs. They devised working-memory tests that separated the measurement of load, maintenance and distraction resistance. Participants repeated several related tasks. In the simplest, they were shown a drawing of a face and then, after a two-second delay, shown a second face and asked whether it was the same as or different from the first one. Variations of this task - initially presenting two faces instead of just one; lengthening the intervening delay; or displaying a different, irrelevant face between the initial and final displays - tested load, maintenance and distraction resistance, respectively. The investigators compared individuals' error rates on the simple version of the task with outcomes on tasks taxing one or another working-memory component more heavily. The smaller the deterioration in performance on a test of a particular working-memory component, the greater the individual's capacity regarding that component was judged to be.

Using an advanced imaging method, the scientists measured GABA levels in the DLPFC and, for comparison, in the visual cortex. GABA, secreted by nerve cells, is an inhibitory neurotransmitter: Its uptake by other nerve cells inhibits their firing. The researchers also measured levels of an excitatory neurotransmitter, glutamate. By far the two most abundant neurotransmitters in the brain, GABA and glutamate are considered to be that organ's stop and go signals. Individuals with higher levels of GABA in their DLPFC performed better on tests of their load capacity - the ability to juggle more bits of information - the researchers found. In contrast, no significant association emerged linking GABA levels in the DLPFC to maintenance or to distraction resistance, or tying participants' load capacity to GABA levels in the visual cortex. Nor did imaging reveal any connection between performance on tests of load capacity and levels of glutamate in the DLPFC.

Link: http://med.stanford.edu/news/all-news/2016/11/more-gaba-in-one-brain-region-linked-to-better-working-memory.html

One of the big questions in Alzheimer's research is the degree to which the pathology of dementia results from aggregates of amyloid-β or the neurofibrillary tangles composed of altered forms of tau protein. That question will probably be best and finally answered via the development of therapies that can effectively remove one or the other, but here researchers offer an interesting study carried out in human tissue samples and mice to suggest that the influence of tau is significant:

Amyloid-β (Aβ) was the focus of most of the studies on Alzheimer's disease (AD) in the last 20 years. However, Aβ is not the only pathological agent involved in AD. Microtubule Associated Protein Tau (MAPT) is also likely to play a major role in the disease. While Aβ species derive from APP processing, six tau isoforms are derived from alternative splicing of the MAPT gene transcript in the adult brain. Aβ forms extracellular amyloid plaques, whereas tau forms intracellular insoluble filaments and neurofibrillary tangles (NFTs). In addition, both Aβ and tau form intracellular and extracellular oligomeric species that are soluble pre-fibrillar aggregates, suggesting that the two proteins might share common mechanisms in AD etiopathogenesis.

The prevailing hypothesis in the AD field is that deleterious effects on synaptic function underlying memory loss caused by tau are initiated by Aβ. As AD progresses, tau pathology spreads from the entorhinal cortex in a contiguous, highly selective and highly reproducible fashion, suggesting that extracellular soluble forms of tau transmit pathology from neuron to neighboring neuron. Moreover, once Aβ triggers tau pathology, the disease would progress independent of Aβ. Therefore, therapies targeting Aβ may not be effective once tau pathology is triggered. Nevertheless, tau toxicity does not involve Aβ pathology in tauopathies, suggesting that Aβ is not necessary for tau pathology to occur, and pointing at the need to better clarify the relationship between tau and Aβ.

Here, we investigated whether and how extracellular oligomeric forms of tau (oTau) affect memory and its cellular correlate, long-term potentiation (LTP), either by themselves or in combination with Aβ. We show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment.

Link: https://dx.doi.org/10.1038/srep19393

I exaggerate in the title of this post, of course, but there is some truth in it. Certainly, a lot more attention is focused on the phenomenon of cellular senescence now that mouse life spans have been extended and aspects of aging have been reversed via clearance of senescent cells. The existence of several startup biotechnology companies aiming to bring senescent cell clearance treatments to the clinic is shining even more of a spotlight on this area. It has been something of a transformation. Five years ago, one of the few groups of researchers interested in this field struggled greatly to raise the funding for the pivotal study to prove that selectively removing senescent cells had a significant impact on health. Five years from now, every major research center will have a cellular senescence arm in the same way that they have a cancer arm today. It is that important to that many aspects of aging and age-related disease.

Cells become senescent when they reach the end of their replicative life span, or in response to damage, or a toxic environment. They cease to divide, and largely destroy themselves or are destroyed by the immune system. It is an evolutionary adaptation that serves, at least initially, to suppress cancer by removing those cells most at risk of uncontrolled replication. Unfortunately not all are destroyed. Some remain, and their numbers grow over the years, secreting a disruptive mix of signal molecules that causes chronic inflammation, corrodes surrounding tissue structures, changes the behavior of healthy cells for the worse, and no doubt more that is yet to be cataloged. Recently researchers have shown that senescent cells contribute directly to the progression of atherosclerosis, as well as declining lung function and loss of tissue elasticity in that organ. The inflammation angle on its own is enough to link greater numbers of senescent cell to an increased risk of most age-related diseases, and a worse prognosis for long-term health. Then, of course, there is the life span study showing extended life in mice as a result of senescent cell clearance.

Senescent cell accumulation is only one of the processes that cause degenerative aging. Fixing it via periodic selective destruction of these cells is only a narrow, partial rejuvenation. There is still everything else in the SENS rejuvenation research agenda to work through. Nonetheless, it is a great improvement over the present state of medicine to have senescence cell clearance therapies on the horizon. Given that senescent cells can be linked to near every age-related condition via at least inflammatory mechanisms, and given the greatly increased awareness of cellular senescence in far-flung parts of the research community that probably weren't paying all that much attention in the past, we are now seeing the first of what will no doubt prove to be a wide selection of efforts to link preexisting theories, data, and viewpoints on aging and age-related disease to what is known of the biochemistry of cellular senescence. I offer the open access paper quoted below as one example of the type, though I wouldn't take everything the authors have to say about oxidative stress in aging at face value. They mention the supporting evidence, but omit the equally numerous counterexamples that demonstrate the relationship between oxidative damage and aging to be far from simple.

A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1-/- mice is correlated to increased cellular senescence

The Free Radical or Oxidative Stress Theory of Aging postulates that reactive oxygen species (ROS) formed exogenously or endogenously from normal metabolic processes play a role in the aging process. The imbalance of pro-oxidants and antioxidants leads to an age-related accumulation of oxidative damage in macromolecules, resulting in a progressive loss in function and aging. Over the past three decades, the Oxidative Stress Theory of Aging has become one of the most popular theories to explain the biological/molecular mechanism underlying aging because several lines of evidence support the theory. First, the levels of oxidative damage to lipid, DNA, and protein have been reported to increase with age in a wide variety of tissues and animal models. Second, studies with animal models showing increased longevity are consistent with the Oxidative Stress Theory of Aging. Longer-lived animals show reduced oxidative damage and/or increased resistance to oxidative stress, e.g., dietary restriction in rodents and genetic manipulations that increase lifespan in invertebrates (C. elegans and Drosophila) and in mice. Thus, the observations that experimental manipulations that increase lifespan in invertebrates and rodents were correlated to increased resistance to oxidative stress or reduced oxidative damage provided strong support for the Oxidative Stress Theory of Aging. However, all of the experimental manipulations that increase lifespan also alter processes other than oxidative stress/damage; therefore, the increase in longevity in these animal models could arise through another mechanism.

Over the past two decades, our group has directly tested the role of oxidative damage/stress in aging by genetically manipulating the antioxidant status of a wide variety of antioxidant genes to increase or reduce the level of oxidative stress/damage and determine what affect these manipulations had on lifespan. Our research with 18 different genetic manipulations in the antioxidant defense system shows that only the mouse model null for Cu/Zn-superoxide dismutase (Sod1) had an effect on lifespan (in this case a decrease in lifespan) as predicted by the Oxidative Stress Theory of Aging. Because it has been reported that more than 70% of Sod1-/- mice developed liver hyperplasia and hepatocellular carcinoma later in life, it was initially believed that the 30% decrease in the lifespan of Sod1-/- mice was not due to accelerated aging but was the result of a dramatic increase in hepatocellular carcinoma, which is rare in C57BL/6 mice. In a more recent study, we found a similar 30% decrease in lifespan of the Sod1-/- mice; however, in our study, only about 30% of Sod1-/- mice developed hepatocellular carcinoma later in life. In addition, we showed that dietary restriction, which is a manipulation that retards aging in rodents, increased the lifespan of the Sod1-/- mice to that of normal, wild type (WT) mice. These data combined with studies showing that Sod1-/- mice exhibited various accelerated aging phenotypes (e.g., muscle atrophy and loss of fat mass, hearing loss, cataracts, skin thinning and delayed wound healing) lead us to conclude that the Sod1-/- mice exhibit accelerated aging. This then raised the question of why we observed a significant decrease in lifespan and accelerated aging in only the Sod1-/- mice and not in other mouse models with compromised antioxidant defense systems that showed changes in oxidative stress/damage.

Sod1-/- mice show a much higher level DNA oxidation (i.e., 8-oxo-dG levels) in tissues than any of the mouse models we have studied, which all have deficiencies in one or more of the antioxidant genes. In addition, DNA mutations have been reported to increase significantly in several tissues in Sod1-/- mice. Because the DNA damage response has been shown to play a central role in the generation of senescent cells and because it has been shown that clearance of senescent cells delays aging-associated disorders and increases lifespan in a progeroid mouse model as well as in normal, wild type (WT) mice, we hypothesized that the increased oxidative damage to DNA in tissues of Sod1-/- mice could activate the DNA damage response and drive cells into becoming senescent. To test our hypothesis, we measured various markers of cellular senescence in kidney tissue, a tissue that shows a significant increase in senescent cells with age. We compared kidney from young-adult and old WT mice and young-adult Sod1-/- mice fed ad libitum or a dietary restriction diet. Our data clearly demonstrate that the level of senescent cells is dramatically increased in the kidney of young-adult Sod1-/- mice compared to young-adult WT mice and are at a level comparable to old WT mice. In addition, we observed that the increase in cellular senescence observed in the Sod1-/- mice was attenuated by dietary restriction. Interestingly, the increase in cellular senescence in the Sod1-/- mice was correlated to increased circulating cytokines. Thus, our data suggest that increased cellular senescence could play a role in the accelerated aging phenotype we have observed in the Sod1-/- mice.

Four years ago, researchers reported that they could use gene therapy to increase levels of Gata4, Mef2c, and Tbx5 in order to provoke the conversion of a fraction of scar tissue into healthy muscle tissue in damaged hearts. This seems a promising approach, but like many fields of research it is proceeding only slowly. Here is a recent update, in which the researchers report on efforts to make the conversion process more efficient and thus practical as the basis for a therapy:

Scientists are exploring cellular reprogramming - turning one type of adult cell into another - in the heart as a way to regenerate muscle cells in the hopes of treating, and ultimately curing, heart failure. It takes only three transcription factors - proteins that turn genes on or off in a cell - to reprogram connective tissue cells into heart muscle cells in a mouse. After a heart attack, connective tissue forms scar tissue at the site of the injury, contributing to heart failure. The three factors, Gata4, Mef2c, and Tbx5 (collectively known as GMT), work together to turn heart genes on in these cells and turn other genes off, effectively regenerating a damaged heart with its own cells. But the method is not foolproof - typically, only ten percent of cells fully convert from scar tissue to muscle.

In the new study, scientists tested 5500 chemicals to try to improve this process. They identified two chemicals that increased the number of heart cells created by eightfold. Moreover, the chemicals sped up the process of cell conversion, achieving in one week what used to take six to eight weeks. "While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient. With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process."

The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack. The scientists also used the chemicals to improve direct cardiac reprogramming of human cells, which is a more complicated process that requires additional factors. The two chemicals enabled the researchers to simplify the process bringing them one step closer to better treatments for heart failure.

Link: https://gladstone.org/about-us/news/scientists-create-heart-cells-better-faster-stronger

There is a fair amount of interest in finding out whether the observations derived from heterochronic parabiosis, where the circulatory systems of an old and a young mouse are linked, can be reproduced by transferring whole blood or blood plasma from a young individual to an old individual. In theory the introduction of young signals into an old environment may adjust cellular behavior for the better, analogous to the effects produced by some forms of stem cell transplant. So far the results are mixed, however, with some studies showing no benefit - it is quite possible that transfer doesn't recreate all of the effects of a fully joined circulation for one reason or another. That said, researchers with Alkahest, involved in trials of plasma transfer as a human therapy, are now presenting initial results from introducing young human blood plasma into old mice, in which benefits were observed:

Blood plasma from young people has been found to rejuvenate old mice, improving their memory, cognition, and physical activity. The method has the potential to be developed into a treatment for people. Previous research has found that stitching old and young mice together has an interesting effect. While sharing a blood system works out well for the older mouse, the younger one isn't so lucky. The young animals started to show signs of brain ageing, while the brains of the older mice started to look younger. The key to youth appears to be in the blood plasma - the liquid part of blood. Several studies have found that injecting plasma from young mice into old mice can help rejuvenate the brain and other organs, including the liver, heart, and muscle.

Could blood plasma from young people have the same benefits? To find out, researchers took blood samples from 18-year-olds, and injected them into 12-month-old mice. At this age, the equivalent of around age 50 for people, the mice start to show signs of ageing - they move more slowly, and perform badly on memory tests. The mice were given twice-weekly injections of the human plasma. After three weeks of injections, they were submitted to a range of tests. The treated mice's performance was compared to young, 3-month-old mice, as well as old mice who had not received injections. Treated mice ran around an open space like young mice. Their memories also seemed to improve, and they were much better at remembering their way around a maze than untreated mice.

The team then examined the brains of the treated and untreated mice. They looked for clues on the birth of new neurons in the hippocampus - a process called neurogenesis, which is thought to be important for memory and learning. Sure enough, the treated mice appeared to have created more new cells in their brain. The researchers have identified some factors in young blood that might be responsible for these benefits, but that won't reveal what they are yet. Some of them seem to be crossing into the brain, while others may be acting remotely, elsewhere in the body.

Link: https://www.newscientist.com/article/2112829-blood-from-human-teens-rejuvenates-body-and-brains-of-old-mice/

Today I'll point out an open access paper in which the authors discuss some aspects of DNA damage with a particular focus on age-related inflammation and immune system dysfunction. Cells are fluid, dynamic landscapes of molecular machinery, near every component constantly damaged by inappropriate chemical reactions, but also constantly repaired and replaced. Little is static or lasting. The greatest, most intricate, and effective repair mechanisms are those that attend nuclear DNA, the blueprints for proteins and cellular operations that reside in the cell nucleus. One of the characteristics of aging is that despite the panoply of repair efforts, cells accumulate random nuclear DNA damage. Since the research community can't yet stop this from happening, there is considerable difficulty in separating out and quantifying this one particular contribution to the broader aging process. Certainly we can talk about cancer risk, and we can talk about rising numbers of cells becoming senescent in response to DNA damage, and researchers can disable DNA repair to observe the shortened life spans that result from such a fundamental breakage in cellular operation, but beyond that it becomes increasingly challenging to quantify effects within the scope of normal degenerative aging. If nuclear DNA damage was removed, such as via the somewhat distant molecular nanomachinery of chromallocytes, programmable nanorobots moving from cell to cell to fix each breakage, then aside from the elimination of cancer, would it have any other measurable effect on health and longevity? This is an unanswerable question at the present time.

Still, it will not remain unanswerable, and even today convincing and well-anchored arguments can be made either way, for and against the significance of nuclear DNA damage in aging. Interestingly, many of those on the side of nuclear DNA damage as being important in aging beyond cancer risk tend to pull senescent cells into the picture they paint. Senescent cells in turn produce inflammation, and chronic inflammation and related aspects of immune system decline are a big part of the broader progression of aging. This may well be more a sign of the times, a measure of the increasing interest in the research community directed towards the role of cellular senescence in aging, rather than something that arises organically. Certainly, much more funding is moving into efforts to treat aging by removal of senescent cells these days than was the case even a decade ago. The lines can be drawn, however, the connections made, but again it is hard to put numbers to these things without a way to remove nuclear DNA damage in isolation, carried out without influencing any other process relevant to degenerative aging.

From a long-term perspective, nuclear DNA damage is a thorny problem. It will be one of the hardest forms of damage to repair via rejuvenation biotechnology; the only one that springs to mind as likely being even more difficult is the matter of damaged nuclear pore proteins in long-lived cells, single molecules that might be as old as you are, doing the same job for an entire human life span. The only plausible methods of repairing stochastic nuclear DNA damage look to be the aforementioned advanced molecular nanotechnology, something that lies some decades in the future, or major advances in gene therapy, to the point at which it could be cost-effective and safe to scan and conditionally alter the majority of genes in the majority of cells all at once. When you stop to think about what would be required, it isn't clear that there is in fact much difference between the two items I mentioned there. Given this, it seems very plausible that in the decades ahead there will be many partially rejuvenated, active, healthy people at advanced ages walking around, all bearing very high levels of nuclear DNA damage, but protected from the consequent cancer incidence by highly effective next generation therapies. We shall see how it goes, but it certainly beats the present alternative of certain frailty and death.

DNA Damage: From Chronic Inflammation to Age-Related Deterioration

To withstand the hazards of existence, multicellular organisms need to preserve their bodily functions for long periods of time and protect themselves against pathogens. Taking the cell as a point of reference, the maintenance is directed inwards to counteract macromolecular damage. This often involves restoring injured nucleic acids back to their native form or replenishing proteins and lipids once damaged by harmful byproducts of metabolism. Further, cellular defense mechanisms, such as the innate immune responses are mainly directed outwards to protect the organism against irritants, pathogens, or injured cells. Since the problem of damage or the invasion of cells by pathogens has existed nearly ab initio, maintenance and defense must have arisen early during evolution. Indeed, even simple unicellular organisms such as bacteria possess multiple caretaking systems.

Remarkably, some prokaryotes employ a structurally distinct family of nucleases with a dual function e.g., in DNA repair and antiviral immunity. Similar to bacteria, mammals provide ample evidence that mechanisms of DNA repair and immunity have evolved together. For example, non-homologous end-joining is involved in the development of lymphocytes in resolving recombination intermediates i.e., DNA strand breaks (DSBs) that occur during V(D)J recombination. Likewise, "programmed" DNA lesions followed by error-prone DNA repair dramatically increase antibody diversity by triggering somatic hypermutation of immunoglobulin variable genes. Nonetheless, the evolutionary transition from one-celled microbes to more complex living systems has pushed for drastic changes in maintenance and defense strategies. In mammals, a single fertilized egg rapidly divides into several trillions of cells grouped into specialized tissues with marked differences in terms of developmental origin, regenerative capacity and ability to cope with damage. Moreover, tissues, organs and organ systems team up to perform specific tasks such as the body's first line of defense against bacteria or viruses. This inherent complexity arising from manifold levels of organization within multicellular life forms requires that genome maintenance, the DNA damage response (DDR) and defense strategies are tightly linked and highly coordinated processes.

Recent evidence points to reciprocal interactions between DNA repair, DNA damage responses and aspects of immunity; both self-maintenance and defense responses share a battery of common players and signaling pathways aimed at safeguarding our bodily functions over time. In the short-term, this functional interplay would allow injured cells to restore damaged DNA templates or communicate their compromised state to the microenvironment. In the long-term, however, it may result in the (premature) onset of age-related degeneration, including cancer. Until recently, there would have been few examples to link DNA damage and inflammation to health and disease. However, recent findings allow us to consider several instances where innate immune responses driven by intrinsic genome instability or chronic exposure to exogenous genotoxins is causal to age-related degeneration, metabolic abnormalities and cancer. Indeed, chronic inflammation is thought to generate an excess of reactive oxygen and nitrogen species (ROS, RNS) triggering DNA damage and malignancy. In support, chronic inflammation in the colon or the gastric cardia of mice is functionally linked to the formation of DNA lesions and the induction of the DDR, as well as with cancer induction.

Cellular senescence is a term used to describe cells that cease to divide in culture and has been one of the first paradigms to link DNA damage and immunity to disease. Cellular senescence is often fueled by nuclear DNA damage followed by chronic DDR activation; telomere shortening, mitogenic oncogenes, or intrinsic DNA damage can lead to different types of senescence limiting the replicative lifespan of cells. Persistent DNA damage and DDR signaling triggers senescent cells to secrete immunomodulatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). SASP factors range from inflammatory and immune-modulatory cytokines to chemokines as well as growth factors, shed cell surface molecules, survival factors and extracellular matrix remodeling enzymes. Together, they impinge on cell-fate decisions in neighboring cells or the tissue microenvironment. As DNA damage accumulates with age, persistent DDR-mediated release of SASP factors could be associated with degenerative changes that manifest with old age; in support, several SASP factors are considered amongst the most reliable biomarkers for age-related diseases.

Nevertheless, any direct evidence linking DNA damage to chronic inflammation stems from recent findings in progeroid (accelerated aging) syndromes and accompanying mouse models that carry inborn DNA repair defects. Patients with Werner syndrome (WS, associated with mutations in the RecQ DNA helicase) manifest with features of systemic chronic inflammation. Eventually, a universal theme arises from these recent findings; it is neither DNA damage nor senescence or cancer per se but persistent DDR that triggers the repertoire of innate immune responses. Thus, any events that could potentially activate DDR could trigger the activation of innate immune responses in the absence of DNA damage; similarly suppressing DDR signaling in the presence of tolerable DNA damage levels could alleviate some of the pathological features associated with DNA damage-driven inflammation.

DNA damage-driven inflammation can be both beneficial and detrimental for organismal survival. To understand this controversy, it may be helpful to consider that such responses have been selected for by having their early benefits outweigh their late costs during evolution. Early in life, priorities in mammals are shifted toward development, growth, and reproductive fitness. As cells divide, gain volume or differentiate, tissues rely on maintenance and defense mechanisms to efficiently detect and remove damaged cells. In doing so, specific cell types may activate immune responses to fine tune cell-fate decisions at the organismal level; for instance, DNA damage in germ cells induces an innate immune response in worms that promotes endurance of somatic tissues to allow delay of progeny production when germ cells are hit by DNA damage. Once reproductive maturity has been reached, the competitive advantage to signal the presence of damaged cells (in youth) is gradually deteriorating. Despite the efficiency of DNA repair mechanisms, some DNA damage is left unrepaired leading to the gradual accumulation of DNA lesions in cells. In turn, the slow but steady buildup of damaged cells within tissues is expected to intensify DDR responses over time. Likewise, the DDR-mediated pro-inflammatory signals may further alarm the neighboring cells and tissues for the presence of cells with compromised genome integrity. The latter triggers a vicious cycle of persistent DDR and pro-inflammatory signals leading to chronic inflammation, tissue malfunction and degeneration with old age; in DNA repair-deficient patients, the rapid accumulation of DNA damage (in view of the DNA repair defect) would trigger the untimely activation of DDR signaling leading to the early manifestation of age-related pathology that is associated with chronic inflammation.

Retinitis pigmentosa is one of a number of forms of retinal degeneration that produce progressive blindness, though in this case it is primarily an inherited condition. Researchers here find a genetic manipulation that slows the progression of this effect. Interestingly, they are inhibiting sirt6 in a mouse model of the condition in order to obtain this outcome. In the broader context, increased levels of sirt6 have been shown to modestly extend the life of male mice. This is perhaps a helpful reminder that things are never simple when it comes to biochemistry and the manipulation of cellular metabolism. It would nonetheless be interesting to see how this approach does in forms of age-related blindness that involve retinal cell death, but since it fails to address underlying forms of molecular damage directly I'm not optimistic. Age-related retinal degeneration is strongly connected to, for example, accumulation of hardy forms of metabolic waste that form lipofuscin and disrupt cellular recycling processes. That may or may not be impacted in any way via altered sirt6 levels, but certainly targeted clearance of lipofuscin - such as the work undertaken by Ichor Therapeutics - should be a much more effective approach than tinkering with metabolism to slow down its accumulation.

Researchers have demonstrated that vision loss associated with a form of retinitis pigmentosa (RP) can be slowed dramatically by reprogramming the metabolism of photoreceptors, or light sensors, in the retina. "Although gene therapy has shown promise in RP, it is complicated by the fact that defects in 67 genes have been linked to the disorder, and each genetic defect would require a different therapy. Our study shows that precision metabolic reprogramming can improve the survival and function of affected rods and cones in at least one type of RP. Since many, if not most, forms of the disorder have the same metabolic error, precision reprogramming could conceivably be applied to a wide range of RP patients."

RP, an inherited form of vision loss, is caused by genetic defects that lead to the breakdown and loss of rods, the photoreceptors in the retina that enable peripheral and night vision. Over time, the deterioration of rods compromises the function of cones, the color-sensing photoreceptors. Rods are among the most metabolically active cells in the body. They are particularly active during periods of darkness, when they burn glucose to release energy. Researchers theorized that rods deteriorate in RP, in part, because they lose the daytime's ability to use glucose to rebuild the rods' outer segment (the light-absorbing portion of the photoreceptor). "We hypothesized that diseased rods could be rescued by reprogramming sugar metabolism."

Researchers tested this hypothesis in mice with a mutation in the Pde6 gene that disrupts rod metabolism, leading to an RP-like disorder. The mice were treated so that their rods could not express Sirt6, a gene that inhibits sugar metabolism. Examination of photoreceptors with electroretinography showed that the mice had significantly greater measures of rod and cone health than untreated controls. While the treatment significantly prolonged survival of the diseased rods and cones, it did not prevent their eventual death. "Our next challenge is to figure out how to extend the therapeutic effect of Sirt6 inhibition. Although the treatment that was used in the mice cannot be applied directly to humans, several known Sirt6 inhibitors could be evaluated for clinical use. Further studies are needed to explore the exciting possibility that precision metabolic reprogramming may be used to treat other forms of RP and retinal degeneration."

Link: http://newsroom.cumc.columbia.edu/blog/2016/11/14/retinitis-pigmentosa-may-be-treated-by-reprogramming-sugar-metabolism/

The increased blood pressure of age-related hypertension is driven by the stiffening of blood vessels. It harms fragile tissues, such as those of the kidney, directly through the physical processes of greater pressure. It also increases the rate at which small blood vessels suffer structural failure, and in the brain that means an ongoing series of minuscule strokes, each unnoticed, but over time adding up to contribute to cognitive decline. Researchers here outline another mechanism by which hypertension causes harm, in this case via alteration of the behavior of a population of macrophages in the brain, leading to greater levels of oxidative stress and vascular dysfunction. The researchers also show that selectively depleting these macrophages can improve the situation, and thus perhaps form the basis for a therapy:

Hypertension afflicts up to one-third of the world population and is a leading risk factor for morbidity and mortality worldwide. The brain is a major target organ of the damaging effects of hypertension. Well recognized as the most important risk factor for stroke and vascular cognitive impairment, hypertension has also been linked to Alzheimer disease, the leading cause of dementia in the elderly. The health of the cerebrovascular system is vital for the brain's functional and structural integrity. The brain has no energy reserves and requires a continuous supply of blood well matched to its dynamic and regionally diverse metabolic needs. Neurons, glia, and vascular cells, key components of the so-called neurovascular unit (NVU), work in concert to assure that the brain is always adequately perfused. Thus, brain activation increases cerebral blood flow (CBF) to support the increased energy demands and remove potentially harmful by-products of cerebral metabolism, a process known as neurovascular coupling. At the same time, endothelial cells, the site of the blood-brain barrier (BBB), regulate the trafficking of molecules and cells between blood and brain, and coordinate microvascular flow by releasing vasoactive agents. Hypertension leads to profound cerebrovascular alterations. In addition to structural changes (hypertrophy, remodeling, stiffening, lipohyalinosis, etc.), hypertension induces alterations in cerebrovascular regulation that promote vascular insufficiency. Thus, in humans as in animal models, hypertension disrupts all the major factors regulating the cerebral circulation, including neurovascular coupling and endothelial vasomotor function. As a result, the brain becomes more susceptible to neuronal dysfunction and damage, which underlies vascular cognitive impairment

The factors responsible for these functional alterations of the NVU are poorly understood, and their exploration is essential to develop preventative or therapeutic approaches to mitigate the impact of hypertension on brain health. Perivascular macrophages (PVMs) and meningeal and choroid plexus macrophages represent the bulk of resident brain macrophages, and are distinct from macrophages infiltrating the wall of large vessels in inflammatory conditions, such as atherosclerosis. Residing in the intracerebral perivascular space, delimited by the glia limitans and the vascular basement membrane, PVMs are closely apposed to the outer vessel wall and originate from hematopoietic precursors. As the vessels penetrate deeper into the substance of the brain, the glial and vascular basement membranes fuse together and the perivascular space disappears. In this study we investigated the contribution of PVMs to the neurovascular and cognitive dysfunction induced by hypertension.

We found that depletion of PVMs in models of chronic hypertension suppresses vascular oxidative stress and ameliorates the attendant impairment in neurovascular coupling and endothelium-dependent responses. Brain PVMs are thought to be beneficial in models of Alzheimer disease by removing amyloid-β peptides from the perivascular space and preventing amyloid accumulation in cerebral blood vessels. On the other hand, hypothalamic neurohumoral signaling by PVMs across the BBB may be deleterious by promoting inflammation and sympathetic activation in models of fever or myocardial infarction, respectively, and may contribute to hypertensive cerebrovascular remodeling. In the present study we discovered that PVMs play a key role in the cerebrovascular dysfunction of hypertension. Our data suggest that PVMs, while serving vital homeostatic functions in the normal state, become the target of neurovascular inflammatory signaling leading to reactive oxygen species production, vascular dysfunction, and cognitive deficits. However, the molecular interactions of PVMs with cells of the NVU and their role in the neurovascular dysfunction and BBB alteration remain to be defined.

Link: http://dx.doi.org/10.1172/JCI86950

Good news! Thanks to the generous pledges of new SENS Patrons, signing up for monthly donations to the SENS Research Foundation over the past two weeks since the fundraiser started, the $24,000 matching fund put up by Josh Triplett and Fight Aging! is nearly met. Just a little more left to reach the target: if you are the next person to sign up, the next year of your donations to the SENS Research Foundation will be matched dollar for dollar. But if you miss out on that, donations made before the end of the year can still be matched. The Forever Healthy Foundation's Michael Greve, who earlier this year pledged $10 million to SENS rejuvenation research and startup companies building rejuvenation therapies, has put up a further $150,000 challenge fund. He will match all donations to the SENS Research Foundation made before the end of 2016, and there is still a way to go in order to meet that target. So help us get this done!

Why support the SENS Research Foundation, and their ally the Methuselah Foundation? Because these organizations have proven capable of using your charitable donations more effectively than any other in order to make significant progress towards an end to aging and age-related disease. For fifteen years now, the principals and their network of advocates and scientists have nudged, debated, and funded researchers to ensure that the broader research community builds the basis for human rejuvenation. Aging is an accumulation of molecular damage, and if that damage is repaired sufficiently well, a goal that modern medicine is only just starting to grapple with despite decades of evidence, then the result will be a halt to the processes of degenerative aging. An end to the disease, dysfunction, and suffering of aging. When you look at near any area where the academic laboratories or biotechnology companies are making good progress towards this end, you'll find the SENS Research Foundation and Methuselah Foundation in the background and the history of that development.

The current brace of senescent cell clearance startup companies, working to bring this treatment to the clinic, after it has been shown to improve health and longevity in mice? SENS Research Foundation funding has for years helped that research progress at the Campisi lab, one of the groups that joined forces to create UNITY Biotechnology, recently funded for $116 million. SENS Research Foundation and Methuselah Foundation provided seed funding for Oisin Biotechnology, where the principals are building a better approach to senescent cell clearance than that fielded by UNITY Biotechnology. Or how about work on allotopic expression of mitochondrial genes, a way to prevent mitochondrial damage from contributing to aging by placing copies of mitochondrial genes in the cell nucleus? The SENS Research Foundation and Methuselah Foundation before it helped to fund the research programs that led to Gensight Biologics, a company now deploying tens of millions of dollars to build a platform to back up mitochondrial genes. Or how about progress towards treatments capable of clearing out the glucosepane cross-links that produce tissue stiffening, such as the loss of elasticity in blood vessels that produces hypertension and tissue damage? The SENS Research Foundation has funded the few interested researchers for years, enabling them to build the toolkit needed to work with glucosepane, and now researchers are at the stage of hunting for the first drug candidate.

I could go on: the advocacy and conferences bringing together academia and industry to build a new development community; the support for thymic rejuvenation and other means of immune system repair; the work on a universal cancer treatment based on blockade of telomere lengthening; the mining of bacterial enzymes to find those capable of removing damaging metabolic waste products that our biology cannot handle. The point is that the SENS Research Foundation and Methuselah Foundation deliver. They take our donations and use them to make a real difference, creating step by step progress towards the therapies that will enable us to live far longer in good health, and effectively treat and prevent age-related disease. If the damage that causes aging can be periodically repaired, even poorly at first, then ultimately aging will be brought under control. As the therapies become better and more comprehensive, no-one will need to suffer. The hundreds of millions with age-related frailty and disease and the more than 100,000 who die from aging every day might be saved. This is the greatest and most important altruistic goal: if we get the job done soon enough, we all win together.

Our community is making this happen: our actions, our donations, our advocacy. We are changing the world, and now that the wheel is beginning to turn, that is no time to slacken in our support. Donate to the SENS Research Foundation in this current fundraiser, and your donations will be matched. The more we raise, the faster that research progresses, and the sooner that real, working rejuvenation therapies will arrive at the clinic.

Researchers here report on thymic activity in dog breeds of varying longevity. The thymus plays an important role in the creation of new T cells, but its activity declines with age, most notably in early adulthood via the process of thymic involution, but then further in later life. A lower supply of new immune cells contributes to the age-related decline of the immune system, which is in part a structural problem of too many memory T cells dedicated to specific pathogens and too few naive T cells capable of dealing with new threats. Those threats are not just invading microorganisms, but also harmful senescent and cancerous cells. The progressive failure of the immune system is one of the reasons why cancer is an age-related condition and the number of senescent cells increase with age. It isn't just a matter of increasing frailty due to vulnerability to infection, as immune decline also influences many other aspects of aging. Given all of this, there is some interest in rejuvenation of the thymus, restoring it to youthful levels of activity. Possible approaches here include engineering of thymus tissue for transplantation, or manipulation with signal molecules that direct thymic growth and function.

With increasing age, there is a gradual deterioration in immune function, leading to a reduced response to infectious agents and vaccination, alongside an increase in prevalence of autoimmune and neoplastic diseases. A similar age-related decline in health is seen comparing humans and companion animals. Intimately linked with the decline in immune function is the age-associated regression of the thymus. Since thymic involution is seen in all mammalian species, this has led to the suggestion that immunosenescence, associated with a decline in thymic output, is an evolutionary conserved event. Thus, identifying the features of immunosenescence in companion animals represents an opportunity for comparative and translational research into how immune function declines with age.

Thymic involution is associated with a progressive decline in T cell output to the peripheral lymphocyte pool and as a consequence, expansion of existing memory T cell populations can take place. However, this might lead to reduced diversity in the T cell repertoire and impairment of immune responses to novel antigens, for example during infection or vaccination. Preservation of immunity is a major contributory factor for maintaining health into old age and although there is evidence for an association between thymic output and longevity, many of these experiments have been performed in inbred or genetically-modified laboratory rodents, which might not reflect the situation in humans. Whilst thymic size may be an indicator of immunocompetence/immunosenescence in mammals it is not easily measured clinically. Evaluation of thymic output in terms of the presence of recent thymic emigrants (RTE) in peripheral blood might be an acceptable surrogate marker.

During T cell development in the thymus, the T cell receptor δ gene segments are excised and form a signal joint T cell receptor excision circle (sj-TREC). Since its formation occurs specifically in the thymus and this DNA does not replicate, sj-TREC has been used as a marker for RTEs in peripheral blood samples. In humans and mice, real-time qPCR has been employed, showing an age-associated decline in sj-TREC values in blood, suggesting a reduction in the number of RTEs with increasing age. However, sj-TRECs are still detectable, even in some very elderly humans, suggesting that thymic output can be maintained into old age in some individuals. A recent study has demonstrated that sj-TRECs can be measured in companion animals. Studies in pedigree dogs have demonstrated that there are breed-related differences in longevity, the rate of aging, and susceptibility to diseases associated with aging. Such differences in longevity suggest that there are likely to be breed effects/genetic factors influencing the aging process that might impact on the onset of immunosenescence. The aim of the present study was to develop a real-time qPCR assay to measure sj-TRECs in canine blood samples and to examine how age and breed influence sj-TREC values in dogs.

When sj-TREC values were assessed in Labrador retriever dogs, normalized against either lymphocyte counts or albumin expression, an age-associated decline was identified in both instances. The greatest decline occurred between the ages of 1 and 5 years, which suggests the largest reduction in thymic output occurs between reaching sexual maturity and early middle age in the canine species. A similar trend is seen in humans, where thymic output remains relatively high until the teenage years, when it begins to decline rapidly, with the greatest decline in sj-TRECs having occurred by middle age, between 40 and 50 years old. After reaching 5 years of age, canine sj-TREC values were found to stabilise, with a mean value approximately 20% of that seen in dogs younger than 1 year old, before declining further at around 9 years of age. In older humans, sj-TREC values show a slow decline between the 6th and 9th decades of life before decreasing significantly in the 10th decade. sj-TRECs were undetectable in many mature and geriatric dogs, suggesting that thymic output in these dogs is very low or that production of naïve T-cells has ceased. However, this was not the case in all dogs of a similar age, suggesting that some individuals can maintain thymic output into old age, which is similar to that reported in human studies.

Breed influences on sj-TREC were investigated by studying two groups that represent the extremes of the canine lifespan spectrum; small breed dogs with a relatively long life expectancy and large breed dogs with a relatively short life expectancy. Studies in humans have proposed an association between maintenance of thymic function and lifespan and have suggested that sj-TREC analysis might be of use as a biomarker for determining longevity. Both groups demonstrated a similar age-related decline in sj-TREC, with the greatest reduction occurring between young adulthood and middle age. However, the onset of the decline in sj-TRECs was found to occur at an earlier age in the short-lived breeds compared with the long-lived breeds, suggesting that thymic involution might occur prematurely in the former. Furthermore, some individuals of short-lived breeds were identified that had undetectable sj-TREC as young as 2 years of age, compared with the other breeds assessed, where this did not occur until around 4-5 years of age. Therefore, if thymic involution is occurring at an earlier biological time point in some dog breeds, this might have an impact on their subsequent lifespan/healthspan. This is consistent with a recent study in which there was a strong relationship between lifespan, body size and rate of aging, with the largest breeds also having evidence of an earlier onset of the aging process.

Link: http://dx.doi.org/10.1371/journal.pone.0165968

Despite the rising proportion of the older population who choose to be overweight or obese, risk of heart disease has declined somewhat in past few decades. This outcome can be attributed to prevention in the sense of at least some people taking better care of their health by specifically targeting measures such as blood pressure and blood lipid levels, coupled with prevention in the sense of treatments such as statins that also reliably influence these measures. Increased blood pressure with age, or hypertension, directly impacts risk of cardiovascular disease and other conditions by putting additional stress on tissue structures and causing the heart to remodel itself detrimentally. Higher blood lipid levels on the other hand contribute to the progression of atherosclerosis, attacking blood vessel walls to form fatty deposits that can later break to cause blockages or ruptures of blood vessels. These are all things best avoided if possible, but until the advent of rejuvenation therapies after the SENS model the best that can be done is to slow down the damage.

Diagnosis and control of coronary heart disease (CHD) risk factors have received particular emphasis in guidelines issued since 1977 (blood pressure) and 1985 (lipids). Yet on a population level, little is known about how these efforts have altered CHD incidence and its association with modifiable risk factors. Researchers pooled individual patient-level data from 5 observational cohort studies available in the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. Two analytic data sets were created: 1 set with baseline data collected from 1983 through 1990 (early era) with follow-up from 1996 through 2001, and l set with baseline data collected from 1996 through 2002 (late era) with follow-up from 2007 through 2011. The study included characteristics of 14,009 pairs of participants in the 2 groups. Participants ages 40 to 79 years who were free of cardiovascular disease were selected from each era and matched on age, race, and sex. Each group was followed for up to 12 years for new-onset CHD (i.e., heart attack, coronary death, angina, coronary insufficiency).

"Examination of adults from 5 large observational cohort studies led to several findings. First, the incidence of CHD declined almost 20 percent over time from 1983 to 2011. Second, although the prevalence of diabetes increased, the fraction of CHD attributable to diabetes decreased over time, due to attenuation of the association between diabetes and CHD. This may have resulted from changing definitions and awareness of diabetes, improvements in diabetes treatment and control, and/or better primary prevention. Third, there was no evidence that the strength of the association between smoking, systolic blood pressure, or dyslipidemia and CHD changed between eras, nor was there evidence that the proportion of CHD due to these factors changed. This underscores the importance of continued prevention efforts targeting these risk factors."

Link: http://media.jamanetwork.com/news-item/study-finds-large-decrease-in-coronary-heart-disease-in-u-s/

Music business entrepreneur Steve Aoki has been a supporter of the SENS rejuvenation research programs for a while now. I'm always pleased to see successful people being vocal about their support for SENS, putting it front and center when talking to their audiences. Placing this important scientific work - as well as the prospects for near future therapies, and the need for philanthropic funding - in front of a bigger audience is vital to the continued growth of our community and progress towards the medical control of aging. We need to reach out to entirely new networks of people, those who would never seek out the longevity science community on their own, as among their numbers are many who will be turn out to be interested, pleasantly surprised, and enthusiastic. Today, I'd wager, a large fraction of those people who will go on to be significant advocates and philanthropic donors of the late 2020s have no idea that we even exist, or that bringing an end to age-related disease, frailty, and suffering is possible outside the realm of science fiction.

Bootstrapping a cause never stops being hard. It was hard when small groups were striving to raise a few thousand dollars for SENS advocacy here and there, when having regular research programs and a million dollar fund looked to be an impossible distance away. It is hard today, when the SENS Research Foundation is trying to make the leap from a few million dollars in yearly research budgets to something ten times that size. Building greater public awareness and enthusiasm for the medical science of human rejuvenation is a very necessary part of that work. The sooner we collectively manage to change the zeitgeist to one in which charitable support for rejuvenation research is just as normal and lauded as support for cancer research, the better off we all are, and the more money that can be raised for scientific projects. So thanks are due to Steve Aoki for stepping up to the plate and taking a swing at this. He is helping with the present year end SENS Research Foundation fundraiser, with the SENS rejuvenation research programs being one part of his broader interest in neuroscience as it can be applied to the long-term health of the brain:

Steve Aoki Throws a Party For Science

Hang with DJ Steve Aoki at a nightclub and you can expect an earful of his electronic bangers and confetti in your hair. Cozy up to Steve Aoki at Brooklyn Bowl on November 15 and you'll get to hit pins alongside neuroscientists, bid on one-of-a-kind experiences in live and silent auctions (think jumping into the foam pit at Aoki's Las Vegas "playhouse") and catch him outside the booth as he hosts the Aoki Foundation's Bowling for Brains fundraiser. The inaugural event supports the Buck Institute on Aging, SENS Research Foundation and Las Vegas' own Lou Ruvo Center for Brain Health, continuing the foundation's ongoing support of regenerative science.

"Anyone who's willing to help out toward brain research and organizations that are focused on cutting-edge research on degenerative brain diseases - I want to meet these people. I want to be in the same room with them and create more collaborations. That's really cool to me. I don't get the opportunity to do that very often because usually when I do events, I'm just DJing. At this one, I get to hang out. It's more of an intimate thing. Anyone who enters can have conversations about brain health and what we can do to raise more money and awareness of these organizations that are doing incredible work. After my father passed away in 2008, I started doing a lot of research on cancer and understanding what killed him. That led to researching general health and nutrition and understanding the body, the brain, then science and technology, seeing how far we've advanced and what kind of trajectories we're heading toward. A lot of it has to do with understanding our brain. It's the single most important phenomenon in civilization - the human brain. Yet we really don't know much about it. At the end of the day, if we don't die from something like cancer, we will have some kind of degenerative issues that will affect us and the people that we love."

"We're going down a path that, at one point, was considered science fiction. There are a lot of things happening in science that you wouldn't even believe. These radical technological advances are something I'm excited about. You don't really hear about it because the science community is so small. In a way, I use this platform to say, hey, the science community is pretty small, but the music community is pretty large. I would love to use this platform to bounce all of these amazing advances off to a community that would never hear about it and let them know, hey, you can help out. We can get there faster, and we can get there more efficiently. We're working toward a world where degenerative brain diseases do not exist. Imagine if we could eradicate that like we eradicated tuberculosis or polio, then we wouldn't ever have to worry about it again. If we don't have a brain that's working, we're not ourselves."

Aoki Foundation

The AOKI FOUNDATION has a primary goal of supporting organizations in the brain science and research areas with a specific focus on regenerative medicine and brain preservation. Our vision is to one day see a world where degenerative brain diseases do not exist and science and technology play a direct role in extending the healthy lives of ourselves and our loved ones. Steve believes strongly that greater research in brain science can lead to healthier and longer lives. He supports various organizations in the neuroscience field, specifically focused on doing research on regenerative medicine, brain health and preservation. He hopes to use his global influence to raise money for organizations conducting research in important brain health areas. Through the AOKI FOUNDATION, he will take issues into his own hands by directly supporting those affecting change when needs arise, in addition to hosting fundraising events and campaigns for specific charitable organizations throughout the year. The human brain is the most complicated biological structure in the known universe. We've only just scratched the surface in understanding how it works and more importantly how it doesn't work when disorders and disease happen.

From the perspective of understanding how cloning affects aging, the field of somatic cell nuclear transfer is still young. Only recently has there been enough data for the longer-lived mammals to draw initial conclusions, and even then much more health and mortality data would be needed to go beyond the simple statistic of maximum observed life span. This is an area of interest to those researchers involved in mapping the detailed relationship between the operation of metabolism and the progression of degenerative aging. If it turns out that individuals of some species do not age normally as a result of being cloned, that may point to specific mechanisms in cellular biochemistry that merit a deeper investigation, especially those involved in the sweeping process of damage repair that occurs early in embryonic development, turning aged parental cells into youthful child cells.

It is a basic, yet still quite mysterious fact that at fertilization the aging clock in metazoans is "reset to zero." While every individual "ages" over time, and consequently dies at some point, the cells in the germline seem completely resistant to age-related changes - otherwise a species would age as quickly as the individual itself. While individual germ cells do age along with its organism, various control and selection mechanisms assure that the next generation starts relatively "unchanged" and healthy. It is, for example, now known that both nuclear and mitochondrial genomes are likely to acquire a small number of mutations between parents and offspring. We regard this minimal change that occurs during natural reproduction, within the physiological reproductive lifespan of the parents, as the ideal 'reset to zero' of the aging clock, against which the aging of cloned animals has to be compared.

In somatic cell nuclear transfer (SCNT), the nucleus of an adult cell is transferred to an enucleated oocyte, and is thought to not only regain pluripotency, but is also "rejuvenated" by factors in the ooplasm. Starting with works based on frogs, SCNT fully took off with the birth of Dolly the sheep. Since then, SCNT has been applied successfully in numerous species. There are relatively high losses of individuals derived from SCNT during their perinatal and early postnatal development, but they are thought to be indistinguishable from controls once they reach higher age. In fact, they are reported to have comparable performance on traits like beef and milk production. While there are clearly factors that limit the efficiency of cloning, at least some nuclei seem to be completely reprogrammed and rejuvenated to result in a completely "normal" adult individual. However, is it possible with a nucleus derived from a somatic cell, to completely start at time point zero, like gametes after a conventional fertilization? One of the biggest concerns regarding aging of cloned animals is the age of the nuclear donor cell. It was argued that if this cell is old, and consequently has shortened telomeres, the clone would already start at the age of the donor cell. However, the telomere length turned out to be at least partly restored during SCNT.

The ultimate outcome of aging is death, and therefore life expectancy is perhaps the most easily measurable parameter of aging (the question of aging can of course not be reduced to life expectancy alone). The time since several species were first cloned outdates, or is at least close to, the life expectancy of the respective species by now: goat, cattle, dog, sheep, mouse, cat, and pig. Therefore, we should be able to finally answer the question of whether at least some cloned animals can reach a life expectancy similar to that of the control animals. In several species, cloned animals reach indeed the expected lifespan. Cloned dogs seem to reach a high age. Snuppy, an Afghan hound and the first cloned dog, was 10 in 2015; and cloned female dogs of the same breed were 9. Also 3 cloned dairy goats lived to a normal age of 15 years, and Yang Yang, China's first cloned goat turned 15 in 2015. Also for cloned mice, several studies report a normal lifespan. While Dolly, the first cloned sheep, only reached 6 years, very recently, important further work on the aging of cloned sheep has been published. Thirteen aged (7-9 years old) cloned sheep, with 4 of them derived from the cell line that gave rise to Dolly, were analyzed. Detailed measurements of blood pressure and metabolism, as well as musculoskeletal tests showed no significant differences from age matched controls. Notably, these cloned sheep are already close to their typical natural lifespan. Copycat, the first cloned cat turned 10 in 2011, which is at least respectable for a cat, if still several years from the maximum lifespan. Pigs were first cloned in 2000, but the highest age reported to the best of our knowledge was 6 years.

Our own data of 33 SCNT-cloned dairy cattle show a maximum age of 14.4 years, with an average lifespan of 7.5 years. The cattle lines were discontinued in 2014 due to the end of the project. Death reasons were qualitatively not different from conventional kept cattle. This mostly anecdotal evidence shows that the aging of cloned animals seems to be qualitatively very similar or even the same as that of normal animals. Once the cloned animal has reached adulthood, most problems of the rather unspecific condition "reprogramming failure of the donor nucleus" seem to be overcome. Unfortunately, there are by far too little data available to measure possible, or even probable quantitative differences.

While the question which age cloned animals can reach is asked very often, it is surprising that actual data in the scientific literature are scarce, even about the "celebrated" first cloned animals of several species. Therefore, we had to resort to own data, personal communication and even newsletters. Nevertheless, including the very recent report about the aging of cloned sheep, it is now possible to say that at least for those species where the question of longevity of cloned animals was addressed (mouse, goat, sheep), a normal lifespan is possible. It would be interesting to find out what proportion of cloned animals indeed reaches old age, but with the current amount data it is impossible to do so. Unfortunately, research on aged cloned animals seems almost non-existent despite the public interest in various "safety" questions of SCNT. This might partly be explained by the fact that SCNT is still a very recent technique when compared to the life expectancy of most cloned species. Moreover, cloned farm animals are unlikely to be kept longer than their productive phase. Cloned sport and companion animals are mainly being kept in private care, and thus are less accessible for scientific studies. Based on the literature available so far, and also in our experience, the aging of cloned animals seems to proceed very similar to control animals. However, a thorough clinical study with a sufficient number of cloned animals, together with control animals over their entire lifespan is clearly needed for every species.

Link: https://dx.doi.org/10.1159/000452444

A web of correlations exist in human data between social status, wealth, education, intelligence, and natural variations in longevity. One can propose possible mechanisms, such as better access to medical technology and greater willingness to use it well, and better care of the health basics such as diet, exercise, and weight. Intriguingly there are some signs that genetics may have some influence over this picture, with studies suggesting that more intelligent individuals tend to also be more robust and longer-lived. This remains far less convincing than the hypothesis that more intelligent people tend to take better care of their long-term health, however, going simply by weight of evidence. Still, here is another paper that runs along these lines:

Individual differences in educational attainment have been linked to variation in life chances and longevity: those with more education tend to be healthier, richer in adulthood, more upwardly socially mobile, and longer-lived. Because education influences - and is influenced by - various personal characteristics and social factors, it has been difficult to disentangle the precise reasons for its prediction of key life outcomes. Despite it being widely used in studies as a social-environmental variable, differences in education are under substantial genetic influence, with heritability frequently estimated at 60% and above in family studies, and 20-30% in molecular genetic studies. Some specific education-associated genetic variants have also been uncovered in genome-wide association studies (GWAS). The present study uses previously-discovered genetic correlates of education to predict variation in arguably the most important life outcome of all: longevity.

The association of educational outcomes-measured either by attained qualifications or by duration of full-time education - with longevity is well established in the scientific literature. The high value placed upon educational qualifications in society and in the labor market forms one possible explanation for this link: the higher-level occupations and socioeconomic positions afforded by better education allow greater access to health-improving resources and surroundings. However, education also acts as a signal for personal characteristics with which it is phenotypically correlated, such as general cognitive ability, motivation, and health, in addition to aspects of a person's socio-economic background. Thus, according to two nonmutually exclusive views, educational attainment might cause improvements in longevity via social mechanisms, or might itself be caused by preexisting - partly heritable - factors that also increase longevity.

Some evidence for the latter view - that some of the variance in educational attainment and longevity is caused by preexisting factors - comes from the pervasive genetic correlations of education with many other longevity-linked traits, indicating that these traits are substantially associated with the same genetic variants. For example, one study used linkage-disequilibrium (LD) regression analysis to show that educational attainment was significantly genetically correlated with lifespan-limiting conditions like cardiovascular disease and stroke. In addition, educational attainment is strongly genetically correlated with general cognitive ability, itself a well-replicated phenotypic and genetic correlate of longevity.

In this study, we tested whether the genetic variants associated with educational attainment are associated with longevity. We thus assessed the extent to which the genetic contributions to educational outcomes, which are preexisting and nonsocial, are related to a key health outcome. To do so, we used the established technique of testing for associations between genotyped subjects and their phenotyped relatives (in this case, the lifespan of parents). Here, we used summary data from an independent GWAS of educational attainment to create polygenic profile scores. These scores quantify the extent to which each participant carried the genetic variants known to be associated with higher educational attainment (in the GWAS, education was measured as the number of years of education). We then linked these polygenic profile scores to data on the participants' parents' age at death. Our hypothesis was that offspring with polygenic profiles for higher educational attainment would have longer-living parents.

This study found that offspring polygenic profiles for education were robustly associated with parental longevity: those with more genetic variants related to better educational qualifications had longer-living parents. We tested the study's principal hypothesis across three large cohorts, totaling over 130,000 participants. The associations were of broadly similar effect size in all three cohorts. Parents with offspring in the upper third of the polygenic score distribution lived an average of 0.55 years longer than those in the lower third. The results - which were comparable to the effect sizes from other known predictors of mortality, such as cardiovascular disease and smoking, and which were bolstered by the finding of a moderate-sized genetic correlation between the two variables - suggest the hypothesis that the ultimate reason education predicts mortality is, in part, because of an underlying, quantifiable, genetic propensity.

Link: http://dx.doi.org/10.1073/pnas.1605334113

The research I'll point out today examines one of the mechanisms by which the damage caused by similar strokes can vary from individual to individual. The researchers focus on the degree to which the vascular network of the brain grows to contain alternative routes to the same destination tissues, and identify a gene in mice that accounts for a fair amount of this difference between individuals. A stroke is the outcome of structural failure in a blood vessel in the brain, weakened by the molecular damage of aging, leading to loss of elasticity, and put under stress by the increased blood pressure of hypertension. The result is either blockage or rupture, disrupting the flow of blood to where it is needed. The largest effects result from the downstream loss of blood flow to a region of brain tissue, ischemia, followed by its sudden return. Most cells survive a short loss of oxygenation and nutrients, but then die in the reaction to a renewed influx of oxygenated blood, an effect known as reperfusion injury. The effects of similar strokes vary from individual to individual for many reasons. To pick one example among many, differences in the cellular reaction to reperfusion can be quite influential, and thus genetically engineered mice lacking the oxygen sensor PHD1 have been demonstrated to experience greatly reduced cell death following a stroke.

The vascular network incorporates some redundancy throughout the body, though nowhere near as much as one would like. Blockage of larger vessels is going to cause trauma: there is a given amount of blood flowing through that channel and it can't all fit through the alternative paths. In many cases enough can get by to keep tissues alive, however, and thus reduce the degree of ischemia. Some people have more of those additional redundant blood vessels than others, and thus suffer less in the event of stroke. Being more resistant to damage is better than being less resistant to damage if that is the only game in town, but aiming higher certainly should be the goal. No-one wants to be put in the position of suffering a stroke in the first place. Prevention is far better than cleaning up after the fact, especially given the high risk of death and permanent disability that accompanies stroke.

Thus consider the forms of rejuvenation therapy that can address the root causes of hypertension, blood vessel stiffness, and damage to blood vessel walls, such as that caused by atherosclerosis - these are the goals to work towards. Of the SENS rejuvenation research portfolio, breaking cross-links will most likely do the most address loss of elasticity, but if you look at the evidence almost all of the fundamental forms of cell and tissue damage that cause aging have some contribution to make. So mitochondrial repair of one form or another will reduce the flux of damaged lipids that contribute to atherosclerosis. Cleaning up the related metabolic waste such as 7-ketocholesterol found in atherosclerotic lesions will no doubt also help. From recent work there are hints that senescent cell clearance will also assist in turning back loss of tissue elasticity, and any approach that reduces chronic inflammation will also slow the decline of the vascular system.

Scientists identify "collateral vessel" gene that protects against stroke damage

Scientists have known that when an artery is blocked, the damage to tissues downstream is often limited because these tissues continue to be nourished by special "collateral" vessels that connect the tissue to other arteries. However, for reasons that haven't been understood, the number and size of these collateral vessels - and thus the protection they afford - can vary greatly from one individual to the next. Scientists have now implicated the Rabep2 gene as a major contributor to this variation in collateral vessel formation. Variants of this gene account for most of the differences in collateral vasculature among laboratory mice. Since humans and mice are more than 90 percent genetically similar, the human version of Rabep2 is likely to have a comparable function.

Through a series of experiments, researchers replaced a defective variant of the gene in a mouse strain with poor collaterals with a normal copy of the gene, resulting in the formation of abundant collateral vessels during embryonic development and much greater resistance to tissue injury and cell death when the mice were subjected to experimental stroke as adults. The scientists hope that one day doctors will be able to use a simple blood test to detect variants of the human form of the gene. This would help doctors quickly gauge the extent of collateral vessels in patients who experience heart attacks, strokes, peripheral artery disease, and occlusive disorders in other tissues. In principle the findings also could help lead to therapies that stimulate the formation of more collateral vessels in healthy people to reduce the severity of tissue injury in the event of a future arterial blockage, as well as in people who already have occlusions, thereby reducing damage and improving their recovery.

This comes nine years after researchers first observed that the extent of the collateral vasculature - and thus the damage after arterial occlusion - can differ greatly between different strains of lab mice, even though no differences in the rest of the circulatory systems were evident. They focused on collateral vessels in the brain, which are easier to image than in other tissues, and undertook experiments involving thousands of mice. By 2014, the group had narrowed the search to a small region on mouse chromosome 7. In the new study, the researchers set out to identify the particular gene in this region that might explain the differences in collateral vessel development. From the 28 protein-coding genes in the region, the scientists were able to exclude 13, after determining that mice lacking any of those genes didn't have more or fewer collaterals. Of the 15 remaining genes under suspicion, the team decided to focus on their top suspect, Rabep2. Little was known about this gene, but the scientists had previously found a Rabep2 variant in mouse strains with low collateral extent, whereas high-collateral strains had the normal version of the gene. The variant differs from the normal gene in only a single DNA "letter," but that change - because of its location - is predicted to impair the function of the resulting protein.

Using new CRISPR gene-editing technology, the team was able to test the effect of this Rabep2 variant. They replaced the DNA letter in normal Rabep2 that is present in the genomes of high-collateral mice with the suspect variant. The result: the mice formed many fewer collaterals during development and had much greater stroke damage as adults. And this shift was even greater when the gene was deleted entirely. Conversely, in mice from the low-collateral strain, replacing the variant gene with the normal one induced the animals to develop the abundant collateral vasculature present in the high-collateral strain. These beneficially "edited" mice were thus far more resistant to damage from stroke.

Variants of Rab GTPase-Effector Binding Protein-2 Cause Variation in the Collateral Circulation and Severity of Stroke

The extent (number and diameter) of collateral vessels varies widely and is a major determinant, along with arteriogenesis (collateral remodeling), of variation in severity of tissue injury after large artery occlusion. Differences in genetic background underlie the majority of the variation in collateral extent in mice, through alterations in collaterogenesis (embryonic collateral formation). In brain and other tissues, ≈80% of the variation in collateral extent among different mouse strains has been linked to a region on chromosome 7. We used additional CNG mapping and knockout mice to narrow the number of candidate genes. Subsequent inspection identified a nonsynonymous single nucleotide polymorphism between B6 and BC within Rabep2 (rs33080487). We then created B6 mice with the BC single nucleotide polymorphism at this locus plus 3 other lines for predicted alteration or knockout of Rabep2 using gene editing. The single amino acid change caused by rs33080487 accounted for the difference in collateral extent and infarct volume between B6 and BC mice. Mechanistically, variants of Rabep2 altered collaterogenesis during embryogenesis but had no effect on angiogenesis examined in vivo and in vitro. Rabep2 deficiency altered endosome trafficking known to be involved in VEGF-A / VEGFR2 signaling required for collaterogenesis.

From a starting point of a few cells, researchers can at present build small amounts of at least partially functional tissue for a range of organs, including lungs. These are known as organoids, limited in size because reliable methods of generating the blood vessel networks needed to support larger tissues have yet to be developed. For some organs, those that largely act as filters or chemical factories, it is possible that organoids alone can have significant therapeutic value: transplant many of them at once and let them integrate into a damaged organ to augment its function, for example. For organs like the lung, however, where overall structure is important, there is further to go. The leap must be made from organoids to, at minimum, large and properly structured tissue sections. Meanwhile, the existence of organoids does allow researchers to gain valuable experience in tissue engineering, and to refine the outcomes achieved to date. That is important. This is a journey of many small steps:

Researchers have transplanted lab-grown mini lungs into immunosuppressed mice where the structures were able to survive, grow and mature. "In many ways, the transplanted mini lungs were indistinguishable from human adult tissue." Respiratory diseases account for nearly 1 in 5 deaths worldwide, and lung cancer survival rates remain poor despite numerous therapeutic advances during the past 30 years. The numbers highlight the need for new, physiologically relevant models for translational lung research. Lab-grown lungs can help because they provide a human model to screen drugs, understand gene function, generate transplantable tissue and study complex human diseases, such as asthma.

Researchers used numerous signaling pathways involved with cell growth and organ formation to coax stem cells - the body's master cells - to make the miniature lungs. The researchers' previous study showed mini lungs grown in a dish consisted of structures that exemplified both the airways that move air in and out of the body, known as bronchi, and the small lung sacs called alveoli, which are critical to gas exchange during breathing. But to overcome the immature and disorganized structure, the researchers attempted to transplant the miniature lungs into mice, an approach that has been widely adopted in the stem cell field. Several initial strategies to transplant the mini lungs into mice were unsuccessful.

The team used a biodegradable scaffold, which had been developed for transplanting tissue into animals, to achieve successful transplantation of the mini lungs into mice. The scaffold provided a stiff structure to help the airway reach maturity. "In just eight weeks, the resulting transplanted tissue had impressive tube-shaped airway structures similar to the adult lung airways." Researchers characterized the transplanted mini lungs as well-developed tissue that possessed a highly organized epithelial layer lining the lungs. One drawback was that the alveolar cell types did not grow in the transplants. Still, several specialized lung cell types were present, including mucus-producing cells, multiciliated cells and stem cells found in the adult lung.

Link: http://www.newswise.com/articles/lab-grown-mini-lungs-successfully-transplanted-into-mice2

This recent popular science article looks at the state of research into Alzheimer's disease and other forms of dementia. There is, so far, little tangible progress in the clinic resulting from the past twenty years of efforts in the laboratory. This is the result of a combination of factors, including a doubling of the imposed costs of medical regulation in those countries with the greatest investment in research, a poor high level strategy on the part of many research and development groups, in that they seek to patch over proximate causes and tinker with the late stage disease state rather than address causes, and the fact that dementia is a hard problem to start with. Much of what is funded as dementia research is in fact fundamental science intended to build a better understanding of the biochemistry of the brain and brain aging, a process of establishing a foundation for future work. That in and of itself is an enormous project, and will probably continue well past the point at which the first effective therapies for Alzheimer's disease arrive. That said, the Alzheimer's research community is one of the few in which sizable efforts are being made to address a root cause of aging, the accumulation of forms of metabolic waste such as amyloid-β and tau, by removing it. This is the right direction to take, and it is a pity that it has so far proved to be much harder than hoped.

By 2050, current predictions suggest, incidence of dementia worldwide could reach more than 130 million, at which point the cost to US health care alone from diseases such as Alzheimer's will probably hit US$1 trillion per year in today's dollars. Funding has not kept pace with the scale of the problem; targets for treatments are thin on the ground and poorly understood; and more than 200 clinical trials for Alzheimer's therapies have been terminated because the treatments were ineffective. Of the few treatments available, none addresses the underlying disease process. But this message has begun to reverberate around the world, which gives hope to the clinicians and scientists. Experts say that the coming wave can be calmed with the help of just three things: more money for research, better diagnostics and drugs, and a victory - however small - that would boost morale. "What we really need is a success. After so many failures, one clinical win would galvanize people's interest that this isn't a hopeless disorder."

The NIH's annual budget for Alzheimer's and other dementias jumped in the past year to around $1 billion, and there is support for a target to double that figure in the next few years - even in the fractious US political landscape. Now, he adds, the research community just needs to work out "what are we going to do with it if in fact we get it?". The answer could depend in large part on the fate of a drug called solanezumab. This antibody-based treatment removes the protein amyloid-β, which clumps together to form sticky plaques in the brains of people with Alzheimer's. By the end of this year, researchers are expected to announce the results of a 2,100-person clinical trial testing whether the drug can slow cognitive decline in people with mild Alzheimer's. It showed preliminary signs of cognitive benefit in this patient population in earlier trials, but the benefits could disappear in this final stage of testing, as has happened for practically every other promising compound. No one is expecting a cure. If solanezumab does delay brain degradation, at best it might help people to perform 30-40% better on cognitive tests than those on a placebo. But even such a marginal gain would be a triumph. It would show scientists and the drug industry that a disease-modifying therapy is at least possible.

On a scientific level, success for solanezumab could lend credence to the much-debated amyloid hypothesis, which posits that the build-up of amyloid-β in the brain is one of the triggers of Alzheimer's disease. The previous failure of amyloid-clearing agents led many to conclude that plaques were a consequence of a process in the disease, rather than the cause of it. But those in favour of the amyloid hypothesis say that the failed drugs were given too late, or to people with no amyloid build-up - possibly those with a different form of dementia. For its latest solanezumab trial, researchers sought out participants with mild cognitive impairment, and used brain scans and spinal-fluid analyses to confirm the presence of amyloid-β in their brains. Another group took the same approach to screening participants in a trial of its amyloid-targeting drug aducanumab. Earlier this year, a 165-person study reported early signs that successfully clearing amyloid-β with that therapy correlated with slower cognitive decline.

Link: http://www.nature.com/news/how-to-defeat-dementia-1.20949

The biochemistry of Alzheimer's disease is complex and varied, still incompletely mapped at the detail level. At the edges it merges into grey areas shared with other forms of neurodegeneration - a large number of Alzheimer's patients are diagnosed with other forms of dementia or cognitive impairment. That Alzheimer's is one item in the official list of diseases, that the borders between various forms of neurodegeneration are drawn as they are, is a historical accident carried across more than a century of the taxonomy of disease, not a reflection of current opinions. The age-related dysfunction of the brain is driven by numerous pathological processes. Differences of relative degree between these progresses, and in the locations in the brain that are worst affected, mix and match to produce the various named age-related conditions, collections of different symptoms. The classification of those symptoms into the buckets called diseases happened in most cases long before modern investigations of neural biochemistry. So we have the country of Alzheimer's disease, whose borders as drawn by symptoms and present fairly crude methods of diagnosis encompass what will probably come to be understood as several distinct conditions. They also likely enclose portions of other known conditions, such as vascular dementia, and this muddies the waters in many ways.

In the years ahead, as the first therapies arrive to effectively address the underlying processes that produce neurodegeneration, there will be a redrawing of borders in the matter of brain aging. Some named conditions will vanish, others will split into categories, and entirely new named diseases will arise. In this way taxonomy loosely reflects progress. Being able to remove one cause in a condition that has several causes is one of the most effective ways to figure out how everything fits together, and what the true classification should look like. For Alzheimer's, this phase of research and development is almost upon us. The condition is characterized by harmful accumulations of amyloid-β and tau, to different degrees in different patients, and in different parts of the brain. It is both an amyloidosis and a tauopathy, but without removing one or the other, it is hard to determine the relative importance of these forms of metabolic waste. Even if both are dealt with, there is still the matter of other conditions such as vascular dementia: if a therapy produces little improvement, is it because the target isn't causing significant pathology, or is it because other, untargeted processes are also causing significant pathology? To complicate matters further, the halo of biochemistry surrounding both amyloid and tau aggregates varies considerably by location within the brain and by the form of the aggregate - not all amyloid and not all tau is the same. They are categories, not single items.

Still, not so long ago, researchers finally demonstrated clearance of amyloid-β in the human brain, and in a way that appears to result in decreased symptoms of cognitive decline. Tau should follow in the years ahead. Over the next few years, the understanding of Alzheimer's will greatly increase, as the fastest way to pin down the roles and relative importance of the contributing processes is exactly this, to remove them and see what happens. Beyond the gains in understanding, it has the added bonus of being the most plausible road towards effective therapies, those that can do more than merely gently slow the progression of neurodegeneration. Exciting times lie ahead, and there will be many more papers like this one, in which the existing borders between diseases are questioned in light of new knowledge:

Primary age-related tauopathy and the amyloid cascade hypothesis: the exception that proves the rule?

Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer's disease (AD) stems from neurotoxic forms of the amyloid-beta (Aβ) peptide. Applying the framework provided by the amyloid cascade hypothesis to diagnosing and treating AD has proven problematic. Early neuropathological criteria for diagnosing AD focused on Aβ burden, but this strategy was not optimal given that total Aβ plaques correlate poorly with cognitive impairment and neuronal loss. Several large phase III clinical trials of therapeutics targeting Aβ have failed due to lack of efficacy, prompting reflection as to whether the amyloid cascade hypothesis is invalid. The reason for these failures remain unclear, but some investigators have cited these failed trials as evidence refuting the amyloid cascade hypothesis. Other investigators and pharmaceutical companies have concluded that the design of the trials, which failed to confirm target engagement, were the reason. Another possibility is that Aβ triggers a complex neurodegenerative cascade with a late amyloid-independent phase. The future success of an Aβ-targeting agent is required for final validation of the amyloid cascade hypothesis.

While the heterogeneity of dementing illnesses has complicated efforts to understand the relationship between Aβ and cognitive failure, recent progress in understanding non-AD dementias has put AD into sharper focus. Some of pathologies are more readily differentiated from AD neuropathologically, such as vascular dementia, but this can be difficult to quantify. The TDP-43 proteinopathies (e.g. amyotrophic lateral sclerosis) are largely devoid of Aβ and tau pathology. The more closely overlapping "plaque-only dementia" cases were found to largely represent an α-synucleinopathy (i.e., diffuse Lewy body disease). Another pattern of degeneration, however, which has been variably called tangle-only dementia (TOD), neurofibrillary tangle predominant senile dementia, tangle-dominant dementia, among many other monikers, has received far less attention. Large dementia autopsy series designed to advance our understanding of AD have allowed TOD to come into sharper focus and culminated in the development of a new diagnostic category termed primary age-related tauopathy (PART). New consensus criteria place TOD on a continuum with age-related tangles, that are universally observed in aged brains. Considerable evidence indicates that subjects with PART have a distinct constellation of features that sets them apart from classical "plaque and tangle" AD and other tauopathies. Studying these differences may provide clues to the pathogenesis of tauopathies and refine the amyloid cascade hypothesis.

The neurofibrillary tangles (NFT) in PART are essentially identical to those observed in AD. They are composed of similar tau isoforms, form paired-helical filaments, and are concentrated within neurons. The NFT in PART are localized to the medial temporal lobe. NFT in this distribution can be observed in subjects with normal cognition, mild cognitive impairment and dementia. In cognitively normal elderly subjects, autopsy studies have demonstrated that medial temporal lobe NFT are essentially universal and in a more limited distribution in many younger individuals. In demented subjects, approximately 2-10% of subjects display such tangles without significant amyloid deposition. The proportion of subjects with age-associated memory impairment or mild-cognitive impairment in association with PART might be high. Finally, given that Aβ-deposition is commonly encountered in cognitively normal subjects, "benign Aβ" deposits might be masking an underlying tauopathy in some patients leading to reduced prevalence estimates. Methods for differentiating PART tangles and AD tangles (e.g., biochemical or immunohistochemical markers) would be extremely helpful for answering this question. Tangle-only dementia (TOD) was first described in a series of patients with clinical features that were very similar to those of classical AD. While this category likely included some subjects with other dementing tauopathies, a large proportion have PART as a primary pathological dementing process.

What exactly PART represents has been the matter of debate, with various investigators considering it an AD variant, a frontotemporal dementia variant, or normal (or "pathological") aging. Toxins and infectious causes are also possible, but less likely. Currently, the evidence fails to support a role for Aβ toxicity in PART. Subjects with PART have no Aβ deposition. The possibility that PART is a form of pathological brain aging deserves attention. Mechanical injury in the form of mild yet repetitive traumatic brain injury (TBI) is an established trigger for tauopathy in chronic traumatic encephalopathy (CTE) in elite athletes and boxers. While subjects develop PART in the absence of documented TBI, the hypothesis that these tangles are caused by very mild repetitive "wear and tear" type injury can be supported by three arguments. First, the geometry of the human central nervous system is such that foci of mechanical stress concentration are predicted to include the medial temporal lobe and basal forebrain. Second, the presence of an uncal notch in the medial temporal lobe that overlies the transentorhinal cortex is very common even in the absence of cerebral edema, providing direct physical evidence that this site is a focus of stress concentration. Third, patients with known repetitive mechanical brain injury (i.e., CTE) develop tangles in an overlapping distribution, however more widespread and of greater magnitude. Thus, it is reasonable to hypothesize that the cause of PART is a very mild repetitive mechanical "wear and tear" type of age-related injury.

In the long run it should be possible to produce safe forms of artificial or augmented blood with superior characteristics to the real thing, whether built on a largely biological or largely non-biological foundation. A fair amount of theorizing and some practical work has gone into ways to enormously increase oxygenation, to the point of not needing to breathe for ten to twenty times longer, for example. There are also lines of research that might improve clotting or reduce side-effects of blood oxygenation, as well as other lines of augmentation. However, meaningful progress past the trial stage has yet to occur. Meanwhile, the ever greater ability to generate large amounts of patient-matched cells of any desired type makes it likely that production of real blood in cell factories will dominate this niche in the near future. True artificial blood still lies some way beyond that.

Understanding the blood behavior at the microcirculation level where blood and tissues come into contact is a key step in the development and application of blood substitutes. Development of an agent properly mimicking the oxygen-carrying capability of blood among its various functions has been of great interest, and many products have been established based on this property. Red blood cells (RBCs) isolated from donated blood are an important component widely used to save patients' lives via oxygen-carrying capacity owing to hemoglobin (Hb). However, there are complications associated with transfusion of RBCs to patients, such as risk of infection. These complications are the most important concerns for the application of RBCs. Furthermore, crossmatch and blood group typing are needed before transfusion, which is challenging in case of emergencies and when rare blood group types are needed. Hence, it is essential to develop efficient RBC substitutes capable of active oxygen and carbon dioxide transfer. RBC substitutes or synthetic oxygen transporters studied so far are of mainly two types: perfluorocarbon and Hb-based substitutes.

Perfluorochemicals (PFCs) are colorless, inert, and apparently nontoxic liquids with low boiling point temperatures and are insoluble in water and alcohol. The level of oxygen dissolved in PFCs has a direct linear relationship with oxygen pressure, and therefore, high oxygen pressure is necessary for maximum oxygen-carrying capacity. Since hydrogen atoms are replaced by fluorine atoms in PFCs, these compounds are not metabolized due to the strong bond between carbon and fluorine atoms. PFCs are insoluble in aqueous phase, and in case of their clinical application, they are solubilized using an emulsifying agent. Oxygen is dissolved in PFCs at a concentration of about 40%-50%, which is 20 times higher than the capacity of water and 2 times higher than plasma. PFCs are heat resistant and can withstand 300°C and higher temperatures without any change, which makes them easily amenable to heat sterilization. Their small sizes enable them to easily pass through the vessels occluded in some diseases, where RBCs cannot pass; hence, their application helps improving the oxygenation rate. An in vitro study showed that use of PFCs as artificial blood is considerably advantageous in occluded coronary artery to maintain myocardial function.

Human hemoglobin (Hb) derived from expired RBC bags is the main source of Hb for the production of Hb-based RBC substitutes. The half-life of Hb is equal inside and outside the RBCs; however, outside the RBCs, the natural tetramer molecule of Hb rapidly converts to dimer and monomer Hb species, which cause severe complications such as kidney damage. On the other hand, it has been shown that Hb scavenges the existing nitrous oxide (NO) molecules by its heme groups. NO is also involved in relaxation of smooth muscles of blood vessels, and this property is responsible for the vasoactivity of Hb-based products. Overall, this type of Hb must be modified before its application as an oxygen carrier. The Hb-based oxygen carriers (HBOCs) are divided into the following two groups: acellular and cellular HBOCs. Acellular HBOCs have been developed to increase Hb performance and decrease its side effects. These are now in various phases of clinical trials and belong to three categories including cross-linked HBOC, polymerized HBOC, and conjugated HBOC. However, among different modifications of Hb, only nanotechnology-based polyhemoglobin (PolyHb) and conjugated Hb are effective. However, due to their short blood half-lives and side effects, a majority of these products did not achieve required criteria in clinical trials.

Cellular HBOCs are those in which Hb is encapsulated in a cell-like structure. In this way, some products with highest similarity to RBCs were produced, which do not cause vasoactivation due to scavenging of NO. Encapsulation of Hb by a phospholipid layer prolonged its half-life and shelf-life comparing to acellular products. These particles are much smaller than RBCs. This small size enables their entry into areas of body that are not accessible for RBCs. Hence, they can pass through clots and blockages causing more oxygenation during stroke. However, this product has a short circulation half-life, which can be solved by a number of approaches for example by PEGylation of the particles' surface. Another series of products used as RBC imitators are biodegradable Hb-loaded polymeric nanoparticle (HbPNP). However, the most important problem with their application is rapid clearance by phagocytes. Other cellular-based biocompatible Hb products with repetitively branched molecular structures are dendrimers. The shape and size of these products are similar to Hb, and they are able to bind and release oxygen. However, their production is time consuming and costly. Therefore, a kind of dendrimer known as hyperbranched polymer has been developed, with reduced problems, which can be used as oxygen carrier by some adaptations. Dendrimers are also used for encapsulation in drug delivery. Therefore, it has been suggested that dendrimers could be used as artificial oxygen carriers by encapsulating Hb.

Due to the increased demand for blood transfusion and concerns about blood-borne pathogens, development of artificial blood substitutes, especially HBOCs, is under intensive focus. However, although many important steps have been taken to date, no oxygen-carrying blood substitutes are approved for use by the US FDA. Side effects and short half-life are the two main reasons that they did not met criteria for being approved. The fact of having no approved product in this field shows that there is an important challenge against formulation and application of promising and effective blood substitutes. In addition, it indicates the immense potential that exists in this field. However, being optimistic, it seems that science and technology would facilitate developing real blood substitutes, at least oxygen-carrying blood substitutes, whose production will substantially alleviate the worldwide shortage of blood needed for transfusion. It seems that future studies on artificial blood substitutes would focus on real blood substitutes, ie, RBCs obtained through differentiation of stem cells, however.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084831/

The Abolition of Aging was pointed out to me a little while ago as a more populist companion to Ending Aging. It offers less of a detailed introduction to the relevant areas of rejuvenation biotechnology, and more of an argument for the manifest destiny of radical life extension, a goal for our species that in this age of biotechnology should be both inevitable and desirable. I'm all for more people putting forward strong moral arguments for the work needed to bring an end to aging. There is no such thing as too much advocacy for this cause; helping to alleviate the vast and ongoing suffering and death produced by degenerative aging is the greatest good that anyone can achieve, and yet so very many people remain to be persuaded.

We live in an era of sweeping change. Every day brings a fresh wave of news reports about apparent breakthroughs by scientists and engineers. As a futurist, when I talk to audiences about the implications of accelerating technology, I'm used to witnessing some powerful reactions. Our untutored gut reactions to hearing about an unexpected future scenario are liable to lead us astray - badly astray. The evaluative principles which served us well in the past may lose their applicability in the very different circumstances that could exist in the future. Therefore, let's try to calmly assess this possibility: practical therapies for the comprehensive reversal of biological aging may be just around the corner. It's my own carefully considered view that, within 25 years - that is, by around the year 2040 - science may have placed into our hands the means to radically extend human longevity. A suite of rejuvenation treatments, administered regularly, could periodically undo the accumulated damage of aging in both body and brain. As a result, life expectancy will shoot upwards. Not long afterward, more and more people will start sailing past the current world record for the longest verified human lifespan.

But when I mention this viewpoint to people that I meet I frequently encounter one of two adverse reactions. First, people tell me that it's not possible that such treatments are going to exist in any meaningful timescale any time soon. In other words, they insist that human rejuvenation can't be done. It's wishful thinking to suppose otherwise, they say. It's bad science. It's naively over-optimistic. It's ignorant of the long history of failures in this field. The technical challenges remain overwhelmingly difficult. Second, people tell me that any such treatments would be socially destructive and morally indefensible. In other words, they insist that human rejuvenation shouldn't be done. It's essentially a selfish idea, they say - an idea with all kinds of undesirable consequences for societal harmony or planetary well-being. It's an arrogant idea, from immature minds. It's an idea that deserves to be strangled. Can't be done; shouldn't be done - in this book, I will argue that both these objections are profoundly wrong. I'll argue instead that rejuvenation is a noble, highly desirable, eminently practical destiny for our species - a "Humanity+" destiny that could be achieved within just one human generation from now. As I see it, the abolition of aging is set to take its place on the upward arc of human social progress, echoing developments such as the abolition of slavery, the abolition of racism, and the abolition of poverty.

Link: https://theabolitionofaging.com/

Today, I'll point out a speculative line of research on the detection of senescent cells. It is in an early enough stage to make it hard to say whether or not it will go anywhere in the years ahead. The authors of the open access paper linked below propose that the electrical properties of senescent and normal cells are sufficiently different to be used to build an assay for cellular senescence. Even if useful, this may not take off because the present molecular biomarkers for cellular senescence are generally agreed to be good enough for a first pass at the job at hand, meaning efforts to destroy these cells while having a fair idea after the fact as to how many succumbed to the therapy. Since the set of present biomarkers are soon going to used much more widely, given the rapid growth of the senescent cell research field, an entirely different approach to assays will face an uphill battle to gain adoption, whether or not it is better. And electrical measurement is indeed an entirely different approach when compared to the established methods of detecting the levels of a senescence-associated protein such as β-galactosidase, one requiring entirely different tools.

Why do we care about the number of senescent cells found in tissues? Well, to start with these cells are killing you. Ordinary cells become senescent when they reach their evolved replication limit, or in response to damage, or a toxic environment, or as a part of the wound healing process. Most such cells self-destruct or are destroyed by the immune system fairly rapidly. This serves to remove those cells most at risk of developing cancer. Some linger, however, and in growing numbers over the years. These cells secrete a mix of harmful signals that produce chronic inflammation, destroy fine tissue structure, and alter the behavior of surrounding cells for the worse. If just 1% of the cells in a tissue become senescent, and that happens to all of us eventually, they collectively cause significant dysfunction and contribute to the development of ultimately fatal age-related conditions. This is I'm very enthused by progress towards therapies capable of selectively destroying these cells. Senescent cell clearance treatments will be the first legitimate, actual, working rejuvenation therapies: limited in scope, but capable of reverting one cause of aging and all of its immediate consequences on the state of health.

To develop new senescent cell clearance therapies cost-effectively and rapidly, however, it is important to be able to determine how well the prototypes work. A field with a body of reliable, agreed upon tests to determine the quality of therapeutic outcomes is a field that can forge ahead and experiment at low cost. The field of senescent cell clearance is already well equipped on that front. Researchers can make a fair determination of degree of clearance, and have been doing just that. The standard assays have been used in one form or another for the past fifteen years or so. They are simple, but well proven. The need and market for new assays will, I think, be driven by uncertainties over whether or not the established assays are actually finding all of the senescent cells of interest, and whether or not the differences between classes of senescent cell are important in the grand scheme of things. For example, in the past couple of years researchers have started to distinguish senescent immune cells and senescent foam cells in atherosclerosis from the bulk of senescent cells, arguing that these have significantly different characteristics. Fortunately it so far appears that all of the potential senescent cell destruction therapies under development are fairly indiscriminate when it comes to the varieties of cellular senescence. Still, after the first generation of therapies there will be a second and a third, and we want those future treatments to be much improved over those presently in development. That will require a greater understanding of the varieties of senescence, as well as better assays for quantifying the results produced by potential therapies. Whether that will turn out to involve measurement of electrochemical properties of individual cells is an open question, but the prototyping of such an approach makes for interesting reading:

Cell Electrical Impedance as a Novel Approach for Studies on Senescence Not Based on Biomarkers

Senescence and disease are the two main contributing factors for the termination of life. Although senescence is one of the major causative factors of disease, senescence can be controlled to extend lifespan. In this context, various biomarkers have been used to measure and analyze senescence. In particular, research on senescence is especially important in cardiovascular research because cardiac myocytes are long-lived postmitotic cells, which need renewal of cellular components as a major ability for lifespan, unlike other short-lived cell types. In general, senescent cells have reduced autophagic activity, reduced telomerase activity, altered contents in mitochondrial phospholipid, increased oxidative stress due to reactive oxygen species (ROS), and increased levels of senescence associated β-galactosidase activity. Additionally, senescence associated changes at various levels of gene transcription and protein translation have also been reported. In all of the aforementioned studies, specific biomarkers have been used to evaluate the potential alterations in cell structure and function. However, such analyses involve complex procedures including chemical modification or tagging. In addition, the acquired data provide only comparative (not absolute) values. Further, given that senescence is a highly complex biological process, it is difficult to assess cellular aging based on the limited number of available biomarkers.

Electrochemical impedance spectroscopy has been utilized to indicate the electrical characteristics of different types of tissues. Even though the measurement of electrical impedance of tissues can provide beneficial information, this method is inconsistent and imprecise owing to the complex structure and composition of tissues. Recently, microelectrochemical impedance spectroscopy has been developed to characterize the electrical properties of cells at the single-cell level owing to the advances in lab on a chip and microfabrication technologies. The electrical impedance measurement at the single-cell level can afford more precise information than that of measurements at the tissue level. This technique contributed to acquire the quantitative information of cells, such as resistance, reactance, capacitance, and conductance, because the electric properties of cells are connected with their physiological states. Therefore, microelectrochemical impedance spectroscopy has been suggested to be a simple, fast, and cost effective diagnostic tool that does not require biomarkers.

Recently, changes in cellular components during senescence were quantitatively analyzed using a new methodology called microelectrochemical impedance spectroscopy for diagnosis of senescence (MEDoS), which involves measurement of electrical impedance of a cell. Since electrical properties of a cell gradually change with changes in the cellular components during senescence, cell impedance can be used to analyze senescence. In addition, cell impedance data can provide quantitative characteristic values for individuals with a higher efficiency than biomarkers. MEDoS was designed to ensure that a captured single cell remains steadily at a certain position during measurement. The MEDoS comprises a microfluidic channel for cell flow, a flexible polymer membrane actuator that functions as a cell trap for capturing, a pair of barriers, and sensing electrodes.

In this study, we investigated age-related changes in cell impedance in cardiac myocytes of zebrafish. MEDoS performed in this study exhibited a high cell-capture rate (90%) for cardiac myocytes from zebrafish hearts. The sequence of cell trapping is as follows. (1) Three groups (3, 6, or 18 months old) of cardiac myocytes in 1% fetal bovine serum solution are injected into the fluidic channel. (2) The membrane actuator is inflated by pneumatic pressure to block the cell flow until a single cell stops in front of the trap. (3) The pressure is reduced so that a single cell can enter the trap in a squeezed state. (4) When a single cell is positioned at the center of the sensing electrodes, the pneumatic pressure is increased again to fix the cell on the central surface of the electrodes. For minimization of cell damage, cardiac myocytes were maintained at 4°C during the experiment, and all experiments were completed within 1 hour.

The resistance of the cytoplasm gradually decreased from the 3-month-old cell group to the 18-month-old cell group. Considering that resistance is inversely proportional to conductance, we reviewed previous aging studies that evaluated changes in cellular components that could affect conductance during senescence. Autophagic activity is especially important in cardiac myocytes, a long-lived postmitotic cell, to maintain homeostasis and longevity. Autophagic activity decreases with senescence, and, accordingly, various reactive oxygen species (ROS) accumulate in the cytoplasm of cardiac myocytes. Thus, accumulated ROS could cause changes in cellular components as well as in electrical impedance. In several studies, an increase in the conductance of induced hypoxic alveolar epithelial cells due to an increase in the ROS level was found. In addition, an increase in the conductivity of hemoglobin caused by high oxidative stress was addressed. In other words, accumulated ROS can increase the conductance of the cytoplasm because of their free-radical characteristics. Therefore, our results could suggest that ROS that accumulate during senescence decrease the resistance of the cytoplasm.

Meanwhile, capacitance, which refers to the cell membrane in the electrical circuit model, gradually increased from the 3-month-old cell group to the 18-month-old cell group. A cell membrane has a phospholipid bilayer, which is composed of different types of molecules such as fatty acids and various proteins. During cell senescence, the level of ROS gradually increases with decreasing autophagic activity. ROS are more soluble in the fluid lipid bilayer than in aqueous solution; thus, the membrane phospholipids and polyunsaturated fatty acids, one of the phospholipid acyl chains, are susceptible to oxidative damage. Peroxidation of polyunsaturated fatty acids in the membrane has been shown to be a cause of senescence. Based on the aforementioned studies, the peroxidizability index (PI) was used to measure the relative age-related susceptibility of fatty acid composition to peroxidative damage in the cell membrane. A high PI value implies that the membrane bilayer is easily affected by lipid peroxidation. Many investigators have found that the PI value and lipoxidation-derived molecular damage increase with aging. In addition, the oxide composition amount increases during the process of lipid peroxidation. These phenomena can be explained by the fact that high PI values are obtained as the oxide composition amount increases. The capacitance of the cell membrane also increases as the oxide composition amount increases in the membrane. Therefore, we hypothesize that the increase in PI values reflects an increase in the capacitance of the cell membrane.

In what seems like an important proof of concept, researchers here demonstrate that transplanted embryonic neurons can integrate fully into an adult brain, and carry out the same functions as existing adult cells. This means that suitable forms of reprogrammed neural cells, such as those derived from induced pluripotent stem cells, should be just as capable. This sort of result reinforces the need to continue the development of cell therapies for the aging brain, intended to replace lost cells and reinforce failing functionality. Lost cells are only one part of the overall problem, as there is the age-damaged cellular environment to repair as well, but in a number of neurodegenerative conditions cell loss is a very significant proximate cause of pathology. Parkinson's disease, for example, involves the loss of the small population of neurons that produce dopamine.

When it comes to recovering from insult, the adult human brain has very little ability to compensate for nerve-cell loss. Biomedical researchers and clinicians are therefore exploring the possibility of using transplanted nerve cells to replace neurons that have been irreparably damaged as a result of trauma or disease. Previous studies have suggested there is potential to remedy at least some of the clinical symptoms resulting from acquired brain disease through the transplantation of fetal nerve cells into damaged neuronal networks. However, it is not clear whether transplanted intact neurons can be sufficiently integrated to result in restored function of the lesioned network. Now researchers have demonstrated that, in mice, transplanted embryonic nerve cells can indeed be incorporated into an existing network in such a way that they correctly carry out the tasks performed by the damaged cells originally found in that position. Such work is of importance in the potential treatment of all acquired brain disease including neurodegenerative illnesses such as Alzheimer's or Parkinson's disease, as well as strokes and trauma, given each disease state leads to the large-scale, irreversible loss of nerve cells and the acquisition of a what is usually a lifelong neurological deficit for the affected person.

The researchers specifically asked whether transplanted embryonic nerve cells can functionally integrate into the visual cortex of adult mice. "This region of the brain is ideal for such experiments. We know so much about the functions of the nerve cells in this region and the connections between them that we can readily assess whether the implanted nerve cells actually perform the tasks normally carried out by the network." In their experiments, the team transplanted embryonic nerve cells from the cerebral cortex into lesioned areas of the visual cortex of adult mice. Over the course of the following weeks and months, they monitored the behavior of the implanted, immature neurons by means of two-photon microscopy to ascertain whether they differentiated into so-called pyramidal cells, a cell type normally found in the area of interest. "The very fact that the cells survived and continued to develop was very encouraging. But things got really exciting when we took a closer look at the electrical activity of the transplanted cells." The researchers were able to show that the new cells formed the synaptic connections that neurons in their position in the network would normally make, and that they responded to visual stimuli. The team then went on to characterize, for the first time, the broader pattern of connections made by the transplanted neurons. They found that pyramidal cells derived from the transplanted immature neurons formed functional connections with the appropriate nerve cells all over the brain. In other words, they received precisely the same inputs as their predecessors in the network. In addition, they were able to process that information and pass it on to the downstream neurons which had also differentiated in the correct manner.

Link: http://www.en.uni-muenchen.de/news/newsarchiv/2016/goetz_neuenerven.html

All age-related disease is built upon a foundation of damage and dysfunction that stretches as far back as decades prior to the evident manifestation of pathology. The normal operation of cellular metabolism produces forms of molecular damage that take a long time - most of a lifetime - to become prevalent enough to produce obvious change and harm. Researchers here examine the development of Alzheimer's disease from this perspective, with a focus on mitochondrial function, something known to be important in the processes of aging:

Alzheimer's disease (AD) - the most common form of dementia - is a progressive, degenerative disease of the brain. While commonly associated with elderly individuals, this devastating illness is now believed to have its origins much earlier, infiltrating the nervous system decades before the onset of clinical symptoms. Indeed, the greatest obstacle to successful treatment of Alzheimer's is the fact that the disease is typically not recognized until its progress has irreparably ravaged the brain. "Although amyloid plaques and tau neurofibrillary tangles remain as the definitive neuropathological hallmark of the disease, plaques do not correlate at all with degree of cognitive impairment in AD and tangles correlate only slightly. We further know that plaques and tangles are late comers in the cascade of events that cause the dementia of AD."

Mitochondria - membrane-bound organelles found in all eukaryotic organisms - are often called the powerhouses of the cell. Through a process known as oxidative phosphorylation, they produce most of the cell's chemical energy in the form of adenosine triphosphate or ATP. In addition to supplying cellular energy, mitochondria are involved in cell signaling, cellular differentiation, and cell death, as well as in cellular growth and the maintenance of the cell cycle. Because mitochondria play such an important role in the cell, mitochondrial dysfunction has been implicated in a broad range of illness. Unsurprisingly, defects in mitochondrial function more severely affect energy hungry organ systems in the body, particularly muscles, the gastrointestinal tract and the brain. In addition to the role of mitochondrial dysfunction in disease, the gradual degradation of mitochondrial integrity is believed to play a central role in the normal process of aging.

The current study examines tissue from the hippocampus, a structure critical for memory and one severely impacted by the advance of Alzheimer's. Using microarray technology, the authors examined hippocampal tissue from an aging cohort - 44 normal brains from 29-99 years of age, 10 with mild cognitive impairment and 18 with Alzheimer's disease. Gene expression was examined for two sets of genes, 1 encoding mitochondrial DNA and the other, in the nuclear DNA. The two sets of genes both coded for proteins associated with a mitochondrial complex essential for oxidative phosphorylation (OXPHOS), producing energy in the form of ATP for the cell. Intriguingly, while the mitochondrial genes themselves were largely unaffected, the nuclear genes associated with the OXPHOS complex underwent significant modification, depending on the tissues examined. The microarray data revealed substantial down-regulation of nuclear-encoded OXPHOS genes in Alzheimer's tissue, a finding also found in normally aging brains. The same genes, however, were up-regulated in the case of mild cognitive impairment, a precursor to Alzheimer's disease. The authors suggest this effect may be due to a compensatory mechanism in the brain in response to early pathology.

The findings are consistent with earlier work establishing that accumulations of amyloid beta (Aβ) in neurons, a hallmark of Alzheimer's, are directly implicated in mitochondrial dysfunction. The pronounced effect on nuclear-encoded but not mitochondrial-encoded OXPHOS genes may point to dysfunctions in the transport of molecules from the cell nucleus to the mitochondria. "Our work on mitochondria offers the promise of a reliable marker appearing earlier in the course of the disease - one which more closely correlates with the degree of dementia than the current diagnostic of plaques and tangles."

Link: https://www.eurekalert.org/pub_releases/2016-11/asu-poi110416.php

Today I'll point out an open access paper on calcification of blood vessels in which the authors show that genetic engineering to alter levels of ATF4 in mice also alters the pace of the calcification process. Calcification of tissues, especially blood vessel walls, is an important component of the blood vessel stiffening that occurs with age. This stiffness causes raised blood pressure, or hypertension, as well as detrimental remodeling of heart tissue. Higher blood pressure in turn causes damage to important but comparatively delicate tissue structures such as those of the kidney and brain, as well as greater rates of structural failure in small blood vessels. It also sets the stage for larger and usually fatal ruptures that occur in blood vessels weakened by atherosclerosis. That the heart changes its structure over time in response to blood vessel stiffness paves the way towards the numerous varieties of heart failure. So, on the whole, we'd all be a lot better off without calcification, or more to the point with therapies that can get rid of it.

There is some debate over where blood vessel calcification sits in the chain of cause and effect that leads from the starting point of cell and tissue damage that occurs as a side-effect of the normal operation of cellular metabolism to the end point of aging, dysfunction, medical conditions, and death. Is it in and of itself a primary cause of aging that would occur even in absence of the others? Or is it secondary to one or more other known age-associated forms of damage, and if so which ones? Since at the present time the research community has only just found out how to safely remove one of the seven classes of fundamental damage that cause aging, which is to say the accumulation of senescent cells, it is still the case that it is very hard to produce good answers to the question of whether A causes B or B causes A (and how this is influenced by C, D, and E) once you are down at the detail level of molecular machinery inside a cell. Everything in living biochemistry is interconnected, and picking apart the connections is a slow and expensive job. That said, on the matter of calcification I'll point you to a great review paper on the topic, as well as results from another line of research that suggest a specific cellular dysfunction causes calcification, both of which imply that this is not a primary cause of aging. It still leaves open the question of which of the fundamental forms of damage are the significant causes of calcification, however. Good candidates include the cross-linking that is itself thought to be very important in blood vessel stiffening, and the accumulation of hardy waste compounds that clog cellular recycling mechanisms, and anything else that involves generation of chronic inflammation.

One interesting point to think about in connection with the research presented here is that it is a global reduction in ATF4 levels that produces benefits in the form of slower calcification. The authors are largely focused on the kidney, as that is one of the organs most damaged by the high blood pressure produced by calcification and stiffened blood vessels. Yet if you look back in the Fight Aging! archives, you'll find that many of the commonly studied methods of slowing aging in mice are characterized by increased levels of ATF4 in the liver - and it is certainly the case that of these methods, some are known to slow the process of vascular stiffening and calcification. Never let it be said that the molecular biology of living beings is anything other than very complicated. Every organ and tissue is its own special case, and most interventions will result in more or less of a specific protein produced in one organ versus another. This is yet another reason why the metabolic tinkering approach to aging, attempting to adjust levels of specific proteins to a more youthful configuration in order to produce benefits, is an enormous undertaking, far greater in scope and difficulty than the alternative approach of repairing the damage found in old tissues.

Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells

Evidence is emerging that endoplasmic reticulum (ER) stress contributes to the pathogenesis of vascular calcification. The ER is a major site for the regulation of calcium and lipid homeostasis. ER stress is an integrated signal transduction pathway involved in the localization and folding of secreted and transmembrane proteins. Vascular calcification is an independent predictor for the mortality and morbidity of patients with chronic kidney disease (CKD). Vascular calcification is classified into two major types, atherosclerotic and medial, both of which are frequently and simultaneously observed in CKD patients. Vascular calcification is a highly regulated process that resembles skeletal bone formation. Many key transcriptional regulators involved in skeletal osteogenesis are expressed in both calcified medial arterial layers and atherosclerotic plaques. We recently reported that these factors induce ATF4 activation through the ER stress response, resulting in osteogenic differentiation and mineralization of vascular smooth muscle cells (VSMCs) in vitro. However, whether in vivo ATF4 activation causes vascular osteogenesis and the molecular mechanism by which ATF4 induces mineralization of VSMCs have not been determined. In this context, we determined the in vivo role of ATF4 in VSMCs in both atherosclerotic and medial calcification and its mechanisms by using several murine models with global ATF4 deficiency, smooth muscle cell-specific (SMC-specific) ATF4 deficiency, and SMC-specific ATF4 overexpression.

ATF4 is known to be a critical transcription factor that regulates skeletal osteogenesis and bone formation. We and other investigators previously reported that ER stress induces expression of aortic ATF4 in a number of in vitro and in vivo models of vascular calcification. In particular, CKD strongly activates the aortic ER stress response, resulting in a significant induction of aortic ATF4. In this study, we demonstrate that ATF4 expression in VSMCs plays a causative role in the pathogenesis of vascular calcification using a series of mouse models. As an initial model, we used global ATF4-haploinsufficient mice, which showed significantly smaller aortic medial calcified lesions under both CKD and normal kidney condition (NKD) conditions. We also used an SMC-specific ATF4-deficient model, in which both medial and atherosclerotic calcifications under NKD and CKD conditions were attenuated. Finally, we generated a mouse model that overexpresses ATF4 only in SMCs, in which severe medial and atherosclerotic calcification developed even under NKD. These findings strongly suggest that the induction of ATF4 in VSMCs through ER stress is a pivotal event in the development of vascular calcification and osteogenesis.

CHOP is a major target of ATF4, and it is a transcription factor that promotes apoptosis contributing to vascular calcification. We previously reported that global CHOP deficiency attenuated CKD-dependent vascular apoptosis and atherosclerotic calcification in ApoE-/- mice. In this study, SMC-ATF4 deficiency reduced aortic CHOP expression and CKD-dependent apoptosis accompanied by a marked attenuation of vascular calcification, whereas SMC-ATF4 overexpression induced CHOP expression and apoptosis. These results suggest that ATF4 mediates vascular calcification through the induction of phosphate uptake in VSMCs through CHOP-dependent and -independent mechanisms.

We all live in societies in which near every formative story and teaching glorifies the process of aging to death. The foundations of our myths paint death through aging as an essential, good thing. This is the natural outcome of thousands of years of creative human culture in which nothing could be done about aging. People came to terms with it by building tools - stories, myths, coping mechanisms - to enable psychological comfort in the face of the horrible and the inevitable. The best of these tools prospered because they allowed the societies that used them to prosper, and so we have today what has been termed the "pro-aging trance". We are now entering a new era, however, and in an age of biotechnology and medicine capable of addressing the causes of aging, these lies that we tell to ourselves about aging and death have outlived their usefulness. They have become a dead weight dragging us down, slowing the growth of support for rejuvenation research that can bring an end to the pain and suffering of aging and age-related disease.

Two clichés really ruined a recent moviegoing experience for me: the implied, groundless cliché that 'living forever is not as nice as you think, it's something only bad guys would want and it comes at a high price' creeping up throughout the entire movie, and the inevitable 'death gives life its meaning' cliché. I am really tired of hearing this false mantra being mindlessly repeated over and over. Books, movies, newspaper articles, people - everyone seems to be persuaded that without death, life would have no meaning. No one, though, bothers explaining why this depressing claim would hold true, and if they do, their arguments boil down to unconvincing, carelessly generalised hand-waving about how you couldn't properly appreciate a good thing without its opposite. That's like saying that in order to appreciate not having cancer, you need to have had cancer first. I appreciate how being mortal may make you see things differently from how an immortal being might see them, but that is not the same as death being mandatory to appreciate life.

So, please, stop. Stop repeating this dangerous and foolish mantra. Don't let movies, books, or anyone tell you that death gives life its meaning. Don't let anyone decide for you what is the meaning of life, or what gives meaning to it, because in general, there is no such thing. Meaning is relative, not absolute, and you get to decide for yourself what gives meaning to your life, not an age-old piece of nonsense people perpetuate merely to sugarcoat death. Death is nothing special. It is not a monster. It is not a foe, no more than the status of 'broken' is for an inanimate object. Death is the name we give to the status of a biological creature whose body is too damaged to keep functioning. That's all it is. I don't know what gives meaning to your life, but I can tell you what gives meaning to mine. People I love. Things I like doing. Music I like listening to. Playing piano. Drawing. Writing. Learning new things. Having fun with friends. Discussing science. Enjoying a beautiful landscape. Wondering about the countless mysteries of nature we haven't solved yet - and many, many other things.

We have hospitals to cure sick people. We have international organisations trying to save people in poor countries from starvation, to put an end to war and help its victims. Why all these initiatives aimed at preserving our lives, if death is what gives it meaning? If you are struck by a fatal illness, why turn to doctors to save your life? Perhaps the time has come for death to give it meaning. Do you see the nonsense yet? The very idea that death gives meaning to life, when we've tried so very hard from time immemorial to stave off death for as long as possible, is absurd-or perhaps, a hint that we don't care that much for our lives to have a meaning after all. Does all that you do, feel, and care for, magically become worthless if you don't die? Are the people you love dear to you only because one day you won't have them any more? What about the things they have done for you, or the fact they understand you like no one else does?

No, I don't think death gives meaning to life. Things I fill my life with give it meaning, and all my death is going to accomplish is taking those things away from me. (Or rather, it's going to take me away from those things.) Ageing is the worst example of this: It gradually makes you more and more unable to dedicate yourself to the things that give your life meaning, thus making your life more and more meaningless. Eventually, it deprives you of life entirely. So please, stop repeating the death mantra. Stop believing in this crazy nonsense. I understand where it comes from, and I understand our need to rationalise death, but it is time to move on. It is time to look at death for what it is and keep on refining our tools to stave it off indefinitely, so that people can live in perfect health for as long as they wish.

Link: https://rejuvenaction.wordpress.com/2016/11/07/please-stop/

There is a long-standing bet between scientists Steven Austad and S. Jay Olshansky on whether or not someone alive when the bet was made will survive to reach the age of 150. In essence this is a bet on the timing of the process of actuarial escape velocity that has been described by Aubrey de Grey: how soon will new medical technologies, those capable of addressing the root causes of aging to produce rejuvenation, start to extend remaining life span at a faster rate than people age? At some point more than a year of additional life will be added with each year of passing time, but even before then incremental gains in the field will provide enough additional time for older people to be able to survive to benefit from the better technologies ahead. If a partial rejuvenation therapy adds ten years to life expectancy, that is ten extra years of life in which further improvements and other partial rejuvenation therapies can be brought to the clinic. The wager was in the news again recently, following a rather controversial and much misinterpreted paper on observed limits to life:

Two US researchers have doubled their 16-year-old wager on whether anyone born before 2001 will reach the age of 150. The scientists have now staked US$600 on the question - but, if the fund in which the cash is deposited keeps growing at its current rate, the descendants of the victor could net hundreds of millions of dollars in 2150. The friendly rivalry began in 2000, when Steven Austad, a biologist who studies ageing, was quoted in an article with the provocative statement: "The first 150-year old person is probably alive right now." Jay Olshansky, another expert on ageing, didn't think so - and the scientists agreed to stake cash on the debate. On 15 September 2000, the two put $150 each into an investment fund, and signed a contract stating that the money and any returns would be paid to the winner (or his descendants) in 2150. The bet also stipulates that Austad will only win if the 150-year-old is of sound mind.

Then last week, a paper suggested - from an analysis of global demographic data - that there may be a natural limit to human lifespan of about 115 years. Olshansky wrote an accompanying commentary which argues that fixed genetic programs stand in the way of significant human life extension. He says he believes a major breakthrough that will significantly extend human lifespan will occur within his lifetime, but that it will come too late to help those born before 2001 to reach their 150th birthday. But Austad disagrees. "I'm more convinced than ever that I was correct in our original bet," he says. He cites recent studies showing that a number of drugs, such as the immune-system suppressor rapamycin, can significantly extend lifespan in animals. And he points to the imminent start of a clinical trial called Targeting Aging with Metformin, or TAME, which hopes to show that a well-known diabetes drug can slow ageing. Austad and Olshansky have now agreed to stake another $150 each. In 16 years, their original $300 stake has already grown to $1,275 (increasing by around 9.5% per year). If the topped-up fund maintains this average annual return, the winning pot could top $200 million by 1 January 2150. On that date, three scientists chosen by the president of the American Association for the Advancement of Science will determine the winner - although neither Austad nor Olshansky expects to be alive to find out.

Link: http://www.nature.com/news/scientists-up-stakes-in-bet-on-whether-humans-will-live-to-150-1.20818

Despite the fact that we stand within reach of human rejuvenation, to be achieved through repair of the known forms of biological damage that cause aging, the majority of research into aging and longevity has next to nothing to do with that goal. It is instead a slow and painstaking process of mapping, an attempt to understand how exactly cellular biology produces aging, at the detailed level of genes and protein interactions. It takes years of work to obtain a useful amount of new information about the role of one specific gene, and there are thousands of genes of interest, formed into networks. There are many ways to influence the behavior of these networks - pick a gene, alter its structure or the amount of protein produced, and the entire network is affected. Pick another gene and the network reacts in a different way.

This is why those researchers who believe that the only way forward is to produce the map, and then use it to alter the operation of metabolism to slow the rate at which it causes aging, generally have a pessimistic view of the future of medicine to enhance human longevity. There is too much work, too little funding, and too few researchers. Further, the gains are modest at best, on a par with the results of practicing calorie restriction or regular exercise. This is why we need a revolution in the field of aging research, one that directs far more resources towards initiatives like SENS rejuvenation research: instead of prioritizing mapping, rather prioritize the application of what is already known about the forms of cell and tissue damage that causes aging, prioritize building the envisaged repair biotechnologies that should result in rejuvenation. Clear the damage in the metabolism we have rather than trying to build an incrementally better form of human being - it will be faster, cheaper, and more effective by far. We don't have all the time in the world to get this job done.

This is a fight that continues. Damage repair is a minority concern in aging research, despite the recent interest and funding for senescent cell clearance. The vast majority of aging research looks exactly like the example presented here, which is to say a matter of exploring genetic alterations known to modestly alter the course of aging in short-lived species. Researchers move step by step and protein by protein by following relationships and correlations. In this case the starting point is established knowledge: when gene expression of Myc is inhibited, the outcome is modestly slowed aging in mice. Further, Mtpb is known to be a regulator of Myc activity, one of the many ways in which proteins can be related to one another. Thus the researchers followed this link to carry out a study on Mtpb and aging in mice, showing that reduced levels of Mtpb also slow aging in mice.

As is usually the case when the effects of two related genes are explored, the result is only similar to the outcome for reduced levels of Myc, not the same. There are always differences: genes and proteins form large networks of cascading interactions, and this network is the machine to keep in mind, built of intricate repeated molecular interactions extending over time. Tinkering with different parts of the network will inevitably alter its operation in somewhat different ways. As you might imagine, at this pace, and at the present size of the research community, it will take a very long time indeed to make meaningful progress towards the grand map of metabolism and aging. No-one alive today should be placing any great hope of a longer healthy life achieved through life-extending medication on such work. If our lives are extended, it will come from the engineering approach exemplified by the SENS portfolio of proposed rejuvenation therapies.

Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice

Aging is a complex biological process controlled by both environmental and genetic factors; however, twin studies suggest 20-30% of lifespan variation is genetic. Altering the activity or expression of specific genes significantly impacts lifespan in animal models. For example, increased expression of the protein deacetylase Sirt1 is known to slow the effects of aging and increase lifespan. In contrast, reduced levels of the oncogenic transcription factor c-Myc (Myc), due to heterozygosity, was recently reported to significantly increase longevity in mice. Myc is estimated to transcriptionally regulate 10-15% of the genome. While Myc has been implicated in processes such as stem cell maintenance, differentiation, and apoptosis, Myc transcriptional activity is closely linked to cell-cycle progression and the vast metabolic machinery required for cellular proliferation. Notably, Myc regulates mitochondrial biogenesis, providing sufficient mitochondria to maintain increased cellular metabolism. Myc also increases overall protein synthesis, a known modulator of longevity, through regulation of genes that control ribosomal assembly.

Based on the broad control Myc exerts over cellular processes relevant to aging and the recent publication directly linking Myc to longevity, proteins that regulate Myc represent potential modulators of the aging process. We recently reported that Mtbp is a Myc transcriptional co-factor. In mice, Mtbp heterozygosity resulted in reduced Mtbp protein expression without altering Myc levels, and this inhibited Myc-mediated transcriptional activation of target genes, proliferation, and B cell lymphoma development. Knockdown of Mtbp expression delayed cell cycle progression. In contrast, elevated Mtbp expression increased the number of cells in S-phase and enhanced Myc-mediated transcription and tumor development. These data indicate Mtbp is a positive regulator of Myc transcriptional activity and downstream biological functions. Thus, we tested whether reduced Mtbp expression would alter aging in similar ways to decreased Myc expression.

Since Myc+/- (heterozygous) mice have increased longevity and we have shown that Mtbp is a positive regulator of Myc, we investigated the contribution of Mtbp to longevity using a cohort of littermate-matched Mtbp+/+ (homozygous) and Mtbp+/- (heterozygous) mice. Mtbp heterozygous mice had increased longevity compared to wild-type controls, exhibiting a median survival of 785 days compared to 654 days, a 20% increase. This significant difference in lifespan was represented in both male and female populations. Mtbp heterozygous males had a median survival of 774 days, compared to 672 days for wild-type control males, a 15.2% increase. Mtbp+/- females had a median survival of 790 days, compared to 650.5 days for Mtbp+/+ females, a 21.4% increase. In addition to median lifespan, Mtbp heterozygosity also increased maximum lifespan. Specifically, Mtbp+/- mice were overrepresented in the longest living decile and quartile of mice with 9 of 11 (81.8%) and 19 of 26 (73.1%) of the mice, respectively. In contrast, Mtbp wild-type mice were disproportionally represented in the shortest lived decile and quartile of mice 90.9% and 80.8%, respectively.

As is commonly seen in C56BL/6 mice, gross and histopathological tissue analysis at time of death of representative mice demonstrated the majority had cancer (17 of 23 Mtbp+/+ mice and 29 of 34 Mtbp+/- mice). Notably, 32.4% of Mtbp+/- mice had lymphoma, which was twice the incidence of lymphoma in Mtbp+/+ mice (17.4%). The lymphomas were detected at an average age of 840 days in heterozygotes, compared to 682.3 days in wild-type controls, a significant delay. Similarly, Mtbp+/- mice developed carcinomas later in life at 848 days (8.8%) compared to 694 days for Mtbp+/+ mice (13.0%). Although twice the proportion of Mtbp wild-type control mice were cancer free at time of death (30.4%) compared to Mtbp heterozygous mice (14.7%), the Mtbp+/- cancer-free mice lived an average of 836.4 days compared to 640.3 days for cancer-free wild-type controls. This difference in Mtbp+/- mice represents a significant delay in mortality among cancer free mice. These data collectively indicate a decrease in Mtbp expression alters the tumor spectrum and age of onset as mice age, as well as extends overall survival independent of cancer development.

Long-lived mouse models will often retain elevated motor function compared to controls, particularly as they age. To determine if Mtbp heterozygosity improved locomotor activity, open field testing was performed for 1 hour on two days with a cohort of old (1.5 year) littermate matched mice. Although there was a trend for Mtbp heterozygotes to travel a greater distance (5737.7 cm) compared to wild-type controls (4551.0 cm), this difference did not reach statistical significance. When locomotor function was actively challenged using a rota-rod endurance test, the Mtbp+/- mice (78.0 seconds) performed similarly to Mtbp+/+ mice (73.6 seconds) after training. In nature, many animal species with increased longevity have reduced reproductive capacity to limit overpopulation. This trend has been reported in some long-lived mouse models. Thus, we compared the reproductive efficiency of Mtbp+/+ and Mtbp+/- female mice. This examination did not reveal a significant difference in the average number of pups per litter birthed by Mtbp+/+ and Mtbp+/- females. Some long-lived mouse models reported to have reduced growth, resulting in smaller body size. We detected no size differences in mature Mtbp+/- mice. Given this observation, it was not surprising that analysis of serum isolated and frozen at time of sacrifice did not show a statistically significant difference in the level of circulating insulin-like growth factor-1, a major growth-promoting factor.

In addition to increased longevity and modulated cancer development, long-lived Mtbp heterozygous mice exhibited a global trend toward elevated cellular metabolism in the liver. Collectively, increased expression of metabolic markers suggests retained vitality in the livers of old Mtbp+/- mice, which coincides with the elevated expression of the well-known anti-aging gene Sirt1. Collectively, the data suggest Mtbp impacts longevity and cellular metabolism, particularly in the liver. These results are in line with a recent report on Myc as well as our previous reports indicating Mtbp is a positive regulator of Myc transcriptional activity. However, the effect of Myc heterozygosity appears broader than the effects observed for Mtbp heterozygosity. The precise reason for these differences is unclear at this time. Part of the downstream effects of Myc are mediated through direct binding to or displacement of other factors. It is unknown how Mtbp expression impacts these functions of Myc or whether these functions of Myc change as animals age. Moreover, it is possible Mtbp may only orchestrate a sub-set of Myc's overall transcriptional activity and may have Myc-independent functions. Therefore, additional research is needed on the interaction between Mtbp and Myc, and Mtbp itself, to better understand the contribution of Mtbp to aging.

An accumulation of senescent cells is one of the causes of degenerative aging. These cells secrete a mix of inflammatory and other signal molecules, producing numerous detrimental changes in surrounding tissues. As the number of senescent cells grows with advancing age, their presence causes dysfunction and pathology that contributes significantly to the progression of age-related disease. Researchers here provide evidence to suggest that, in addition to the range of harmful outcomes that are already fairly well known, the presence of senescent cells may also make viral infections worse, though the degree to which this is the case is a question mark:

Aging is suggested to be promoted by cellular senescence because senescent cells accumulate in tissues and organs with age. Replicative senescence refers to a stage which normal cells undergo growth arrest after proliferating for a limited number of population doublings. Influenza virus (IFV) and Varicella Zoster Virus (VZV) are the pathogens that cause the most common infectious diseases worldwide and the elderly populations are most vulnerable to IFV and VZV infections. The efficacy and effectiveness of influenza vaccines decrease with age, due to the negative impact of aging on the development of the immune system and its ability to function. The detailed role and mechanisms of senescence that underlie the increase in the levels of susceptibility to influenza infection have not been well elucidated.

Previous work has highlighted the age or senescence-associated decline of innate immune receptor function. For example, decreased toll-like receptor (TLR) function in dendritic cells, dysregulated signaling cascades, and decreased cytokine production have been shown to contribute to impaired innate immune responses. Similarly, age-associated defects in retinoic acid inducible gene-I (RIG-I) signaling specifically impairs interferon (IFN) signaling. In addition to gene expression changes in receptors, senescence is known to cause inflammaging, characterized by the up-regulation of the inflammatory response that occurs with advancing age. Altered secretion levels of pro-inflammatory cytokines and chemokines, such as interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), were observed in elderly mice. These aberrant cytokine responses are thought to contribute to the inability of the elderly to mount appropriate immune responses to pathogens, vaccines, and self-antigens.

Human sirtuins are composed of a family of seven nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases that removes acetyl groups from wide ranges of essential proteins. SIRT1 has a broad range of physiological and biological functions, which play an important role in controlling gene expression, metabolism and aging. At cellular level, overexpression of SIRT1 was shown to prevent replicative senescence. Recent studies identified SIRT1 as an ancient antiviral defense factor. They showed that siRNA-mediated inhibition of each of the seven sirtuins could enhance the virus plaque formation for human cytomegalovirus (HCMV) and influenza A virus. The detailed mechanisms of SIRT1-mediated antiviral activities remain to be fully determined. In the present study, we used a replication-induced senescence in vitro model to illustrate the role and the mechanisms of senescence on viral replication and host response during viral infection.

In our study, we used two different virus infection models to examine the impact of replication-induced senescence and anti-senescence gene, SIRT1, on viral replication efficiency and host innate immune signaling pathways. A significant increase in viral replication efficiency was detected by replicative senescence during IFV and VZV infection. Furthermore, we confirmed that SIRT1 is an important antiviral factor, and SIRT inhibitor treatment or knockdown of SIRT1 resulted in the enhancement of virus plaque formation. As one of possible mechanisms for the increase in viral replication in senescent cells, a reduction in interferon (IFN) response after viral infection may account for it. Although DNA damage response caused by senescence-induced cell growth arrest can lead to increased basal expression levels of IFN and IFN-associated genes, our data suggests that virus-mediated induction of IFN and IFN-associated genes are down-regulated in senescent cells. Another possibility for the enhanced viral replication associated with senescence may largely attributed to the disruption of mitochondrial dynamics in that a defect in mitochondrial dynamics in senescent cells may contribute to down-regulation of early interferon response by inactivating the fission factor dynamin-related protein 1 (DRP1) in favor of viral replication. Further studies are required to test this hypothesis.

Among senescence-associated genes, SIRT1 is the best studied and currently considered to be the most important controlling factor involved in senescence and aging. Nicotinamide (NAM) is a well-known SIRT1 inhibitor and we wanted to assess whether NAM-mediated inhibition of deacetylase activity of SIRT1 was able to modulate viral replication. As expected, SIRT1 inhibition led to increased viral plaque formation. Recent studies also indicate that human SIRT1 shows a broad range antiviral function against DNA and RNA viruses, suggesting that sirtuin-modulating drugs can be used to treat viral diseases. Thus, sirtuin-modulating drugs can have a significant impact on the potential therapeutic approach for influenza infection. Considering that SIRT1 can be induced by viral infection and potentially affect the host immune response, further studies on the in vivo role of SIRT1 in determining susceptibility to viral infection may shed light on the function of SIRT1 in the amelioration of viral infection-associated symptoms.

In conclusion, our data demonstrate that cellular replicative senescence can contribute to increased viral replication. Furthermore, we provide the evidence that replicative senescence-associated changes could affect IFN expression, but not IFN-mediated antiviral response, which could result in an increased susceptibility of senescent cells to viral infection. A better understanding of immunosenescence during viral infection will greatly improve our knowledge of the pathogenesis of IFV and VZV and provide insight for therapeutic improvements in the response to IFV and VZV infection treatment in the elderly.

Link: https://doi.org/10.4110/in.2016.16.5.286

BACE1 is involved in the production of amyloid-β, the protein aggregates implicated in the pathology of Alzheimer's disease. Levels of amyloid in the brain are actually quite dynamic, so any method that safely increases clearance or reduces creation of amyloid will likely prove beneficial. As reported here, inhibition of BACE1 seems to achieve that goal, and is making progress towards human clinical trials. That said, Alzheimer's appears to be at least as much caused by aggregation of altered tau protein as by amyloid, so it is likely that both forms of metabolic waste will need to be cleared.

Researchers have reported results of early human and animal trials of a drug called verubecestat, which targets the production of protein plaques associated with the disease. Definitive conclusions will have to await the results of larger, ongoing phase III clinical trials to assess their efficacy, effectiveness and safety, but the results are promising, experts say. Verubecestat is a so-called BACE1 inhibitor. BACE1 (for Beta-site Amyloid precursor protein Cleaving Enzyme 1, aka beta-secretase 1) is an enzyme involved in producing amyloid beta, a protein that clumps together, eventually forming the plaques surrounding neurons that are the disease's key hallmark. The amyloid hypothesis of Alzheimer's proposes that the accumulation of amyloid beta aggregates in the brain drives a cascade of biological events leading to neurodegeneration. By blocking BACE1, the hope is this approach could prevent the buildup of these clumps in the first place. But until now, development of these drugs has been hindered by problems finding molecules with the right characteristics, and concerns over theoretical and actual side effects.

Amyloid is formed when amyloid precursor protein (APP) is cleaved into pieces by BACE1 and another enzyme called gamma-secretase. APP protrudes from cell membranes into the space between cells, where the enzymes can cut it. Production of amyloid beta involves two snips. First, BACE1 cleaves it some distance from the cell (producing fragments called sAPP beta) then gamma-secretase cuts the remaining stub off at the cell membrane. The fragment released by this cut is amyloid beta. BACE1 inhibitors work by attaching to the enzyme and preventing it from cleaving APP, thereby decreasing production of amyloid. Researchers have been studying its function using mice engineered to lack the BACE1 gene, and these studies have revealed numerous consequences including problems with insulation and guidance of neural wiring, retinal pathology and neurodegeneration, raising concerns that BACE1 inhibitor drugs might have side effects. Another challenge was developing molecules big enough to attach to BACE1 but still able to cross the blood-brain barrier. Several candidate drugs have now been developed, but a recent clinical trial was halted due to evidence of liver toxicity.

Researchers developed a molecule that appears to overcome these challenges. They tested the drug on animals and found it significantly reduced levels of both amyloid and sAPP beta in the blood, cerebrospinal fluid and brain in a dose-dependent manner. There were no signs of toxicity, even after treatment of up to six months in rats and nine months in monkeys. The only obvious side effect was reduced fur pigmentation in mice and rabbits, although this wasn't seen in monkeys. The researchers then moved on to small, early-stage human trials to assess safety and tolerability and inform the choice of suitable doses for later trials. Verubecestat reduced amyloid and sAPP beta in the cerebrospinal fluid of healthy adults who took the drug for two weeks and patients with mild to moderate Alzheimer's who took it for one week. "This is the first detailed report of what a BACE inhibitor does in humans. The good news is they didn't see evidence so far of any of the side effects we're concerned about with BACE inhibition." This is probably because the doses used did not fully inhibit BACE1 activity. "It might be you only need a little bit of BACE active in the brain and body to prevent side effects." Another possibility is that some of the consequences for mice lacking BACE1 from birth are developmental effects that don't apply when the enzyme's activity is lowered in adults.

Link: https://www.scientificamerican.com/article/new-alzheimer-s-drug-clears-milestone-in-human-clinical-trial1/

Efforts to build rejuvenation therapies that work by selectively destroying senescent cells are very much in the news of late. One class of senolytic drug candidates works by inducing apoptosis, a form of programmed cell death, via reduced levels of Bcl-2 family proteins, such as Bcl-2 itself, Bcl-xL, and Bcl-W, all of which normally act to suppress apoptosis. Senescent cells are inclined towards apoptosis already, so a modest nudge in that direction can destroy a fair proportion of these unwanted cells without causing harm to healthy cells. These apoptosis-related proteins have numerous other roles as well, however, since evolution is very much in favor of reusing the tools to hand. For example, Bcl-xL is also involved in mitochondrial damage protection, the immune response, cellular respiration and DNA repair: quite the portfolio, and all items that are connected to aging in one way or another. I noted an open access paper today that muddies the water considerably on the topic of Bcl-xL, as it shows that more Bcl-xL rather than less (a) reduces incidence of cellular senescence in tissue cultures, (b) extends life in nematode worms, and (c) is found in human centenarians, but not younger individuals.

Ordinary somatic cells, the vast majority of the cells in the body, become senescent when they reach the Hayflick limit at the end of their replicative life span, or in response to damage, or a toxic local environment, or as a part of the wound healing process. Senescent cells cease dividing, and most either self-destruct or are destroyed by the immune system soon afterwards. This behavior has evolved because it suppresses cancer incidence, at least initially, by removing those cells most at risk. Unfortunately not all are destroyed, and those that linger cause harm to surrounding tissues via a potent mix of inflammatory signals known as the senescence-associated secretory phenotype (SASP). Given enough senescence cells, as few as 1% or less of all the cells in an organ, significant dysfunction and inflammation is the result, contributing to the development and progression of age-related disease. It even comes to a point at which the presence of larger numbers of senescent cells raises the risk of cancer and allows tumors to grow more readily. Getting rid of these cells has been demonstrated to improve tissue function and extend healthy life spans in mice, and we are all looking forward to forthcoming human trials of this class of rejuvenation therapy - the first of which will most likely use apoptosis-inducing drugs that work via inhibition of Bcl-2 family proteins.

Given this, how is it that increased levels of Bcl-xL can be associated with longevity and lesser degrees of cellular senescence? The authors in the paper linked below, perhaps wisely, do not speculate all that much and largely restrict themselves to reporting their findings. The lesson we must constantly learn is that biochemistry is complicated. It is a linked system of countless feedback loops, many of which share protein machinery. Nothing can be accomplished in isolation, and there is always a way for very similar interventions to result in diametrically opposed results. Once might speculate that, for example, reduced levels of Bcl-xL are only useful in conjunction with reduced levels of other Bcl-2 family members. Or that drugs like navitoclax are pushing other levers and buttons whose significance is not yet as well understood in this picture. Alternatively, consider that in the short term reduced levels of Bcl-xL could induced senescent cell destruction, and resulting health benefits, but in over the long term, and without any intervention to clear senescent cells, higher levels of Bcl-xL could aid cellular health via other mechanisms such as mitochondrial function, immune function, and DNA repair. It is plausible that better functionality for those line items might reduce the number of cells entering senescence. Or, alternatively, there is the explanation proposed by the authors of the paper involving different paths to apoptosis under different circumstances, not all of which are necessarily desirable. But this is all speculation at this stage, to be confirmed by further research. Regardless of the role of Bcl-xL in natural variations in longevity, it is certainly the case that senescent cell clearance will be a beneficial procedure. Someone who undergoes that procedure will have an incrementally longer life expectancy than someone who didn't - and the plan is to keep doing it as often as needed to keep senescent cell counts beneath the level at which they produce a meaningful contribution to aging and age-related disease.

Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging

Centenarians, for example, exhibit medical histories with remarkably low incidence rates of common age-related disorders such as vascular-related diseases, diabetes mellitus, Parkinson's disease, and cancer. Over 80% of centenarians delay their first experience of diseases often associated with high mortality till beyond the age of 90 years or escape these morbidities entirely. Moreover, centenarians may have better cognitive function and require minimal assistance for activities of daily living compared with younger elderly who exhibit normal aging. The Spanish Centenarian Study Group, founded in 2007 as a population-based research program focused on centenarians living in various areas of Spain, previously investigated molecular mechanisms by which centenarians maintain homeostasis and thereby evade age-related morbidities as evidenced by changes in their microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMCs). Our previous analysis of miRNA microarray data ("miRNome") showed that miRNA expression in centenarians (successful aging) exhibited significant overlap with that in young people but not with septuagenarians (normal aging). We thus hypothesized that expression patterns of mRNAs in centenarians versus septuagenarians and young people might provide further insights into what discriminates those with exceptional longevity from normal aging. In the present study we sought to identify expression patterns of mRNAs in centenarians as means to elucidate factors that influence why these individuals live such long, healthy lives. We have identified Bcl-xL as one of these factors that influence longevity in humans.

Analysis of the genes over-expressed in centenarians reveals relations to three genes: Bcl-xL (also known as BCL2L1), Fas and Fas ligand (FasL), all of them involved in the control of apoptosis. Moreover, using Gene Ontology we detected that apoptosis is one of the processes most commonly conserved in centenarians. Fas and FasL are mainly involved in the control of the extrinsic pathway to apoptosis, whereas Bcl-xL inhibits the intrinsic, mitochondrial pathway to apoptosis. Bcl-xL down regulates apoptosis and promotes cell survival by migrating to mitochondrial outer membrane, counteracting mitochondrial permeabilization (pore formation) activity, and inhibiting cytotoxic adaptors needed for activation of caspases that dismantle the cell. We evaluated centenarians' expression of BcL-xL and confirmed that it is indeed up-regulated compared with septuagenarians and young people. To validate the results obtained in the Spanish cohort, we measured BcL-xL expression in another well characterized centenarian population, i.e., that of the Sardinian centenarians. We found that, as in the Spanish cohort, Sardinian centenarians display a higher Bcl-xL expression than septuagenarians and maintain an expression similar to young individuals. The same pattern is shown when measuring Bcl-xL protein expression.

As stated before, BcL- xL is important in the development and maintenance of the immune system. Moreover, immunosenescence (age-related decline of immune function) has been posited responsible at least in part for the well-known increased incidence rates of infections, cancer, and autoimmune diseases that arise in elderly persons who display normal aging. We thus analyzed lymphocyte function in centenarians and showed that leukocyte chemotaxis and NK cell activity were significantly impaired in septuagenarians compared with young people whereas in centenarians these indicators of immunosenescence were similar to the picture noted in young people. Therefore, using centenarian-donated PBMCs, we observed a number of similarities between centenarians and young persons, which were not reflected in cells donated by septuagenarians, in a variety of biological factors suggestive that centenarians may evade the relentless onset of immunosenescence that is seen in normal aging.

The general picture that emerges from our series of experiments is that centenarians have an intact extrinsic pathway of apoptosis thus killing cells that may be damaged by environmental insults but down-regulated intrinsic apoptosis thus sparing cells that have not been exposed to genotoxic or other challenges. Upregulation of Bcl-xL as noted in our gene expression studies suggests that regulation of apoptosis is deranged in septuagenarians (normal aging) yet preserved in centenarians (exceptional aging). Taken together, our results demonstrate that, similar to what we found in microRNA expression, septuagenarians (normal aging) display a cell health impairment which is not so evident in young people or centenarians (exceptional aging). Moreover, they suggest that Bcl-xL may play a major role in healthy aging.

To assess if increased activity of Bcl-xL promotes longevity in vivo we turned to the simple model organism C. elegans. This nematode has several advantages for aging studies: it has a short life span of around twenty days, it shares the main hallmarks of human aging and around 70% of the human genome has a C. elegans ortholog, including the apoptotic pathway that was originally described in this organism. ced-9 is the only C. elegans member of the Bcl2 anti-apoptotic family and thus the ortholog of human Bcl-xL, showing 44% homology and the same protein domains. Among the multiple available ced-9 alleles, ced-9(n1950) is a missense G to A substitution that confers constitutive activity to the CED-9 protein. We hypothesized that this mutation could mimic the increased Bcl-xL levels of centenarians and thus we performed longevity curves of ced-9(n1950) compared to wildtype worms. Interestingly, ced-9(n1950) animals showed a significant increase both in the mean and maximum survival time. Moreover, at 25 days, which can be considered a very advanced age for a worm, the percentage of ced-9(n1050) survivals was more than double compared to wildtype.

Heat shock proteins are involved in the cellular response to stresses, including heat, hence the name. They assist in protein quality control and correct function, one important part of the larger panoply of cellular maintenance activities. Here, researchers find that the heat shock protein Hsp60 also influences the role that the immune system plays in wound healing, and can be used to spur greater regeneration:

Researchers have identified a novel role for a gene known as heat shock protein 60 (Hsp60), finding that it is critical in tissue regeneration and wound healing. The study found that topical treatment of an Hsp60-containing gel dramatically accelerates wound closure in a diabetic mouse model. The study also describes the mechanism by which this works, finding that Hsp60 protein is released at the site of injury, signaling wound healing to initiate. The findings may help in the development of effective therapeutics for accelerating wound closure in diabetic patients, as well as for normal wound healing and scar reduction. "This study proposes an unusual role for a well-known gene. This gene is found in every organism from bacteria to man. We have shown that in vertebrates, it has a surprising role in immunity that is essential for wound healing."

Protein products of the Hsp60 gene are known primarily for their role in ensuring that other proteins are folded correctly. The Hsp60 protein has also been reported to serve as a signaling molecule that induces an inflammatory response to bacterial infection from a cut. Based on previous findings that the Hsp60 protein was necessary for an inflammatory response, the researchers hypothesized that the molecule might also be involved in an organisms' ability to regenerate. Using zebrafish - an ideal model for this work because fish can regenerate many tissues, including fins - the researchers used targeted mutagenesis, making specific and intentional changes to the DNA sequence of a gene, to "knock out" Hsp60 from the genome. The mutant fish appeared to develop normally, but when the researchers wounded them by injuring the cells involved in hearing or amputating a caudal fin, the fish were unable to regenerate their cells and fins, respectively. Using fluorescently tagged leukocytes (immune cells that flock to the site of injury as part of the inflammatory response under normal conditions), the researchers demonstrated that without the Hsp60 gene, there were significantly reduced numbers of leukocytes at the injury site. This suggested that the Hsp60 protein was somehow acting as an attractant that promoted inflammation, a necessary component of wound healing. "When we injected Hsp60 directly to the site of injury, the tissue surrounding the wound started to regenerate faster. That's when we got really excited."

However, the most striking finding from the study was that actually applying a topical treatment of the Hsp60 protein to a puncture wound in diabetic mice stimulated complete healing after only 21 days. Mice without the treatment did not show improvement over the same time frame. Although promising, this finding has only been shown in mice and is yet to be tested in humans. "We hope that topical treatment with Hsp60 will act the same way in humans. And we believe it will, but more work is needed. We also want to know if it will help any wound heal, not just wounds encountered by people with diabetes. Will it reduce scarring and increase the speed of healing?"

Link: https://www.nih.gov/news-events/news-releases/nih-researchers-unveil-new-wound-healing-role-protein-folding-gene-mice

KrioRus is a Russian cryonics provider, and only the third such organization in the world after Alcor and the Cryonics Institute in the US. A number of other groups have for some years been inching towards launch, in Canada, Australia, and Switzerland, and there are numerous for-profit and non-profit companies involved in providing services to the cryonics industry, but the folk at KrioRus are to be commended for managing to make the leap. As is the case in the US, the Russian cryonics community has a large overlap with transhumanist and longevity science organizations, such as the Science for Life Extension Foundation. Cryonics is in essence the backup plan for those who will age to death prior to the advent of working rejuvenation therapies, and is the only other approach to offer any chance at a much longer life in the future.

The only obvious sign this is the office of a cryonics company sits on the windowsill: a stainless-steel vacuum vessel about the size of a lobster pot. It's meant to transport a human brain, and if used for its true purpose and not as a decoration, it would deliver that brain to a larger storage container filled with liquid nitrogen. The brain would be preserved there - the liquid nitrogen topped off once in a while - for however long the science and technology community takes to solve some vexing problems. First, how to repair the tissue damage caused by freezing. Second, and more important, how to gain access to the data inside - the neurons and connections and impulses that constitute a person's memories, emotions, and personality - and bring it all back to life, either in another, healthier body or uploaded into a computer. Otherwise, the office looks like a small apartment, and it is also that. It's the pied-a-terre of Danila Medvedev and Valerija Pride, life partners and co-founders of Moscow-based KrioRus, as well as a crash pad for eager young transhumanists who need a place to stay while working on projects intended to expedite the quest for immortality.

They're discussing the fate of a brain in Spain - the brain of a man described by Medvedev as "Spain's leading cryonicist," who's just died. Despite running a Spanish-language site dedicated to cryonics, the man had no plans in place to actually be frozen upon his death. His wife has managed to get his body put on ice, and now Medvedev and Pride are trying to figure out how to have his brain removed and stored in a way that will allow it to be transferred into KrioRus's care. These are the kinds of logistical challenges Medvedev is trying to iron out as he and Pride work to make KrioRus the leading cryonics company for Europe and Asia. The best way to cryopreserve is to replace all the water in the body with a chemical that essentially turns the tissue into glass as it freezes. Vitrification, as the process is known, prevents the damage caused by ice crystals when a body is frozen in its natural state. But vitrification has its own flaw: No one knows how to reverse it. Medvedev describes this as a minor challenge. The important thing, he says, quoting American nanotechnologist Ralph Merkle, is that "information is not destroyed" by freezing. They'll work it out later.

"Of course, the goal is to have the perfect preservation, but it depends on the situation," Medvedev says. "You can have the best technology in the world, but if it's not available in Barcelona it doesn't help you much." And any preservation, cryonicists say, is better than none. Truly, it's all just a best guess. Cryonics was first proposed by the physicist Robert Ettinger in his 1964 book, The Prospect of Immortality. Five years later, the first human was frozen, and a small, devoted community of cryonicists (almost all of them in America) have been debating best practices ever since. Today, the world leader is Alcor Life Extension Foundation, started in 1972 and based in Scottsdale, Ariz. Alcor has 148 patients stashed in tanks filled with liquid nitrogen. Then there's the Cryonics Institute, established in 1976. It has 114 patients in storage in a suburb of Detroit and is known for being cheaper than Alcor and for having a strong preference for freezing heads over full bodies.

Unlike its American rivals, KrioRus doesn't use stainless steel for its dewars. Instead, it uses a fiberglass and resin composite made by a company that builds racing yachts from the same material. The dewars stand inside a 2,000-square-foot hangar, but they don't really need to. "The walls of the building are actually weaker than the walls of the dewars," Medvedev says. "People tend to think that patients should be stored in buildings. There are few technical reasons behind it, just tradition and irrationality." "First you need everything functional," adds Dmitry Kvasnikov, who's been listening quietly. "Then once it is functional, you can make it look pretty." The company has big plans. It will soon move to a permanent home at an agricultural college outside Tver, a few hours west of Moscow. And KrioRus's principals and clients all make clear that the cryonics operation is merely the opening salvo of a far larger campaign, the quest for immortality. Medvedev and Pride are also co-directors of the Russian Transhumanist Movement (RTM), an activist organization and incubator for ideas to advance the cause of extending the human life span until we've achieved immortality. Generally speaking, transhumanists believe that technology is advancing at an exponential rate and that sometime in the future, death will be overcome. They like to speak of aging as a disease that can be cured, and depending on the transhumanist you're speaking with, she probably believes either that new bodies will be engineered and hooked up to our heads or that our minds and memories will live forever inside a machine. In either case, all you need is your brain, which is why most transhumanists, Medvedev and Pride included, think it's unnecessary to freeze your entire body.

KrioRus was born out of their enthusiasm for the transhumanist cause. Cryonics is the starting point. "It is Plan B," Medvedev admits. No one wants to be frozen. But dying is worse. As Mikhail Batin, an entrepreneur, transhumanist, and KrioRus client says: "It's the only alternative we have at the moment to death. It is definitely better to be frozen than buried or burned. Cryonics is the best action in the worst circumstances."

Link: https://www.bloomberg.com/features/2016-decapitate-and-chill/

My attention was recently drawn to Bioquark, where the principals are clearly interested in tackling regeneration and aging. The founders and scientific staff originate from the clinical stem cell medicine and medical tourism end of the spectrum, and appear to be approaching their goals via a programmed aging framework, the view of aging as a genetic program that can in principle be reversed by providing suitable signals to cells and the cellular environment. This stands in opposition to the more mainstream view of aging as an accumulation of cell and tissue damage, as expressed in the SENS rejuvenation research view, for example, but also by most researchers, even those who disagree with SENS. The various SENS damage repair companies, such as those working on senescent cell clearance, represent efforts to step beyond the present medical paradigm of merely patching over symptoms of aging, to produce large effects by repairing the damage that causes aging, taking the view of aging as damage to its logical conclusion. Bioquark might be seen an an analogous attempted leap forward for the programmed aging view, taking the very same critique of the present medical paradigm, and seeking large gains by adjusting the cellular environment to incorporate a more regenerative, youthful set of signals - taking the programmed view of aging to its logical conclusion.

To be clear, personally I'm solidly in the aging as damage camp, and I think that efforts like Bioquark are doomed to, at best, produce marginal success since their high level strategy is based on an incorrect view of aging. In particular, I think that any view that sees reversal of aging via cell signaling alone as a possibility for humans is badly misguided: it ignores, for example, the evidence for forms of harmful metabolic waste such as persistent cross-links that our biology cannot clear through its normal operation, even when youthful. The folk at Bioquark might nonetheless turn out to have found a decent path towards recapturing some of the known effects of stem cell transplantation via the use of cell signal molecules only; we shall see. Either way, the sooner we get to the point at which rejuvenation through damage repair after the SENS model is conclusively demonstrated to work well, and rejuvenation by adjusting cell behavior after the programmed aging model is conclusively demonstrated to work poorly, the better off we all are. The present medical paradigm of patching over symptoms without addressing causes should be cast into the waste basket of history. High profile failure has an important and necessary role to play in the near future of medical research, now that things are moving rapidly and biotechnology is cheap. Proving specific theories of aging right and wrong by building interventions that either work or do not work is an important activity.

One of the reasons I found the high level philosophy of action at Bioquark to be interesting is that it is one of the first new companies I've seen to start down the path of explicitly rejecting the cell therapy and transplantation side of regenerative medicine in favor of aiming towards in situ regeneration. It is my view that stem cell therapies in the current model, as well as a fair amount of tissue engineering for transplantation, will be replaced at some point in time by sophisticated ways to reprogram and direct existing patient cells in situ. It is an exercise in futurism and speculative economics to predict just how this will pan out over the decades ahead, but there is a fair amount of preliminary work along those lines taking place in the laboratory even now. Will we see 50 years of increasingly effective tissue engineering and transplantation, coupled to ever-better cell therapies and cell source production lines, or will those fields fade by the early 2030s in the face of surprisingly effective ways to make existing patient cells perform extensive regrowth and healing? Very hard to say at this point.

Who wants to live forever?

So, what's novel about Bioquark?

Bioquark is an innovative life sciences company focused on the development of novel products focused on complex organ regeneration, disease reversion, and age reversal in humans. Today, if a person loses their leg, it's forever. However, some animals can replace lost or damaged organs and tissues. Many of the species that can do this regrowth trick also have the ability to repair and reverse disease-causing cellular and genetic damage. We focused on the three "Rs": regeneration, reversion, and rejuvenation. What we ultimately discovered was that these were connected by an underlying capability in such organisms to turn back biological time in targeted tissues, and start the development process over again. In essence, we found that disease, degeneration, and aging were all intimately connected by this single underlying biological regulation process. This realisation led us to develop an integrated platform, which could eventually help humans to reawaken and mimic these abilities for purposes of health, wellness and longevity. This is a platform which the company believes can change the paradigm, and the way we think about healthcare and disease.

How does this area of regenerative medicine compare to what currently goes on in the pharmaceutical industry in regard to traditional drug development?

This is a very different approach. The current model is based primarily on treating disease, while regenerative medicine offers the promise of actual cures for these ailments. For the last century, the pharmaceutical industry has attempted to reduce and study human health and disease at the level of their most basic components - proteins, genes, cells, etc. They're continually looking for new drug targets, so that they can interfere in some fashion with specific biological processes. This approach has allowed the pharmaceutical industry to grow in size to around $1 trillion in annual sales. However, with exceptions such as antibiotics, we still have very few real cures for disease. Most drugs are developed without regard for, or knowledge of, any of the biological factors that precede these abnormalities. In short, the current healthcare model usually ignores the actual causes of disease. Additionally, this reductionist approach used to identify therapeutic targets continues to ignore the fact disease is not usually a result of an abnormality in a single gene product. Instead, it is an emergent state - involving multiple biological processes that interact in complex ways. Regenerative medicine offers to completely change the status quo, by finally allowing us to alter the underlying causes of disease. This gives us the hope of developing actual cures.

How does aging and longevity relate to regeneration?

Aging and longevity, like all of the chronic diseases mentioned above, are purely a function of your cell's regulatory states. If that regulatory state can be altered from point B back to point A, a human can technically become biologically younger. Some animals can do this already. This is how several species of jellyfish accomplish real time, whole body "age reversal". This is the ultimate path humans will follow, in order to achieve the same results.

How widely accepted are the claims you're making?

Actually, quite widely. The concept of using combinations of biologic materials derived from eggs (ooplasms) for age reversal has its beginning in the original cloning experiments of the 1950s. The study of regenerative biology, and dynamics such as tumour reversion, began prior to that - in the 1940s. Hence, we are just revisiting and recombining an old body of knowledge for a new and beneficial purpose.

Bioquark: Therapeutic Programs

Our lead candidate BQ-A, directly alters the regulatory state of diseased, damaged, or aged tissues, creating micro-environments that provide for both efficient regeneration and repair. BQ-A is a novel combinatorial biologic that mimics the regulatory biochemistry of the living human egg (oocyte) immediately following fertilization. During this period, oocytes perform an unparalleled set of tasks including: resetting cell age, reprogramming DNA to eliminate genetic and epigenetic damage, remodeling of organelles, and protection of the embryo from inflammatory, oxidative, and infectious damage. All of this is done in synergy to initiate the embryo's developmental genetic program, and start it on its complex, stepwise path through organogenesis and morphogenesis. In developing BQ-A, Bioquark has found a novel way to standardize this unique combinatorial biochemistry, in the form of a biologic, and apply it for the induction of tissue specific micro-environments that lead to effective regeneration and repair.

BQ-A has been tested in animal models and has been administered by several methods including subcutaneously, intraperitoneally, intratumorally, and topically. These studies have served to highlight broad potential across a range of tissues and administration methods, as well as to validate the universal nature of its tissue remodeling concept. ... Conducted chronic administration in both mice and fruit flies (Drosophila melanogaster) - Experimental mice lived 1.7 times longer than animals in control group and experimental Drosophila melanogaster flies lived 2.2 times longer than control group.

It is true that early human embryonic development involves a lot of very interesting processes. Rejuvenation of cellular features of aging certainly happens at that stage - babies are, after all, born young. It is one of their defining characteristics. The big question is the degree to which that sort of process is in any way safe to deploy in adult tissues, or how to make it safe, or at least to explore it further with these questions in mind. So it is good that some people are thinking along those lines and feel themselves sufficiently far along to be launching a company.

That said, the scientific materials they provide fail to cover and support all of their claims. To pick on one thing that jumped out at me, the figures given for life span effects only make sense if they are using accelerated aging models, for example. Those numbers would be big news if true in normal mice, since that is around the record for mouse life extension, achieved through forms of growth hormone signaling suppression. A doubled lifespan is still pretty unusual and interesting in flies, as few interventions achieve that in normally aging individuals. But in accelerated aging models, this size of effect can be entirely expected if using a therapy that in some way rescues the biological damage in the model that produces pathology and a shorter life span - and that may or may not have anything useful to say about aging and longevity in normal individuals. It depends strongly on the details. Unfortunately, the available materials don't clarify these life span claims. So on the whole I'd be inclined to wait and see on this company; the people seem legitimate, but I'd want to see trials and peer reviewed studies beyond the couple they have on their site to cover the various claims they are making.

Cellular senescence is an evolutionary adaptation of a mechanism of embryonic development that serves to to suppress cancer incidence. Cells that become senescent in response to damage or a toxic environment cease to divide, and usually go on to self-destruct or be destroyed by the immune system, which serves to remove from the picture those cells most at risk of becoming cancerous. Unfortunately, that isn't all they do, and not all are destroyed. Some fraction of senescent cells linger and accumulate to cause widespread harm in the body, despite their small numbers, through the secretion of various signal molecules. These signals produce chronic inflammation, damage the fine structure of tissue by remodeling the extracellular matrix, and alter the behavior of surrounding cells for the worse. They are one of the root causes of aging and age-related disease. While the primary, and I think most effective, approach to dealing with senescent cells as a cause of aging is to destroy them, a sizable contingent of researchers are more interested in finding ways to alter the behavior of these cells. This includes cancer researchers who would like to see more cellular senescence rather than less as a way to combat cancers. These researchers believe that by modulating senescent signaling, senescent cells can in principle be rendered largely harmless. This, however, is a long road in comparison to simply destroying the unwanted cells. Senescent cell signaling is by no means fully mapped or understood, and considerable effort to damp one type of signal would still leave all of the rest. Meanwhile, senescent cell destruction is forging ahead to towards clinical translation quite rapidly.

Cellular senescence is a state in which normal healthy cells do not have the ability to divide. Senescence can occur when cancer-causing genes are activated in normal cells or when chemotherapy is used on cancer cells. Thus, senescence induces a mechanism that halts the growth of rapidly dividing cells. Once thought to only be beneficial to halt cancer progression, work has shown that during senescence there is an increase in secreted factors called cytokines and chemokines (small proteins important in immune responses) that may have detrimental, pro-tumorigenic side effects. Researchers have identified a protein that plays a critical role in the expression of cytokines and chemokines, and that decreasing this protein suppresses the expression of these secreted factors. This suggests that there may be ways of promoting the positive effects of senescence while suppressing its negative effects.

The researchers focused on chromatin, a cellular structure responsible for holding the DNA in our cells together. During senescence, some of the chromatin is reorganized into senescence-associated heterochromatin foci (SAHF). When this happens, genes that are responsible for promoting proliferation are silenced. However, the expression of cytokine and chemokine genes - known collectively as the senescence-associated secretory phenotype (SASP) - is increased. "When senescence happens, you have two closely linked phenomena occurring, yet one of these helps to halt tumor progression while the other causes an increase in potentially harmful inflammatory cytokines and chemokines. We pinpointed the architecture of chromatin and the proteins that influence chromatin organization as the proper place to start to try and solve this paradox."

The scientists looked at a set of proteins known as high mobility group proteins, which are responsible for altering chromatin architecture in order to regulate gene transcription. One such protein called high mobility group box 2 (HMGB2) binds to DNA to increase chromatin's accessibility to transcription factors. They showed that HMGB2 promotes SASP gene expression by preventing the spreading of heterochromatin and therefore preventing SAHF from silencing SASP genes. When the researchers silenced HMGB2, SASP genes were successfully silenced by SAHF, suggesting that the detrimental effects of senescence might be negated by inhibiting HMGB2. "Understanding senescence is critical for understanding how tumor growth can be successfully suppressed. With the information from this study, we may be able to increase the effectiveness of chemotherapeutic agents that are able to induce senescence by silencing HMGB2 and decreasing the expression of unwanted secreted factors."

Link: https://www.wistar.org/news-and-media/press-releases/key-protein-implicated-negative-side-effects-senescence

Aging is nothing more than a medical condition, and one that should be treated. There is a considerable amount of residual inertia on this topic, however, many people yet to be convinced that aging is anything other than set in stone, or that it is desirable to prevent the suffering and death caused by aging. At the large scale and over the long term, funding for medical research and pace of progress is determined by public support for the goals of that research. This is why we need advocacy, fundraising, and continued public discussion on the plausibility and desirability of building therapies capable of treating the causes of aging.

The concept of aging is undergoing a rapid transformation in medicine. The question has long been asked: Is aging a natural process that should be accepted as inevitable, or is it pathologic, a disease that should be prevented and treated? For the vast majority of medicine's history, the former position was considered a self-evident truth. So futile was any attempt to resist the ravages of aging that the matter was relegated to works of fantasy and fiction. But today, the biomedical community is rethinking its answer to this question. The controversy has been fanned, to a great extent, by one Aubrey de Grey, a Cambridge University-trained computer scientist and a self-taught biologist and gerontologist. Over the past decade, de Grey has undertaken an energetic campaign to reframe aging as a pathologic process, one that merits the same level of attention as, say, cancer or diabetes. Although many of de Grey's claims remain controversial - notably, that the first person who will live to 1,000 years old is already among us - I agree that we can and should pathologize aging. In fact, it seems we already have.

The human body comprises a number of different systems that each develop at its own pace. The nervous system seems to reach full maturity in our 20s, for instance, while the skeletal system may peak a decade later. Of course, this physiologic natural history is subject to environmental influence. Nevertheless, these environmental factors ultimately act on a foundation that, beyond a certain age, is inexorably deteriorating. There is a finite limit beyond which environmental factors cannot save us. The changes of aging vary in their specifics from one system to another, but common mechanisms are at work. For instance, wear-and-tear of joints results from depletion of articular cartilage, just as the thinning of skin is due to a loss of elastic connective tissue. Other age-related changes arise from errors in cellular activity or the accumulation of metabolic by-products, the probabilities of which rise over time. As these natural changes proceed, they lead to readily recognizable disease. The accumulation of fat in blood vessel walls provides a particularly good demonstration of this. Lipids are an essential part of our diet, but as processed lipids continue to accumulate in vessel walls, these vessels harden and narrow, eventually failing to supply the heart with enough blood. If the narrowing blocks vessels entirely, the heart is starved of blood, causing heart muscle death, or heart attack. This simplified example illustrates that perfectly normal processes that are critical to survival will quite naturally lead to disease. In a biological sense, the mere passage of time is pathological. Importantly, most of the early changes in this progression, such as high cholesterol, are symptomless. Yet they are precursors to life-threatening illness and are therefore considered pathologic entities in their own right, to be prevented and treated. The same can be argued of the more subtle and gradual damages of aging.

We can and should view these diseases, whose prevention and treatment are standard medical practice, as the clinical manifestations of natural age-related changes. Doctors have long targeted such changes to prevent disease. For instance, by recommending their patients limit the fat and carbohydrate content of their diets or take statin medications, doctors have strived to stave off heart disease. In so doing they unknowingly have been battling aging itself. Yet there are those who find this view of aging contentious, a reaction that likely stems from the misperception that the terms "natural" and "pathologic" are conflicting. There's a common yet unwarranted sense that these two terms are mutually exclusive; that what is natural can only be right, and what is pathologic cannot be natural. This is untrue. Because "natural" typically describes what conforms to the usual course of events, and "pathologic" describes what is harmful, the question posed in the opening paragraph presents a false dichotomy. Both "natural" and "pathologic" describe aging fairly. Thus, the controversy is largely semantic. If I were to replace the call for a "fight against aging" with an invitation to "combat age-related changes," I would expect a far more positive response. A call to "prevent the early stages of disease" would surely receive virtually unanimous support. I contend that the three phrasings are synonymous.

Link: http://www.the-scientist.com/?articles.view/articleNo/47264/title/Aging--Just-Another-Disease/

The year-end fundraiser in support of the SENS Research Foundation kicks off today - and all donations are matched dollar for dollar. Funds raised will, as always, go towards speeding up and unblocking currently languishing fields of research that are necessary for the production of effective, working rejuvenation therapies in the years ahead. The SENS Research Foundation has a proven track record on this front, and for years now has used the philanthropic donations provided by our community to generate meaningful progress in research like mitochondrial repair, clearance of senescent cells, clearance of cross-links that stiffen tissues, building the basis for a universal cancer therapy, and much more. More than just funding research directly, the SENS Research Foundation has also brought new attention and new sources of funding to formerly stuck and slow moving fields of research, and is working to assemble the biotechnology industry needed to move research from lab to clinic. This is working: areas like senescent cell clearance that ten years ago were going nowhere are now heading towards clinical therapies by leaps and bounds.

There is much more to be done yet, however! When the wheel is finally starting to turn, that is no time to slacken in our support. This is why Josh Triplett and Fight Aging! have put up a $24,000 matching fund, and will match the next year of donations for anyone that signs up as a SENS Patron. Head over the SENS Research Foundation site, take a look at their new home page presentation that shows off the high points of this past year of achievements, and pledge a recurring monthly donation. Every dollar you give that way over the next year, we'll match. This support makes a real difference, but don't take our word for it. David Spiegel is a noted researcher who runs the Spiegel Research Group at Yale University and works on finding ways to safely remove glucosepane cross-linking, one of the forms of tissue damage that causes aging. In his view, funding from the SENS Research Foundation has been instrumental to the creation of important progress in this field:

The SENS Research Foundation funding has been critical to our work studying and developing methods to reverse the effects of advanced glycation end-products (AGEs) in aging. AGEs are non-enzymatic modifications that build up on proteins as people age, leading to inflammation and tissue damage. Early on, our lab focused significant effort on developing the first total synthesis of glucosepane - a major AGE cross-link found in human tissues - but we were unable to find funding from any of the traditional sources. The SENS Research Foundation came to our aid, and supported this research for over 5 years. In 2015, our glucosepane synthesis efforts were published in Science, and lay a foundation for developing drugs capable of detecting and reversing tissue damage in aging. We are deeply grateful to the SENS Research Foundation and Fight Aging! for all of their support and look forward to exciting, life-extending work to come!

If becoming a SENS Patron for the long term isn't for you, then you can still make a year-end charitable donation to support this research and have it matched, as the Forever Healthy Foundation has put up a $150,000 matching fund for donations made between now and the end of the year. You might recall that this is Michael Greve's venture, and earlier this year he pledged $10 million to SENS rejuvenation research, half to advance the research, and half to support the startup companies that will be needed to take these therapies to the marketplace. It is more or less our duty as a community to ensure that this matching fund is met, as thanks for his generous support of these vitally important scientific projects. We will all live that much better and that much longer in the future as a result. From the latest SENS Research Foundation newsletter:

SENS Research Foundation's year end fundraising goal this year is $150,000. Every dollar that you contribute will be matched by the generous grant we have received from the Forever Healthy Foundation. So every dollar you give will be turned into $2 with the Forever Healthy Foundation's support. Please help us reach our $150,000 goal (which could turn into $300,000 thanks to the matching grant!) by donating generously today! Remember, your support is crucial to our continued fight against age-related disease.

Finally, please help spread the word. Mention the work of the SENS Research Foundation in your circles. Talk to your friends. A movement is made up of many small efforts, one person talking to another. That is how the tipping point of support is reached, how bootstrapping towards large-scale support for the development of rejuvenation therapies works. By all means make use of these simple fundraising posters as well. As they say, aging is a medical condition, and it is well past time to treat it like one.

2016 SENS Patron Fundraiser #1: 4200 x 2800px and 600 x 400px

2016 SENS Patron Fundraiser #2: 4200 x 2800px and 600 x 400px

The heart is one of the least regenerative organs in mammals, and the scientific community has for some time put in considerable effort to search for viable strategies to overcome this limitation. While much of the focus of this research is on cell therapies, such as the use of stem cell transplants, there are other possible approaches. The researchers here uncover an interesting possibility involving decreased oxygen intake, or hypoxia. It is known that mild hypoxia induces many of the same beneficial responses, such as increased cellular repair and maintenance, as are produced by calorie restriction. That seems to be enough to generate a greater regenerative response in heart tissue as well:

The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the devastating impact of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both these scenarios, cardiomyocyte renewal occurs through proliferation of pre-existing cardiomyocytes, and is regulated by aerobic respiration-mediated oxidative DNA damage. Therefore, we reasoned that systemic hypoxemia inhibits aerobic respiration and alleviates oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals.

Here we report that gradual exposure to severe systemic hypoxemia, where inspired oxygen is gradually decreased by 1% and maintained at 7% for two weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species (ROS) production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Intriguingly, we found that exposure to hypoxemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Finally, genetic fate mapping confirmed that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.

Link: http://dx.doi.org/10.1038/nature20173

Cancer is a numbers game: there is some risk per unit time of cells acquiring the necessary mutations, coupled to some risk of the immune system failing to destroy those cells before they get going in earnest. Cancer is predominantly an age-related condition because the number of mutations rises with age, the cellular environment becomes progressively more inflammatory and conducive to cancer growth, and the immune system declines in effectiveness. But if cancer is a numbers game by count of cells, why do mammals with a very large total number of cells, such as elephants and whales, have a low rate of cancer incidence? Obviously whales could not have evolved to in fact have hundreds of times the cancer incidence of humans to match the hundreds of times as many cells in their bodies. What are the mechanisms in these larger species that reduce the cancer risk per cell? Researchers are interested in this aspect of comparative biology from the perspective of determining a potential basis for new cancer prevention strategies. Here, the authors of this commentary review the evidence for low cancer risk per cell in elephants to result from extra copies of the TP53 gene:

Cancer is a genetic disease in which cells divide uncontrollably. Some of the mutations that cause cancer are inherited, but most are the results of mistakes made when DNA is copied during cell division. By the time a person reaches adulthood, their DNA will have been copied about 30 trillion times, and each of these events could result in a cancer-causing mutation. Since large, long-lived organisms experience more cell divisions than small, short-lived ones, they have a greater chance of accumulating cancer-causing mutations. Indeed, models suggest that if elephants and whales had the same risk of cancer per cell division as humans they could not exist. Instead, they would all die of cancer at a young age. Clearly elephants and whales do exist, and neither of them have unusually high rates of cancer. This puzzle is referred to as Peto's Paradox, and it hints that large-bodied animals must have mechanisms to compensate for experiencing so many cell divisions. Recently, two groups of researchers set out to discover how elephants evolved to prevent or suppress cancer, and both arrived at a single gene - TP53.

In humans, the TP53 gene protects against cancer, and mutations that prevent the gene from working are behind many cancers in adults. Last year, researchers reported a number of interesting results on TP53 genes in elephants. First they confirmed that an elephant's cancer risk is about 2-5 times lower than a human's; they then went on to show that elephants actually have 20 copies of TP53. They also noted that while one of the elephant's TP53 genes was comparable to those in other mammals, the other 19 were slightly different. Most genes contain a mix of protein coding sections (which are called exons) and non-coding sections (called introns). Typically, introns are removed after a gene has been transcribed into messenger RNA but before it is translated into a protein. However, all but one of the TP53 genes in elephants lacked true introns. This indicates that the 19 extra TP53 genes likely originated when an edited RNA molecule, which had had its introns removed, was converted back to DNA. Genes with this kind of history are known as "retrogenes". One way that the TP53 gene protects against cancer is by causing cells with damaged DNA (which is likely to contain cancer-causing mutations) to commit suicide, via a process known as apoptosis. The researchers exposed elephant cells to ionizing radiation (which causes DNA damage) and found that they were twice as likely to undergo apoptosis as cells from healthy humans. However, based on this pair-wise comparison, it was not clear whether the elephant cells are more prone to apoptosis, or if human cells are relatively insensitive to DNA damage.

Now another team report answers to many of the remaining open questions about TP53 in elephants. First they searched 61 genomes of animals ranging from aardvarks to whales for TP53 genes and retrogenes. Some of these animals - such as manatees and the rock hyrax - had only a few TP53 retrogenes, whereas others had multiple copies of TP53 retrogenes. By mapping the data onto a phylogenetic tree, the researchers showed that the number of TP53 genes had increased as body size increased in the lineage that led to elephants. They confirmed that some of the TP53 retrogenes are transcribed and translated in elephant tissue, and that these transcripts give rise to multiple forms of the proteins. Also, elephant cells up-regulated TP53 signaling and induced apoptosis in response to lower levels of DNA damage (from drugs and radiation) than cells from other mammals. This indicates that elephant cells are especially sensitive to DNA damage and more prone to apoptosis. Next, the researchers showed that elephant cells need the retrogenes for their enhanced apoptosis response. Finally, adding the same retrogenes to mouse cells made these cells more sensitive to DNA damage too. Cell division despite DNA damage is a hallmark of cancer, and so the researchers concluded that elephants had likely solved Peto's Paradox (at least in part) by enhancing TP53 signaling, a feat that they achieved by duplicating the TP53 gene.

Link: http://dx.doi.org/10.7554/eLife.21864