Fight Aging!

Not so long ago, the standard rhetoric on treating aging from the research establishment was silence. Talking in public about research indicating that aging could in principle be treated to extend healthy life was strongly discouraged, and was in fact a great way to harm your ability to raise funding and build a career in the field. That state of affairs continued for far too long, and held back progress as a result. Over the past fifteen years advocates within and outside the research community have brought about real change, however, and now many researchers talk about the prospects for slowing or reversing degenerative aging with no fear of repercussion. Indeed, anyone with a sense for these things should be able to see that the application of aging and longevity research is about to blossom into a massive, productive, and very energetic field of medicine: names will be made, and great deeds done.

At this stage in the process, things have advanced to the point at which we see bold statements of principle from researchers previously silent, but which are coupled to unambitious plans of action for the next few decades that are almost certainly doomed to produce marginal outcomes at best. The inertia of the research and development methodology that dominated the past fifty years guides researchers into drug development, aiming to alter the operation of metabolism in the late stages of aging, targeting processes that are very far removed from the actual causes of aging. You can't fix a worn engine by changing the oil, and you can't repair an age-damaged human by altering metabolism so as to slow down ongoing aging.

In some areas this doesn't matter because - fortunately - there are few steps between cause and end result, and the cause itself is something that can in principle be addressed via the drug development approach, or at least where the drugs are designed compounds with very precise modes of operation. Think of age-related macular degeneration caused by a buildup of metabolic waste compounds in retinal cells. Some mainstream researchers do end up working on the direct and most useful ways to break down those compounds rather than on some much more fanciful and much less helpful scheme of altering the metabolism of retinal cells to be more resistant to a later consequence of the damage process. In this case there are few steps between aggregation of waste and dysfunction, so less room for researchers to spend a lot of time and effort on investigating later stages in the condition. It still happens, but nowhere near as much as elsewhere in the aging process.

In most other relevant areas of medical research, however, attempts at building useful implementations of aging research are not yet moving in the right direction. So while we stand at a point at which earnest development could be underway on all aspects of rejuvenation biotechnology, the basis for treatments that can repair the damage that causes aging and thus restore health to the old, and prevent the development of age-related disease, for the most part the new rhetoric emerging from the research community steps over these opportunities. Plans for realizing rejuvenation treatments exist, but much of the research community remains bound to the old incremental roadmap of drugs and metabolic manipulation to attempt to produce marginal gain in the late stages of disease: that is what they know, where they can obtain grants, and where the gatekeepers and not going to challenge you just because you are doing something different. All inertia, and very slow to change.

So researchers these days are willing to set out bold goals to include the defeat of aging and elimination of age-related disease and decline, in principle at least, but at the detail level fall back to anemic plans that cannot possibly produce meaningful results any time soon:

Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity

Most nations of the world are undergoing rapid and dramatic population aging, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population aging has been "compression of morbidity" and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological aging research, "Geroscience", is focused on healthspan extension. Superimposed on this background are new attitudes and demand for "optimal longevity" - living long, but with good health and quality of life.

A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with aging, which causes functional limitations (e.g., reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan center on slowing the fundamental biological processes of aging such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global aging. Effective strategies should delay, reduce or abolish reductions in function with aging (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention).

Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel "nutraceutical" compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with aging, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioral approaches for enhancing adherence to healthy aging practices in diverse populations, and ongoing analysis of the socio-economic costs and benefits of healthspan extension will be important supporting goals.

At least the principles are aimed high: getting that said out loud on a frequent basis by researchers in the field is half the battle. The rest of it is just a matter of pointing out that the prevalent implementation strategy is terrible in comparison to one based on repair of cellular and molecular damage, such as that proposed - in detail - in the SENS outline.

In recent years researchers have made good progress towards a biomarker of age based on patterns of DNA methylation that change over time. The trick here is pulling out meaningful changes that are characteristically related to aging in much the same way in everyone versus the much larger set of changes that vary widely between individuals. As aging is a process of damage accumulation, some of these epigenetic changes in DNA methylation are responses to that damage, meaning that somewhere in all of this is a methodology to rapidly evaluate potential rejuvenation treatments that are based on repair of damage. That is the real significance of this ongoing field of research:

Researchers studied chemical changes to DNA that take place over a lifetime, and can help them predict an individual's age. By comparing individuals' actual ages with their predicted biological clock age, scientists saw a pattern emerging. People whose biological age was greater than their true age were more likely to die sooner than those whose biological and actual ages were the same.

Four independent studies tracked the lives of almost 5,000 older people for up to 14 years. Each person's biological age was measured from a blood sample at the outset, and participants were followed up throughout the study. Researchers found that the link between having a faster-running biological clock and early death held true even after accounting for other factors such as smoking, diabetes and cardiovascular disease.

Researchers measured each person's biological age by studying a chemical modification to DNA, known as methylation. The modification does not alter the DNA sequence, but plays an important role in biological processes and can influence how genes are turned off and on. Methylation changes can affect many genes and occur throughout a person's life. "The same results in four studies indicated a link between the biological clock and deaths from all causes. At present, it is not clear what lifestyle or genetic factors influence a person's biological age. We have several follow-up projects planned to investigate this in detail."

Link: http://www.eurekalert.org/pub_releases/2015-01/uoe-dch013015.php

Low-density lipoproteins (LDL cholesterol) are involved in the progressive damage to blood vessel walls that leads to atherosclerosis. The initial presence of oxidatively damaged LDL can cause a cascade of inflammation responses and further retention of LDL in the inflamed area. Macrophage cells arrive to clean up, some of which are overwhelmed by the amount of LDL to deal with and die. Their debris attracts more macrophages and changes local cell behavior, and all of this leads to a dysfunctional remodeling of the blood vessel wall and eventual growth of fatty plaques that can block the blood vessel or break off to cause a blockage elsewhere.

One source of damaged LDL is the small population of cells with dysfunctional, damaged mitochondria that exist in older people. Getting rid of those through some form of repair treatment yet to be developed would help the issue. The authors of this open access review paper propose interfering elsewhere in the process, targeting the molecular biochemistry involved in other aspects of damaged LDL behavior in the blood vessel wall:

An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted 'response-to-retention hypothesis', LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis.

Although the molecular mechanism of LDL retention and lipid droplet formation in the arterial subendothelium is not fully understood, it is increasingly clear that aggregation and fusion of modified LDLs prevent their exit from the arterial wall and contribute to atherogenesis. In contrast to modified LDLs, native LDLs do not readily aggregate or fuse under physiological conditions, suggesting that lipoprotein modifications drive these transitions. Many aspects of these reactions remain unclear, e.g., how do the apparently disparate chemical or physical modifications exert similar structural responses in LDL? Is there a synergy among numerous factors that influence LDL fusion? Which enzymatic or nonenzymatic modifications are particularly important in promoting or preventing LDL fusion in vivo? What are specific steps in LDL aggregation, fusion, and lipid droplet formation, and what therapeutic agents can block these pathogenic processes? These and other unanswered questions reflect the fact that atherosclerosis is a very complex chronic disease that can be influenced by an immense number of factors, many of which are not well understood.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154560/

The path of the life sciences is to learn all there is to know about human biochemistry, regardless of use or application. The path of medicine, like the path of engineering, is to take what is known today and build the best and most useful technologies possible in that environment of incomplete knowledge. In the case of senescent cells there is certainly a lot left to learn, as is the case for all cellular biology: the massed data that the research community possesses at present is only an outline in comparison to the vast forest of low-level details and interactions yet to be uncovered.

Senescent cells are those that permanently exit the cell cycle and cease replication in response to damage or circumstances such as the presence of toxins that indicates a strong possibility of damage. This serves at least initially as a defense against cancer: some portion of those cells most likely to become cancerous are removed from the picture via senescence. Unfortunately senescent cells can linger, and they behave in ways that cause harm to surrounding tissue structures. The more senescent cells there are then the worse the resulting damage. Many of these cells are destroyed by the immune system or by their own programmed cell death mechanisms, but nonetheless a sizable fraction of many tissues consist of senescent cells by the time late life rolls around. This is a material contribution to many of the dysfunctions and frailties of degenerative aging.

For all that I can repeat the summary above, scientific institutions still have a long way to go in deciphering every last aspect of cellular senescence. But in the medical world there is a very clear path to producing meaningful treatments in the very near future, which is to simply destroy these cells on an ongoing basis. This has been demonstrated in mice engineered to suffer accelerated aging, and better studies on more normal mice are presently underway. A few research groups are working on a variety of ways to clear senescent cells from tissues, but are still quite early in the process of moving from laboratory to clinical applications of research. Nonetheless, this is a very viable way to circumvent present lack of knowledge: if researchers can selectively destroy senescent cells and show benefits as a result, then for this purpose the fine details of how senescence progresses and causes harm don't really matter.

Back to the science, here is an example of ongoing investigation of some of those fine details. Here researchers compare ordinary cellular senescence with the dysfunctional state of cells obtained from Hutchinson-Gilford progeria syndrome patients. This condition has many of the appearances of accelerated aging, though it is not that, and there is some interest in understanding whether any of the mechanisms involved in progeria have relevance to normal aging:

Understanding cellular ageing

Researchers have mapped the physical structure of the nuclear landscape in unprecedented detail to understand changes in genomic interactions occurring in cell senescence and ageing. Their findings have allowed them to reconcile the contradictory observations of two current models of ageing: cellular senescence of connective tissue cells called fibroblasts and cellular models of an accelerated ageing syndrome.

In the first model, cellular senescence triggers large-scale spatial rearrangements of chromatin and the formation of dense nuclear domains called SAHF (senescence associated heterochromatic foci). Chromatin is the complex of DNA and proteins that forms the chromosomes in the nucleus. The second model uses fibroblast cells from people with a syndrome causing accelerated ageing (Hutchinson-Gilford progeria syndrome, HGPS) and these cells show reduced compaction of chromatin and do not show the creation of SAHF domains.

Unexpectedly, the researchers found that SAHF regions, thought to be highly condensed and structured, show a dramatic loss of local interconnectivity and internal structure in senescence chromatin and that this effect was also seen in the genomes from HGPS cells. "The seemingly opposite changes in chromatin behaviour between cell senescence and cells from HGPS patients have been an obstacle to understanding their contribution to ageing. Using physical interaction mapping, a direct measure of the genome architecture, our study suggests that the chromatin does initially change in a similar way in cell senescence and HGPS. We can now focus our studies on these early events common to both model systems."

Global Reorganization of the Nuclear Landscape in Senescent Cells

Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria.

We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.

That last point ties in nicely with the concept of cellular senescence as a tool initially evolved to steer embryonic development, and only later emerging as a system to reduce cancer incidence in damaged tissues.

There is a large body of evidence to link cognitive decline in aging with corresponding decline in blood vessel integrity. A variety of processes in aging contribute to failing elasticity and structural remodeling of blood vessel walls, which in turn cause deterioration in the whole cardiovascular system as it tries to adapt to changing characteristics of blood flow. It is probably the case that a fair degree of cognitive deterioration in every individual is caused by physical damage to the brain resulting from issues in the vascular system: many ongoing instances of tiny blood vessels failing, causing blockages or bleeds that harm small areas of brain tissue.

Individually these events are unnoticeable, but over time they add up, and the worse the state of your cardiovascular system the worse the impact on your brain. Thus we should expect to see strong correlations between decline in cognitive function and risk of catastrophic structural failure in the cardiovascular system. The interesting part of this ugly process is that because of the way the brain works, this distribution of physical damage results in very different levels of harm to various different aspects of cognition:

Although stroke is known to result in executive dysfunction, little is known about executive dysfunction as a risk factor for stroke. Canadian Study of Health and Aging (CSHA), a longitudinal population based study of elderly Canadians, was conducted in three waves in 1990-1991 (CSHA-1), 1995-1996 (CSHA-2), and 2001-2002 (CSHA-3). In a cross-sectional analysis on CSHA-1 subjects, any association between stroke history and cognitive function was studied. In a prospective analysis, CSHA-1 stroke-free subjects were followed to CSHA-2 to see if there was any difference in stroke incidence among subjects with different baseline cognitive status. And, in a validation study CSHA-2 stroke-free subjects were followed to CSHA-3 to see if the prospective analyses findings could be replicated.

In the cross-sectional analysis, subjects who had stroke in their history had significantly lower executive function, not memory function, scores than subjects without any stroke in their history. In the prospective and validation studies, stroke incidence was affected by neither executive nor memory scores. When the analysis was restricted to normal cognition subjects, lower executive function, not memory function, scores predicted stroke incidence, and remained significant after controlling for stroke risk factors. We found executive dysfunction to be a powerful stroke risk factor among cognitively normal subjects. Testing for executive dysfunction may help identify individuals at risk for stroke in time to prevent them.

Link: http://dx.doi.org/10.1016/j.jns.2015.01.010

Efforts to treat Alzheimer's disease by clearing the amyloid beta (Aβ) deposits and related precursors associated with the progression of the condition have proven to be challenging, beset with failures and complications. Wherever there is slow progress in this sort of work, there is always the question of whether the problem is just hard, or whether the whole strategy is the wrong direction. Alternative hypotheses and approaches will spring up, and there is a lot of that going on in Alzheimer's research. Still, the presence of amyloids of various forms are a hallmark of aged tissues, and they should be cleared as a part of the activity of any potential rejuvenation toolkit. The work on clearing Aβ will hopefully contribute meaningfully to the development of a general technology platform to achieve this goal, even if it turns out that Aβ removal isn't the right path for Alzheimer's treatment.

Most people nowadays are familiar with the advice that "correlation does not imply causation." However, this is difficult advice to take when considering human disease where we are unable to ethically experiment on humans without exceptionally good justification. To get that justification we have to rely on studying the effects of a disease in order to make an informed guess about what causes it. The problem with this is that distinguishing the effects of a disease from its causes can get murky.

A good example of this confusion between effects and causes is Alzheimer's disease (AD). AD is defined by the presence of "amyloid plaques" (sticky globs of a protein fragment called amyloid beta or Aβ) in the brains of people with dementia. There is lots of good evidence that Aβ can cause AD. For example, there are families that inherit early-onset forms of AD, and have mutations in the protein itself or in enzymes that process the protein into sticky fragment forms. When these mutants are expressed in mice, the mice develop some (but not all) of the symptoms of AD. Additionally, there are people who naturally produce 50% more of the precursor to Aβ in their cells due to a completely different genetic disease: individuals with trisomy-21, or Down's Syndrome. Down's syndrome is cause by an extra copy of chromosome 21, which adds a whole extra copy of the Aβ precursor. An unfortunate side effect of this disease is that the majority of individuals with trisomy 21 go on to develop dementia and AD in their 30's and 40's.

So stopping Aβ formation is a good way to stop AD, right? That has been the main approach that pharmaceutical companies have taken to treat the disease in the past. Many drugs that aim to reduce Aβ levels in a variety of different ways have been tested, and have all more or less failed to show significant effects in people with mild cognitive impairment (mild memory loss that can develop into AD) or AD. These failures have been costly, surprising, and a bit disheartening.

So why does targeting Aβ fail?

Link: http://sage.buckinstitute.org/amyloid-beta-and-alzheimers-disease/

A point I frequently make is that while there exists a wide range of potential approaches to the development of therapies to treat aging, it is important to divide these approaches into two buckets. Firstly there are potential therapies that aim to repair the root cause cellular and molecular damage that leads to degenerative aging, and which are in principle capable of rejuvenation, indefinite prevention of all age-related disease, and indefinite extension of healthy life. Whether any particular package of implemented therapies achieves this or not is a matter of how much damage is repaired: it depends on the effectiveness and coverage of the treatments in question. Are they repairing all the types of damage that cause aging, and are they repairing enough of each type in all tissues that matter?

The larger second category contains all other potential therapies that do not aim to repair the fundamental damage that causes aging. These either aim to alter the operation of metabolism to slow down the accumulation of that damage, or try to adjust or repair secondary effects of the root cause damage - neither of which is going to be anywhere near as effective an approach, even though they may be far more troublesome and costly to implement. These therapies are not in principle capable of more than fleeting and partial rejuvenation, and definitely can't achieve indefinite prevention of disease or extension of healthy life.

Outside the stem cell research community there is far more ongoing work on the second type of treatment at this time. This might make little sense to an outsider who imagines that things proceed completely rationally in the scientific world. Developing drugs to tinker with metabolism based on the study of dysfunctional end states of disease is the modus operandi of much of modern medicine, and has been for a century. There is a lot of inertia in the institutions involved, and mere details such as this being a far worse approach to take in work on treating aging won't slow down this train all that much. Change must come from disruption of the entire status quo, and disruption must come from the newcomers and the iconoclasts and the rebels. It is happening, thanks to the work of organizations like the Methuselah Foundation and SENS Research Foundation, but in the highly regulated medical research and development community this sort of change is slow. It has taken a decade of persistent advocacy for even some of the most evident and easily explained of the SENS proposals, such as senescent cell clearance, to get a little traction in the last couple of years.

(Remember that the SENS proposals for the treatment of aging really aren't the SENS proposals at all: they are a consensus on aging and our biology derived from scores of research groups and publications from past years, drawn together and presented in a coherent fashion. The SENS proponents are organizers. Every field of science goes through periods of great diversity and expansion that must necessarily be followed by a process of synthesis, as the shards of the field have diverged too far for the researchers involved to have a good vision of the whole. The SENS view of aging is a part of an ongoing period of synthesis of all fields of medical research relevant to aging: a great deal was discovered over the past thirty years, but only in the past decade has an earnest reconciliation and exchange of knowledge begun for the purposes of building new technologies).

Meanwhile, even as researchers could be making significant progress on actual rejuvenation therapies were there the funding and the will, the mainstream continues to consider itself radical for initiating tests of existing drugs that might, maybe, cause some health benefits in humans, and possibly an extension of life by just a few years if taken over the long term. It is a terrible thing to watch, knowing that time is ticking away for all of us.

Aging interventions get human (PDF)

Over the last three decades, aging research has made great strides. At least in non-vertebrate animal models such as yeast and worms, it is possible to extend lifespan through reduced or ablated expression of hundreds of genes. The number of genes tested in mice are substantially less but the data so far is consistent with modulation of aging by numerous genes and pathways. More importantly, evidence exists that many of these genetic interventions extend healthspan and protect against the onset of age-associated chronic diseases. Recently, small molecules have entered center stage, with both natural products and clinically approved compounds reported to delay aging.

These findings raise the question of whether it is possible to forestall aging as an approach to maintain vitality and delay the onset of multiple chronic diseases simultaneously. However, there are significant hurdles to testing human aging drugs and many have been skeptical that aging interventions will ever enter the clinic. Among the foremost challenges, aging is not formally considered a disease by the FDA and the prospects of testing whether drugs extend human lifespan directly promises to be a long and exorbitantly expensive process. There is also the challenge of performing clinical trials in aging individuals who are still generally healthy. Foremost among these is the extra level of safety that will need to be incorporated since care must be taken not to do harm to healthy, older people. One potential solution is to test compounds against deleterious phenotypes associated with human aging - but which compound and which phenotype? This question has been debated extensively.

Sometimes the best approach is to start testing and let the results dictate the path forward. In this vein, Mannick et al. recently reported the results of the first human aging trial. They chose a first generation derivative of the drug rapamycin (known as everolimus or RAD001), which has been shown to extend lifespan in all four major animal models of aging: yeast, worms, flies and mice. Importantly, rapamycin, which is a direct inhibitor of the mTOR kinase, can extend lifespan by 25% in mice and even show efficacy when initiated in 20 month old mice. Most studies indicate that rapamycin extends healthspan as well. Rapalogs, or rapamycin derivatives, are approved for treatment of several disease indications, but also have a range of side effects.

Mannick et al. chose to administer RAD001 to healthy people 65 and older over a six week period, followed by flu vaccine inoculation two weeks after suspending drug treatment. The findings from the Mannick study are encouraging. Importantly, Mannick et al. found efficacy at both lower dose regimens of RAD001, demonstrating at least a 1.2 fold increase in the serologic hemagglutinin inhibition geometric mean titer ratio (HI GMT) of two of the three influenza viruses represented in the vaccine at four weeks after inoculation. This is a relevant target since prior studies have shown that a 20% increase in GMT ratio has been associated with reduced influenza illness. Interestingly, RAD001 also appeared to broaden the serologic response, causing enhanced seroconversion to heterologous influenza strains not in the chosen influenza vaccine. This finding is also suggestive of enhanced protection against influenza illness.

The study by Mannick et al. is groundbreaking but it sets the stage for testing drugs associated with delayed aging in healthy older human populations. Whether rapalogs are the right drugs and immunosenescence is the right marker for healthspan remains to be determined, but it is critical for aging research to enter the clinic and this study is a fascinating initial foray.

The general consensus among researchers is that over the last few centuries of increasing human life expectancy most of the early gains were due to reductions in mortality in youth, such as those caused by infectious disease, malnutrition, and the like. Over time the ongoing gains in life expectancy have shifted to occur in later life due to other forms of improvement in medicine and related technologies: present trends are as much in adult life expectancy as in life expectancy at birth. This study takes a novel approach to gain a different confirming perspective from the existing data:

Life expectancy has increased continuously for at least 150 years, due at least in part to improving life conditions for the majority of the population. A substantial part of this historical increase is due to decreases in early life mortality. In this paper we analyse the longevity of four privileged sets of adults, who have avoided childhood mortality and lived a life more similar to the modern middle class. Our analysis is focused on writers and musicians from the 17th through the 21st Centuries. We show that their average age at death increased only slightly between 1600 and 1900, but in the 20th Century increased at around 2 years/decade.

We suggest that this confirms that modern lifespan extension is driven by delay of death in older life rather than avoidance of premature death. We also show that Productive Lifespan, as measured by writing and composition outputs, has increased in parallel with overall lifespan in these groups. Increase in age of death is confirmed in a group of the minor British aristocracy, and in members of the US Congress from 1800 to 2010. We conclude that both lifespan and Productive Lifespan are increasing in the 20th and early 21st Century, and that the modern prolongation of life is the extension of productive life, and is not the addition of years of disabling illness to the end of life.

Link: http://dx.doi.org/10.1089/rej.2014.1629

Klotho is one of a range of longevity-associated genes identified in animal studies. You might recall that last year researchers identified a klotho variant associated with better cognitive function in humans. It didn't appear to protect against age-related decline as the researchers hoped, however. Here is more on this topic:

People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making. The finding bolsters their previous discovery that middle-aged and older people who carry a single copy of the KLOTHO allele, called KL-VS, performed better on a wide range of cognitive tests. When they modeled KL-VS in mice, they found this strengthened the connections between neurons and enhanced learning and memory. KLOTHO codes for a protein, called klotho, which is produced in the kidney and brain and regulates many different processes in the body. About one in five people carry a single copy of KL-VS, which increases klotho levels and is associated with a longer lifespan and better heart and kidney function. A small minority, about 3 percent, carries two copies, which is associated with a shorter lifespan.

Researchers scanned the brains of 422 cognitively normal men and women aged 53 and older to see if the size of any brain area correlated with carrying one, two or no copies of the allele. They found that the KLOTHO gene variant predicted the size of a region called the right dorsolateral prefrontal cortex (rDLPFC), which is especially vulnerable to atrophy as people age. Deterioration in this area may be one reason why older people have difficulty suppressing distracting information and doing more than one thing at a time. Researchers found that the rDLPFC shrank with age in all three groups, but those with one copy of KL-VS - about a quarter of the study group - had larger volumes than either non-carriers or those with two copies.

Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, such as working memory - the ability to keep a small amount of newly acquired information in mind - and processing speed. Both tests are considered to be good measures of the planning and decision-making functions that the rDLPFC controls. In statistical tests, the researchers concluded that the larger rDLPFC volumes seen in single copy KL-VS carriers accounted for just 12 percent of the overall effect that the variant had on the abilities tested. However, the allele may have other effects on the brain, such as increasing levels or changing the actions of the klotho protein to enhance synaptic plasticity, or the connections between neurons. In a previous experiment, they found that raising klotho in mice increased the action of a cell receptor critical to forming memories.

Link: http://www.ucsf.edu/news/2015/01/122761/brain-region-vulnerable-aging-larger-those-longevity-gene-variant

It would be an interesting and possibly rather depressing exercise to compare funding for reversal of age-related hair loss to that for the effective treatment of various other aspects of aging. Hair restoration, I think, is fairly well funded in comparison with many lines of research that I consider to be far more important. What moves the needle for you: looking good or living in good health? It would be a tremendous improvement over the present state of the human condition to find oneself at age 80 and balded, yet with internal organs repaired by rejuvenation biotechnologies, and the health and vigor to complain loudly about the terrible state of hair regrowth medicine. Instead I rather fear the order of development is going to be the other way around, with elderly people continuing to crumble inside in a score of ways yet having the option of a naturally flowing head of hair should they so desire. Progress happens most rapidly where the funding flows, and vanity has never been well restrained by common sense.

In reality we'd like to see unrestrained research funding sufficient for rapid progress on all fronts of regeneration and rejuvenation, whether merely vain and secondary or connected to the essential function of organs actually required for healthy life. Funding for medical research is such a tiny fraction of the resources spent on frivolous things that there is always room for growth through persuasion.

Researchers develop method to induce human hair growth using pluripotent stem cells

"We have developed a method using human pluripotent stem cells to create new cells capable of initiating human hair growth. The method is a marked improvement over current methods that rely on transplanting existing hair follicles from one part of the head to another. Our stem cell method provides an unlimited source of cells from the patient for transplantation and isn't limited by the availability of existing hair follicles."

The research team developed a protocol that coaxed human pluripotent stem cells to become dermal papilla cells. They are a unique population of cells that regulate hair-follicle formation and growth cycle. Human dermal papilla cells on their own are not suitable for hair transplants because they cannot be obtained in necessary amounts and rapidly lose their ability to induce hair-follicle formation in culture. "We developed a protocol to drive human pluripotent stem cells to differentiate into dermal papilla cells and confirmed their ability to induce hair growth when transplanted into mice. Our next step is to transplant human dermal papilla cells derived from human pluripotent stem cells back into human subjects. We are currently seeking partnerships to implement this final step."

Derivation of Hair-Inducing Cell from Human Pluripotent Stem Cells

Dermal Papillae (DP) is a unique population of mesenchymal cells that was shown to regulate hair follicle formation and growth cycle. During development most DP cells are derived from mesoderm, however, functionally equivalent DP cells of cephalic hairs originate from Neural Crest (NC). Here we directed human embryonic stem cells (hESCs) to generate first NC cells and then hair-inducing DP-like cells in culture.

We showed that hESC-derived DP-like cells (hESC-DPs) are able to induce hair follicle formation when transplanted under the skin of immunodeficient NUDE mice. Engineered to express GFP, hESC-derived DP-like cells incorporate into DP of newly formed hair follicles and express appropriate markers. We demonstrated that BMP signaling is critical for hESC-DP derivation since BMP inhibitor dorsomorphin completely eliminated hair-inducing activity from hESC-DP cultures.

DP cells were proposed as the cell-based treatment for hair loss diseases. Unfortunately human DP cells are not suitable for this purpose because they cannot be obtained in necessary amounts and rapidly loose their ability to induce hair follicle formation when cultured. In this context derivation of functional hESC-DP cells capable of inducing a robust hair growth for the first time shown here can become an important finding for the biomedical science.

Immunotherapy is a promising approach for the treatment of Alzheimer's disease, in which immune cells are directed to attack amyloid aggregates or precursor proteins associated with the condition. More pertinently, this field of research could produce a successful and mature technology platform for targeting all forms of amyloid, and possibly other types of metabolic waste, that should be cleared from the body in order to remove their contributions to degenerative aging. Unfortunately progress is slow and challenging: Alzheimer's is complex, the immune system is complex, and both are incompletely understood. There continue to be many more failures than successes in the process of development.

One more recent line of work is to focus on tau aggregates rather than amyloid. There is evidence to suggest that these neurofibillary tangles are also significant in the progression of Alzheimer's disease, but again understanding of the mechanisms involved is at this point sketchy. From an engineering point of view forging ahead to build a removal mechanism in advance of full knowledge is a good approach, if it can be done given the present state of knowledge. It stands a reasonable chance of cutting straight to a viable treatment even in absence of greater knowledge, or at least shedding more light on the situation if it clears tau and yet still fails to improve the outcome for a treated individual. In this case researchers encounter a fairly typical result in this work, which is that they are floundering on unanticipated complexity, but learning as they go:

The amyloid β (Aβ)-protein and microtubule-associated protein, tau, are the major components of the amyloid plaques and neurofibrillary tangles that typify Alzheimer's disease (AD) pathology. As such both Aβ and tau have long been proposed as therapeutic targets. Immunotherapy, particularly targeting Aβ, is currently the most advanced clinical strategy for treating AD. However, several Aβ-directed clinical trials have failed, and there is concern that targeting this protein may not be useful. In contrast, there is a growing optimism that tau immunotherapy may prove more efficacious.

Here, for the first time, we studied the effects of chronic administration of an anti-tau monoclonal antibody (5E2) in amyloid precursor protein transgenic mice. For our animal model, we chose the J20 mouse line because prior studies had shown that the cognitive deficits in these mice require expression of tau. Despite the fact that 5E2 was present and active in the brains of immunized mice and that this antibody appeared to engage with extracellular tau, 5E2-treatment did not recover age-dependent spatial reference memory deficits. These results indicate that the memory impairment evident in J20 mice is unlikely to be mediated by a form of extracellular tau recognized by 5E2.

In addition to the lack of positive effect of anti-tau immunotherapy, we also documented a significant increase in mortality among J20 mice that received 5E2. Because both the J20 mice used here and tau transgenic mice used in prior tau immunotherapy trials are imperfect models of AD our results recommend extensive preclinical testing of anti-tau antibody-based therapies using multiple mouse models and a variety of different anti-tau antibodies.

Link: http://dx.doi.org/10.1016/j.neurobiolaging.2014.11.022

More than six years ago a research group demonstrated that autophagy can be boosted in the liver to reverse some of the age-related decline in function of that organ. Old mice were shown to have some measures of liver function little different from young mice. Science is a slow business, however. These researchers are still working their way around this area of study, and at this time there is no significant movement in the direction of translating this and other potential autophagy enhancing treatments into human therapies. This is very much the standard story when it comes to potential treatments for aging, sad to say:

Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging.

Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.

Link: http://dx.doi.org/10.1111/acel.12310

One slice of the comprehensive package of biotechnologies needed to reverse the causes and consequences of degenerative aging involves next generation cell therapies. The aged body has lost needed cells, while other vital but small cell populations fall into a state of damage and dysfunction. Replacements will have to be generated, and cell therapies are how this goal will be achieved. These future therapies are presently in the early stages of development; they follow on from and will greatly improve on today's stem cell transplants. The introduction of new stem cells is the present best tool for achieving beneficial changes in native cell behavior, but the destination for this field is to discard the stem cells and simply make the desired changes directly. The stem cell therapies available now are a stepping stone to future treatments that directly repair cells and adjust their behavior in situ.

Cell therapies are neither more noteworthy nor more needed than any of the other items in the proposed rejuvenation toolkit, such as repair of mitochondrial damage and targeted clearance of metabolic waste, but they are considerably further along in the long path leading from first concepts to commercial therapies. A lot of money is available for stem cell research, and there is much to be said for making hay while the sun shines. Success here in steering groups within the community towards the treatment of aging will hopefully lead to successful businesses that branch out into other needed areas of development in rejuvenation biotechnology.

The 2014 World Stem Cell Summit was held last month in Texas. As you might expect, there is an ongoing discussion at such events prompted by those who are interested in going beyond merely treating age-related disease in its late stages, the traditional approach in medicine that has produced only marginal gains when it comes to extension of healthy life. These researchers want to turn the tools of regenerative medicine to tackle the causes of aging:

How to Best Hinder or Halt the Aging Process, a Roundtable Discussion on Regenerative Medicine

Medicine is the diagnosis, treatment, and, increasingly, hopefully, the prevention of what ails us. Most people's experience of medicine is likely focused on diagnosis and, unfortunately, the treatment of symptoms, the mitigation of the condition, with time bringing an amelioration of the problem. The excitement of regenerative medicine is the ability to replace or regenerate cells, tissues, or organs. So instead of a lifetime of taking injections, tablets, or using prostheses, patients actually become healthy again. Looking at tissue engineering, the classic approach is cells + scaffold = restored functionality.

It may be useful for researchers to think further out of the box regarding regenerative medicine than the areas that the term conventionally encompasses. Stem cell therapies are, in essence, a form of damage repair: they restore the number of cells of a given type that have been depleted, thus leading to ill-health. But tissue engineering restores not only cell number but also the structure of the extracellular matrix, among other things. Emerging technologies, often utilizing gene therapy or immune stimulation, powerfully complement these approaches. For example, in many cases they act to remove superfluous cells or detritus that the body is unable to eliminate naturally. The potential combined benefit of these therapies and classic regenerative medicine far exceeds the sum of its parts so there is considerable value in viewing the entire arsenal as facets of the same kind of medicine and thereby promoting cross-disciplinary thinking and research.

Clearly, heterochronic parabiotic studies have shown that the aged environment is hindering normal regenerative processes. How much these results can be recapitulated in humans is up for grabs right now. Anyone who works with rodents and humans knows that rodents are much more forgiving in terms of recovery from injury than humans. If the disease is one of aging, like age-related heart disease, macular degeneration, Alzheimer disease, or Parkinson's disease, we have no choice but to develop therapies that will work for older people. What is regenerative medicine if not the treatment of an event or condition that is increasingly likely to occur with years lived?

Researchers here show that intermittent fasting in older rats beneficially alters one narrow measure of function in the hippocampus, an area of the brain that is well-studied in connection with age-related cognitive decline:

Diminished glucocorticoid signaling is associated with an age-related decline in hippocampal functioning. In this study we demonstrate the effect of intermittent, every other day (EOD) feeding on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the hippocampus of middle-aged (18-month-old) and aged (24-month-old) Wistar rats.

In aged ad libitum-fed rats, a decrease in the level of total GR and phosphorylated GR (pGR) was detected. Conversely, aged rats subjected to EOD feeding, starting from 6 months of age, showed an increase in GR and pGR levels and a higher content of hippocampal corticosterone. Furthermore, prominent nuclear staining of pGR was observed in CA1 pyramidal and dentate gyrus granule neurons of aged EOD-fed rats. These changes were accompanied by increased Sgk-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR. EOD feeding also induced an increase in the expression of the mineralocorticoid receptor.

Our results reveal that intermittent feeding restores impaired GR signaling in the hippocampus of aged animals by inducing rather than by stabilizing GR signaling during aging.

Link: http://dx.doi.org/10.1016/j.jsbmb.2015.01.013

Proteostasis is the desired state of correctly function in maintaining specific protein levels and an absence of damaged or misfolded proteins in cells over time. Various regulatory systems and quality control mechanisms - such as those associated with proteasomes and lysosomes - are involved in maintaining correct function in this fashion. Like other aspects of cellular biology, proteostasis is negatively impacted over the course of aging, and exceptionally long-lived species seem to have better versions of the mechanisms involved in maintaining this desirable state of continued function:

Our previous studies have shown that the liver from Naked Mole Rats (NMRs), a long-lived rodent, has increased proteasome activity and lower levels of protein ubiquitination compared to mice. This suggests that protein quality control might play a role in assuring species longevity. To determine whether enhanced proteostasis is a common mechanism in the evolution of other long-lived species, here we evaluated the major players in protein quality control including autophagy, proteasome activity, and heat shock proteins (HSPs), using skin fibroblasts from three phylogenetically-distinct pairs of short- and long-lived mammals: rodents, marsupials, and bats.

Our results indicate that in all cases, macroautophagy was significantly enhanced in the longer-lived species, both at basal level and after induction by serum starvation. Similarly, basal levels of most HSPs were elevated in all the longer-lived species. Proteasome activity was found to be increased in the long-lived rodent and marsupial but not in bats. These observations suggest that long-lived species may have superior mechanisms to ensure protein quality, and support the idea that protein homeostasis might play an important role in promoting longevity.

Link: http://dx.doi.org/10.1016/j.bbrc.2015.01.046

One of the more important ways in which the immune system declines with age is that its composition shifts towards large duplicated collections of comparatively useless cells involved in coordination and memory of threats, and this is at the expense of a shrinking population of cells capable of destroying those threats. The supply of new immune cells is a slow trickle in adults; evolutionary pressures led to a system that starts up very rapidly in youth and generates large numbers of cells at that time. By adulthood the organ responsible for marshaling new T cells of the adaptive immune system, the thymus, has atrophied. The pressures put on the immune system to shift cells into roles other than attacking and destroying pathogens don't let up, however. The end result is an immune system become ever more poorly configured as a whole: too many librarians and bureaucrats, too few warriors. The body is always under attack from pathogens, but the immune system is also responsible for destroying errant cells, such as those become cancerous or senescent. That the immune system falls down on this front is just as bad as the frailty that stems from a growing inability to resist common infectious diseases.

None of this considers the age-related toll of cellular damage or other harms caused to the stem cell populations responsible for generating immune cells. That is also an issue. Putting that to one side for the moment, however, there are several ways in which the aging immune system could be reconfigured. All of them are within reach of modern biotechnology, and have been demonstrated in the laboratory to some extent: all are in that awkward period of being technically feasible but not yet earnestly in development as a therapy. Firstly, the supply of new immune cells cells could be increased by regenerating the thymus such that it behaves as though the patient is young once more. Secondly the population of useless immune cells could be cleared away by targeted cell destruction technologies, which will prompt the body to replace them with new cells capable of attacking pathogens. Lastly large numbers of immune cells could be generated from the patient's own stem cells and delivered via infusion on a regular basis; in theory far more cells than usually present in the body could be provided in this way, greatly increasing the capabilities of the immune system while they survive.

The open access research quoted below is an example of that third approach. It is worth noting that I have painted with very broad strokes in the description above. The immune system is a city of many different specialized classes of inhabitant, each performing just a few of a very wide range of jobs. It is a very complex and dynamic system of interactions and behaviors. So it is the case that benefits might be obtained just by focusing down on a few specific subtypes of immune cell when generating and delivering large numbers of them as a therapy. The full paper is available in PDF format only at this point, but worth a look.

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells

Invariant natural killer T (iNKT) cells comprise a small population of αβ T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies, and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo (∼0.01-1% in mouse and human blood).

Here, we report a new method to generate large numbers of iNKT cells in mice through T-cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells.

When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy.

Telomeres are the protective caps of repeated DNA sequences found at the end of chromosomes. Telomere length is a part of the regulatory system that prevents cells from dividing indefinitely: a little length is lost with each cell division, and a cell destroys itself or otherwise ceases to divide when its telomeres become too short. In stem cell populations, responsible for delivering fresh batches of long-telomere daughter cells into tissues to replace those lost due to reaching the limits of replication, the enzyme telomerase is active to maintain lengthy telomeres by adding extra repeating sequences to the ends. Cancer cells also make use of telomerase or other methods of lengthening telomeres in order to maintain their ability to rapidly and continually divide, but this process isn't normally active in the majority of the cells in the body. Average telomere length in white blood cells tends to decrease with age and illness, and this is really a proxy measure that blurs some combination of cell division rates and stem cell activity.

Researchers have lengthened healthy life in mice by boosting the activity of telomerase via genetic engineering, though it is still the case that there is no definitive experiment to show which of the possible mechanisms causes this life extension. Is it a matter of more stem cell activity, some secondary effect of having long telomeres such as increased cell life span, or another aspect of telomerase, such as its influence on mitochondrial biology? There is considerable interest in the research community in continuing to explore what might happen when telomeres are lengthened, and so it is inevitable that better methods of lengthening will be developed:

A new procedure can quickly and efficiently increase the length of human telomeres, the protective caps on the ends of chromosomes that are linked to aging and disease. The procedure, which involves the use of a modified type of RNA, will improve the ability of researchers to generate large numbers of cells for study or drug development. Skin cells with telomeres lengthened by the procedure were able to divide up to 40 more times than untreated cells. The research may point to new ways to treat diseases caused by shortened telomeres.

The researchers used modified messenger RNA to extend the telomeres. RNA carries instructions from genes in the DNA to the cell's protein-making factories. The RNA used in this experiment contained the coding sequence for TERT, the active component of a naturally occurring enzyme called telomerase. Telomerase is expressed by stem cells, including those that give rise to sperm and egg cells, to ensure that the telomeres of these cells stay in tip-top shape for the next generation. Most other types of cells, however, express very low levels of telomerase.

The newly developed technique has an important advantage over other potential methods: It's temporary. The modified RNA is designed to reduce the cell's immune response to the treatment and allow the TERT-encoding message to stick around a bit longer than an unmodified message would. But it dissipates and is gone within about 48 hours. After that time, the newly lengthened telomeres begin to progressively shorten again with each cell division. "We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase. Previous attempts to deliver mRNA-encoding TERT caused an immune response against telomerase, which could be deleterious. In contrast, our technique is nonimmunogenic. Existing transient methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent."

Link: http://med.stanford.edu/news/all-news/2015/01/telomere-extension-turns-back-aging-clock-in-cultured-cells.html

Researcher Valter Longo is presently working on, among other things, packaging up intermittent fasting as a treatment with the sort of rigor needed to get it through clinical trials with the FDA. The work leading up the clinical trials involved putting numbers to the short term term benefits provided by fasting: how often and how long must someone fast in order to achieve specific changes in biomarkers of health, and how long do those effects last? The data will be useful for people who practice intermittent fasting as a health strategy, moving the state of scientific support for this strategy closer to that existing for the practice of calorie restriction with optimal nutrition.

Calorie restriction is a very wide-ranging word. We focus more on periodic fasting - we're not really big believers in having people be on special diets or restrictions all the time. We just believe in interventions that are short and lasting, that can last a long time and protect from aging and age-related diseases. But also the use of these in improving disease treatment.

It has been very effective. Originally we did this in simple organisms to understand the molecular basis for it, and then moved to mice, and now we're finishing a number of clinical trials. The effects have been very, very promising. Most of it is not published in humans yet but a lot of it is already finished. So in the next year or so we're going to have at least 3 papers and clinical trials showing normal subjects, cancer subjects and also other diseases, showing the efficacy of these techniques, but also the high compliance that we get in doing this. So it's really something that we've found that most people can do.

As soon as the clinical trial is over basically that's it - people can start doing it. Now for the cancer one people could do it, but not to treat the cancer, only to reduce the side effects of chemotherapy. The cancer itself is regulated by the FDA so we'll have to continue our trials until these are FDA approved if we want to have the treatment included in therapy for delaying cancer progression. But of course people will do it anyway, because if you can use it with chemo obviously you're already using it to treat cancer but you just can't say.

The reduction of IGF-1 is really key in the anti-aging effects of some of the interventions. Both the dietary ones and the genetic ones. We've been putting a lot of work into mutations of the growth hormone receptor that are well established now to release IGF-1 and also cause a record life span extension in mice. So we know for example with chemotherapy resistance if you fast mice and inject IGF-1 you reverse a lot of the protective effects of fasting. So it's important; it's not the only factor, but it's certainly one of the key ones.

Link: http://michelsonmedical.org/2014/12/26/igf-1-fasting-discussion-valter-longo/

The transcription factor myc has shown up in cancer research over the past decade, and it is possible that reducing its abundance can turn off rapid cellular proliferation in many cancers. Researchers can't get rid of myc entirely, however, as its presence is necessary for a range of fundamental cell processes. Myc is also important in modern stem cell research, as it is one of the factors used in reprogramming somatic cells to become induced pluripotent stem cells, a potentially important source of customized cells for research and therapies. This is one of many examples that illustrate cancer and regeneration to be opposite sides of the same coin from a mechanistic point of view: the same proteins show up in similar roles on both sides of the fence.

Researchers investigating the role of myc in cancer recently stumbled upon an unexpected finding, demonstrating that reduced levels of myc caused improvements in health and longevity in laboratory mice. This was not the result they were looking for at all, but arguably it is far better for everyone involved for their project to be derailed in this fashion:

Benefits of Missing MYC

Compared to wild-type mice, those missing one copy of Myc live longer and suffer less severe aging-associated problems. The mice that we created are long-lived, but they are incredibly normal, and they are incredibly healthy." Myc's apparent broad role in aging comes as a surprise to those who study the gene. "We've been so focused on [MYC's] normal function and its cancer function. I don't think any of us really thought about what happens in terms of longevity."

At first, researchers genetically engineered mice to lack a copy of Myc because they thought this might increase cellular senescence, an aging-associated process in which cells cease to divide. To the researchers' surprise, the mice did not show increased cell senescence but rather increased longevity compared with wild-type animals. As expected given MYC's role in cancer, the loss of one copy appeared to slow progress of the disease. But loss of a Myc copy also reduced hardening of heart muscle, osteoporosis, and age-related decline in immune function. Mice with reduced MYC displayed better motor function, showed reduced age-related changes in cholesterol than control mice. The engineered mice showed reduced levels of insulin growth factor-1. Reduction of this growth factor has also previously been shown to be associated with increased lifespan.

"It's pretty clear that the [Myc-mutant] mice live longer for a variety of reasons, or at least if you look at their overall health, you see effects in a bunch of different organs." Because the Myc-mutant mice were smaller than average, the researchers wondered whether the engineered animals were eating less than the control mice, as caloric restriction has been shown to slow aging. But the researchers found that the engineered mice were in fact eating more than the control animals.

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/-) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism.

Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/- mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

It would be interesting for researchers to now try this in conjunction with some of the other longevity-enhancing genetic alterations that are thought to work through alterations to quality control and repair systems: do they stack? By the sound of it reduced levels of myc work to extend life via many of the same mechanisms as produce the health and longevity benefits of calorie restriction, so there again it would be interesting to see what the outcome is for calorie restriction myc-reduced mice. If there is no or little additive effect there, then perhaps carefully designed drugs capable of suppressing myc levels might prove to be a form of calorie restriction mimetic.

Like all tissues, those of the blood-brain barrier in blood vessel walls deteriorate due to the cellular and molecular damage of aging. Researchers here correlate that deterioration with progressive cognitive impairment, further reinforcing existing data on the contribution of blood vessel functional decline to age-related damage in the brain:

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD.

The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

Link: http://dx.doi.org/10.1016/j.neuron.2014.12.032

Parabiosis involves joining together the circulatory systems of two individuals. Joining together an old and a young mouse has proved to be very instructive now that researchers can measure quite detailed aspects of cellular biology, and in recent years it has been used to investigate age-related changes that take place in levels of various proteins in the blood. Some of those proteins can alter cellular behavior in important ways, and manipulating them in old individuals can improve degraded tissue function. This article provides a recent history of this research and hopes for the near future:

Experiments with parabiotic rodent pairs have led to breakthroughs in endocrinology, tumour biology and immunology, but most of those discoveries occurred more than 35 years ago. For reasons that are not entirely clear, the technique fell out of favour after the 1970s. In the past few years, however, a small number of labs have revived parabiosis, especially in the field of ageing research. By joining the circulatory system of an old mouse to that of a young mouse, scientists have produced some remarkable results. In the heart, brain, muscles and almost every other tissue examined, the blood of young mice seems to bring new life to ageing organs, making old mice stronger, smarter and healthier. It even makes their fur shinier. Now these labs have begun to identify the components of young blood that are responsible for these changes. And last September, a clinical trial in California became the first to start testing the benefits of young blood in older people with Alzheimer's disease.

"I think it is rejuvenation," says Tony Wyss-Coray, a neurologist at Stanford University in California who founded a company that is running the trial. "We are restarting the ageing clock." Many of his colleagues are more cautious about making such claims. "We're not de-ageing animals," says Amy Wagers, who has identified a muscle-rejuvenating factor in young mouse blood. Wagers argues that such factors are not turning old tissues into young ones, but are instead helping them to repair damage. "We're restoring function to tissues."

Six out of a planned 18 people with Alzheimer's, all aged 50 or above, have already begun to receive plasma harvested from men aged 30 or younger. In addition to monitoring disease symptoms, the researchers are looking for changes in brain scans and blood biomarkers of the disease. Wagers is eager to see the results, but she worries that a failure would be difficult to interpret and so could set the whole field back. Plasma from a 30-year-old donor may not contain factors beneficial to patients with Alzheimer's, for example. She and others would prefer to see testing for a specific blood factor or combination of known factors synthesized in the lab, for which the mechanism of action is fully understood.

There are also lingering concerns as to whether activating stem cells - which is what the young blood most often seems to do - over a long period of time would result in too much cell division. "My suspicion is that chronic treatments with anything - plasma, drugs - that rejuvenate cells in old animals is going to lead to an increase in cancer. Even if we learn how to make cells young, it's something we'll want to do judiciously."

Link: http://www.nature.com/news/ageing-research-blood-to-blood-1.16762

This probably doesn't need to be said to anyone who reads Fight Aging! on a regular basis: old people do not die from old age. They die because of specific biological system failures that are caused by a sequence of consequences that can in principle be traced back to an accumulation of cellular and molecular damage, and that damage is a direct byproduct of the normal operation of metabolism. Think of the progression of rust in a complex metal structure as a crude analogy for this situation: simple causes, and a complex progression of structural failure.

Given sufficient time and resources at the time of death it is usually possible to determine with a reasonable degree of accuracy the actual class of system failure responsible. Given a vastly greater knowledge of the exceedingly complex progression of aging in terms of metabolic changes and reactions we could then draw lines of cause and effect all the way back to the fundamental damage. That requires far more effort than the answer is worth, however: the research community will be decades more in making meaningful progress towards that goal, but they will do that work, as the point of science is to gather knowledge. It is fortunate for us that this enormous job can be bypassed on the way to producing treatments for aging; researchers can instead focus on repairing the well-known and well-described fundamental damage resulting from the operation of metabolism. We don't need a full accounting of its progression to effectively treat aging if researchers work on producing ways to periodically repair its causes.

There are other places where people decide that knowledge isn't worth the effort required, and that is in the recording of the cause of death. Statisticians who analyze death records for the old are plagued by the bad habits of pathologists, who in different eras have used various different shorthand notations for "I don't know, I don't have time to find out, this person was old, it happens, moving on now." It used to be the case that "old age" was a fine thing to put on a death certificate, and it still is in many countries, but other more scientific-sounding catch-all categories have come to dominate, giving the appearance of providing information but actually doing nothing of the sort. Some regions are better than others, of course.

Does this matter, really, though? After all, we are interested in repair therapies, which means we are focused on the roots of aging, not its end. Fix the causes and the consequences take care of themselves. Further, the dominant causes of death as a result of the aging process are much more common than the lesser causes, meaning that even with problems in the data is remains fairly clear as to what are the greatest threats to health. Forms of heart disease account for a majority of deaths in the old, for example, and for that collection of age-related diseases you'll find less of the fuzziness in death certificates. Further still, isn't it pedantic and little else to make this distinction between dying from specific things and dying from old age? For regular readers here, maybe. But we still have to convince much of the world, the public at large, that aging is something other than a mysterious process set in stone. I think it makes a difference to talk about dying from specific causes versus "old age." A mystery is something you can't pick apart into jobs to be done and items to be fixed, while a specific cause and mechanism of death invites the question of whether we can do something about it.

The article quoted below is trying, and I think failing, to explain another point of view on why it is that you can't say that people die of old age, via the work of David Gems on aging in model organisms such as nematode worms. If I am following correctly this is the philosophical difference between being killed by accumulating biological damage and its consequences versus being killed by a specific named pathology that could only take hold because you are suffering a high level of damage. To me that's more or less the same thing, damage leading to pathology, but I could envisage situations in which one could frame it the other way. You might look at Gems' recent papers on the evolution of human aging and a definition of longevity enhancing therapies for a better insight into his views.

Can People Really Die Of Old Age?

The answer is no. (Alright, thanks for stopping by!)

Just kidding. But really, people don't die of old age. Though it may seem like a trivial thing to find out, the biology of aging - and the research trailing in its wake - drills down to some pretty profound questions about the nature of existence. But we're getting ahead of ourselves.

"The idea that people die of pure aging, without pathology, is nuts," said Gems, the deputy director of the Institute of Healthy Aging and a professor at the University College London. Here Gems uses "pathology" to refer to something that can kill you - some sort of condition, disease, or ailment - not something so boring and normal as having a lot of birthdays. Something else has to be going on.

"The problem with aging is that it's about the most ghastly and tragic aspect of the human condition. Up until recently, there's been practically nothing one can do about it, so the best thing to do is to lie to oneself about it to make it bearable," said Gems, referring to the relative ease of dying from "old age," rather than crippling pneumonia or the dreaded C-word. "I can't really blame anyone for that, but as a scientist you have to try to understand things as they really are and hope good things come out of that."

If that conclusion feels anticlimactic, or at best grim, you're not alone. Scientists and sci-fi buffs alike haven't been satisfied knowing why we die. The real question, of course, is how we stop dying. If death is just the result of physical breakdown letting in disease, what if the body never breaks down?

As regular readers know, I advocate for the development of treatments for aging based on periodic repair of the low-level cellular and molecular damage that causes aging. There is at least one detailed plan of action on how to produce the necessary treatments, the Strategies for Engineered Negligible Senescence (SENS) research proposals. Enough is known to work on this with a good expectation of success. Outside of factions within the stem cell research community this is still at this time a minority path in the scientific community, however. Most research groups are much more interested in developing a greater understanding of the fine details of metabolism so as to alter it in order to slow down aging. Unfortunately this latter path is nowhere near the point of producing a working plan, and it has proven to be enormously expensive and time consuming to investigate even tiny slices of the necessary reach of knowledge. See the much hyped past decade of research on sirtuins, for example, that has consumed the cost of implementing SENS in the laboratory several times over without producing any meaningful treatment.

In this piece, the author chooses the hard, slow, expensive, largely unknown path of altering the fundamental operation of metabolism as the better way forward for egalitarian reasons - that a one-time alteration that slows aging is better than a frequent treatment to repair aging because it is somehow more equal, or less prone to ongoing costs. This seems silly. For one, even setting aside the much greater difficulty and time required to develop means of altering metabolism, that approach cannot produce rejuvenation as it only slows down the pace of damage accumulation. Thus it cannot help the old, and it cannot extend healthy life indefinitely. Repair therapies can in principle achieve these goals, it's just a matter of how well they repair the damage. When it comes to costs, the mature evolution of SENS-like repair treatments would be a mass-produced infusion given by a bored clinician once every twenty years or so. Mass produced infusions such as TNF inhibitors today cost less than $10,000, even in the dysfunctional US medical system. So this seems like another example of death for everyone before even the vague possibility of inequality for someone, a position sadly prevalent in many areas of our society:

Let me give you my nightmare scenario for a world of superlongevity. It's a world largely bereft of children where our relationship to our bodies has become something like the one we have with our smart phones, where we are constantly faced with the obsolescence of the hardware and the chemicals, nano-machines and genetically engineered organisms under our own skins and in near continuous need of upgrades to keep us alive. It is a world where those too poor to be in the throes of this cycle of upgrades followed by obsolescence followed by further upgrades are considered a burden and disposable. It's a world where the rich have brought capitalism into the body itself, an individual life preserved because it serves as a perpetual "profit center".

The other path would be for superlongevity to be pursued along my first model of healthcare focusing its efforts on understanding the genetic underpinnings of aging through looking at miracles such as the bowhead whale which can live for two centuries and gets cancer no more often than we do even though it has trillions more cells than us. It would focus on interventions that were cheap, one time or periodic, and could be spread quickly through populations. This would be a progressive superlongevity. If successful, rather than bolster, it would bankrupt much of the system built around the second model of healthcare for it would represent a true cure rather than a treatment of many of the diseases that ail us.

Yet even superlongevity pursued to reflect the demands for justice seems to confront a moral dilemma that seems to be at the heart of any superlongevity project. The morally problematic features of superlongevity pursued along the second model of healthcare is that it risks giving long life only to the few. Troublingly, even superlongevity pursued along the first model of healthcare ends up in a similar place, robbing from future generations of both human beings and other lifeforms the possibility of existing, for it is very difficult to see how if a near future generation gains the ability to live indefinitely how this new state could exist side-by-side with the birth of new people or how such a world of many "immortals" of the types of highly consuming creatures we are is compatible with the survival of the diversity of the natural world.

I see no real solution to this dilemma, though perhaps as elsewhere, the limits of nature will provide one for us, that we will discover some bound to the length of human life which is compatible with new people being given the opportunity to be born and experience the sheer joy and wonder of being alive, a bound that would also allow other the other creatures with whom we share our planet to continue to experience these joys and wonders as well. Thankfully, there is probably some distance between current human lifespans and such a bound, and thus, the most important thing we can do for now, is try to ensure that research into superlongevity has the question of sustainable equity serve as its ethical lodestar.

Link: http://utopiaordystopia.com/2015/01/19/there-are-two-paths-to-superlongevity-only-one-of-them-is-good/

Aneuploidy is the state in which a cell has an abnormal number of chromosomes and is dysfunctional as a result. Like all forms of cellular malfunction, there is more of it in old tissues. But is it significant in aging? In recent years researchers demonstrated that one way of reducing aneuploidy is to boost levels of BubR1, which normally declines with age. As a genetic alteration this extends life in mice, but of course has a range of other effects beyond influencing aneuploidy, so the meaningful mechanism in this extension of healthy life isn't clearly defined. This is the case for many ways to slow aging in mice. Here is a piece on another group studying aneuploidy in aging:

Dr. Dunham has recently focused her efforts on the role of aneuploidy in aging. In the last few years, her lab has generated disomic yeast strains, in which each individual chromosome is duplicated, for all the yeast chromosomes (yeast are haploid organisms and normally only have one set of chromosomes). Interestingly, she found that strains with individually duplicated chromosomes had a dramatic decrease in replicative lifespan. Furthermore, her lab identified a suppressor mutation that rescued lifespan decline in these strains. The suppressor mutation was a missense mutation in Bul1, which is part of the Rsp5 E3-ubiquitin ligase complex and is involved in protein quality control. This finding supports a potential mechanism by which aneuploidy effects aging via perturbing protein quality control.

"My lab has already developed tools for studying aneuploidy using genomics and genetics, and the aging phenotype is just another interesting phenotype that we could apply our suite of existing tools too. I've always been interested in aging. I did a rotation in an aging genetics lab in graduate school. What I like about the aging field also is that so much fundamental biology is touched on by aging. And I really like studying metabolism. If you ask who is still interested in studying metabolism...the answer is the aging people! They get that metabolism is really cool and fundamental! I am interested in what happens in general when you have the wrong number of chromosomes: what things go right, and what things go wrong? Can cells tolerate it, and how do they do so if they can? I think that aging is a good phenotype because it's another aspect of what the cell has to do. Being able to look at a cell from birth to death and across environments and phenotypes and determine where aneuploidy and DNA copy number variation can have an effect, this is just one piece of that."

Link: http://sage.buckinstitute.org/interview-with-dr-maitreya-dunham-aneuploidy-adaptation-and-aging/

Every culture throughout recorded history had its seekers after agelessness, all of whom were deluding themselves. As science replaced alchemy the seekers remained just as prevalent, but adopted the superficial trappings of science in their futile quest. A few even adopted the scientific method, or emerged from the scientific community of the time, and were thus much more rapidly and reliably disappointed by the results of their experiments. The power of the scientific method lies as much in its ability to close off potential paths ahead as to open up new ones: it clears out wishful thinking and delusion for those willing to adopt its rigors.

Technology and other applications of scientific knowledge have steadily lengthened healthy life spans since the late 1700s, once the positive feedback loop of growth in wealth and knowledge really kicked in. For most of the past few hundred years much of that growth has stemmed from reducing the burden of infectious disease, not just a matter of reducing death rates in the young, but also lowering the damage load carried by those reaching middle age and older. Nowadays the continued growth in life span in the wealthier regions of the world is largely achieved through improvements in treating and preventing age-related disease. As before this is a very incremental process, however, with trends adding a year of life expectancy at 60 in every decade.

In the 1970s futurists were very enthused about the prospects for medicine, and especially in the prospects for their own personal longevity. They are all aged to death or near as gone now. They were absolutely wrong about how much could be achieved with then new and exciting applications of biotechnology. Yet so very much has been achieved. In comparison to the tools of today, 1970s biotechnology is clunky and expensive: halls of manually tended machinery have now shrunk to a single chip, and a graduate student today can accomplish tasks in a few weekends that would have strained the largest laboratory in the country for years back then.

So we're all pretty excited about what can be done today in medicine, and the prospects for our own personal longevity. When it comes to our understanding of biochemistry and ability to manipulate our cells, we are as far beyond the 1970s as the 1970s were beyond the gentlemen-scientists working at the end of the 19th century. Why, however, is it different this time? Why are the seekers after agelessness now rational scientists rather than another crop of self-deluded fools? This is a question that crops up. I can recall numerous conversations over the years in which I was informed that someone knew an older fellow who was, back in the day, quite confident in the forthcoming existence of longevity-enhancing therapies, and yet where are those treatments decades later? Nowhere in evidence, but here I stand telling you that now is the time, that the Strategies for Engineered Negligible Senescence (SENS) are a viable, plausible road to rejuvenation treatments that could indefinitely extend human life, and that given sufficient funding we could make enough progress in the next 20 years to hit actuarial escape velocity, the point at which medicine adds more healthy life faster than aging takes it away.

As an aside, there is an unfortunate tendency for successful futurists to be those who predict useful and interesting things to happen soon enough to catch the interest of the audience, regardless of the merits of that claim. Most of the really good communicators have also convinced themselves of their message. It is somewhat challenging for a non-technical person to tell the difference between the self-convinced fraud versus someone who happens to be right about an opportunity for development that happens to be in the near future. Many of these opportunities are in the range of 20-30 years distant, assuming funding goes well at each stage, far beyond the point at which you'll see a lot of corroboration in the form of investment in companies trying to achieve these goals directly.

So why is it different this time? For one there is SENS, a detailed plan of development leading to rejuvenation treatments that could be prototyped in mice given a billion dollars and ten years, give or take. No such plan could have been formed a century ago, and while much of the basic knowledge that informs the SENS viewpoint of aging as an accumulation of cellular and molecular damage existed in the 1970s, SENS could not have been proposed as a serious project at that time even had someone had the realization. There was simply no way to even guess at how much time and money it would have required to build the tools to build the tools to develop the validation of the theories so as to build the tools to build the tools to develop the therapies, and so forth: it would have been a project on the scale of going to the moon, and with far less certainty of success.

More importantly none of the proposed paths to add decades or more of healthy life put forward in past generations, now obviously naive and wrong, were in any way rigorous or supported by large fractions of the scientific community. Only now do we have that, built on the vast body of knowledge of biology accumulated over the last century, and on the new tools of biotechnology of the past few decades. Only now are large numbers of scientists putting their careers and their reputations into the extension of healthy life.

Why is it different this time? The fact that funding for various scientific establishment efforts to extend life is growing rapidly. Most of these are in fact not going to move the needle all that much, but that isn't the point. The point is that the consensus in a significant fraction of the scientific community and its surrounding institutions of funding and review is that the time has come. Investment and interest in any given field are cyclic, and this present cycle will see billions poured into this field, and old narrow views of the implausibility of life extension swept away. Scientists are the arbiters of truth in our culture, though this is sometimes hard to see, and the rest of the world will follow their lead when deciding whether to take something seriously. That will create a feedback loop of funding and progress in which, yes, a lot of less useful work will thrive, but so will significant approaches such as SENS.

None of this was the case for past generations of what turned out to be deluded optimism. It is the case now. The times have changed, and it is different this time around.

In recent years the data gathered from large epidemiological studies have suggested that more time spent sitting correlates with higher mortality independently of the level of exercise undertaken by an individual. This association seems fairly robust as it has been replicated in a number of different data sets and by different research groups. Here is a survey of these results:

The amount of time a person sits during the day is associated with a higher risk of heart disease, diabetes, cancer, and death, regardless of regular exercise. "More than one half of an average person's day is spent being sedentary - sitting, watching television, or working at a computer. Our study finds that despite the health-enhancing benefits of physical activity, this alone may not be enough to reduce the risk for disease." The meta-analysis study reviewed studies focused on sedentary behaviour. The authors found the negative effects of sitting time on health, however, are more pronounced among those who do little or no exercise than among those who participate in higher amounts of exercise.

"The findings suggest that the health risk of sitting too much is less pronounced when physical activity is increased. We need further research to better understand how much physical activity is needed to offset the health risks associated with long sedentary time and optimize our health." Future research will help determine what interventions, in addition to physical activity, are effective against the health risk of sedentary time. "Avoiding sedentary time and getting regular exercise are both important for improving your health and survival. It is not good enough to exercise for 30 minutes a day and be sedentary for 23 and half hours."

Link: http://www.newswise.com/articles/sitting-for-long-periods-increases-risk-of-disease-and-death-regardless-of-exercise

These results suggest that a modest reduction in heart rate leads to a modest increase in life span. The researchers here at least monitored body weight, as I would otherwise immediately suspect inadvertent calorie restriction as a more likely cause of life extension than the proposed mechanisms related to heart rate:

Heart rate correlates inversely with life span across all species, including humans. In patients with cardiovascular disease, higher heart rate is associated with increased mortality, and such patients benefit from pharmacological heart rate reduction. However, cause-and-effect relationships between heart rate and longevity, notably in healthy individuals, are not established. We therefore prospectively studied the effects of a life-long pharmacological heart rate reduction on longevity in mice. We hypothesized, that the total number of cardiac cycles is constant, and that a 15% heart rate reduction might translate into a 15% increase in life span.

C57BL6/J mice received either placebo or ivabradine at a dose of 50 mg/kg/day in drinking water from 12 weeks to death. Heart rate and body weight were monitored. Autopsy was performed on all non-autolytic cadavers, and parenchymal organs were evaluated macroscopically. Ivabradine reduced heart rate by 14% throughout life, and median life span was increased by 6.2%. Body weight and macroscopic findings were not different between placebo and ivabradine. Life span was not increased to the same extent as heart rate was reduced, but nevertheless significantly prolonged by 6.2%.

Link: http://dx.doi.org/10.1007/s00395-014-0460-7

One of the main reasons that we managed to collectively raise $150,000 at the end of 2014 to assist in expanding ongoing SENS Research Foundation's projects is that the whole process of organization started much earlier in the year, somewhere around June in fact. Preparation is everything. It gave people time to think about how they could help, and many people in fact put in a lot of time and money to make it a success. Thank you all.

At this point in the evolution of rejuvenation biotechnology after the SENS model of damage repair raising money is clearly one of the best things we can be doing. Almost all of the present hurdles involve moving early stage research along to the point of prototypes, or even just close enough for biotech entrepreneurs to pick up the ball. That is a long road for some items, such as telomerase and ALT interdiction, but other areas are much closer to realization, and could get to that point given even modest sustained funding. Early stage research is very cheap in comparison to later development in medicine. In fact we can see this happening at the moment for senescent cell ablation with the recent news that a company has been founded to try one possible approach. Maybe it will work out, maybe it won't, but that isn't the point. The point is that all the various biotechnologies needed for a range of different attempts at senescent cell ablation therapies are within striking distance, and this is the first venture of a number that will arise in the next few years, I'd predict.

So what should the Fight Aging! community do this year? There are a few options to consider, along with all of those I haven't yet thought of.

Stick With What Works, Increase the Goal

We ran an impromptu matching fund to raise $60,000 for the SENS Research Foundation in 2013, a more planned matching fundraiser last year that raised $150,000, and we could attempt pretty much the same thing this year for some larger amount. The fundraiser runs via this site, donations are made to the SENS Research Foundation directly, we start by gathering up a matching fund, and the size of that fund determines the goal for later grassroots fundraising. I'll note that at least $45,000 of last year's fund came from one-time sources, so while there are more doors to knock on this year it is still a scary amount of money to raise from the community when you are the one doing the asking. Equally, half-way through the 2014 fundraiser I was fairly convinced I was overreaching and yet that succeeded in the end. So it makes sense to keep raising the target until you fail, as how else can you tell how much the community is willing to provide to help advance research efforts?

Switch to a Science Crowdfunding Platform

Is there a science crowdfunding platform that will give us more than it takes from us? By this I'm skipping over the intangibles to mean that the platform results in more donations than their fee. This could be because of additional audience reach, payment options that are easier for some people than the current PayPal implementation used by the SENS Research Foundation, or some other combination of factors. In the case of Experiment the additional fee is going to be 5% or so, so for a $150,000 project you need to find another $7,500 in donations to cover that.

If I was going to take this approach my contribution would probably be to cover that cost and then help with the materials needed. The real downside of the crowdfunding platform approach is that it is more of a load on the SENS Research Foundation in terms of producing materials: video, glossy PDFs, that sort of thing. Most crowdfunding sites are also going to require some sort of a project specific focus for the fundraiser, and sorting this out and tracking funds later and reporting back on it is a further pain for the Foundation staff. Money always comes with strings, but we want to be helping, not making things harder.

Over the past couple of years my reluctance to engage with science crowdfunding sites has come down to the fact that they really don't have much of a halo of interested users in the same way that Kickstarter does. If you put up a project on Kickstarter you are getting a new audience that wouldn't have otherwise noticed you, but I'm really not seeing that effect in science crowdfunding yet. It is possible that we never will, and that this is an unreasonable expectation. It is also the case that better payment systems don't necessary have a beneficial effect given that the weight of donations to research leans heavily towards a demographic of a few people writing a $10,000 check and putting it in the mail rather than a hundred people each sending $100 via PayPal or credit card.

That said I remain optimistic about the field of crowdfunding for research in the mid- to long-term, whether as a platform for better interacting with your community of supporters or as a way to reach out and expand it. I just question whether it is actually better at this point in comparison to the ad-hoc system we've assembled here in the past few years.

Raise for a Specific Research Project

I should start this with the caveat that you should never approach someone to say "I'm going to give you some money, but it will come with annoying reporting requirements, and you'll have to do more tracking internally as well, oh and you'll have to chase up the people you're funding with it to make them do more of this as well." Past fundraising for the SENS Research Foundation has largely been project agnostic for the reasons given above: we trust them to put the money to where it will do the most good based on the detailed annual reports they publish. If we had all of the relevant connections and life science knowledge, we could spend the money ourselves just as well, but we do not. Middlemen can have an important role in some circumstances.

Would it make a difference to our fundraising if we did lay out a specific project, however? Pick something on the SENS wish list roadmap for 2016 that a rough project plan estimates to cost $200,000 and see how far we get towards making it happen. This has many of the downsides noted above for the crowdfunding approach in that it puts the onus on the SENS Research Foundation and the scientists involved to assist in the production of video and other materials. I have to think that this compares favorably with writing grant proposals, but equally it has in the past proven to be blood from a stone to extract this sort of stuff from researchers, especially updates on ongoing research after the fact.

There is also the question of whether people really are more interested in funding specific projects versus funding a cause or a team. There is a view of the future that sees a large disintermediation of the present review and funding function of research non-profits, drive by an increasingly informed public bypassing these gatekeepers to participate in a science crowdfunding industry. Equally this may be unrealistic: people have limited time and attention, and the reason these gatekeepers exist is because supporters of the cause are willing to pay someone else to take the time to figure out how to make things move faster.

Move Towards Assembling a Tithing Group

This would be more of a radical change, a move away from grassroots fundraising and towards cultivating a smaller group of donors. Much of the success of last year's fundraising came from having a group of people willing to pitch in $5,000 to $20,000 each. It occurs to me that the community of people of unexceptional wealth capable and willing to do this year after year is not well explored at this time. Could Fight Aging! serve as the starting point to build up a group of 100 or so people donating $10,000 apiece to fund research over the next five years? This strikes me as enormously ambitious, especially for someone as little involved in outreach as myself, and would result in big changes to this site and its focus, but the fact that there were a number of people making that leap last year gives me an inkling that this might just be made to work.

Skip to the Chase, Seed Fund a Company

If the Methuselah Foundation can seed fund a new company working on an approach to the SENS-related tactic of senescent cell ablation, why can't we? Seed rounds can be in the low few hundred thousand dollar range for many types of biotechnology nowadays. US law changed not so long ago such that it would be perfectly legal for any group of us to crowdfund a startup's seed round and hand over the equity to the SENS Research Foundation for safekeeping: we'd still be donating to the SENS Research Foundation, but in a more speculative and long-term way.

Ah, but the caveats. Firstly this is highly risky in the same way that funding research is highly risky, but much more so. A majority of the best-looking startup companies vanish into the earth, never to be seen again, and you'll need to go digging to even get some sort of documentation or a published paper out of the effort. Secondly the reason that the Methuselah Foundation can do this is that the organization is headed by a very well connected entrepreneur who has been embedded in the biotech community for some years now: the only reliable way to have the option to fund a seed round at a reasonably price is to know the people who are founding the company in question.

Lastly there is an important element of timing that makes this somewhat challenging. If a company raises a seed round of $100,000 (say), then its founders are looking to raise a few million a few months later, or abandon the effort, one or the other. In biotechnology this usually means the seed round is to get you past some version of "does this actually work?" To close the gap between promising research papers and reality, as it were. Crowdfunding is much less rapid, however, or at least around here it is. Last year's process ran from June to December with a short break in the middle to wonder what I'd got myself into. If you tried to sync that up with the breakneck speed of an early stage company then by the time you finished up, you'd find that they are off into the land of raising millions, and thus you are irrelevant, and if they are not then that's probably a compelling sign not to throw good money after bad.

Lastly there just aren't that many people in the position to start companies to do SENS-relevant things at the moment. I was pleasantly surprised to see one turning up now for senescent cell ablation, a most unexpected outcome this year. If wagering, I'd put a little money on the next set of SENS-related startups to emerge from the folk working on glucosepane breakers, assuming they make good progress on their tooling. In the years ahead there will be ever more opportunities to fund SENS-relevant startup biotech companies, but I suspect the process of lining this all up will be something that has to be accomplished via well connected intermediaries and also tend to happen too rapidly when a possible deal finally arises. A better model is to have someone with the $100,000 to spend right now and run the fundraiser to return that money. But that setup doesn't exactly inspire people to donate.

Suggestions Taken

This meandering post by no means covers every possibility that has occurred to me. Suggestions are always taken. Success in past years was largely a matter of people taking it into their own hands to do something to help, after all.

Much of modern aging research, too much in my view, focuses on regulation of aging and the prospects for changing regulatory processes to modestly slow the progression of age-related frailty and disease. Aging is caused by the accumulation of a few types of cellular and molecular damage and so these regulatory processes and their changes in aging are largely reactions to that damage. They are the wrong place to be intervening for best effect, and the focus should instead be on repair of the root cause damage. That remains a minority view at this time, unfortunately, which is why it is so important to raise enough funding to produce definitive proof of its greater effectiveness as a basis for therapies.

This paper is more indicative of how a majority of researchers think about the situation, however. This view explains why those interested in enhancing longevity are most often found working on expensive, marginal ways to alter the very complex reaction to damage rather than addressing the damage itself:

In the consideration of life-extending effects of aging-modulating drugs, a logical error can occur as a result of reductionist thinking peculiar to gerontologists in the middle of the last century when major aging theories including the free radical theory of aging were proposed. From the reductionist point of view, the organism was considered as a sum of relatively independent processes and mechanical components, and interventions designed to prolong life were seen as those being similar to car repairing. If this were indeed the case, then it would be possible to slow the rate of aging by affecting molecular pathways that influence specific aspects of aging, analogous to how antioxidants can slow down the rate of aging of plastic.

However, by summarizing the accumulated information, one can conclude that a reductionist approach in experimental gerontology has proved rather ineffective until now. This is not surprising, since aging is a classic "complex trait," in other words, a trait that is influenced by a plurality of genetic pathways. For example genome-wide research in Drosophila shows that hundreds of genes are involved in the control of aging. Therefore, it seems very difficult, if not impossible, to develop effective pharmaceutical interventions that may slow aging and extend longevity by targeting single genetic pathways.

On the contrary, more modern systemic ("holistic") thinking considers the organism as a whole. Taking into account the complexity of the aging process, the systemic approach addressed primarily to central regulation mechanisms seems more appropriate to developing aging-modulating treatments. From a systemic point of view, aging is not a disease in the sense of being caused by disturbance in several specific pathway(s), but is rather an inevitable consequence of realization of some (probably still substantially unknown) central regulatory processes making the organism more vulnerable to disease with age. According to these conceptual frameworks, the aging process is not primarily a result of accumulation of stochastic damage but is rather a co-product of developmentally regulated processes.

One potential mechanism of central regulation of the whole life cycle including aging is a process of epigenetic control of gene expression having important features in the given context. Indeed, it is: (1) potentially adaptive; (2) linking development and aging; (3) generalizing at the whole-organism level.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271728/

Factors in the blood that affect the behavior of tissues in beneficial ways are a popular topic in aging research at the moment. Researchers are beginning to identify proteins whose amount in circulation changes in reaction to rising levels of damage in aging, and which if altered in old animals can partially reverse some aspects of age-related decline in tissue function. Aging is one set of changes, but what about other differences between individuals such as the beneficial changes to the operation of metabolism brought on by calorie restriction? Researchers would very much like to recreate calorie restriction benefits without the need to eat less, and as a result of findings elsewhere the approach of altering levels of various factors in the blood is now getting a second look. The example quoted here is a study in cell cultures only, but is still somewhat interesting:

The cumulative effects of cellular senescence and cell loss over time in various tissues and organs are considered major contributing factors to the ageing process. In various organisms, caloric restriction (CR) slows ageing and increases lifespan. Here, we use an in vitro model of CR to study the effects of this dietary regime on replicative senescence, cellular lifespan and modulation of the SIRT1 signaling pathway in normal human diploid fibroblasts.

While all of the reported CR-mediated effects in vitro have been observed after incubation of cells for short periods with CR sera from various species, little is known about the long-term effects of CR serum treatment in cultured cells. An important cellular consequence of the process of ageing is replicative senescence, whereby cells lose their replicative capacity and irreversibly exit the cell cycle. Decreased senescence in vivo is believed to contribute to delayed ageing and the increased tolerance to stress observed in organisms subjected to CR regimens; however, the study of this cellular process in vivo (either in animals or humans) is experimentally challenging. Therefore, we decided to test the effects of CR serum on cellular senescence in vitro using normal human diploid fibroblasts, which undergo replicative senescence after several passages in culture.

We found that serum from calorie-restricted animals was able to delay senescence and significantly increase replicative lifespan in these cells, when compared to serum from ad libitum fed animals. These effects correlated with CR-mediated increases in SIRT1 and decreases in p53 expression levels. In addition, we show that manipulation of SIRT1 levels by either over-expression or siRNA-mediated knockdown resulted in delayed and accelerated cellular senescence, respectively. Our results demonstrate that CR can delay senescence and increase replicative lifespan of normal human diploid fibroblasts in vitro and suggest that SIRT1 plays an important role in these processes.

Link: http://www.impactaging.com/papers/v7/n1/full/100719.html

An intriguing open access paper was published earlier this week in which the authors made significant headway in understanding the details of a mechanism by which flies eliminate less functional cells on an ongoing basis. The researchers then manipulated this mechanism via gene therapy so that a greater proportion of these less fit cells were destroyed, and as a result the genetically altered flies lived longer. The effect on median life span is a 50-60% increase, and for maximum life span a more modest 10-20% gain:

Prolonging lifespan: Researchers create 'Methuselah fly' by selecting best cells

"Our bodies are composed of several trillion cells, and during aging those cells accumulate random errors due to stress or external insults, like UV-light from the sun." But those errors do not affect all cells at the same time and with the same intensity: "Because some cells are more affected than others, we reasoned that selecting the less affected cells and eliminating the damaged ones could be a good strategy to maintain tissue health and therefore delay aging and prolong lifespan."

To test their hypothesis, the researchers used Drosophila melanogaster flies. The first challenge was to find out which cells within the organs of Drosophila were healthier. The team identified a gene which was activated in less healthy cells. They called the gene ahuizotl (azot) after a mythological Aztec creature selectively targeting fishing boats to protect the fish population of lakes, because the function of the gene was also to selectively target less healthy or less fit cells to protect the integrity and health of the organs like the brain or the gut.

Normally, there are two copies of this gene in each cell. By inserting a third copy, the researchers were able to select better cells more efficiently. The consequences of this improved cell quality control mechanism were that the flies appeared to maintain tissue health better, aged slower and had longer lifespans. However, the potential of the results goes beyond creating Methuselah flies, the researchers say: Because the gene azot is conserved in humans, this opens the possibility that selecting the healthier or fitter cells within organs could in the future be used as an anti aging mechanism. For example, it could prevent neuro- and tissue degeneration produced in our bodies over time.

Elimination of Unfit Cells Maintains Tissue Health and Prolongs Lifespan

Individual cells can suffer insults that affect their normal functioning, a situation often aggravated by exposure to external damaging agents. A fraction of damaged cells will critically lose their ability to live, but a different subset of cells may be more difficult to identify and eliminate: viable but suboptimal cells that, if unnoticed, may adversely affect the whole organism. What is the evidence that viable but damaged cells accumulate within tissues? The theory is supported by the experimental finding that clonal mosaicism occurs at unexpectedly high frequency in human tissues as a function of time. Does the high prevalence of mosaicism in our tissues mean that it is impossible to recognize and eliminate cells with subtle mutations and that suboptimal cells are bound to accumulate within organs? Or, on the contrary, can animal bodies identify and get rid of unfit viable cells?

In Drosophila, cells can compare their fitness using different isoforms of the transmembrane protein Flower. The "fitness fingerprints" are therefore defined as combinations of Flower isoforms present at the cell membrane that reveal optimal or reduced fitness. The isoforms that indicate reduced fitness have been called FlowerLose isoforms, because they are expressed in cells marked to be eliminated by apoptosis called "Loser cells". However, the presence of FlowerLose isoforms at the cell membrane of a particular cell does not imply that the cell will be culled, because at least two other parameters are taken into account: (1) the levels of FlowerLose isoforms in neighboring cells: if neighboring cells have similar levels of Lose isoforms, no cell will be killed; (2) the levels of a secreted protein called Sparc, the homolog of the Sparc/Osteonectin protein family, which counteracts the action of the Lose isoforms.

Here, we aimed to clarify how cells integrate fitness information in order to identify and eliminate suboptimal cells. We find Azot expression in a wide range of "less fit" cells, such as WT cells challenged by the presence of "supercompetitors," slow proliferating cells confronted with normal proliferating cells, cells with mutations in several signaling pathways, or photoreceptor neurons forming incomplete ommatidia. In order to be expressed specifically in "less fit" cells, the transcriptional regulation of azot integrates fitness information from at least three levels: (1) the cell's own levels of FlowerLose isoforms, (2) the levels of Sparc, and (3) the levels of Lose isoforms in neighboring cells. Therefore, Azot ON/OFF regulation acts as a cell-fitness checkpoint deciding which viable cells are eliminated. We propose that by implementing a cell-fitness checkpoint, multicellular communities became more robust and less sensitive to several mutations that create viable but potentially harmful cells. Moreover, azot is not involved in other types of apoptosis, suggesting a dedicated function, and - given the evolutionary conservation of Azot - pointing to the existence of central cell selection pathways in multicellular animals.

We show that active elimination of unfit cells is required to maintain tissue health during development and adulthood. We identify a gene (azot), whose expression is confined to suboptimal or misspecified but morphologically normal and viable cells. When tissues become scattered with suboptimal cells, lack of azot increases morphological malformations and susceptibility to random mutations and accelerates age-dependent tissue degeneration. On the contrary, experimental stimulation of azot function is beneficial for tissue health and extends lifespan.

The paper makes for an interesting read, as it is the first I've heard of this line of research and the details of this particular quality control mechanism. I look forward to seeing the results of further studies conducted in mammals whenever they might take place: is the process in fact similar in higher animals such as mammals, and similarly open to beneficial manipulation? The gain in maximum life span here is on a par with that seen in lower animals as a result of boosting the operation of other, better known quality control systems, such as autophagy. There is probably going to be a sizable grey area in the future between the undesirable approach of "messing with metabolism" and the desirable approach of repair of damage as the two distinct possible strategies when building treatments for degenerative aging, and this result is a good illustration of the midpoint of that grey area, I think.

One possibility that occurred to me is that this may be a path towards putting some numbers to the degree to which we should expect stochastic nuclear DNA damage to be a significant contributing cause of degenerative aging. As you might know the consensus is that yes of course the random accumulation of this damage leads to less well regulated cells, and thus should be relevant to aging - and not just in the matter of cancer, but in the more general dysfunction of tissues. This is not a consensus without debate, however, and at present there are no good studies providing evidence to quantify the degree to which nuclear DNA damage contributes to aging. That might fall out of further study of azot, though I see that the categories of less fit cells quoted above include a wide range of states and situations that probably have no direct relationship with nuclear DNA damage.

One of the ongoing themes in stem cell research is that cells and environments in old people do not function correctly, this interferes with most potential treatments in numerous ways, and thus scientists are in search of fixes and workarounds. Most potential applications of regenerative therapies involve the treatment of age-related diseases, and so the industry must address these issues in order to succeed. It is good for all of us that this incentive exists, as it spurs progress in an important area of research. The paper referenced below is a modest example of one approach in this field, in which researchers catalog some of the differences between the stem cells of healthy individuals and heart failure patients, noting that these cause issues when trying to expand a cell sample into a large enough number of cells for a transplant treatment:

Chronic heart failure (HF) is one of the most common causes of death worldwide, and the only radical treatment for severe chronic HF remains to be heart transplantation. It is necessary to search for new therapeutic approaches to restore the structure and function of cardiac muscle. In the past two decades cell therapy has been considered as the prospective therapeutic approach to the treatment of cardiovascular diseases including HF. The cells intended for cell therapy must have certain characteristics: they should be relatively easy available, safe, and demonstrate efficiency in stimulation of reparation of cardiac muscle. Different cell types were tested in regeneration protocols and by now multipotent mesenchymal stromal cells from bone marrow (BM-MMSC) remain to be the most attractive, and one of the best characterized substrates for clinical applications: these cells could be rapidly and efficiently expanded in vitro and this type of cells is known to be immunologically privileged.

Many researchers still believe that the ideal substrate for cell therapy are autologous cells. However, it was demonstrated in several animal-based studies that donor-specific factors could attenuate stem cell functions and reduce regenerative potential. Influence of donor's age and gender on the properties of BM-MMSC has been studied actively in recent years in many laboratories, but the studies of impact of chronic cardiovascular disorders, including HF, on multipotent progenitor cells are limited.

In present work we have found that a number of properties were altered in BM-MMSC derived from HF patients compared to healthy donor-derived BM-MMSC. In particular, in HF-derived BM-MMSC a decrease in proliferative activity during in vitro expansion was detected, accompanied by upregulation of signaling pathways that control both tissue regeneration and fibrosis. We have demonstrated that decrease in efficiency of expansion could be markedly improved by culturing of BM-MMSC under moderate hypoxic conditions and substantial decrease in cell seeding density. Further experiments are necessary to learn how to manipulate the culturing conditions in order to predict and, most importantly, control the balance between proliferation rate, replicative senescence, regenerative potential, pro-fibrotic and anti-fibrotic properties of cellular sample intended for experimental or therapeutic protocols.

Link: http://www.impactaging.com/papers/v7/n1/full/100716.html

This work on iron and aging in nematodes is interesting but still quite speculative at this stage: wait for studies along these lines to take place using mice before paying too much more attention to it.

It's been known for decades that some metals, including iron, accumulate in human tissues during aging and that toxic levels of iron have been linked to neurologic diseases, such as Parkinson's. Common belief has held that iron accumulation happens as a result of the aging process. But research in the nematode C. elegans shows that iron accumulation itself may also be a significant contributor to the aging process, causing dysfunction and malfolding of proteins already implicated in the aging process.

Researchers began manipulating the nematode's diet. "We fed iron to four day-old worms, and within a couple of days they looked like 15 day-old worms. Excess iron accelerated the aging process." Excess iron is known to generate oxidative stress and researchers expected to see changes in the worm based on that toxicity. "Instead, what we saw looked much more like normal aging. The iron was causing dysfunction and aggregation in proteins that have already been associated with the aging process. Now we're wondering if excess iron also drives aging."

Researchers also treated normal nematodes with the FDA-approved metal chelator CaEDTA - a drug that's used in humans at risk for lead poisoning. The drug slowed age-related accumulation of iron and extended the healthspan and lifespan of the nematodes. Researchers also gave the drug to worms genetically bred to develop specific protein aggregations implicated in human disease. The chelator was also protective in those animals. "This is a phenomena that has not been extensively studied by aging researchers and it's an area that has potential for positive exploitation, but CaEDTA has a very blunt mechanism of action and is associated with dangerous side effects in humans and the track record for other chelators is not well established."

Link: http://www.buckinstitute.org/buck-news/there-connection-between-heavy-metals-and-aging

The Methuselah Foundation is one of the more important small non-profits involved in steering the near future course of aging research and human longevity. It is generally the case that the larger non-profits in medical research fund the status quo only, and so it is up to more nimble and driven organizations to make the status quo better - to really change the world, in other words. Organizations like the Methuselah Foundation and its core of dedicated supporters lead the way, change minds, and steer the broader community towards new and better directions more likely to extend healthy lives sooner rather than later.

It is worth remembering that, like the SENS Research Foundation, the Methuselah Foundation grew and established its presence due to the generosity of hundreds of donors of largely modest means. Their support helped to ensure the Foundation's important role in the sweeping changes that have taken place in the field of aging research and its goals over the past decade, shifting the leaders in the field towards open support for treating aging as a medical condition and the goal of extending healthy life spans. In the years since spinning off the SENS Research Foundation, the Methuselah Foundation has focused more on tissue engineering, but that is far from the only research activity funded and promoted by the Foundation staff.

A recent update on the activities of the Methuselah Foundation turned up in my in-box today, and I think many of you will be most interested to see that the Foundation is now funding a biotech startup effort to clear senescent cells and thus remove their contribution to degenerative aging. Senescent cell clearance is on my list as the most likely of the SENS repair-based technologies to be implemented first, even though funding is very limited for this area of research, as (a) there are a range of groups working on the problem or aspects of the problem, and (b) all of the various technologies needed to assemble a viable treatment either exist already or are very close to realization. It is good to see the Methuselah Foundation stepping in to support this field.

2014 was a year to remember. With a $10,000 Methuselah Prize awarded to Dr. Huber Warner of the National Institute on Aging's Interventions Testing Program, the first six teams officially announced for the New Organ Liver Prize, and our first Organovo 3D printer awarded to the Yale School of Medicine, we've certainly been keeping busy.

Thanks to all of you, and especially to the passionate support of our many generous donors, we're also looking forward to an impactful 2015. We're still gathering more teams for the Liver Prize, exploring a possible New Organ Vasculature Challenge with federal agency partners, looking forward to the inaugural Organ Banking Summit in February, and much more.

We closed out last year by taking part in a successful $150,000 fundraiser for the SENS Research Foundation, and we're ringing in the new one with a founding investment in Oisin Biotechnology. We also look forward to sharing more illuminating conversations with you from around the world of tissue engineering and regenerative medicine on our blog, "The Bristlecone."

Backing Oisin Biotechnology

The Methuselah Foundation has become a founding investor in Oisin Biotechnology, Inc, an early-stage company that aims to provide targeted biological solutions to degenerative aging conditions. We are also now represented on Oisin's Board of Directors. Initial research and development at Oisin will focus on controlled removal of senescent cells that underlie certain degenerative aging conditions. Both proprietary treatment protocols as well as proprietary methods for delivery of biologics to affected cells will be employed. Oisin is currently performing in vitro studies to confirm the expected mode of action of its therapy.

"We invested in Oisin," Methuselah CEO Dave Gobel explained, "because of the promise of their highly targeted approach to removing senescent cells without causing collateral damage or side effects. To put it more colloquially, I like to think of this as 'getting the crud out' - one of our key themes at Methuselah." We hope this founding investment will enable Oisin to establish proof of principle (does it work in vitro or not?). If it does work, we believe that Oisin will become extremely important in the field of longevity science - and provide us with a mission-aligned solution that is industrializable by harnessing infotech, biotech, and the body's own systems. We'll keep you posted.

New Federal Grant Program for Organ Cryobanking

We're excited to announce that the Organ Preservation Alliance, one of New Organ's partner organizations, has informed the development of three new federal grant programs by the Department of Defense targeting complex tissue and organ cryobanking for transplantation. These three unique but complimentary "Small Business Innovation Research" (SBIR) grants, the first of their kind, will launch on January 15, 2015. Together, they could fund research for 20 or more U.S. teams, with strong candidates potentially receiving $3-$3.5 million across phase one and phase two awards. Congratulations to the Organ Preservation Alliance for its critical role in this landmark moment for the undervalued field of cryopreservation.

Bowhead Whale Study Published

We've seen great news coverage recently of the bowhead whale research we funded at the University of Liverpool, and the full paper by Dr. Joao Pedro de Magelhaes and his team is being published in the journal Cell Reports. According to Magelhaes, "The bowhead whale is the longest-lived mammal, possibly capable of living over 200 years. Thanks to generous support from the Methuselah Foundation, we sequenced the bowhead genome and transcriptome and performed a comparative analysis with other cetaceans and mammals. We found that changes in bowhead genes related to cell cycle, DNA repair, cancer, and ageing could all be biologically relevant."

Exploring c60oo and Cancer Growth

Ichor Therapeutics, Inc., an exciting pre-clinical biotechnology company funded in part by Methuselah donors, is preparing to commence pilot studies to investigate the effects of c60oo administration on human cancer proliferation in vivo. It has been theorized that c60oo may be a potent inhibitor of primary tumor growth or metastasis. Data about human leukemia growth rates in the presence and absence of c60oo is expected to pave the way for additional studies of c60oo's effects on a variety of tumor models. "We are grateful to the Methuselah Foundation," Ichor CEO Kelsey Moody said recently, "for providing much of the necessary funding for this project, without which this important research could not be completed."

All things being equal if you extend life by slowing aging, meaning a slowing of the pace of damage accumulation, then you end up with a longer period of disease and frailty in later life simply because life is longer overall. More time is spent at a given level of damage. All things are not equal, however, and the mechanisms and interaction between damage and biological systems are quite complicated: it isn't a straightforward linear path from youthful function to aged dysfunction. So the end result of slowing aging by altering the operation of metabolism could be either less frailty or more frailty, and the outcome could vary widely by both species and method of slowing aging.

Overall it is better to aim for rejuvenation through repair of damage rather than altering metabolism to slow down aging by reducing the pace of damage accumulation. In the case of damage repair there is no ambiguity about outcomes: there will be a restored set of biological systems with less dsyfunction as a result, and the more comprehensive the repair treatments, the better the outcome for the treated individual.

Despite the fact that there are now many, many ways of lengthening life in lower animals such as the nematode species Caenorhabditis elegans, I don't recall much in the way of examination of time spent in frailty, as is carried out in this study:

Aging research has been very successful at identifying signaling pathways and evolutionarily conserved genes that extend lifespan with the assumption that an increase in lifespan will also increase healthspan. However, it is largely unknown whether we are extending the healthy time of life or simply prolonging a period of frailty with increased incidence of age-associated diseases. Here we use Caenorhabditis elegans, one of the premiere systems for lifespan studies, to determine whether lifespan and healthspan are intrinsically correlated.

We conducted multiple cellular and organismal assays on wild type as well as four long-lived mutants until animals reached 80% maximum lifespan (insulin/insulin-like growth factor-1, dietary restriction, protein translation, mitochondrial signaling) in a longitudinal manner to determine the health of the animals as they age. We find that some long-lived mutants performed better than wild type when measured chronologically (number of days). However, all long-lived mutants increased the proportion of time spent in a frail state.

Together, these data suggest that lifespan can no longer be the sole parameter of interest and reveal the importance of evaluating multiple healthspan parameters for future studies on antiaging interventions. We show lifespan and healthspan can be separated and all of the long-lived mutants extend the period of frailty as a consequence. If applied to humans, this would likely lead to unsustainable healthcare costs and demonstrates the importance of examining healthspan as opposed to lifespan for future research.

Link: http://dx.doi.org/10.1073/pnas.1412192112

You may be familiar with the research interest in heat shock proteins and their role in cellular health and repair. They are a part of the reaction to heat necessary to allow individuals to survive high temperatures. There is an analogous but different reaction to the other end of the temperature scale, also intended to assure survival under potentially damaging low temperatures. Here is an interesting result in which researchers investigate some of the mechanisms involved in the cellular reaction to cold, arising out of the study of hibernation in mammals:

It has long been known that during hibernation, where a mammal's core temperature cools to well below normal body temperature, synapses (the connections between brain cells) are depleted. This allows the animal to enter a state of 'torpor', similar to a very deep sleep but where no brain activity occurs, allowing the animal to survive without nutrition for weeks or months. As the animal comes out of hibernation and warms up, connections between brain cells are reformed and the number of synapses once again rises, restoring normal brain activity. In humans, a reduction in body temperature (hypothermia) is known to protect the brain. For example, people have survived hours after a cardiac arrest with no brain damage after falling into icy water. Artificially cooling the brains of babies that have suffered a loss of oxygen at birth is also used to protect against brain damage.

Cooling and hibernation lead to the production of a number of different proteins in the brain known as 'cold-shock' proteins. One of these, RBM3, has been associated with preventing brain cell death, but it has been unclear how it affects synapse degeneration and regeneration. Knowing how these proteins activate synapse regeneration might help scientists find a way of preventing synapse loss, without the need for actual cooling.

Researchers reduced the body temperature of healthy mice to 16-18ºC - similar to the temperature of a hibernating small mammal - for 45 minutes. They found that the synapses in the brains of these mice, which do not naturally hibernate, also dismantled on cooling and regenerated on re-warming. The team then repeated the cooling in mice bred to reproduce features of neurodegenerative diseases (Alzheimer's and prion disease) and found that the capacity for synapse regeneration disappeared as the disease progressed, accompanied by a disappearance of RBM3 levels. When the scientists artificially boosted levels of the RBM3 protein they found that this alone was sufficient to protect the Alzheimer and prion mice, preventing synapse and brain cell depletion, reducing memory loss and extending lifespan.

Link: http://www.mrc.ac.uk/news-events/news/scientists-link-brain-cooling-and-prevention-of-neurodegeneration/

Looking over the day to day aspects of an ordinary life that an individual has control over, those with the greatest negative influence on long-term health are as follows: a diet that leads you to be overweight or obese for years, lack of regular exercise, and smoking. Studies suggest that these cause around the same level of harm, a loss of perhaps five years to a decade of life expectancy, and the addition of many more years spent in ill health rather than in good health. In the golden future ahead medicine will be capable of efficiently and effectively rescuing you from all the consequences of poor health practices, but we do not yet live in that future, and neglecting your health today reduces the odds of living to benefit from the impressive medical technologies of tomorrow.

There are of course strong correlations between diet, level of exercise, and excess weight, but that doesn't stop epidemiologists from peering deeply into the statistics of large population studies to try to pick apart the various contributions to shorter rather than than longer lives. This latest study of hundreds of thousands of people provides confirming evidence for a number of themes set out in past research. For example, it is fairly easy to establish sizable differences between the long term outcome for no exercise and the long term outcome for regular moderate exercise, but there is little to show that any greater benefits result from more exercise or different types of exercise. Obviously there are studies of elite athletes such as cyclists wherein these individuals live a decade longer than the rest of the population, but this is only correlation: are they long-lived because of the exercise, or is it instead because only the most robust individuals tend to become successful athletes? For everyone else there is no good study out there to say that twice as much exercise is twice as good. The big threshold is between none and some, and after that the data is increasingly nebulous.

Lack of exercise responsible for twice as many deaths as obesity

Physical inactivity has been consistently associated with an increased risk of early death, as well as being associated with a greater risk of diseases such as heart disease and cancer. Although it may also contribute to an increased body mass index (BMI) and obesity, the association with early death is independent of an individual's BMI. To measure the link between physical inactivity and premature death, and its interaction with obesity, researchers analysed data from 334,161 men and women across Europe participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Using the most recent available data on deaths in Europe the researchers estimate that 337,000 of the 9.2 million deaths amongst European men and women were attributable to obesity (classed as a BMI greater than 30): however, double this number of deaths (676,000) could be attributed to physical inactivity. The researchers found that the greatest reduction in risk of premature death occurred in the comparison between inactive and moderately inactive groups. The authors estimate that doing exercise equivalent to just a 20 minute brisk walk each day - burning between 90 and 110 kcal ('calories') - would take an individual from the inactive to moderately inactive group and reduce their risk of premature death by between 16-30%. The impact was greatest amongst normal weight individuals, but even those with higher BMI saw a benefit.

Physical activity and all-cause mortality across levels of overall and abdominal adiposity in European men and women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC)

The higher risk of death resulting from excess adiposity may be attenuated by physical activity (PA). However, the theoretical number of deaths reduced by eliminating physical inactivity compared with overall and abdominal obesity remains unclear. We examined whether overall and abdominal adiposity modified the association between PA and all-cause mortality and estimated the population attributable fraction (PAF) and the years of life gained for these exposures.

This was a cohort study in 334,161 European men and women. The mean follow-up time was 12.4 y, corresponding to 4,154,915 person-years. Height, weight, and waist circumference (WC) were measured in the clinic. Significant interactions (PA × BMI and PA × WC) were observed, so hazard ratios were estimated within BMI and WC strata. The hazards of all-cause mortality were reduced by 16-30% in moderately inactive individuals compared with those categorized as inactive in different strata of BMI and WC. Avoiding all inactivity would theoretically reduce all-cause mortality by 7.35%. Corresponding estimates for avoiding obesity (BMI of more than 30) were 3.66%.

The greatest reductions in mortality risk were observed between the 2 lowest activity groups across levels of general and abdominal adiposity, which suggests that efforts to encourage even small increases in activity in inactive individuals may be beneficial to public health.

The difference in projected mortality reductions from eliminating lack of exercise versus eliminating clinical obesity stems, I think, from the demographics: many more people live sedentary lives than are overweight to that level.

Synapses of the neuromuscular junction (NMJ) connect nerves to muscles. Researchers have observed age-related detrimental changes in the NMJ and its ability to regenerate, though at this point it isn't completely clear how these alterations arise from underlying damage. Here is an open access review on this topic:

Autopsy studies in persons who died of acute trauma while relatively healthy have shown that aging is associated with a gradual loss of motor neurons. The mechanism that leads to neuronal loss with aging is still unclear and may involve both impaired trophic signaling from the central nervous system, local degeneration, and feedback from dysfunctional muscle.

Regardless of the cause, when a motor neuron is lost, fibers previously innervated by that neuron, globally defined as a motor unit, are no longer controlled by the nervous system and fail to contribute to the force generated during a volitional muscle contraction. In the attempt to counteract the functional consequence of this process, denervated orphan fibers express proteins and produce chemotactic signals that stimulate the sprouting of new dendrites from residual motor neurons. This process leads re-innervation by the expansion of pre-existing motor units and is aimed at returning to function previously denervated muscle fibers. This dynamic denervation/re-innervation cycle successfully compensates for neuronal loss, with little decline in global strength and only slightly reduced control. However, there is evidence that this compensatory mechanism starts failing with aging. Some denervated fibers are not successfully re-innervated, become apoptotic, and are not replaced by new fibers. It is hypothesized that this phenomenon contributes to a progressive decline in muscle mass and strength with aging.

The reason for a progressive impairment of the re-innervation process with aging is unknown, but some lines of evidence point to changes that occur with aging in the neuromuscular junction (NMJ), which is the synaptic interface between a branch of a motor neuron and muscle cells. Over the last decade, age-associated degeneration of the NMJ has been reported. It has been proposed that such changes may be causally related to the decline in muscle mass and function that occurs in most aging individuals. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. In this report, we review our current understanding of the events that lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. We propose that interventions aimed at preventing the deterioration of the NMJ should be aimed at reversing the mechanisms that lead to NMJ degeneration with aging. It is important to underline that our comprehension of the global mechanism that lead to NJM impairment with aging is still patchy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127816/

Researchers are making further progress towards fully functional muscle tissue grown from cells, though at this point the principal use for such engineered tissue is in research rather than treatment. Scaling up the size of the tissue produced remains a tough challenge due to the need to produce complex blood vessel networks within the engineered tissue. This is why techniques such as decellularization of a donor organ are making headway, as that provides a scaffold complete with a framework for blood vessels and the chemical cues needed to guide cells to repopulate them, something that cannot yet be produced from scratch:

Researchers started with a small sample of human cells that had already progressed beyond stem cells but hadn't yet become muscle tissue. They expanded these "myogenic precursors" by more than 1000-fold, and then put them into a supportive, 3D scaffolding filled with a nourishing gel that allowed them to form aligned and functioning muscle fibers. "We have a lot of experience making bioartifical muscles from animal cells in the laboratory, and it still took us a year of adjusting variables like cell and gel density and optimizing the culture matrix and media to make this work with human muscle cells."

Researchers subjected the new muscle to a barrage of tests to determine how closely it resembled native tissue inside a human body. They found that the muscles robustly contracted in response to electrical stimuli - a first for human muscle grown in a laboratory. They also showed that the signaling pathways allowing nerves to activate the muscle were intact and functional. To see if the muscle could be used as a proxy for medical tests, the researchers studied its response to a variety of drugs, including statins used to lower cholesterol and clenbuterol, a drug known to be used off-label as a performance enhancer for athletes. The effects of the drugs matched those seen in human patients. The statins had a dose-dependent response, causing abnormal fat accumulation at high concentrations. Clenbuterol showed a narrow beneficial window for increased contraction. Both of these effects have been documented in humans. Clenbuterol does not harm muscle tissue in rodents at those doses, showing the lab-grown muscle was giving a truly human response.

Link: http://www.pratt.duke.edu/news/first-contracting-human-muscle-grown-laboratory

Over the decades to come we will become an immortal species. Immortality is a word somewhat degraded from its old absolute meanings, and now people tend to use it as a lazy shorthand for an end to degenerative aging and disease achieved through medical science, such that no-one will grow frail or die. In that sense immortality means a life expectancy of about a thousand years or so given today's accident rates, but there is no reason to expect those rates to stay the same. Imagine every science fiction technology that might possibly be developed over the next few centuries, all of which will be applied to reduce the risk of injury and accident in everyday life. That will happen. It won't stop there, of course. A life expectancy of millions of years, involving a transition to become something far larger and more resilient than the present human form, existing as a distributed machine entity that can shrug off local supernovae as a passing inconvenience - well, that also is on the cards. Someone alive today will do that or something similar: all it takes is for that person to live sufficiently far into the decades ahead to enter the time in which medical advances increase future life expectancy faster than aging eats it away.

The big deal in today's advocacy is to help determine whether it is plausible to talk about people in middle age reaching that upward curve of life expectancy versus today's newborns. That latter demographic are, I think, almost certainly going to benefit from a life no longer limited by aging. They have time to wait out half a century of technological development at today's breakneck pace. It seems unlikely that they will miss out. The point of advocacy is to speed up what is inevitable for the 2060s and make a reality for the 2030s, as that is by no means a sure thing. There are all too many examples in the past of technological innovators and early advances making their mark and setting out the foundations of their field, only for it to take decades for interest to grow to the point of widespread development and availability.

Immortality as a term is often used to mock people who aim to speed progress towards even modestly extended life spans, attained through advances in medicine. This is somewhat interesting given modern cultural relationships with death. We have become a society that hides the ugly reality of the end of life behind curtains. It is the thing not shown, not talked about. I was struck by this comment from a writer who attained some popularity a little while back:

Living Longer, Dying Differently

"We're seeing death in a new way. Instead of taking it for granted, the people I know see it as a personal catastrophe. I get emails from people who are actually surprised that someone has died. They regard it as an injustice. I understand their feelings, I get it, but this is a fairly new perspective on death. Nobody in the 1900s would have regarded death as a personal catastrophe. They would have mourned and might have been grief-stricken, but they saw death all around them."

This is another part of the strange puzzle that is the indifference and even hostility of the public at large towards efforts to treat aging as a disease and thus extend healthy life: (a) few people acknowledge death and aging in the same way as was the case in the past, (b) yet billions are spent on obviously fake ways to obscure the cosmetic consequences of aging, or to try to slow its progression, and (c) at the same time all sorts of accusations are thrown at those who are engaged in serious scientific work to actually slow or reverse aging, while (d) people are largely supportive of efforts to treat specific conditions that are caused by aging, such as cancer and Alzheimer's disease. I have always found this mix of views and opinions, often all held at the same time by a single individual, to be mystifying.

One of the ways in which people reject even the possibility of modest life extension is to talk about how bored they would be, and how terrible it is to be alive and bored versus dead. After ten years of following progress in longevity science and advocacy for longer healthy lives it remains unclear to me just how much of that is a matter of rolling out any old argument to justify a predetermined position of opposition, the pro-aging trance as Aubrey de Grey has it, versus it being an actual heartfelt belief in the endless dull grey doldrums that await should anyone dare set foot past their 120th year of life. Like many of the arguments against treating aging as a disease and extending healthy lives as far as possible as quickly as possible, it doesn't stand up to even a cursory logical examination. In all probability it is not meant to - that isn't the point.

Longer Lives and the Alleged Tedium of Immortality

Categorical desires are more significant desires. They are akin to life projects or plans. They are desires around which our self-worth is organised, e.g. the desire to write a great novel, raise happy and successful children, make important scientific discoveries, and so forth. Williams claims that the satisfaction of contingent desires, while important, is not really what makes life worth living. It is the satisfaction of categorical desires that does that. Since they are the focal point of what we do on a daily basis, it is their satisfaction that makes us want to live. Williams's worry is that there are only so many categorical desires that one self can pursue. In the course of an immortal life, you would end up pursuing and satisfying every achievable categorical desire. Eventually, you would have nothing left to make your life worth living. You would be bored, listless and tired of life.

Which all seems pretty silly to be concerned about to me. Boredom is a high class problem to have in comparison to pain, frailty, and the drawn-out death of everyone you care about. First things first: make the world a better place incrementally, and don't try to pretend that arm-waving about mental states in as yet hypothetical futures are in any way important in comparison to the prevention of suffering and death today.

Many of the alterations found to extend life in lower animals like the nematode species Caenorhabditis elegans involve changes in the response to cellular stresses such as heat, starvation, and rising levels of oxidative damage due to cellular and other dysfunctions in aging. Stress response mechanisms such as increased cellular housekeeping and repair activities are important determinants of longevity in short-lived animals, but evolution has not optimized their operation for the longest possible life span. Thus a range of genetic changes can make these systems work more effectively from that perspective. Here is another example:

Stress is a fundamental aspect of aging, but it is unclear whether the molecular mechanisms underlying stress response become altered during normal aging and whether these alterations can affect the aging process. In this study, we found a GATA transcription factor called egl-27, whose targets are significantly enriched for age-dependent genes and stress response genes, and whose expression increases with age.

In contrast to previous work describing factors that are causal for aging, we found that egl-27 activity is likely beneficial for survival since egl-27 overexpression extends lifespan. egl-27 promotes longevity by enhancing stress response; specifically, increased levels of egl-27 protect animals against heat stress, while reduced egl-27 activity impairs survival following heat and oxidative stress. These results suggest that aging is not simply a process of constant decline. Some factors, such as egl-27, are more active in old animals, working to restore organismal function and to improve survival. Our work offers novel insight into the interplay between stress and aging, and suggests that aging is not simply a process of moving from an ideal young transcriptome to an inadequate old transcriptome. Rather, age-dependent changes in gene expression are likely comprised of a mix of beneficial, detrimental, and neutral changes.

Link: http://dx.doi.org/10.1371/journal.pgen.1003108

Comparative biology is a field gathering momentum these days. The tools of biotechnology have advanced to the point at which it is worth asking exactly how it is that some species are longer-lived, or more resistant to cancer, or capable of regenerating organ damage and lost limbs. It is especially useful to find similar species in which one is very different from the other in one of these aspects, as that gives a better chance of pinning down the important mechanisms. The end goal is better medicine: is there any possibility of deriving the basis for enhancements or therapies for humans from the longevity of whales, or the cancer immunity of naked mole-rats, or the regenerative prowess of salamanders? The answer will probably vary on a case by case basis: it is not unreasonable to expect that some aspects of biology in another species will be very hard to recreate in humans. The only way to find out is to make further progress in research.

Bats are on the list of exceptional species for many of the same reasons as those mentioned above, though not yet as well studied as naked mole-rats or salamanders. The evolution of flight has necessitated a set of unusual metabolic adaptations for a mammal, and as a result there are bats that are certainly unusually long-lived for their size, possibly cancer resistant, and so forth. This is an opportunity for researchers to learn more about how the operation of metabolism determines these outcomes:

The bat immune system is astonishingly tolerant of most pathogens. Evidence is mounting that bats can serve as reservoirs of many of the world's deadliest viruses, yet bats appear largely immune to the many viruses they carry and rarely show signs of the diseases that will rapidly overwhelm any human, monkey, horse, pig or other mammalian host the microbes manage to infiltrate. Scientists have also learned that bats live a seriously long time for creatures of their small size. The insectivorous Brandt's bat of Eurasia, for example, weighs an average of just six grams, compared with 20 grams for a mouse. But while a mouse is lucky to live for a year, the Brandt's bat can survive well into its 40s. Bats may be girded against cancer, too. "At this stage, the evidence is anecdotal. But of all the bat biologists I've spoken with, I've only heard of one or two cases of bat tumors."

Researchers found an "unexpected concentration" of genes involved in repairing damaged DNA. Those fix-it factors, the scientists proposed, are the bat's solution to the blistering demands of flight. When a bat flies, its heart beats an impressive 1,000 times a minute, and its metabolism ramps up 15-fold over resting rate. By contrast the metabolism of a running rodent is seven times normal, "and that's only for a short burst, whereas a bat can fly at 15-fold metabolic rate for hours." All that fiery flapping ends up generating a huge number of metabolic byproducts called free radicals, which could mutilate the bat's DNA were it not for its extra-strength molecular repair crew. And countering DNA damage happens to be a great strategy for overall health, which could explain bats' exceptional longevity and apparent resistance to cancer. Researchers suggest that changes to the bat's immune system originated as part of the heightened demand for DNA repair, and later proved valuable for its general life strategy.

Link: http://www.nytimes.com/2015/01/13/science/no-time-for-bats-to-rest-easy.html

Most people would like to focus on the impact of regenerative medicine on age-related conditions, but there is every reason to suspect the existence of a negative impact in the other direction. These conditions may well have varied detrimental effects on the class of cell transplant therapies that are presently fairly widely available via medical tourism. Aging is a matter of cellular and molecular damage, but damage spirals out to cause systematic dysfunction that in turn leads to more and different forms of damage: it is an accelerating curve downwards towards frailty and death once it gets going in earnest. These later types of damage and system failure can certainly turn around and influence the progression of earlier root cause damage, and can also potentially interfere in efforts to fix that root cause. It is the same in every complex machine, and things can break in ways that actively hinder repair. It all depends on the details of course, but even though researchers can now very partially treat the attenuation of a few of the various important cell populations and loss of tissue maintenance via cell transplants, that doesn't mean there is a direct and unhindered path to the goal of ending this contribution to aging.

So far the data somewhat mixed on the degree to which cell transplant treatments work less well in the old than in the young. A number of studies suggest that old stem cells can work just as well as young ones, if given the same cues. Other studies suggest the opposite, and it may well be that outcomes can vary widely by cell type and by the methodologies used in the clinic. Many types of stem cell transplant are producing clear and measurable benefits, and are somewhat better than any of the other available treatment options, but others are struggling in the labs or trials to bring reliable benefits to older patients.

A while back I suggested that we should feel fairly good about the long term development of regenerative medicine and tissue engineering as it pertains to aging because near all of the potential profits in this industry involve treating age-related diseases. Therefore the research and development community is highly motivated to identify and fix all of the potential problems inherent in treating older people. At the core that essentially boils down to understanding why stem cell activity fails with age, and in enough detail to be able to safely reverse that process at least for the duration of a cell therapy, but there will be much more to than that. Cell therapies themselves are going to become far more broad than simply a matter of stem cells and transplants. Ultimately the goal is a sophisticated control over cellular behavior wherever those cells might be. Currently the tools and outcomes are very crude, but they will become much sharper in the years ahead.

Here is a consideration of some of the hurdles that might be presented by the existence of specific age-related diseases in a patient, considered distinctly from the underlying aging process. What to do when one part of the machinery is very much more broken in this particular machine? That line of thought seems useful, I think, all part of the nuts and bolts of making the next generation of therapies work reliably and well:

Is stem cell therapy less effective in older patients with chronic diseases?

A promising new therapeutic approach to treat a variety of diseases involves taking a patient's own cells, turning them into stem cells, and then deriving targeted cell types such as muscle or nerve cells to return to the patient to repair damaged tissues and organs. But the clinical effectiveness of these stem cells has only been modest, which may be due to the advanced age of the patients or the effects of chronic diseases such as diabetes and cardiovascular disease.

Autologous Stem Cell Therapy: How Aging and Chronic Diseases Affect Stem and Progenitor Cells

Cardiovascular diseases (CVD), particularly coronary artery disease (CAD), are the most frequent causes of mortality worldwide, and along with metabolic pathologies, especially diabetes mellitus type 2 (T2DM), they approach an epidemic status. An ongoing high frequency of CVD is caused both by the progressive aging of the population and an unhealthy lifestyle associated with risk factors such as obesity, hyperglycemia, hyperlipidemia, and arterial hypertension, which promote early development of atherosclerosis and progression of cardiovascular pathologies.

Aging is characterized by numerous morphological and functional changes within different tissues and organs. The elasticity of blood vessels declines with age along with an increase in their stiffness, which predetermines the progression of arterial hypertension. As people age, their adipose tissue mass increases, while their muscle volume decreases, leading to the development of insulin resistance, the most important pathogenic factor of T2DM. Aging is also associated with comorbidities, the simultaneous presence of two or more different diseases, often with chronic long-lasting progression. The most frequent age-associated comorbidities confounding each other are CAD and T2DM and obesity, arterial hypertension, and T2DM.

The target affected by the most CVD risk factors is the blood vessel wall. Endothelial dysfunction is considered to be the key pathogenic mechanism of angiopathies associated with CAD and T2DM. It should be noted that endothelial dysfunction develops as a result of the interaction of different risk factors, such as insulin resistance, hyperglycemia, and dyslipidemia. The long-term presence of these factors affects endothelial cells and promotes their apoptosis, which leads to the nitric oxide (NO) production failure. As a consequence, the vasodilatation and anti-aggregation functions of the endothelium are dysregulated along with its ability to inhibit smooth muscle cell proliferation. These factors potentiate atherosclerosis progression, forming the morphological basis of CAD.

Many types of stem/progenitor cells, including mesenchymal stem cells (MSCs), have already been used in clinical trials of cell therapy for ischemic pathologies, and their safety and feasibility have been demonstrated, but the clinical effectiveness of these protocols was relatively modest and could not corroborate the promising results of preclinical studies. One reason for the insufficient effectiveness of autologous cell therapy may be a lack of understanding about stem/progenitor cells properties in patients with CVD. Most data regarding the regenerative potential of these cells were obtained from cells derived from relatively healthy young donors. However, aging and disease itself may negatively affect stem/progenitor cells and their microenvironment, and impaired stem/progenitor cell functional properties may diminish the effectiveness of autologous cell therapy in aged patients with CAD and metabolic disorders. In this review, we analyze how aging and chronic diseases such as CAD and T2DM affect the properties of stem/progenitor cells.

Contact inhibition is a mechanism that suppresses cell division, halting the cell cycle in a densely packed cluster of cells. Much more efficient contact inhibition is presently a leading candidate for the reason why naked mole-rats do not suffer cancer: cancer creates dense masses of cells, and thus is halted at the outset in this species. There is considerable interest in the research community in finding ways to exploit this sort of mechanism, bringing it to humans as a therapy of some sort. Hence investigations are presently underway on a range of related mechanisms in cellular biology.

Here a researcher focused on the role of mTOR considers contact inhibition in that context, which spans cancer, cellular senescence, and numerous other aspects of aging. Of particular interest are the mechanisms determining the difference between reversible arrest of cell division, called quiescence, and irreversible arrest as occurs in cellular senescence:

Numerous studies have been aimed to pinpoint the difference between quiescence and senescence based on either the point of cell cycle arrest, the nature of stresses or peculiarities of Cyclin Dependent Kinase-inhibitor (CDKi)-induced arrest (p21 versus p16). Yet, despite all efforts, the distinction remained elusive. In fact, the difference between quiescence and senescence lies outside the cell cycle. A senescent program consists of two steps: cell cycle arrest and mitogen-activated and growth-promoting signaling pathways. Rapamycin suppresses geroconversion, maintaining quiescence instead. Furthermore, any condition that directly or indirectly inhibits mTOR in turn suppresses geroconversion.

The two-step model is applicable to contact inhibition. Given that contact inhibition is reversible, we predicted that mTOR is inhibited. In fact, we found that mTORC1 targets are dephosphorylated in contact inhibited cells. Furthermore, activation of mTOR shifts reversible contact inhibition towards senescence. Thus, it is deactivation of mTOR that suppresses geroconversion in contact inhibited cells. Deactivation of mTOR was associated with induction of p27. In cancer cells, there is no induction of p27 in high cell density. Accordingly, cancer cells do not get arrested in confluent cultures.

There is a complex relationship between p27 and mTOR. It turned out that the mTOR pathway was inhibited in dense cultures of cancer cells. Yet, cancer cells do not induce p27 and do not undergo contact inhibition. mTOR is constitutively activated in cancer and induction of p21 by itself does not inhibit mTOR. So why mTOR is deactivated not only in contact-inhibited but also in confluent cancer cells? The answer is that cancer cells with highly increased metabolism rapidly exhaust and acidify the medium, thus inhibiting mTOR by starvation-like mechanism. In fact, change of the medium restored mTOR activity. Therefore, in normal cells with low metabolism, mTOR is deactivated by contact inhibition and the change of the medium only marginally affects mTOR. In cancer cells, mTOR is inhibited due to exhaustion of the medium. And some cell lines are somewhere in between.

Link: http://www.impactaging.com/papers/v6/n12/full/100714.html

This popular press article takes a look at some of the present initiatives aimed at producing ways to treat aging and extend healthy life spans. The world at large is slowly coming to notice the position of the more forward-looking factions of the research community, which is that aging is just another medical condition and thus amenable to treatment:

In Palo Alto in the heart of Silicon Valley, hedge fund manager Joon Yun is doing a back-of-the-envelope calculation. According to US social security data, he says, the probability of a 25-year-old dying before their 26th birthday is 0.1%. If we could keep that risk constant throughout life instead of it rising due to age-related disease, the average person would - statistically speaking - live 1,000 years. Yun finds the prospect tantalising and even believable. Late last year he launched a $1m prize challenging scientists to "hack the code of life" and push human lifespan past its apparent maximum of about 120 years (the longest known/confirmed lifespan was 122 years).

Yun believes it is possible to "solve ageing" and get people to live, healthily, more or less indefinitely. His Palo Alto Longevity Prize, which 15 scientific teams have so far entered, will be awarded in the first instance for restoring vitality and extending lifespan in mice by 50%. But Yun has deep pockets and expects to put up more money for progressively greater feats. He says this is a moral rather than personal quest. Our lives and society are troubled by growing numbers of loved ones lost to age-related disease and suffering extended periods of decrepitude, which is costing economies. Yun has an impressive list of nearly 50 advisers, including scientists from some of America's top universities.

In September 2013 Google announced the creation of Calico, short for the California Life Company. Its mission is to reverse engineer the biology that controls lifespan and "devise interventions that enable people to lead longer and healthier lives". Though much mystery surrounds the new biotech company, it seems to be looking in part to develop age-defying drugs.

In an office not far from Google's headquarters in Mountain View, with a beard reaching almost to his navel, Aubrey de Grey is enjoying the new buzz about defeating ageing. For more than a decade, he has been on a crusade to inspire the world to embark on a scientific quest to eliminate ageing and extend healthy lifespan indefinitely (he is on the Palo Alto Longevity Prize board). It is a difficult job because he considers the world to be in a "pro-ageing trance", happy to accept that ageing is unavoidable, when the reality is that it's simply a "medical problem" that science can solve. Just as a vintage car can be kept in good condition indefinitely with periodic preventative maintenance, so there is no reason why, in principle, the same can't be true of the human body, thinks de Grey. We are, after all, biological machines, he says.

His claims about the possibilities (he has said the first person who will live to 1,000 years is probably already alive), and some unconventional and unproven ideas about the science behind ageing, have long made de Grey unpopular with mainstream academics studying ageing. (Even his critics say he funds some good science, however). But the appearance of Calico and others suggests the world might be coming around to his side, he says. "There is an increasing number of people realising that the concept of anti-ageing medicine that actually works is going to be the biggest industry that ever existed by some huge margin and that it just might be foreseeable."

Link: http://www.theguardian.com/science/2015/jan/11/-sp-live-forever-extend-life-calico-google-longevity

Mitochondria are the powerplants of the cell, more or less. There is a herd of mitochondria in every cell, dividing like bacteria as necessary to keep up their own numbers. Their most important - but by no means only - activity is the generation of adenosine triphosphate (ATP) molecules used as chemical energy stores to power cellular processes. Mitochondria have their own DNA separate from that in the cell nucleus, and it encodes a few vital pieces of protein machinery used in the process of generating ATP. Unfortunately this DNA often becomes damaged in ways that evade cellular quality control mechanisms and lead to a takeover of the cell by malfunctioning mitochondria. The details of this takeover are still under investigation: researchers never see it happening, only the before and after state, which suggests that it is fairly rapid at least. Cells in this dysfunctional state are thought to contribute to a range of age-related conditions by exporting a flood of reactive molecules and damaged proteins into surrounding tissues.

One of the challenges in studying the progression of mitochondrial damage is that mitochondrial dynamics are highly complex. Mitochondria are like bacteria in that they multiply by division, copying their DNA and assembling new ATP-creation machinery in the process. Equally they are also like other cell components in that various complicated processes monitor them and destroy them when they show signs of wear. Further, they can also fuse together, and any two individual mitochondria can contain more than one copy of the mitochondrial genome and differing amounts of molecular machinery. To make matters even more entertaining individual mitochondria promiscuously swap components of that molecular machinery between one another. So you can probably see that it is not exactly straightforward to track the process by which a few thousand of these entities in one cell move rapidly from a state in which one mitochondrion has damaged DNA to that same DNA damage being present in all of the mitochondria. There are dozens of distinct mechanisms at work, few of which are fully understood at this time, and all of which have their own particular constraints and reactions to circumstances.

As is the case for many areas in aging, however, researchers could skip over all of this complexity and bypass full understanding in order to sprint down a more direct path towards treatments. The SENS approach to work on rejuvenation treatments, for example, picks out provision of proteins encoded in mitochondrial DNA as the key point. Provided that those proteins are supplied, it doesn't matter what happens to the mitochondrial DNA, as the necessary machinery is still there. The mitochondria will continue to function correctly rather than malfunction. On that basis there are a number of ways to go: deliver replacement mitochondrial genomes while clearing out existing genomes, put copies of mitochondrial genes into the cell nucleus (plus solve the thorny problem of how to transport the proteins produced back into the mitochondria), deliver RNA that will manufacture proteins at the mitochondria, and so forth. None of these methods requires a full understanding of how mitochondrial damage progresses in order to be effective, but as is usually the case in these matters none of them are well funded in comparison to efforts to generate the full understanding of mitochondrial dynamics. Science as practiced is very much biased towards the generation of understanding first and foremost, which sometimes leaves practical paths towards treatments lost and languishing.

In any case, back to the complexity of mitochondrial dynamics: there is yet another level to all of this that has come under investigation in recent years, which is that cells can under some circumstances exchange components such as mitochondria. Stem cells have been shown to donate mitochondria to other cells in tissues where they are needed due to dysfunction, for example. Here researchers investigate another case in which this happens, making use of some of the more recent advances in the tools of biotechnology:

Wandering mitochondrial DNA hint at new ways to fight disease

Researchers discovered that when mitochondrial DNA was removed from mouse models of breast cancer and melanoma, after about a month or so, this DNA was naturally replaced by the surrounding healthy tissue. This allowed the cancer to form tumours and continue spreading around the body, because mitochondrial DNA is responsible for encoding key proteins that are used in the process of converting the energy from our food into the chemical energy that we use to fuel our brain and muscle function.

"Initially we thought the cells had learned to grow without needing mitochondrial DNA. But when we presented the research at a conference, a well-known scientist asked if we had tested the growing cells to see if they contained mitochondrial DNA. We hadn't. Our findings overturn the dogma that genes of higher organisms are usually constrained within cells except during reproduction. It may be that mitochondrial gene transfer between different cells is actually quite a common biological occurrence."

Defective mitochondrial DNA is known to cause around 200 diseases, characterised by the way they affect a person's hearing, eyesight, brain and muscle function, and is being investigated for a whole lot more. The researchers suggest that perhaps synthetic mitochondrial DNA could be custom-designed to replace the defective genes and stop tumours and other diseases from developing. "This appears to be a basic physiological mechanism in the body that no one has seen before because they lacked the exploratory tools. Whether this new phenomenon is important in tumour formation is still unclear, but we are interested in pursuing the research to see if the transfer occurs more widely in the body. Preliminary evidence indicates it may be a common occurrence in the brain."

Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA

We report that tumor cells without mitochondrial DNA (mtDNA) show delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory (super)complexes was correlated with acquisition of respiratory function.

Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest pathophysiological processes for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.

Senescent cells accumulate with age. Transition into a senescent state is, at least initially, a defense against cancer in which cells that are damaged or likely to become damaged due to a dysregulated tissue environment permanently suppress their ability to divide. Many destroy themselves or are destroyed by the immune system, but all too many of them linger on intact. In old skin a large portion of tissue is made up of senescent cells, for example. Cellular senescence as a cancer defense is likely an adaptation of a tool used to shape tissue growth during embryonic development, which might explain why senescent cells secrete a range of molecules that cause harm to surrounding extracellular matrix structures and negatively impact the behavior of nearby cells.

The more senescent cells you have the more their presence degrades the function of tissues and organs. Eventually a large enough number of senescent cells and their secreted signals tip over from being protective against cancer due to removing the ability for damaged cells to replicate to a state of promoting cancer by creating inflammation and other harms in tissue. The best solution to all of this is periodic clearance of senescent cells via some form of targeted cell killing technology, such as those under development in the cancer research community. That approach, like most related to repairing the causes of aging, receives comparatively little attention and funding, however. Here is another of the many examples of the damage done to a particular organ by growing numbers of senescent cells:

Age-associated decline in organ function governs life span. We determined the effect of aging on lung function and cellular/molecular changes of 8- to 32-month old mice. Proteomic analysis of lung matrix indicated significant compositional changes with advanced age consistent with a profibrotic environment that leads to a significant increase in dynamic compliance and airway resistance. The excess of matrix proteins deposition was associated modestly with the activation of myofibroblasts and transforming growth factor-beta signaling pathway. More importantly, detection of senescent cells in the lungs increased with age and these cells contributed toward the excess extracellular matrix deposition observed in our aged mouse model and in elderly human samples.

Mechanistic target of rapamycin (mTOR)/AKT activity was enhanced in aged mouse lungs compared with those from younger mice associated with the increased expression of the histone variant protein, MH2A, a marker for aging and potentially for senescence. Introduction in the mouse diet of rapamycin, significantly blocked the mTOR activity and limited the activation of myofibroblasts but did not result in a reduction in lung collagen deposition unless it was associated with prevention of cellular senescence. Together these data indicate that cellular senescence significantly contributes to the extracellular matrix changes associated with aging in a mTOR 1-dependent mechanism.

Link: http://dx.doi.org/10.1093/gerona/glu241

A number of research groups are working towards growing intestinal tissue, but this area of the field of tissue engineering is still at the exploratory stage, with no-one much past the level of creating small sections of usefully structured tissue. Getting the structure right is one of the challenging parts of tissue engineering; every organ is different and requires the development of its own particular recipe and methodology.

Tissue-engineered small intestine (TESI) grows from stem cells contained in the intestine and offers a promising treatment for short bowel syndrome (SBS), a major cause of intestinal failure. TESI may one day offer a therapeutic alternative to the current standard treatment, which is intestinal transplantation, and could potentially solve its largest challenges - donor shortage and the need for lifelong immunosuppression. Scientists had previously shown that TESI could be generated from human small intestine donor tissue implanted into immunocompromised mice. However, in those initial studies - published in 2011 - only basic components of the intestine were identified. For clinical relevance, it remained necessary to more fully investigate intact components of function such as the ability to form a healthy barrier while still absorbing nutrition or specific mechanisms of electrolyte exchange.

The new study determined that mouse TESI is highly similar to the TESI derived from human cells, and that both contain important building blocks such as the stem and progenitor cells that will continue to regenerate the intestine as a living tissue replacement. And these cells are found within the engineered tissue in specific locations and in close proximity to other specialized cells that are known to be necessary in healthy human intestine for a fully functioning organ. "We have shown that we can grow tissue-engineered small intestine that is more complex than other stem cell or progenitor cell models that are currently used to study intestinal regeneration and disease, and proven it to be fully functional as it develops from human cells. Demonstrating the functional capacity of this tissue-engineered intestine is a necessary milestone on our path toward one day helping patients with intestinal failure."

Link: http://www.chla.org/site/apps/nlnet/content2.aspx?c=ipINKTOAJsG&b=7632571&ct=14440563¬oc=1

The Methuselah Foundation and SENS Research Foundation are two of the more important organizations involved in changing the face of aging research from a field of investigation to a field of intervention, speeding progress towards the effective treatment of aging and production of actual, working rejuvenation therapies. Over the past year the staff at these two foundations have collaborated on a series of biotechnology-focused newsletters for supporters, each issue detailing recent research relevant to the goal of repairing and reversing the causes of degenerative aging. I tend to mention them when they turn up in my in-box for those not on the list, and here is the latest. This issue focuses on (a) heterochronic parabiosis, in which the circulatory systems of a young and old individual are linked in order to identify important changes in circulating signal proteins, and (b) indirect evidence for the benefits of targeted clearance of senescent cells from aging tissue, among other items:

Rejuvenation Biotechnology Update, January 2015

We have been following GDF-11 research and are pleased to bring you these two new reports. In the first study, researchers showed that exposing older mice to GDF-11 either through parabiosis, or by administering injections of recombinant GDF-11, was able to induce remodeling of the blood vessels in their brains, inciting the growth of new neurons. Most excitingly, this had a functional impact on older mice. With advanced age, the mice had lost much of their sense of smell, but parabiosis completely restored it to youthful function. In the second study, the research group showed that, again, exposing older mice to GDF-11 - either through parabiosis or injection of recombinant GDF-11 - was able to reverse age-related impairments in the function of their skeletal muscles. The genomes of the muscle cells in aged mice treated with GDF-11 showed greater integrity, their muscle structure and function improved, and they could perform better in tests of strength and endurance.

At this point, GDF-11 appears to be able to exert "rejuvenative" effects on the heart muscle, skeletal muscle, and brains of old mice who have suffered declines in those areas. It is possible that it may have effects on other body systems as well; further research will be needed to test this. It seems unlikely that parabiosis itself could be brought into the clinic for human use, given all the youthful blood (and related ethical concerns that raises). There may also be significant potential roadblocks for recombinant GDF-11 for human clinical use. For example administration of GDF-11 itself would require unmanageably large quantities of the protein. However, it could be used as the basis of a modified version or a drug that targets the same metabolic processes as GDF-11 itself.

On the other hand, there do exist examples of protein drugs in clinical use in large quantities, such as recombinant insulin for diabetics. To illustrate the order of magnitude of recombinant protein production currently in clinical use, researchers estimate that by 2025, there could be a need of approximately 16,000 kg/year of recombinant insulin for diabetics. So it also seems possible that recombinant GDF-11 could be used clinically, but it might be very challenging and expensive. Interestingly, GDF-11 has no effect on young mice at the doses tested. In the skeletal muscle study, the researchers treated both young and old mice with an identical regimen of GDF-11 injections, and it did not change young mouse muscle stem cell number, DNA integrity, or function. In the older mice, the dose of GDF-11 given was meant to recreate the physiological levels of GDF-11 in young mice (which decline with age). So, while restoring GDF-11 to "youthful" levels in older animals appears to rejuvenate several of their tissues - for example, restoring their muscle strength and endurance to "youthful" levels - it does not, for instance, make young mice abnormally strong for their age. Whether GDF-11 at higher doses would have greater effects is not yet known.

A major concern among rejuvenation biotechnology researchers is the accumulation of "senescent" cells in the body with age. Senescent cells are cells that have accumulated DNA damage, lost the ability to divide, and may create areas prone to the development of cancer within tissues where they reside. These "tissue microenvironments" (the biochemical environment in an extremely small area of tissue) near senescent cells may become more prone to the development of cancers because of secretion of molecules such as growth and inflammatory factors and enzymes that break down the supporting tissue around the senescent cells. Senescent cells accumulate in all tissues with age. A reason for attempting to eliminate senescent cells is the possibility that this hormonal and biochemical milieu in aged tissue microenvironments, in addition to the cells themselves, may contribute to some of the problems in aging, such as the development of cancer.

In this study, researchers exposed rats to chemical toxins that induce liver cancer. They next transplanted the rats with healthy liver cells from other, younger rats; the donor rats were genetically matched to the recipients to avoid problems with immune rejection of the transplanted cells. They performed the transplant by simply infusing the cells into the portal veins of the recipient rats. The transplanted cells then took up residence in the recipient rats' livers. One year later, 50% of the control rats that had not received transplanted liver cells had developed liver cancer. However, there was zero liver cancer observed in the group of rats that had received the liver cell transplant. The researchers also observed that after one year, the control group of rats had lots of senescent liver cells (induced by the cancer-causing protocol), but the transplant recipients had fewer senescent liver cells.

Although it was a small sample size (8 rats in the treatment group), it was remarkable that the researchers were able to change the incidence of development of liver cancer from 50% in the control group to 0% in the treatment group. We cannot help but wonder: if more time had passed, would liver cancer have developed in the treatment group? On the other hand, a 1-year follow-up is a relatively long time for rats. Although it is an impressive result, some things about this study are still unclear. The authors claimed that senescent cells in the livers of transplant recipient rats were removed, but it's not clear whether this truly happened. Senescent cell numbers may simply have been "diluted" by the influx of donor liver cells. There is no clear mechanism by which the senescent cells could have been removed, since the transplanted cells were liver cells, not the "natural killer cells" that carry out the body's own, limited ability to clear senescent cells from tissues.

Although the senescent cells may not have been cleared as the authors claimed, this study still provides evidence that via a relatively simple protocol (infusing healthy liver cells), the tissue microenvironment can be changed and malignancies can be kept at bay. We may eventually be able to apply this strategy to human tissues to create tissue microenvironments where cancers do not thrive.

To add to the caveats above, as I said at the time, I'd like to see this cell transplant study repeated in old rats with natural levels of cellular senescence before giving it too much more attention. Based on another study of liver cell senescence and cell transplantation it is vaguely possible that these cell populations can to some degree reverse their senescent status given the right environmental cues. It is perhaps worthy of note that liver tissue is naturally more regenerative than other tissues in mammals, capable of regrowing lost portions of the organ if necessary. But this is all quite speculative, and while there is a lot more that might be done here to iron out uncertainties and fill in the gaps, none of that is terribly relevant to the more direct path of building targeted cell clearance mechanisms and trying them out. The results of that experiment would be far more useful.

The adaptive immune system declines with age for reasons that are partially structural. The slow rate of production of new immune cells in adults and the pace of turnover results in an effective cap on the number of these cells present at any one time. Immune cells are devoted to remembering threats as they occur, but some otherwise largely innocuous and widespread pathogens like cytomegalovirus cannot be effectively cleared from the body. Ever more memory T cells are devoted to that particular topic over the years, and this leaves ever less space for naive T cells capable of destroying invading pathogens. So to a first approximation the more memory cells you have in old age the worse off you are.

Here is a correlation between that measure of immune system dysregulation and age-related declines in cognitive function. We can speculate that linking mechanisms might include the chronic inflammation that accompanies age-related immune system dsyfunction or a decline in aspects of the supporting role played by portions of the immune system that are specific to brain tissue:

Immunosenescence and cognitive decline are common markers of the aging process. The current view is that the immune system plays a modulatory role in brain function, including in cognitive abilities and neurogenesis, which supports the notion that throughout life the brain is not "immune privileged" but rather "enjoys the privilege" of immune-dependent maintenance. Taking into consideration the heterogeneity observed in aging processes and the recently described link between lymphocytes and cognition, we herein explored the possibility of an association between alterations in lymphocytic populations and cognitive performance. In a cohort of cognitively healthy adults (n = 114), previously characterized by diverse neurocognitive/psychological performance patterns, detailed peripheral blood immunophenotyping of both the innate and adaptive immune systems was performed by flow cytometry.

Better cognitive performance was associated with lower numbers of effector memory CD4+ T cells and higher numbers of naive CD8+ T cells and B cells. Furthermore, effector memory CD4+ T cells were found to be predictors of general and executive function and memory, even when factors known to influence cognitive performance in older individuals (e.g., age, sex, education, and mood) were taken into account. This is the first study in humans associating specific phenotypes of the immune system with distinct cognitive performance in healthy aging.

Link: http://dx.doi.org/10.1212/NXI.0000000000000054

Here is a study that gives some idea of the degree to which the majority of people who do not maintain a good level of fitness are harming themselves over the years:

The study of amateur older cyclists found that many had levels of physiological function that would place them at a much younger age compared to the general population. The study recruited 84 male and 41 female cycling enthusiasts aged 55 to 79 to explore how the ageing process affects the human body, and whether specific physiological markers can be used to determine your age. Men and women had to be able to cycle 100 km in under 6.5 hours and 60 km in 5.5 hours, respectively, to be included in the study. Smokers, heavy drinkers and those with high blood pressure or other health conditions were excluded from the study.

The results of the study showed that in these individuals, the effects of ageing were far from obvious. Indeed, people of different ages could have similar levels of function such as muscle strength, lung power and exercise capacity. The maximum rate of oxygen consumption showed the closest association with age, but even this marker could not identify with any degree of accuracy the age of any given individual, which would be the requirement for any useful biomarker of ageing.

"An essential part of our study was deciding which volunteers should be selected to explore the effects of ageing. The main problem facing health research is that in modern societies the majority of the population is inactive. A sedentary lifestyle causes physiological problems at any age. Hence the confusion as to how much the decline in bodily functions is due to the natural ageing process and how much is due to the combined effects of ageing and inactivity. In many models of ageing lifespan is the primary measure, but in human beings this is arguably less important than the consequences of deterioration in health."

Link: http://www.kcl.ac.uk/newsevents/news/newsrecords/2015/January/Exercise-allows-you-to-age-optimally.aspx

Technology is the application of scientific knowledge. The scientific culture and scientific process as it is practiced today embodies a strong bias against any sort of shortcut towards the production of technology, however. If it seems plausible at a lesser level of understanding of a system that you could achieve some beneficial application, then the peer pressure in the scientific community is always to hold off and work instead towards a full understanding. This situation is not uncommon in medicine: many discoveries are serendipitous, but to try to turn demonstrated positive results in the laboratory into positive results in the clinic will be opposed at every turn until the underlying mechanisms can be fully explained.

The bias against action and towards understanding as the primary goal is baked into every level of the research establishment and surrounding institutions. The scientific method has researchers moving eternally towards greater understanding. It has nothing to say about what you do with that understanding, however. Application to produce technology is where you step from the Platonic ideal and into the messy real work of engineering: the art of creating meaningful solutions in the absence of full understanding. This boundary between knowledge and technology produces all sorts of cultural friction, and I think it is fair to say that scientists who depart to be engineers are not treated as well as they might be by their former peers. There is little disapproval in the world quite like that of pure scientists directed towards one of their own who steps away to start a technology business.

At root there are very good reasons for this bias: the scientific method is required for progress, yet it is constantly under attack from opportunists and fallible human nature: wishful thinking, the desire to find progress where there is none, the desire for short-term gain over long-term gain, and so forth. If shortcuts are not treated as heresy, then there will be all too many research programs led astray, and development predicated on false results, and in the worst cases outright fraud. This happens even with the scientific culture of disapproval, but far less so than it otherwise might.

While the core of the scientific method is centuries old, to some degree this strong bias against early attempts at practical application is a phenomenon of modern times. In the institution of medical research everything that moves beyond early stage exploration must be explicable to the standards of the day, but matters were not always so rigorous. There any number of grandfathered treatments available today that are not sufficiently well understood at the level of molecular biology to get into clinical trials if they were discovered today. Regulation as it stands today in the US states that you shall only treat named conditions, and you shall present a full understanding of how you are doing it. Since everything else is actually outright forbidden, you end up with a situation in which all funding and effort - even back down the chain to supposedly unconnected free-ranging fundamental research - is focused on the molecular biology of late stage disease and the proximate causes thereof. For most researchers that's the only work with a future if you want to contribute to something that might actually end up approved for clinical use.

So these influential edifices of thought, and all the funding that is influenced by them, say that any approach in research that specifically aims to circumvent our lack of knowledge in some areas is simply Not The Done Thing. Yet there are many lines of research in which it is clearly plausible that great benefits could be derived by doing just this, and - as currently constructed - the walls that the scientific institution is forced to erect for its own defense exclude all of this good, solid work that might lead to better therapies. As one example you might look at leukocyte/granulocyte transfer therapies for cancer. These came to prominence on the basis of very promising results in animal studies, but have not seen significantly funding or much work on human studies precisely because researchers cannot yet present a full accounting of how these treatments work. Without that, you won't see much movement.

In this context we of course come to the Strategies for Engineered Negligible Senescence (SENS). This is not just a proposal for the shortest path to the best results when treating aging, a research plan to create rejuvenation in the old and prevent all age-related frailty and disease, it is also a critique of the scientific community and its way of doing business. The present system is broken by virtue of the fact that its members have gone too far in building defenses against failure modes in the scientific method. They now systematically marginalize useful endeavors aimed at the production of meaningful results in absence of complete knowledge of the biological systems involved. Application of partial knowledge can be good engineering, and is viable, necessary, and needed in medicine, where every delay costs lives. The past shows that the engineering approach can be perfectly workable, as many drugs in use today were brought into use through exactly this sort of methodology, and their full mechanisms are in fact still not understood.

Still, the mainstream of the aging research community will continue to spend billions on efforts that have no greater expectation of practical utility than the sirtuin research of the past decade. They are working towards a full understanding of the overlap of metabolism and aging as a primary objective. This in and of itself is a fine thing if knowledge is the desired end result, but I object to its presentation as a sensible path toward therapies to extend healthy life to any significant degree in the near future. This is just not plausible for the drug development approach to altering metabolism: the best that might be done here in the next couple of decades is to gently slow the progress of aging. Researchers involved tend to think that adding five years of healthy life by 2030 is an ambitious goal. If that five years is all that happens, and when it does it certainly won't be five years for those people already old when treatments arrive, then what a waste of opportunity that would be.

No, we want to see work on rejuvenation, on ways to reverse aging by repairing its causes - work after the SENS model that has a clear plan to produce results in absence of a full understanding of metabolism throughout aging. What is needed is a comprehensive list of damage that distinguishes old tissues from young tissues. This exists, and given this list there is no great need to fully understand how the damage interacts and progresses in intricate detail: researchers just need to periodically repair it. In this environment drawing more researchers to work on SENS repair biotechnologies is a bootstrapping process of attention and funding and results, just like the disruption of any industry by new technologies and new approaches. Things like clearance of senescent cells seem like one of the areas of research that will eventually get grudging attention by virtue of the fact that it will work far more effectively than anything the mainstream is producing with their drugs and their messing with the operation of metabolism in the late stages of disease. If you are trying to make a damaged engine work slightly better when damaged, rather than trying to address the damage itself, why would you expect good results?

The replacement of the present mainstream culture of aging research by SENS-like research focused on periodic repair of the causes of aging to achieve rejuvenation will proceed gradually and through the demonstration of effectiveness. There is a lot of of replacing to be done, however. It's a long road yet, and conservative institutions will continue to support work that does nothing but add knowledge of the fine details of metabolism long after rejuvenation research is much more of a going concern, I'd imagine. Groups like Google's Calico venture do not fund SENS because they are run by exemplars of the current institutions of medical science, who have worked their entire careers in the world of full knowledge as a requirement and where the primary strategy is a struggle to alter metabolism in the late stages of age-related disease, people who live and breath the drug pipeline and FDA dictates. Why should it be any surprise that what they are going to do is simply a continuation of existing programs of aging research? Calico will fund SENS at the same time that other institutions of the mainstream are doing so as a matter of course, which is to say when the disruption has come full circle and when people talk about aging research they usually mean the SENS approach of repair of primary causes.

Researchers aiming to produce a mouse model of accelerated sarcopenia, the characteristic loss of muscle mass and strength that occurs with aging, instead found that depleting muscle stem cell populations had no effect on this condition. This implies that the loss of stem cell activity in muscle tissue associated with aging may not be all that important in the development of sarcopenia after all:

Sarcopenia affects millions of aging adults. Age-related loss of muscle mass and strength not only robs elderly people of the ability to perform even the most basic tasks of daily living, but also significantly increases their risk of suffering devastating injuries and even death from sudden falls and other accidents. The literature on aging research, particularly muscle aging, postulates a strong correlation between the loss and/or dysfunction of muscle stem cells and sarcopenia, the scientific term for the age-related loss of skeletal muscle mass and strength. Currently entire research programs are focused on developing muscle stem cell therapy to delay, prevent or even reverse sarcopenia.

[Researchers] developed an animal model that allowed them to deplete young adult muscle of stem cells to a level sufficient to impair muscle regeneration throughout the life of a mouse. They expected the mouse to be a model of premature muscle aging. "To our surprise, the mice aged normally; life-long depletion of skeletal muscle stem cells did not accelerate nor exacerbate sarcopenia. Our negative results show a clear distinction between therapeutic strategies that may effectively treat degenerative myopathies, such as dystrophies and cachexia, versus sarcopenia. While degenerative conditions are expected to benefit from a stem cell-based therapy, this does not appear to be a viable approach for treating age-associated muscle wasting. Hopefully, our work will help to refocus aging muscle research on new therapeutic targets to effectively maintain muscle function and prevent frailty in the elderly."

Link: http://uknow.uky.edu/content/uk-study-disputes-previous-theories-loss-muscle-stem-cells-and-aging

It has been suggested that greater levels of solar radiation may reduce life expectancy by raising the likelihood of damage during embryonic and later development, and researchers have in the past mined historical data in search of correlations. At this point discussion of possible mechanisms is still quite speculative, however. Here is another example of this line of research:

Ultraviolet radiation (UVR) can suppress essential molecular and cellular mechanisms during early development in living organisms and variations in solar activity during early development may thus influence their health and reproduction. Although the ultimate consequences of UVR on aquatic organisms in early life are well known, similar studies on terrestrial vertebrates, including humans, have remained limited.

Using data on temporal variation in sunspot numbers and individual-based demographic data (N = 8662 births) from Norway between 1676 and 1878, while controlling for maternal effects, socioeconomic status, cohort and ecology, we show that solar activity (total solar irradiance) at birth decreased the probability of survival to adulthood for both men and women. On average, the lifespans of individuals born in a solar maximum period were 5.2 years shorter than those born in a solar minimum period. In addition, fertility and lifetime reproductive success (LRS) were reduced among low-status women born in years with high solar activity. The proximate explanation for the relationship between solar activity and infant mortality may be an effect of folate degradation during pregnancy caused by UVR. Our results suggest that solar activity at birth may have consequences for human lifetime performance both within and between generations.

Link: http://rspb.royalsocietypublishing.org/content/282/1801/20142032

Late last year the German Society for Applied Biostasis (DGAB) held a scientific symposium on cryonics. A number of researchers from the aging research community attended, as there is some overlap between people interested enough in radical life extension to have become members of the aging research community and people interested enough in cryonics to help advance that work. It is similar to another overlap with the field of artificial general intelligence research. If you move in these circles you'll keep bumping into some of the same people regardless of the topic of the present conference.

Why is this the case? Well, there was a coming together of many disparate futurists in the 1990s and a years-long blossoming in the exchange and synthesis of ideas relating to the rapid advance of computing, medicine, and materials science. This happened as a natural result of the accelerating growth in English-language internet usage at the time, and in particular due to a newly enhanced ability to easily organize ad-hoc communities with similar interests but whose members are widely separated geographically. If you trace the people who were present for those online discussions you'll find that a modest but significant number of them have since forged their careers from what they want to see for the future of humanity: radical life extension, cryonics, molecular nanotechnology, artificial general intelligence, and so forth. There was a period of comparative unity and consensus back then, when fewer people were online and it was all still fairly new, followed by a diaspora of ideas and efforts into diverse but conceptually linked fields of technological development, of making the future real.

This is why there are people who work on the molecular biology of aging found at cryonics conferences, why there are people who fund both general AI and aging research and consider both part of a greater whole, and it is also the explanation for many other similar connections in a still growing web of relationships that started with enthusiastic online discussions of futurist goals that took place a couple of decades ago. The futurism - the transhumanism - of the 1990s is the everyday scientific groundwork of today, and those young futurists are often one and the same individuals as the older team leaders now performing that work.

In any case, here is Aubrey de Grey of the SENS Research Foundation presenting on the topic of rejuvenation biotechnology to the DGAB, many of whom are supporters. If you are up for cryonics as an option, then you should certainly be in favor of extending healthy life through other engineering applications of medical science. If you are already familiar with SENS as a strategy for the development of therapies to reverse aging, then you might want to skip ahead to about 25 minutes in to get an update on ongoing research programs: what is being done, and where things stand at present.

If you have an interest in the science of cryonics and cryopreservation, then you'll find a range of other presentations from the symposium available online:

• Possible Mechanisms of the Cryoprotective Effect of Xenon
• Functional genomics of cryoprotectant toxicity
• History of cryonics
• Definitions of Death
• Age related degeneration
• Protocol for Vitrification of Bulky Biological Objects
• New cryonics technologies
• [1/2] How to sustain an organization for over a century
• [2/2] How to sustain an organization for over a century

Lysosomes within cells recycle cellular waste and damaged cellular structures, ingesting them and then breaking them down with a range of enzymes. Over time, however, lysosomes in long-lived cells such as those of the central nervous system become bloated with a buildup of comparatively rare waste products that they cannot recycle and their functional activity declines. This certainly has a serious impact on the ability of an older cell to function, but is this only because of the growing level of unrecycled garbage in the cell? Researchers here uncover another way in which lysosomes are influencing longevity in a lower animal, and it will be interesting to see if comparable mechanisms also operate in mammals:

Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80.

We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.

Link: http://dx.doi.org/10.1126/science.1258857

MicroRNA (miRNA) molecules play a complex and quite indirect role in the process of producing proteins from genetic blueprints, their activities adjusting the amount of protein produced for a range of genes. Since protein levels change in aging, we should expect to also see changes in miRNAs also. The system reacts to the cellular and molecular damage that causes aging, and this is another part of the reaction:

Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication.

MicroRNAs are estimated to regulate as many as 60% of all human mRNAs, which represent practically all cellular and molecular functions. MiRNAs are known to be key players in the regulation of transcripts involved in processes as diverse as embryonic development, differentiation, cellular proliferation, apoptosis, metabolism and adaptation to environmental stress. Given the involvement of miRNA regulation in multiple cellular processes, it is unsurprising that this process plays a part in complex, multifactorial and environmentally-influenced cellular processes such as human disease and cellular and organismal ageing.

In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198923/

The comparative biology of aging is a field that attempts to use differences between species to better understand the genetic and metabolic roots of longevity. Why do some neighboring species of a similar size, such as mice and naked mole-rats, have such radically different life spans, wherein the mole-rats can live nine times as long? Why are humans very long-lived in comparison to other primates? How is it that individuals in some whale species can live for two centuries or more with a thousand times the cell count of a human and yet not have a thousand times the cancer incidence? On the one hand this is a potentially effective way to seek out the few important parts of a very complicated system, mammalian biology, that is poorly understood in depth at this time. It is a short-cut through the vast unknown. On the other hand, the promise at the end of the day is not just knowledge, but the possibility that perhaps therapies or other beneficial alterations to human biology could be produced as a result of these investigations.

It is hard to say whether it is plausible to hope for cross-species porting of useful features of biochemistry, even between mammals. The devil is in the details, and the details are going to vary widely on a case by case basis. It is very possible that researchers will in the next couple of years uncover a beneficial feature in whales that is clearly and evidently useful, but linked to particulars of their biochemistry in ways that make it absolutely impossible to recreate in humans. The investigations of naked mole-rats are much further along in comparison to of those of whales and are turning up some items that sound plausible to attempt as human therapies and other items that sound near impossible to safely recreate in humans at our presently level of technology. Equally the same job might be a walk in the park for the biotechnology of the 2030s: at this point far too little is known to do more than speculate.

Step one in all of this is to sequence the genome of the species in question - it's hard to get too far into the details without that. You might recall a recent publication on the bowhead whale genome from one of the two teams working separately on that project. Here is an article on the work of the other team, who have put up an online searchable database for those interested in exploring the genome:

Could a 200-year-old whale offer clues to help humans live longer?

Joao Pedro de Magalhaes and his team at the University of Liverpool sequenced the genome of the bowhead whale, the longest living mammal on earth. The team wanted to understand why they live so long and don't succumb to some of the same illnesses as humans do earlier in life. "One of the big mysteries of biology is understanding species differences including species differences in aging. For example, mice age 20 to 30 times faster than human beings and we don't know why ... Even primates which are closely related to us age considerably faster than human beings. There has to be some genetic basis to why humans age slower than chimpanzees for instance which are very genetically very similar to us. Likewise, there has to be some genetic basis as to why bowhead whales live so long and appear protected from diseases."

With a 1,000 times more cells than a human, the whale should have a much higher probability of cell death and disease. It doesn't. In their findings the team found as many as 80 candidate genes that may help protect the whale from cancer or contribute to it being the longest living mammal on earth. The team found that the whales have genes related to DNA repair, as well as those regulating how cells proliferate, that differ from those found in humans.

There is a huge industry searching for that elixir which could help humans live longer. Some research has gone into finding what is called longevity genes that could lead to new drug therapies while other research promotes such things as exercise and healthy eating to extend your life. Two groups which funded most of the whale research - the Life Extension Foundation and the Methuselah Foundation - are seeking that magic potion. Life Extension focuses on such things as hormonal and nutritional supplements to fight aging while Methuselah is heavily invested in tissue engineering and regenerative medicine "to create a world where 90 year olds can be as health as 50 year olds, by 2030."

Methuselah's co-founder and CEO Dave Gobel said it invested in the whale research as part of its "hypothesis that the best way to find out how to become longevity outliers is to study those who already are genetic outliers within mammalian species" and then find "what genetic complexes, pathways seem most common among these outliers and to explore what they do, how they act, and what if any advantages can be derived from them to apply in humans."

The Bowhead Whale Genome Resource

The mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown, but it is clear these animals must possess aging prevention mechanisms. In particular in context of cancer, bowhead whales must have anti-tumour mechanisms, because given their large size and longevity, their cells must have a massively lower chance of developing into cancer when compared to human cells. As such, we sequenced the genome of the bowhead whale to identify longevity assurance mechanisms.

A high-coverage genome assembly, and corresponding annotation, of the bowhead whale is made available to the scientific community to encourage research using data from this exceptionally long-lived species. Overall, this project aims to provide a key resource for studying the bowhead whale and its exceptional longevity and resistance to diseases. By identifying novel maintenance and repair mechanisms we will learn what is the secret for living longer, healthier lives and may be able apply this knowledge to improve human health and preserve human life.

As it is turning out the study of comparative biology over the next decade or so will probably not produce much in the way of practical applications in treating aging, but rather be of relevance to advances in (a) cancer treatment, through what is learned from naked mole-rats and possibly from whales, and (b) regenerative medicine, through investigations of proficient regenerators such as salamanders. Those items are where the money is flowing. That said, this research should lead to faster progress in the scientific goal of fully mapping the process of aging and its interaction with metabolism at the detail level, but as outlined elsewhere at Fight Aging! this is not the road to human rejuvenation. At best, given the field as it stands at present, altering the operation of our metabolism can only aim at modestly slowing the accumulation of cellular and molecular damage, not repairing it or reversing it, and even this will be a vast and complicated undertaking. If we want rejuvenation, we must instead aim at repair of the metabolism we have as the primary objective, and fortunately significant progress towards this goal does not require much more knowledge than we have already.

A post on age-related loss of muscle mass and strength can be found at the Science of Aging blog of the Buck Institute for Research on Aging:

Sarcopenia comes from the Greek words sacra, "flesh", and penia, "poverty". More specifically, sarcopenia is the gradual loss of muscle mass and strength with age. It's not a disease, not a condition, and not a syndrome, but rather an unfortunate consequence of the natural aging process. Not to be confused with cachexia (accelerated muscle loss secondary to a disease such as cancer), sarcopenia is slow, progressive, and unnervingly unsuspecting. The 0.5-1% loss of muscle mass each year is deceptive, and unlike many of the consequences of aging, sarcopenia actually starts when we are quite young, generally around the age of 30. The loss of muscle mass and strength has profound consequences on day-to-day living.

Sarcopenia alters muscle structure and function in many different ways. First and foremost with sarcopenia comes muscle atrophy. Muscle atrophy is the shrinking of individual muscle cells, called muscle fibers. So while you do not lose a substantial number of muscle fibers, the smaller diameter muscle fibers result in reduced strength and mass. Interestingly, not all muscle undergoes atrophy equally. Muscle fibers can be separated based on size, contraction properties, and metabolic abilities, into different "fiber types". With sarcopenia, the larger more powerful muscle fibers preferentially undergo atrophy and contribute to the loss in overall strength. However, the loss of muscle size is not the only factor that contributes to a loss in muscle strength. A change in muscle quality also occurs with sarcopenia. Healthy muscle is just that, muscle. However, with sarcopenia, muscle becomes increasingly infiltrated with alternative cells types such as fibroblasts (cells that contribute to tissue structure) or adipocytes (fat cells).

How and whether these two physiological processes, loss in muscle size and loss in muscle quality, interact is not entirely known. One theory involves the muscle satellite cells or muscle stem cells. Normally, when muscle fibers are damaged muscle precursor cells that hang out next to the muscle fibers and wait to be called into action replace them. With aging however these muscle stem cells can become dysfunctional and instead of muscle replacing muscle, pesky fibroblast or adipocytes either show up or may be produced by the muscle stem cells (the jury is still out). A number of labs (Campisi Lab, Rando Lab, Blau lab, Conboy lab) in the Bay Area are studying how muscle stem cells function normally and in disease.

Link: http://sage.buckinstitute.org/staying-strong-countering-the-effects-of-sarcopenia/

A combination of advances in medicine and a decline in smoking are reducing the mortality rates due to cancer. The effect of smoking is large because so many people do it and it is an effective road to the development of lung cancer. It is worth noting that the decrease in cancer mortality rates is in a time when the demographic profile of the population is shifting to include a larger number of older people with a greater risk of suffering cancer, as well as a concurrent rise in the number of overweight and obese individuals, a condition that is also associated with increased risk of suffering many cancers:

The American Cancer Society's annual cancer statistics report finds that a 22% drop in cancer mortality over two decades led to the avoidance of more than 1.5 million cancer deaths that would have occurred if peak rates had persisted. Largely driven by rapid increases in lung cancer deaths among men as a consequence of the tobacco epidemic, the overall cancer death rate rose during most of the 20th century, peaking in 1991. The subsequent, steady decline in the cancer death rate is the result of fewer Americans smoking, as well as advances in cancer prevention, early detection, and treatment.

During the most recent five years for which data are available (2007-2011), the average annual decline in cancer death rates was slightly larger among men (1.8%) than women (1.4%). These declines are driven by continued decreases in death rates for the four major cancer sites: lung, breast, prostate, and colon. Lung cancer death rates declined 36% between 1990 and 2011 among males and 11% between 2002 and 2011 among females due to reduced tobacco use. Death rates for breast cancer (among women) are down more than one-third (35%) from peak rates, while prostate and colorectal cancer death rates are each down by nearly half (47%).

The most common causes of cancer death are lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women. These four cancers account for almost one-half of all cancer deaths, with more than one-quarter (27%) of all cancer deaths due to lung cancer.

Link: http://www.eurekalert.org/pub_releases/2014-12/acs-mt1123014.php

The functions of many important tissues in the body depend on physical properties such as elasticity or ability to bear load. These properties derive from the particular structure of the extracellular matrix formed by a tissue, an arrangement of proteins constructed as a mesh to surround and support the cells it holds. The structural properties of the extracellular matrix are increasingly degraded over the course of aging, however, such as by the formation of advanced glycation end-products (AGEs) that can link together proteins of the extracellular matrix in ways that alter the physical properties of the tissue. In the case of blood vessels, rising levels of these cross-links lead to a progressive loss of elasticity, and that in turn causes a whole range of issues in the cardiovascular system that start at hypertension and culminate in catastrophic structural failure of the heart or important blood vessels.

Biochemistry is as a rule always more complicated than we'd like it to be, and so there are many areas of open investigation when it comes to the chemistry of stiffening blood vessels. Metabolic waste products come in many varieties, and it isn't always the case that any given class is actually doing what it is thought to do. Small consensus positions are quietly overturned on a daily basis at the edges of the field, given the falling costs of performing the necessary work, and the foundations of tomorrow are being built beneath the notice of even most researchers.

One of the more important lines of research at the moment, for all that is has little funding and is paid little attention, is to create the means for more research groups to work on glucosepane in human tissues. This appears to be the most prevalent type of AGE forming cross-links in our species - and here it is worth noting that a part of the complexity of this issue is that the chemistry of extracellular matrix cross-linking is very different in various different mammalian species. Lessons learned in mice are only relevant in a very general sense. You'll see few papers on glucosepane despite its importance in our biochemistry, as good tools for working with the class of compounds that glucosepane belongs to in the context of cells and tissues really don't exist yet. For a variety of not-so-good reasons no major research establishment has yet turned its eyes to building them, and so it has fallen on forward-thinking philanthropy to bridge the gap.

As I said, however, there are a lot of different waste products: it is a large space to explore. Those researchers not working on glucosepane are putting in time on other chemicals thought to be relevant to the issue of blood vessel stiffening, but they often draw a blank or find that presence of waste in cells doesn't necessarily correspond to a significant impact on the function of the extracellular matrix, as is the case here. That may not always be the case, of course, and there are certainly good reasons to think that stiffening isn't just AGEs. Science is as much a process of opening doors to empty rooms as it is of finding the one that hides the goal.

Elastin aging and lipid oxidation products in human aorta

In normal arteries, the proteins of the extracellular matrix (ECM) (collagen, elastin, fibrillin, glycoproteins and proteoglycans) produced by smooth muscle cells (SMC) ensure the stability, resilience, and compliance of arteries. Collagen and elastin, two major scaffolding ECM proteins provide structural integrity and elasticity to the vessels, allowing them to stretch while retaining their ability to return to their original shape when the pressure is over. Vascular aging is most of the time associated with structural and functional modifications of the arteries, even in healthy elderly, and particularly by an increase in arterial wall thickening in the intima and the media, mainly resulting from the accumulation and structural modification of ECM components and a disorganization of SMC.

Arterial stiffness is characterized by structural and functional alterations of the intrinsic elastic properties of the arteries and an increased resistance to vessel deformation, resulting from a decrease in artery elasticity (compliance) and an increase in pulse wave velocity (pwv), generating an increased systolic pressure, with deleterious consequences on the heart, generating cardiac hypertrophy and increased ventricular oxygen consumption. Arterial stiffening is a hallmark of vascular aging, and a major risk factor for the development of cardiovascular diseases, that can be exacerbated by diabetes, hypertension or atherosclerosis. It is a direct cause of ventricular hypertrophy, renal dysfunction and stroke, independently of the other causes of vascular aging. It is an independent risk factor for cardiovascular diseases, which may predispose to atherosclerosis, and vice-versa.

Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA) form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging.

The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that [these] adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by [these adducts].

Over the long term leading a sedentary lifestyle is about as harmful to health and longevity as smoking. Thus there should also be short term changes that can be observed and measured, as is shown to the be the case here:

Researchers found that reducing daily physical activity for even a few days leads to decreases in the function of the inner lining of blood vessels in the legs of young, healthy subjects causing vascular dysfunction that can have prolonged effects. The vascular dysfunction induced by five days of inactivity requires more than one day of returning to physical activity and taking at least 10,000 steps a day to improve. "We know the negative consequences from not engaging in physical activity can be reversed. There is much data to indicate that at any stage of a disease, and at any time in your life, you can get active and prolong your life."

The researchers studied the early effects on the body's blood vessels when someone transitions from high daily physical activity - 10,000 or more steps per day - to low daily physical activity, less than 5,000 steps per day. Counting steps and daily physical activity is different than defined exercise, such as working out at the gym. While there are significant benefits to defined exercise, [this] research is based on what amounts to 30 minutes of moderate activity per day. "The impairment we saw in just five days was quite striking. It shows just how susceptible the vascular system is to physical inactivity."

The researchers studied inactivity and glycemic control as well as how inactivity affects blood flow and vascular function through the body. A decrease in blood vessel function has been shown in previous studies to be linked to early cardiovascular death and hypertension. Now, this research shows that even an acute period of inactivity of five days changes the measure that is already known to be important for long-term cardiovascular health. Also, although blood flow responses to glucose ingestion were not affected by five days of inactivity, impairments in glycemic control and insulin sensitivity are also a consequence of reduced daily physical activity.

Link: http://medicine.missouri.edu/news/0252.php

In addition to being very long lived for their size and showing few signs of degenerative aging over their life span, naked mole-rats are essentially immune to cancer. Arguably there is more research interest in this latter point than in the life span question. So far scientists have focused on contact inhibition of cellular replication, which seems to be much more aggressive in naked mole-rat cells: when cells begin to crowd, as in a potential cancer, their ability to divide is rapidly shut down. This better contact inhibition is probably partially due to a different form of the protein hyaluronan, involved in the processes by which the p16 gene acts as a cancer suppressor.

Here researchers find another new angle to add to these discoveries. Naked mole rats generate a novel protein from the same area of the genome as p16, one not produced in other mammals, and it seems to be a better tumor suppressor than the other proteins produced from that region. Since it can be produced via genetic engineering in the cells of other mammals, the logical next step might be to create a lineage of mice that have it and see what happens:

The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15INK4b, ARF (alternate reading frame).

p16INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15INK4b exon 1 joined to p16INK4a exons 2 and 3. We have named this isoform pALTINK4a/b (for alternative splicing). We show that pALTINK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALTINK4a/b expression is induced during early contact inhibition and upon a variety of stresses. When overexpressed in naked mole rat or human cells, pALTINK4a/b has stronger ability to induce cell-cycle arrest than either p15INK4b or p16INK4a. We hypothesize that the presence of the fourth product, pALTINK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.

Link: http://dx.doi.org/10.1073/pnas.1418203112

For all that I think it isn't an efficient path forward, one likely to produce meaningful results in moving the needle on human life spans, there is considerable interest in testing combinations of existing drugs and various dietary compounds in mice to see if healthy life is extended. I expect that as public interest grows in the prospects for aging research to move from being an investigative to an interventional field, wherein researchers are actively trying to treat aging, we'll only see more of this. There is certainly a sizable portion of the research community who think that the the best path ahead is in fact the pharmaceutical path of drug discovery in search of ways to slightly slow the aging process. To their eyes slightly slowing the aging process is all that is plausible, and adding five healthy years to life by 2035 would be a grand success. Google's Calico initiative looks set to take that path, for example, which I is why I'm not all that hopeful it will produce meaningful results in terms of healthy years gained and ways to help the old suffer less.

There is a considerable overlap between researchers aiming to gently slow aging via drug discovery and researchers whose primary motivation is still investigation, not intervention: to produce a complete catalog of metabolism and how it changes with age, and it's someone else's problem to actually use that data. So we have, for example, the Interventions Testing Program at the NIA. This program was long fought for by researchers tired of the lack of rigor in most mouse life span studies, and the people involved are essentially engaged in replacing a lot of carelessly optimistic past results with the realistic view that very little other than calorie restriction and exercise actually does reliably extend life in mice if you go about the studies carefully. This is good science, but it isn't the road to extended human life spans: it instead has much more to do with understanding the process of aging at a very detailed level. That task is vast and will take a very long time even in this age of computing and biotechnology.

To my eyes the right way to go is the repair approach: build the biotechnologies needed to repair the forms of cellular and molecular damage produced as a side-effect of the normal operation of metabolism, and which clearly distinguish old tissues from young tissues. If you want rejuvenation of the old, a path to adding decades to healthy life, and to eliminate all age-related disease, then repair is the way to go. Fix the damage, don't just tinker with the engines of life in ways that might possibly slow down damage accumulation just a little. This strategic direction can allow researchers to largely bypass the great complexity of the progression of aging and focus instead on fixing things that are already well known and well cataloged. But I say this a lot, and will continue to do so until more than just a small fraction of the research community agree with me.

Back to mice and life span studies: in this day and age institutional research is far from the only way to get things done. Early stage research is becoming quite cheap as the tools of biotechnology improve, and the global economy allows quality scientific work to be performed in locations that are lot less expensive than the US or Western Europe. We have crowdfunding, the internet, and a supportive community, which means that any group of ambitious researchers can raise a few tens of thousands of dollars and set an established lab in the Ukraine to running a set of mouse life span studies. So that happened back in 2013, and has been ongoing since then despite the present geopolitical issues in that part of the world. It is perhaps worth noting that this is the same group that found no effect on longevity from transfusions of young blood plasma into old mice. The studies mentioned below used pre-aged mice, starting at old age as a way to try to discover effects more rapidly, an approach that is fairly widespread.

I am a little mouse and I want to live longer: updates

Dear contributors, we wish you a happy New Year! We are sorry to be taken by a very-expected but very time-consuming c60 lifespan study to digest the data in a way to make the long report we had announced. So, for the New Year and in order for you not to wait longer, please find at least the main results so far:

1) 23 months old C57BL6 mice received a mixture of 6 therapies that had already been reported to extend the lifespan of mice: Aspirin; Everolimus (mTOR inhibitor, similar action as rapamycin); Metoprolol (beta blocker); Metformin (anti-diabetic drug); Simvastatin (lowers LDL cholesterol); Ramipril (ACE inhibitor).

The drugs were given in the food, at doses that had been reported to extend lifespan ... when taken individually. Some people are given that combination of medicines so we hoped that the drug interaction would not be too damaging, and we had wondered if some lifespan synergy within some of these drugs could lead to an overall high lifespan (eg if the different drugs improve different functions). But we observed a lifespan reduction in males and in females.

2) In the food of some remaining females we mixed low doses of 4 medications against cardiovascular conditions: Simvastatin; Thiazide (lowers blood pressure); Losartan potassium (angiotensin receptor blocker, lowers blood pressure); Amlodipine (calcium channel blocker, lowers blood pressure).

The question was: taken at a low-to-medium dose, could these drugs that many aged persons take have some overall preventive effect? We transposed to mice an ongoing polypill clinical trial in the UK, using a basic human-mouse conversion scale. Again, a decrease in lifespan was observed.

3) Adaptations of the first combination of drugs actually extended lifespan!

We started at age 18 months instead of 23 months, reduced the dose (as a function of weight) and gave a) the 6 compounds b) 'only' aspirin+metformin+everolimus. The results are to be analysed in greater details as we haven't analyzed the latest data yet. Also, whatever the refined analysis, we would already like to indicate that it would be good to reproduce the experiment in some other conditions, eg hybrid mice; in particular as the mortality rates of these mice was higher than the first series (but in a consistent way that supports the life extending effect).

4) Ongoing C60 experiments

After many difficulties in setting the experiment (cross-border transportation in current geopolitical times, checking absorption in mice/ detecting C60/correct source of C60, administration tried in food and replaced by gavage, training for gavage and various measures) we have transposed the popular lifespan test with c60 fullerenes reported in rats by Baati et al. to mice (CBA strain, common in the lab) and with more animals (N=17 per group). There are three groups (gavage of water, of olive oil, of C60 dissolved in olive oil), there are ... a lot of health measures and a lot of gavage (at the beginnings of the experiment as administrations are first very frequent and then gradually less frequent). Given that the experiment starts with mid-aged animals, the results are expected for the beginning of 2016.

The original C60 results from a few years back were greeted with some skepticism in the research community, given the very large size of the effect claimed and the small number of animals tested. There was, I think, also a certain annoyance: now that someone had made what was on the face of it an unlikely claim of significant life span extension via administration of C60, then some other group was going to have to waste their time in disproving it. We'll see how that all turns out, I suppose. This is science as it works in practice.

At some point the broad structural classes of research illustrated by the Interventions Testing Program and this crowdfunded mouse study will meet in the middle, and the process of funding and organizing scientific programs will be a far more complicated, dynamic, and public affair than is presently the case. I think this will be for the better. All that we have we owe to science, and a majority of the public thinks all too little of the work that will determine whether they live in good health or suffer and die a few decades from now. The more they can see what is going on the better for all of us in the end, I think.

Klotho is a longevity-associated gene that has been under investigation for some years. Increasing its expression lengthens life in mice, while reducing it has the opposite effect. Here is an open access review on the topic with a focus on mechanisms relating to cardiovascular disease (CVD):

Klotho, a gene originally identified in 1997 codifying for a novel anti-aging protein, has been implicated in a multitude of biological processes, most of them related to human longevity. Mice lacking the Klotho gene develop a phenotype similar to premature human aging, which includes endothelial dysfunction, vascular calcification, progressive atherosclerosis and shortened lifespan. A reduction in Klotho levels is observed in chronic kidney disease (CKD) patients, similar to other premature vascular aging diseases, such as hypertension or diabetes mellitus. Even normal aging is associated with a reduction in serum and urine concentration of Klotho.

More recently, the involvement of Klotho in vascular protection through different mechanisms has been demonstrated. These mechanisms include inhibition of oxidative stress, modulation of inflammation or attenuation of vascular calcification. Therefore, Klotho has been suggested as a master regulator of CVD. The disruption in the homeostasis of this factor seems to be a key element in the development of CVD. The reduction of circulating levels of Klotho is associated with the presence and severity of coronary artery disease (CAD) and is also an independent marker of some forms of vascular dysfunction such as arterial stiffness. Likewise, various genetic studies have shown the association between gene variants of human Klotho gene with CAD or stroke.

Link: http://dx.doi.org/10.4330/wjc.v6.i12.1262

Advocates for cancer research often bemoan the enormous complexity of cancer, the vast range of differences between types of cancer and even between cancers of the same type in different individuals. A cancer is cellular evolution on fast forward, rampant growth and mutational damage, which has made it a thousand moving targets for the research community. However there is a commonality to all cancer, and that is the need for cancer cells to maintain lengthy telomeres through the use of telomerase or less well understood alternative lengthening of telomeres (ALT) methods. Without this abuse of telomere lengthening mechanisms cancerous cells would not be able to continuous replicate to a degree that makes their presence life-threatening. A little of the length of telomeres are dropped every time a cell divides, and when they become too short the cell permanently ceases replication and usually activates its own programmed cell death process. This insight is the basis for the SENS approach to cancer, which is to aim at suppressing all mechanisms by which the body can lengthen telomeres.

What other approaches might be taken to attack this potential single point of failure in all cancers? These researchers are attempting to corrupt the process of telomere lengthening via telomerase in cancer cells so as to generate telomere sections that a cell considers to be damaged. This then results in much the same outcome as for very short telomeres, which is to say no more replication for the affected cells:

[Researchers] have targeted telomeres with a small molecule called 6-thio-2'-deoxyguanosine (6-thiodG) that takes advantage of the cell's 'biological clock' to kill cancer cells and shrink tumor growth. 6-thiodG acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of aging clock. This biological clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides. Once telomeres have shortened to a critical length, the cell can no longer divide and dies though a process known as apoptosis.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm' signal that is recognized by the cell as damage. As a result, the cell stops dividing and dies. Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials, researchers noted. "Using telomerase to incorporate toxic products into telomeres is remarkably encouraging at this point." Importantly, unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver and kidneys of the mice that were treated with 6-thiodG. "We observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumor burden shrinkage in mice."

Link: http://www.eurekalert.org/pub_releases/2015-01/usmc-rtt123114.php