Fight Aging!

The paper and publicity materials I'll point out today are one example of a range of recent investigations of blood-brain barrier dysfunction in Alzheimer's disease patients. The interior of the brain is its own strange domain, shut off from the rest of the body by the blood-brain barrier. Every system fails over the course of aging, however, and this barrier is no exception. There is a good amount of evidence linking increased leakage of the blood-brain barrier with the progression of neurodegenerative conditions such as Alzheimer's disease. Though, as in all such things, we must remember that aging is a global phenomenon, based on the accumulation of forms of cell and tissue damage that occur throughout the body, and thus correlations between many diverse aspects of aging can be found even when there are no direct links between them. Good research must include additional evidence beyond mere association.

What is the blood-brain barrier? The brain is laced with an intricate network of blood vessels large and small, pumping in oxygenated blood, nutrients, and an enormous range of proteins and other materials from the rest of the body. The blood-brain barrier is made up of cells that line every last millimeter of those blood vessels, each joined membrane to membrane with its neighbors in what are called tight junctions. These cells act as gatekeepers, allowing only a specific range of molecules to pass either to or from the brain tissue beyond the blood vessels. If the wrong materials leak or spill into the brain, the result is inflammation and damage - and all of the important neurodegenerative conditions are accelerated by higher levels of inflammation in brain tissues. Equally problematic is failure in the opposite direction, in which a faulty blood-brain barrier traps metabolic waste and other problem molecules in the brain rather than allowing their removal.

What to do about all of this? There is some evidence to suggest that exercise slows blood-brain barrier degeneration, but then exercise modestly slows aging across the board. Calorie restriction is much the same. Beyond these methods of slightly putting off the inevitable, one of the few plausible approaches to addressing blood-brain barrier failure is implementation of the SENS repair-based approaches to aging. Fix all of the fundamental cell and tissue damage known to cause aging, and see how things go from there. Accurately mapping the many, many intermediary steps of cause and consequence between initial damage and end result of blood-brain barrier failure is a massive project for the research community, far harder than fixing damage, even for this one small slice of aging - so why prioritize that path? The faster approach is to repair damage and observe results; if we are truly concerned about treating aging as a medical condition, alleviating suffering and rejuvenating the old rather than merely gathering data, then speed of action is a primary concern.

Leaky blood-brain barrier linked to Alzheimer's disease

Researchers using contrast-enhanced MRI have identified leakages in the blood-brain barrier (BBB) of people with early Alzheimer's disease (AD). The results suggest that increased BBB permeability may represent a key mechanism in the early stages of the disease. For the study, researchers used contrast-enhanced MRI to compare 16 early AD patients with 17 healthy age-matched controls. They measured BBB leakage rates and generated a map called a histogram to help determine the amount of the leaking brain tissue.

The BBB leakage rate was significantly higher in AD patients compared with controls and the leakage was distributed throughout the cerebrum - the largest part of the brain. AD patients had a significantly higher percentage of leaking brain tissue in the gray matter, including the cortex, the brain's outer layer. The researchers also found very subtle BBB impairment in the brain's white matter. Indeed, the researchers found a relationship between the extent of BBB impairment and decline in cognitive performance, suggesting that a compromised BBB is part of the early pathology of AD and might be part of a cascade of events eventually leading to cognitive decline and dementia. The connection between BBB impairment and AD pathology was strengthened by the fact that the addition of diabetes and other non-cerebral vascular diseases to the analysis model did not change the results.

Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease

For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter and cortex. Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter, normal-appearing white matter, deep gray matter, and cortex. When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter and cortex.

Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.

The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis. We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.

Valter Longo's research group has for the past few years been gathering data in clinical trials on the effects of a short-term low-calorie diet that achieves enough of the benefits of fasting to be useful. In essence the researchers have been in search of the 80/20 point in reduced caloric intake at which most of the triggers of outright fasting are hit, and thus the resulting changes in metabolic processes look fairly similar to those produced by fasting for the same period of time. The result, a fasting-mimicking diet, has been deployed as a cancer adjuvant therapy, but the researchers are interested in finding other uses as well. Here, results are presented for a study of its effects on multiple sclerosis in animal models of the disease and human patients.

As much as the science and the new data, the progress achieved by this group has been a matter of attracting new funding to calorie restriction and intermittent fasting research. Formulating the fasting mimicking approach as a medical diet that companies can package, sell, and bill for within the current dysfunctional medical system - even though anyone can easily replicate it on their own - has proven to be a very viable way to gain research funding from sources that have previously had little interest in this field.

Evidence is mounting that a diet mimicking the effects of fasting has health benefits beyond weight loss, with a new study indicating that it may reduce symptoms of multiple sclerosis. Scientists discovered that the diet triggers a death-and-life process for cells that appears critical for the body's repair. "During the fasting-mimicking diet, cortisone is produced and that initiates a killing of autoimmune cells. This process also leads to the production of new healthy cells." These latest findings follow studies that showed cycles of a similar but shorter fasting-mimicking diet, when paired with drug treatments for cancer, protect normal cells while weakening cancerous ones. The lab found that the diet can cut visceral belly fat and reduce markers of aging and diseases in mice and humans. "We started thinking: If it kills a lot of immune cells and turns on the stem cells, is it possible that maybe it will kill the bad ones and then generate new good ones? That's why we started this study."

For the first part of the study, researchers put a group of mice with autoimmune disease on a fasting-mimicking diet for three days, every seven days for three cycles, with a control group on a standard diet for comparison. Results showed that the fasting-mimicking diet reduced disease symptoms in all the mice and "caused complete recovery for 20 percent of the animals." Testing the mice, the researchers found reductions in symptoms attributed to health improvements such as increased levels of the steroid hormone corticosterone, which is released by the adrenal glands to control metabolism. They also saw a reduction in the inflammation-causing cytokines - proteins that order other cells to repair sites of trauma, infection or other pain. They also saw improvements in the white blood "T cells," responsible for immunity. Finally, the researchers found that the fasting-mimicking diet promotes regeneration of the myelin - the sheath of proteins and fats that insulate nerve fibers in the spine and brain - that was damaged by the autoimmunity.

The researchers also checked the safety and potential efficacy of the diet on people who have multiple sclerosis through a pilot trial with 60 participants with the disease. Eighteen patients were placed on the fasting-mimicking diet for a seven day cycle and then placed on a Mediterranean diet for six months. Also for six months, 12 participants were on a controlled diet, and 18 others were on a ketogenic diet (a high-fat diet). Those who received a fasting-mimicking diet cycle followed by the Mediterranean diet and those on a ketogenic diet reported improvements in their quality of life and improvements in health, including physical and mental health. The researchers noted that the study is limited because it did not test whether the Mediterranean diet alone would cause improvements, nor did it involve a functional MRI or immune function analysis.

Link: http://news.usc.edu/101187/diet-that-mimics-fasting-may-also-reduce-multiple-sclerosis-symptoms/

This popular science article takes a look at efforts to develop nanoparticles capable of reducing the size of plaques in blood vessels produced by the processes of atherosclerosis. These plaques narrow and deform blood vessels, ultimately breaking apart to cause blockages and ruptures of blood vessels that are often fatal. Atherosclerosis is caused at root by damaged lipids that enter the circulation and lodge in blood vessel tissue. This is followed by an unfortunate set of self-reinforcing signals sent by cells in the blood vessel wall and then by immune cells that turn up to try to deal with the problem. When immune cells become overwhelmed by ingesting damaged lipids, their destruction produces yet more debris, and plaques consisting of lipids and dead cells grow. Chronic inflammation can also accelerate this process, and aging is characterized by rising levels of inflammation. Treatments like the one profiled in this article do not treat the root causes of the problem, but regardless of success in addressing those root causes, large plaques will still need to be removed in people old enough to have developed them:

Careening through the bloodstream, a single nanoparticle is dwarfed by red blood cells whizzing by that are 100 times larger. But when specially designed nanoparticles bump into an atherosclerotic plaque - a fatty clog narrowing a blood vessel - the tiny particles can play an outsized role. They can cling to the plaque and begin to break it down, clearing the path for those big blood cells to flow more easily and calming the angry inflammation in the vicinity. By finding and busting apart plaques in the arteries, nanoparticles may offer a new, non-surgical way to reduce a patient's risk for heart attack and stroke. Some nanoparticles home in on the plaques by binding to immune cells in the area, some do so by mimicking natural cholesterol molecules and others search for collagen exposed in damaged vessel walls. Once at the location of a plaque, either the nanoparticles themselves or a piggybacked drug can do the cleanup work. Today, cardiovascular nanoparticles are still far from pharmacy shelves. Most have not reached safety testing in patients. But in mice, rats and pigs, nanodrugs have slowed the growth of the plaques that build up on vessel walls, and in some cases have been able to shrink or clear them. "I think the effect we can have with these nanoparticles on cardiovascular disease is even more pronounced and direct than what we've seen in cancer."

Many of the immune cells involved in atherosclerosis are macrophages, white blood cells that gulp pathogens, dead cells or debris in the body. At the site of a plaque, macrophages become swollen with fats and transform into what are called "foam cells" because of their foamy appearance. As they digest fats, foam cells send out chemical signals to recruit more inflammation-causing cells and molecules to the area. Because they're so intimately involved in the formation of plaques, macrophages and foam cells are a prime target for nanoparticles. One research group has designed nanoparticles that bind to molecules on the surface of macrophages, preventing them from gobbling fats and becoming foam cells. The researchers made the nanoparticles specifically target a subtype of macrophage that's involved in atherosclerosis, not the macrophages that might respond to other injuries in the body. When nanoparticles were injected into mice with narrowed arteries, the blockages decreased by 37 percent.

Another research group has designed HDL-mimicking nanoparticles. The particles deliver statins that make a beeline for macrophages and plaques, letting them administer the drug at lower-than-usual doses. The researchers were inspired by earlier studies that showed how extremely high doses of statins, given to mice, could lower LDL levels while also packing anti-inflammatory properties. Of course, in humans, such high doses would probably cause liver or kidney damage. The solution: tack the statins to a nanoparticle to send them, missile-like, to the plaques. That way, a low dose of the drug could achieve the high concentration needed at the site of the atherosclerosis. The group reported that plaque-filled arteries in mice given the nanoparticle were 16 percent more open than arteries in mice with no treatment, and 12 percent more open than in mice given a systemic statin.

The inflamed vessel wall around an atherosclerotic plaque goes through several changes in addition to the accumulation of belligerent immune molecules. As vessel walls are stretched and inflamed, the structural protein collagen, meant to keep the vessels taut and tubular, becomes exposed the way the threads of a tire begin to appear as it wears down. Scientists are using the exposed collagen to their advantage. Their nanoparticle combines a collagen-binding protein with nitric oxide, a molecule that stimulates the growth of new cells at wounds. To maximize the surface area of the drug that contacts the vessel wall, the team arranged the molecules in a line, forming a nanofiber, rather than a sphere. As the fiber is swept through the bloodstream, it binds to exposed collagen, anchoring the nitric oxide in place to spur healing of the artery. The researchers added fluorescent tags to the nanofibers and showed that the fibers congregated at injured spots on mouse arteries within an hour of injection. The tagged particles remained there for three days and the treated vessels ended up 41 percent more open.

Link: https://www.sciencenews.org/article/nanoparticles-beat-back-atherosclerosis

Today I'll point out a review paper that covers a few approaches to stem cell therapy in the context of treating osteoarthritis, a degenerative condition of the joints. Arguably the most demonstrably successful branch of stem cell medicine today is that focused on treating the issues that arise in aging joints: deterioration of tissues, wearing of bone and cartilage, and associated inflammation, pain, and loss of function. The methodologies used for mesenchymal stem cell transplants, developed over the past fifteen to twenty years, today have a good expectation of delivering noticeable improvement to patients. A short turnaround to improvement that is self-evident to the patient is an important component for success in medicine. Therapies that deliver only statistical improvements to function and risk of disease without rapid and obvious physiological improvement from the perspective of the patient - and this category still includes many stem cell therapies for internal organ damage at this point - are a much harder sell at all levels of development.

Stem cell activity declines with age, a reaction to growing levels of cell and tissue damage. This decline is thought to trade off risk of death by cancer on the one hand, the result of damaged cells undertaking more activity, with risk of death due to loss of tissue function on the other hand, the result of stem cells becoming less active and thus delivering fewer replacement cells to the tissues they support. Restoring stem cell populations to their youthful undamaged and active state is a necessary component in any future rejuvenation toolkit. Present day stem cell therapies do not achieve this goal, however. They appear to work largely by altering the local signaling environment for a short period of time, putting existing cells back to work, spurring greater regeneration, and reducing inflammation. The transplanted cells in many cases live only a short time. Most stem cell therapies available today should be viewed as a burst of rebuilding, but rebuilding that uses damaged tools and damaged materials. Nonetheless, even though this is compensation, not rejuvenation, it can result in significantly better patient outcomes than the other presently available options.

Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review

Osteoarthritis (OA) is a major cause of disability and chronic pain, characterized by progressive and irreversible cartilage degeneration. The capacity of articular cartilage to repair is inherently poor, with the relative avascularity of cartilage, and hence lack of systemic regulation, likely leading to an ineffective healing and reparative response. With advances in modern medicine improving the prevention, diagnosis and treatment of many diseases that were once life-threatening, the population is now living longer. This increased life expectancy has led to an increased burden of degenerative conditions including osteoarthritis. Current medical treatment strategies for OA are aimed at pain reduction and symptom control rather than disease modification. These pharmaceutical treatments are limited and can have unwanted side effects. The health and economical impact of OA has seen it become an international public health priority and has led to the active exploration and research of alternative regenerative and joint preservation therapies including mesenchymal stem cells.

Whilst both mechanical, genetic and other factors influence development of OA, the primary risk factor is age. Components of the cartilage extracellular matrix (ECM) including type II collagen and proteoglycans undergo age-related structural changes, leading to likely alteration in the biomechanical properties of the ECM. Advanced glycosylation end products also accumulate within cartilage, leading to increased cross-linking and altered biomechanical properties. These changes lead to a loss in the ability of cartilage to adapt to mechanical stress/load. Chondrocytes within the cartilage matrix also exhibit age related changes. It has been proposed that reactive oxygen species (free radicals) induced by mechanical or biological stressors may lead to cell senescence. Cell senescence is accompanied by reduced growth factor response and production, coupled with an observed upregulation of inflammatory cytokine expression. Evidently there are a host of enzymatic compounds that are involved in the disruption of the collagen matrix leading to the degradative process of OA.

Interestingly, evidence indicates that osteoarthritis is associated with a depleted local population of stromal mesenchymal stem cells (MSCs), and those that exist exhibit reduced proliferative and differentiation capacity. The depletion and functional alteration/down regulation of MSC populations with reduced differentiation capacity has also been postulated as a cause for progressive degenerative OA. Despite these findings, it has been noted that there exists MSCs with chondrogenic differentiation potential in patients with OA, irrespective of age or the etiology of disease.

MSCs, due to ease of harvest and isolation with minimal donor site morbidity, coupled with an ability to expand into chondrocytes, have meant that they have been actively explored in regards to tissue engineering and repair. Preclinical trials using techniques similar to autologous harvesting of cartilage from a non-weight bearing area, but substituting chondrocytes with MSCs, have shown positive results with formation of tissue with histological properties consistent with hyaline cartilage and a high type II collagen presence. Others have successfully transplanted isolated MSCs - seeded onto a type I collagen network - to an area of chondral defect, resulting in successful filling of the defect. Later biopsy at two years indicated hyaline like cartilage with type II collagen on histological evaluation.

Recognizing the limitation of biological scaffolds in the treatment of OA - where there exists more diffuse cartilage loss rather than an isolated cartilage lesion - other researchers have sought to assess the effect of intra-articular MSC injections. Preclinical trials have successfully indicated the benefit of MSC intra-articular injections on improvement in function, though results have been inconsistent on cartilage restoration. Some studies, whilst indicating significant pain and functional improvement, have not seen any observable difference in disease progression against controls, whilst others have successfully shown disease modification. Similarly to preclinical results, clinical trials using injectable MSC techniques have reproducibly shown pain and function improvements, though observation of disease modification has been less consistent. Most recently, Phase I and II trials using expanded adipose derived MSCs in the treatment of OA have shown MRI evidence of cartilage regrowth. Following a single intra-articular injection of 100 million MSCs, radiological (MRI) follow-up at 6 months showed increased cartilage volume and histological assessment confirmed hyaline-like cartilage regeneration with the presence of type II collagen.

Despite MSCs being commonly associated with regenerative medicine, and level IV evidence of chondral regrowth and disease modification, there is a paucity of well-controlled trials assessing structural outcome. The reproducible pain and functional improvement seen with MSC injectable therapies, raises the question of whether the biological mechanism of action may be a strong anti-inflammatory effect - including on neurogenic inflammation - rather than regeneration. Further, the observed disease modification in studies that use combination therapy suggests that the efficacy of MSC therapies may be influenced by additional agents including platelet concentrates and hyaluronic acid - though this creates a further layer of confusion regarding cause and effect. Nonetheless, MSC based cell therapies offer an exciting possibility in the treatment of OA and importantly show promise in disease modification, with potential inhibition of progression and recent evidence of reversal of this degenerative process.

In past years researchers have demonstrated in animal studies that reduced levels of klotho can shorten life span while increased levels modestly extend life span. The underlying mechanisms are complex and not fully understood. As is also the case for other longevity-related proteins, altering levels in circulation through gene therapy or other methods changes many aspects of cellular metabolism. Unraveling this complexity is a slow and expensive process. One small part of the bigger picture in this case is the relationship between klotho and fibroblast growth factor 23 (FGF23). The review paper below examines what is known on this topic:

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption and vitamin D hormone production in the kidney. Klotho was originally discovered as an anti-aging factor, but the functional role of Klotho is still a controversial issue. Three major functions have been proposed, a hormonal function of soluble Klotho, an enzymatic function as glycosidase, and the function as an obligatory co-receptor for FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23 and Klotho signaling in the kidney, in the parathyroid gland, in the cardiovascular system, in bone, and in the central nervous system.

Recent advances in the field of FGF23 and Klotho biology have revealed major new functions of FGF23 and Klotho signaling in the kidney, in the heart, in bone, in blood vessels, and in the parathyroid gland. It is now clear that FGF23 is far more than only a phosphaturic bone-derived hormone. Rather, FGF23 has emerged as a pleiotropic endocrine and auto-/paracrine factor not only involved in phosphate homeostasis, but also in calcium and sodium metabolism, in bone mineralization as well as in the development of cardiac hypertrophy. These novel findings have linked phosphate with volume homeostasis, and may have major pathophysiological implications for chronic kidney disease, cardiovascular diseases, and disorders of bone mineralization.

Link: http://dx.doi.org/10.1016/j.mce.2016.05.008

Evolution has left mammals with only a limited ability to regenerate heart tissue. Unlike very regenerative species such as salamanders or zebrafish, we lose most of our ability to heal the heart very early in life. Here, researchers suggest that this is keyed to reduced telomere length in heart cells, but in a way that is very different to the more familiar erosion of average telomere length that occurs over the course of aging. In this case that reduced length is a developmental process occurring in early childhood. If this work bears out, it actually sounds like a much more compelling argument for the use of telomerase therapies in medicine than those based on trying to address age-related telomere erosion, as that erosion is most likely only a marker of age-related damage, not a cause:

Researchers have discovered that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells' ability to proliferate and replace damaged heart tissue. Newborn babies can repair injured myocardium, but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Newborn mice can also regenerate damaged heart tissue. Their heart muscle cells, or cardiomyocytes, can proliferate and repair the heart in the first week after birth, but this regenerative capacity is lost as the mice grow older and the majority of their cardiomyocytes withdraw from the cell cycle.

Researchers wondered whether the cause of this cell cycle arrest might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. If telomeres grow too short - due, for example, to a loss of the telomere-extending telomerase enzyme - cells can mistake chromosome ends for segments of damaged DNA, leading to the activation of a checkpoint that arrests the cell cycle. The researchers therefore examined the length of telomeres in newborn mouse cardiomyocytes and found that the telomeres rapidly eroded in the first week after birth. This erosion coincided with a decrease in telomerase expression and was accompanied by the activation of the DNA damage response and a cell cycle inhibitor called p21.

Telomerase-deficient mice have shorter telomeres than wild-type animals, and, the researchers discovered, their cardiomyocytes already begin to stop proliferating one day after birth. When the researchers injured the hearts of one-day-old mice, telomerase-deficient cardiomyocytes failed to proliferate or regenerate the injured myocardium. In contrast, wild-type cardiomyocytes were able to proliferate and replace the damaged tissue. They also found that knocking out the cell cycle inhibitor p21 extended the regenerative capacity of cardiomyocytes, allowing one-week-old p21-deficient mice to repair damaged cardiac tissue much more effectively than week-old wild-type animals. Maintaining the length of cardiomyocyte telomeres might therefore boost the regenerative capacity of adult cells, improving the recovery of cardiac tissue following a heart attack. "We are now developing telomerase overexpression mouse models to see if we can extend the regenerative window."

Link: http://www.eurekalert.org/pub_releases/2016-05/rup-msl052516.php

Disruption is a part of progress. All communities of research and development go through cycles in which (a) the established mainstream and its insiders become slow and ineffective, (b) outsiders become frustrated given the unrealized potential for faster progress and better outcomes, (c) some of these outsiders succeed in developing a vastly better path forward, despite being opposed at every turn by the mainstream, (d) the new path forward displaces the existing mainstream, and the outsiders become the new leaders and insiders, (e) with time, this new mainstream becomes slow and ineffective. So the cycle repeats.

In the matter of medicine, aging, and longevity, we are presently somewhere in the midst of step (c). The mainstream of ineffective, expensive approaches to the treatment of age-related conditions is ineffective and expensive because it fails to consider or address the root causes of aging. Try making any damaged machine work better and longer while not actually repairing the damage - it isn't easy. The typical approach to research is to start with the end stage disease state and work slowly and painfully backwards through a very complex dysfunctional metabolism. At the first proximate cause, stop and try to build a treatment that can manipulate the diseased metabolic state so as to make the proximate cause less onerous to the patient. Then return to tracing the disease backwards towards root causes. There are so many layers of proximate causes in most diseases that this type of approach can continue - and has continued - for decades without ever getting close to the cell and tissue damage that is the root cause of aging, and thus the root cause of all age-related disease.

This, however, is the mainstream, the default approach. It is an established culture, reinforced by regulation and tradition, and will change but little without disruption. The most important outsiders attempting to disrupt aging research in favor of effective progress towards treatment of aging are those of the small community that built and supported the Methuselah Foundation and SENS Research Foundation, pulling in philanthropic funding and gathering allies in support of a repair-based approach to the treatment of aging. The fundamental, root causes of aging are well cataloged, forms of cell and tissue damage caused by the normal operation of metabolism, so why wade through the mud of how exactly aging progresses in detail from these causes, and why start at the end and work backwards? Just fix the known causes using any of the envisaged and planned potential classes of repair therapy and see what happens. The potential for cures first, full understanding later: too many people are dying to indulge the mainstream's preferred approach.

We are far enough into this process of disruption that some outsiders have become scientists and some scientists have joined the insurrection. There are thousands of supporters of rejuvenation research, there is respectful and informed press attention, and tens of millions of dollars have been deployed to advancing this cause. The first rejuvenation therapies are under development in startup companies. We're almost at the stage where the people who at the beginning carried out the hard, thankless work of spreading new ideas, obtaining support, and kicking shins - telling the scientific community that they were going about everything the wrong way - start to be buried by the second wave. It is the fate of all pioneers to be forgotten and trodden upon by a collaboration between later newcomers, those with more resources to claim the mantle of leadership, and those of the former mainstream who decide to pretend that they agreed all along. Such is life. It is frustrating, but the important thing is not the credit, but that the job will be done, that repair-based therapies for aging will become the new mainstream on the basis of obtaining far better results than the present approaches to aging. Life and health before pride.

The article linked below struck me as exhibiting a nice mix of many of the agendas that come to the fore during the disruption of an industry, ranging from the several factions intent on burying the original disruptors to individuals with the mainstream attempting to present a slight adjustment of their methods as an alternative to the still vastly better disruptive technology. I'm not sure I agree with all of the core thesis. Some of those presented as outsiders, such as Larry Ellison and Paul Glenn, were almost immediately co-opted by the mainstream of the time. There isn't enough of a distinction made between for-profit and philanthropic funding, as the latter has been vastly more influential and important over the years in which I've been observing progress in aging research. But see what you think.

I've been led here by Sonia Arrison, a Silicon Valley local and author of 100-Plus: How the Coming Age of Longevity Will Change Everything. Arrison has agreed to show me around her strange Californian world, populated with very wealthy, very smart dreamers, who share her certainty that a longevity revolution is on its way. We've arrived on Joon Yun's doorstep to learn how and why he, along with a small group of big power players, plan to "cure" aging and extend human health span - and possibly even human life - by decades, if not centuries. "I essentially made a wager to myself that aging is a code," Yun explains to me from across a shiny conference table. "If aging is a code, that code could be cracked and hacked. The current system in healthcare is a whack-a-mole of your symptoms until you die. It addresses the diseases of aging, but not curing the underlying process behind aging itself. The healthcare system is doing a good job of helping people live longer and stronger lives, but aging is still a terminal condition." In 2014, Yun created the Race Against Time Foundation and Palo Alto Prize, which will award $1 million to a team that can demonstrate the capacity to mitigate aging by, among other things, extending the life of a mammal by 50 percent.

Faith that science will conquer aging is common in Silicon Valley these days. The language Yun uses to explain his dream - especially the use of the word "cure" - makes traditional researchers in the field of aging cringe. But few are complaining about the interest of the big-spending Silicon Valley crowd. In recent years, public institutions like the National Institutes of Health have been slow to commit any more than a token of their overall budgets to aging research. It is the private funders with big dreams who are galvanizing the field. The Ellison Medical Foundation has spent nearly $400 million on longevity research. Oracle founder Ellison told his biographer, "Death makes me very angry." PayPal cofounder and venture capitalist Peter Thiel helped fund the SENS Research Foundation, a longevity organization co-led by British gerontologist Aubrey de Grey, who's argued we might someday halt aging and extend life indefinitely. (Arrison, Thiel's longtime friend, introduced the two).

In 2013, the founders of Google launched Calico, short for California Life Company, to research aging and associated diseases. A year later Calico teamed up with the biopharmaceutical company AbbVie, with which it plans to invest up to $1.5 billion to develop age-related therapies. "With some longer term, moonshot thinking around healthcare and biotechnology, I believe we can improve millions of lives," wrote Google cofounder Larry Page. The quest to extend longevity makes perfect sense in Silicon Valley, explains Lindy Fishburne, a longtime lieutenant of Thiel's, in her stately office in San Francisco's Presidio, a former military base that sits on a pictorial tip of the San Francisco Bay. "It's the engineering culture which says we'll build our way out of it, we'll code our way out of it, there has to be a solution. I also think it's coupled with a very unique optimism that is pervasive in Silicon Valley."

It is worth noting that all too few of the people and funding sources mentioned in the article are in fact backing the repair-based approaches to rejuvenation that are, to my eyes, the most likely to realize a future of greatly extended healthy lives, and to accomplish these gains soon enough to matter to you and I. Many of those involved are either already or on their way to being captured by the present ineffective mainstream, just like Ellison and Glenn. Nonetheless, disruption is underway, and threads of meaningful work will continue to grow. It is still early enough in this process that ordinary folk like you and I can make a mark: our philanthropy and support for the SENS Research Foundation and similar organizations in past years has produced meaningful change in the status quo, and that change is spreading.

Most laboratory species - such as flies, worms, mice, and other mammals - have been shown to age somewhat more slowly in response to calorie restriction; it changes near every measure of metabolism and improves near every measure of health. The effects on lifespan are much more pronounced in short-lived species than in long-lived species such as our own, but the effects on human health are still pretty impressive. It has been a few years now since researchers first found that the calorie restriction response has some dependency on sensory perception of food in species such as nematode worms and flies. This is an as yet largely unexplored avenue for the development of calorie restriction mimetic drugs that might recapture some of the benefits of eating less without the need to eat less:

Researchers have shown a new effect on aging via a small drug-like molecule that alters the perception of food in the nematode C. elegans. The researchers "tricked" the worm's metabolism into a state of caloric restriction, extending the animal's lifespan by 50 percent. The study provides a new avenue of inquiry for researchers around the world who are attempting to develop human drugs that mimic the positive effects of a Spartan diet. "This small molecule blocks the detection of food in the worm's mouth. The worm senses that its mouth is empty even when it is full of food, tricking the animal into shifting its physiology into a caloric restricted-state even when it's eating normally. Our study suggests that primary sensory pathways represent new targets for human pharmacology."

Researchers screened 30,000 synthetic, drug-like compounds in nematodes and identified several structurally related compounds that acted on mechanisms tied to caloric restriction. They found that the small molecule, NP1, impinged upon a food perception pathway by promoting glutamate signaling in the pharynx of the animal. The chemical activated a neurotransmitter-controlled food deprivation signal which altered the animal's normal metabolism into a caloric restriction state. Exploring sensory pathways as potential drug targets should be of interest to age researchers interested in mimicking caloric restriction in order to extend healthspan. The mechanisms involved in sensory pathways may be more specific than secondary pathways that detect energy levels or absorbed nutrients at the cellular level, such as the intracellular pathways mTOR and AMPK which are under study in many labs around the world. "Targeting sensory pathways may lead to a more rapid response to changing diet. Altering these higher level, specific response mechanisms may also have fewer effects on other systems in the body."

Link: http://www.eurekalert.org/pub_releases/2016-05/bifr-cwe052616.php

The authors of this paper argue that stochastic mutational damage to nuclear DNA is important in the progression of vascular aging, the declining function and structural integrity of blood vessels. It is more or less the consensus hypothesis that nuclear DNA damage does broadly contribute to all facets of the aging process by causing a growing random dysregulation of cellular activity, and is not just a matter of cancer risk. There those who argue the opposite position, however, that while this is damage, outside of cancer risk nuclear DNA mutations don't create enough disarray over a normal human lifetime to matter in comparison to other forms of cell and tissue damage. As for most of the molecular damage of aging, there is a lot of room to argue over relative importance because there are few presently available ways to repair any one form of damage in isolation to see what happens. If all forms of damage could be so repaired, then the research community would certainly know how important each was, but that still lies in the future.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, responsible for killing 17.3 million persons per year. The onset of CVD is triggered by vascular endothelial alterations characterized by an impaired endothelium-dependent vasodilation, the overproduction of pro-inflammatory and prothrombotic molecules, and oxidative stress. Age is the strongest independent predictor for CVD in risk scores in middle-aged persons, and an important determinant for cardiovascular health in the population aged 65 or older. Aging is characterized by the complex interaction of cellular and molecular mechanisms that leads to a collection of functional problems. Focusing on the vasculature, such problems are closely associated with each other, and include worsened vasodilation, increased arterial stiffness and overt remodeling of the extracellular matrix, diffuse intimal thickening and a dysfunctional endothelium. The mechanisms through which age actually contributes to cardiovascular risk remain the subject of speculation.

A recently proposed alternative view on vascular aging has emerged that presents new mechanistic alternatives for understanding the process of vascular aging. In this novel paradigm, causal mechanisms for the process of aging itself, most notably genomic instability, including telomere attrition, drive the detrimental changes occurring increasingly with (biological) aging. In the present review we summarize the evidence that supports the role of genomic instability in vascular aging. In addition, we present mechanisms through which genomic instability generates the functional changes that are typical for the aging vasculature.

Nuclear DNA lesions, among which is telomere erosion, and mitochondrial DNA damage are strongly associated with several main features of vascular aging, such as diminished vasodilator capacity and increased vasoconstriction, increased blood pressure, increased vascular stiffness and atherosclerosis. Pivotal cellular biological changes involved in these pathological features comprise cellular senescence, apoptosis, autophagy, stem cell exhaustion and altered proliferative capacity of vascular cells. The role of gene mutation and of compromised transcription remains unknown. Potential mediating signaling pathways involved include components of the survival response, notably antioxidants under regulation of Nrf2 (beneficial), increased inflammatory status (detrimental) and decreased IGF-1/GH signaling (detrimental), as well as the interplay between mTOR, AMPK and NFκB, SIRT-1, and PAI-1, p53- and p21- and p16-related signaling. Proposed remedies against genomic instability-related vascular aging include PAI-1 inhibition, mTOR inhibition, dietary restriction, senolytics, PDE1 and PDE5 inhibitors and stimulators of Nrf2.

Link: http://www.mdpi.com/1422-0067/17/5/748/htm

It is an unfortunate fact of life that many promising avenues of medical research languish partially developed and unfunded. It isn't unusual to see potentially transformative medical technologies linger with little further progress for a decade or more after their first triumphant discovery. The innovative antiviral DRACO technology is one such, offering the potential of therapies for persistent infections that cannot currently be treated. Another is the use of immune cell transplants to attack cancer, presented in its initial form of granulocyte infusion therapy (GIFT) with accompanying compelling animal data at the third SENS conference in 2007, but under development for years prior to that point. Where is this approach to cancer treatment today, nearly a decade down the line? Little advanced beyond that point, I'm sorry to say. In fact so little progress has occurred and so little attention has been given to this style of cancer treatment that other researchers are now and then independently finding their way to the same place from different directions, as noted in the paper and publicity materials that are linked below.

Why does this waste of potential continue to happen over and again in the field of medical research and development? One challenge is that a life in the fairly rigid hierarchy of the sciences is typically poor preparation for the cut and thrust of bringing a new technology into the marketplace, raising funding outside the established channels of grants, and working with businesses. That is an entirely different set of skills and talents. Some scientists have those skills and talents, and you'll tend to see those people starting companies or leading laboratories. Most do not - just as there are few entrepreneurs and leaders in the general population, there are also few entrepreneurs and leaders within the scientific community. There are only so many hours in the day, time spent on one set of skills is not spent on another, and science is a demanding partner. Just because a team makes a solid advance in their field doesn't mean they are well positioned or qualified to make it a success after that point.

Another issue, important in this case, is that the combination of heavy regulation of medicine, regulatory capture, and the consequent dominance of very conservative large developers and very expensive development processes means that medicine rarely moves forward for any potential treatment in which the biochemical mechanisms cannot be explained. Ten years ago, there was no good explanation for why GIFT was so good at defeating cancer in mice. Progress within the system and the present cultural edifice of cancer research required that explanation - the idea of moving ahead based purely on great results doesn't win you support from Big Pharma, and without that support there are few organizations with deep enough pockets to move ahead through the burdensome FDA processes as they stand these days. So while there have been trials of immune infusion therapies for cancer, these were small and funded from other sources. That backing is not extensive. There have been some signs of availability in the medical tourism space, but without more of a mainstream interest in the field that is also so far anemic.

An entirely different class of problem contributing to the existence of moribund fields of research is the lack of funding and attention given to medical research in general. Very little of medical research is funded to anywhere near a reasonable level given the potential expectations for resulting benefits. To a first approximation, no-one cares about medical research and medical progress, or at least not until it is far too late to do anything about it. Research survives on the scraps and margins of philanthropy of this wealthy society. Bread and circuses before progress, and near all of the money in medicine goes towards using the technology that exists, even when there are much better alternatives within reach, just a few years of development away.

Fighting cancer with the help of someone else's immune cells

Researchers decided to test whether a "borrowed immune system" could "see" the cancer cells of the patient as aberrant. The recognition of aberrant cells is carried out by immune cells called T cells. All T cells in our body scan the surface of other cells, including cancer cells, to check whether they display any protein fragments on their surface that should not be there. Upon recognition of such foreign protein fragments, T cells kill the aberrant cells. As cancer cells harbor faulty proteins, they can also display foreign protein fragments - also known as neo-antigens - on their surface, much in the way virus-infected cells express fragments of viral proteins. To address whether the T cells of a patient react to all the foreign protein fragments on cancer cells, the research teams first mapped all possible neo-antigens on the surface of melanoma cells from three different patients. In all 3 patients, the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient's tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients' T cells. "In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens. The receptor that is used by these donor T-cells can then be used to genetically modify the patient's own T cells so these will be able to detect the cancer cells. Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput."

Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen specific T cell responses are therefore attractive. Here, we demonstrate that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11/57 predicted HLA-A2-binding epitopes from three patients. Many of the T cell reactivities involved epitopes that in vivo were neglected by patient autologous tumor-infiltrating lymphocytes. Finally, T cells re-directed with T cell receptors identified from donor-derived T cells efficiently recognized patient-derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such "outsourced" immune responses in cancer immunotherapy.

This paper explores the mechanisms by which the amyloid associated with the progression of Alzheimer's disease can be cleared naturally outside the brain. It raises the possibility that finding ways to reduce amyloid outside the brain will allow existing transport and clearance mechanisms to export and remove more of the amyloid from the brain. A counter-argument to this hypothesis is that these transport and clearance mechanisms become damaged and dysfunctional with age. There are, for example, research groups examining the drainage of cerebrospinal fluid, one of the ways in which amyloid might leave the brain, who have found this fluid flow diminished in Alzheimer's patients. There is similar work on age-related declines in the mechanisms for filtration of cerebrospinal fluid that are located in the choroid plexus. It is a still open question as to the degree that these various mechanisms - and others - contribute to the overall progression of Alzheimer's disease. The best way to answer that question is to repair individual suspected causes one at a time, and see what happens as a result.

Alzheimer's disease (AD) is the most common form of dementia among the elderly. Senile plaques containing amyloid-beta protein (Aβ) in the brain are a pathological hallmark of AD and they play a pivotal role in AD pathogenesis. The steady-state level of Aβ in the brain is determined by the balance between Aβ production and its clearance. In the brain, Aβ can be cleared via microglial phagocytosis and proteolytic degradation by enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE). Transport of Aβ from the brain into the peripheral blood has been demonstrated in both animal models and humans. There are several potential pathways for the efflux of brain Aβ into the periphery. These include transport across the blood-brain barrier (BBB) mediated by low-density lipoprotein receptor-related peptide 1 (LRP1), drainage from interstitial fluid (ISF) into cerebrospinal fluid (CSF) via perivascular or glymphatic pathways, reabsorption from CSF into the venous blood via arachnoid villi and blood-CSF barrier, or into the lymphatic system from the perivascular and perineural spaces, and possibly via meningeal lymphatic vessels.

The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected 125I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575389/

In this open access paper, the author argues for greater investigation of the fundamentals of aging in various species, for more comparisons of the biochemistry of aging between wild and laboratory populations, and for greater collaboration between some of the distinct communities within the aging research community:

Aging (senescence) is an increase in mortality risk with age due to deterioration of vital functions. Understanding the mechanisms and consequences of aging is not only an intriguing evolutionary question but also a matter of practical concern with pressing demographic and societal implications. The two aspects of aging research - fundamental understanding of why organisms age and how aging patterns in nature vary on the one hand, and an applied perspective dealing with biomedical treatments of aging on the other - have entered an exciting phase. I argue that the next steps to understand the biology of aging should combine approaches and concepts used by the two research communities.

Biogerontologists are interested in proximate mechanisms of aging, use laboratory models and focus on means of mitigating specific functional declines associated with aging. Advances in biogerontology have demonstrated that these proximate mechanisms of aging and interventions to modify lifespan are shared among species. Evolutionary biologists seek to understand why aging has evolved and how and why it varies among populations and species. Long-standing theories to explain the evolution of aging have recently been found unsatisfactory in their ability to explain many observed patterns of aging, revealing how incomplete our understanding of the evolutionary aspects of aging (and variation in aging rates within and among species) currently is. A systematic feedback between functional and evolutionary research on aging is needed to provide mutually beneficial critical insights into the biological basis of aging.

In nature, aging patterns have proven more diverse than previously assumed. The paradigm that extrinsic mortality ultimately determines evolution of aging rates has been questioned and there appears to be a mismatch between intra- and inter-specific patterns. The major challenges emerging in evolutionary ecology of aging are a lack of understanding of the complexity in functional senescence under natural conditions and unavailability of estimates of aging rates for matched populations exposed to natural and laboratory conditions. I argue that we need to reconcile laboratory and field-based approaches to better understand (1) how aging rates (baseline mortality and the rate of increase in mortality with age) vary across populations within a species, (2) how genetic and environmental variation interact to modulate individual expression of aging rates, and (3) how much intraspecific variation in lifespan is attributable to an intrinsic (i.e., nonenvironmental) component. I suggest integration of laboratory and field assays using multiple matched populations of the same species, along with measures of functional declines.

Link: http://onlinelibrary.wiley.com/doi/10.1002/ece3.2093/full

The paper I'll share today takes a look at stem cells over the course of aging in different sea urchin species that exhibit radically different life spans, ranging from a few years to somewhere north of a century. A fair number of marine species, some urchins included, are negligibly senescent, meaning that they show few signs of degeneration or increased mortality due to intrinsic causes until very close to natural death. In some cases it has been impossible to measure life span in a random sample gathered from the ocean, as was true for lobsters until recently, and that combined with the paucity of funding for investigating the aging of sea life has meant that the research community has no good, certain data for the maximum life span of many of these species.

When looking at lower life forms that appear to be ageless or very close to ageless, such as hydra, a common theme is hyperactive, proficient, constant regeneration of all tissues. Since distinct populations of stem cells serve this purpose in hydra and higher species, both those that are negligibly senescent and those that age gracelessly, it makes sense to gain a better understanding of how stem cell biology differs between those who age and those who age less. This isn't just longer lives versus shorter lives, but perhaps more importantly how much of an age-related decline occurs across the life span. There are also other compelling reasons for such an investigation, such as the differences between salamanders, capable of regrowing limbs and organs, and mammals, who cannot. That may be somewhat orthogonal to the question of how stem cell biology affects aging, since it is debatable as whether or not salamanders are negligibly senescent. This isn't a classification with a clear dividing line, and many species are happy to occupy the large grey area. Still, that is a problem solved by gathering more data, and by gaining more knowledge - and thus at root by funding more research.

In our species, and most others of interest, stem cell activity declines with age. The conventional wisdom, not unchallenged, is that this serves to give us additional time free from cancer at the expense of a loss of tissue maintenance, producing growing frailty and increasing organ failure. Damaged cells undertaking activity raise the risk of cancer. If those cells instead remain quiescent, there is less of a risk. In the view of aging as an accumulation of cell and tissue damage, stem cells shut down in response to rising levels of damage. But how does this all work in negligibly senescent species, and - as ever - how might the research community port over some of those benefits into our biochemistry in a cost-effective manner? For my money, I'd guess that this line of development is destined to be lengthy and expensive, but that is the way of most research. The better path as I see it is to repair the damage that causes stem cells to react by retreating from their work, and to replace those stem cell populations wholesale where the cells have themselves become damaged. The present stem cell industry is a good first step on that road, but there is much more yet to be done to reach the desired endpoint.

Is aging inevitable? Not necessarily for sea urchins

Sea urchins are remarkable organisms. They can quickly regrow damaged spines and feet. Some species also live to extraordinary old ages and - even more remarkably - do so with no signs of poor health, such as a decline in regenerative capacity or an increase in age-related mortality. Researchers study the regenerative capacity of sea urchins in hopes that a deeper understanding of the process of regeneration, which governs the regeneration of aging tissues as well as lost or damaged body parts, will lead to a deeper understanding of the aging process in humans, with whom sea urchins share a close genetic relationship.

Researchers studied regenerative capacity in three species of sea urchins with long, intermediate and short life expectancies: the red sea urchin, Mesocentrotus franciscanus, one of the world's longest-lived organisms with a life expectancy of more than 100 years; the purple sea urchin, Strongylocentrotus purpuratus, with a life expectancy of more than 50 years; and the variegated sea urchin, Lytechinus variegatus, with a life expectancy of only four years. The scientists hypothesized that the regenerative capacity of the species with shorter life expectancies would decline as they aged. Much to their surprise, however, they found that regenerative capacity was not affected by age: as with the very long-lived sea urchin, the regenerative capacity of the species with a shorter life expectancy did not decline with age. "We wanted to find out why the species with short and intermediate life expectancies aged and the long-lived species didn't. But what we found is that aging is not inevitable: sea urchins don't appear to age, even when they are short-lived. Because these findings were unexpected in light of the prevailing theories about the evolution of aging, we may have to rethink theories on why aging occurs."

Maintenance of somatic tissue regeneration with age in short- and long-lived species of sea urchins

Sea urchins exhibit continued growth and reproduction throughout their lives and yet different species are reported to have vastly different life expectancies in the wild. The proper balance of cell division and cell death is important for life-long growth and homeostasis and maintaining this balance with age would be essential to achieve negligible senescence, whereas failure to maintain this balance would promote aging and shortened lifespan. In this study, cell proliferation was measured using in vivo incorporation of 5-bromo-2′-deoxyuridine (BrdU).

It was determined that there was a low level of BrdU incorporation and apoptosis in the internal tissues of three species of sea urchins with different lifespans, regardless of age. The low levels of cell proliferation are consistent with the low metabolic rates that have been reported for sea urchins, and suggest that unlike Hydra, sea urchins do not avoid senescence by continually replenishing tissues at a high rate. As expected for animals that grow indeterminately, there were higher levels of cell proliferation compared to apoptosis in the tissues. The low levels of apoptosis in the tissues of young and old animals are consistent with low levels of cellular damage that does not increase with age. Interestingly, in L. variegatus and S. purpuratus, which have a ~ 10-fold difference in lifespan, there were few differences in the amount of cell proliferation and apoptosis in tissues compared within age categories.

To determine whether regenerative potential was maintained with age in sea urchins, the regrowth of amputated spines and tube feet was measured in L. variegatus and S. purpuratus. The data demonstrate that the regenerative potential of both types of appendages was maintained with age in these sea urchin species. A prediction from the evolutionary theories of aging is that level of extrinsic mortality influences the rate of aging, such that high levels of extrinsic mortality would be associated with tissue decline once an organism reaches reproductive maturity and survivorship in the wild becomes increasingly unlikely. L. variegatus is predicted to have a much lower annual survival rate than S. purpuratus and M. franciscanus and an estimated lifespan in the wild of about 4 years, and yet the results did not show evidence of decline in regenerative capacity in larger/older animals. It is possible that L. variegatus have the potential to live much longer than has been reported in the wild (and hence that the animals used in this study were not approaching their maximum lifespan potential), or that longevity in these animals is not limited by investment in (or capacity for) maintenance and repair of damaged tissues.

The lack of age-related differences in the maintenance of tissue homeostasis and regenerative potential in sea urchin species with different lifespans were unexpected in light of current evolutionary theories of aging, and further study is required to understand the factors underlying the short lifespan of L. variegatus in particular.

Researchers have uncovered evidence for a rare natural genetic mutation in our species that lowers blood cholesterol and thus reduces risk of some forms of cardiovascular disease. Given the results reported in the research noted here, we might add ASGR1 deletion or knockdown to the growing list of possible gene therapy enhancements that one might want to undergo as the cost of such treatments falls, should the evidence for benefits without drawbacks hold up in replication studies:

According to new research, just less than one per cent of the population is naturally protected against developing chronic coronary artery diseases. The study involved 292,000 participants of European origin. Applying advanced gene sequencing techniques, the researchers located an area - a deletion - in the human genome, which lacked twelve DNA building blocks in 0.8 per cent of the participants. Subsequent cell experiments revealed that due to the deletion, the serried gene - ASGR1 - is unable to establish the normal structure and function of the protein called the asialoglycoprotein receptor. The receptor protein binds certain sugars and surprisingly, it now turns out that the receptor plays an important role in our cholesterol metabolism and potentially related to vascular inflammation, and in whether or not we develop arteriosclerosis in coronary arteries.

"What's spectacular about the discovery is the fact that individuals with this rare and particular mutation have a lower level of cholesterol in their blood and their risk of developing arteriosclerosis is 34 per cent less. In other words, just under 1 per cent of the European population is fortunate to have been born with a mutation that decreases their cholesterol levels and thus to a certain extent protects them from developing coronary atherosclerosis. The mutated protein is expressed in a part of human biology which we have not previously been focused on in our attempts to understand the mechanisms behind arteriosclerosis. This unexpected finding will undoubtedly result in many researchers examining the underlying biological systems very thoroughly; hoping to utilize this new knowledge to develop new preventive measures and treatments for cardiovascular diseases."

Link: http://healthsciences.ku.dk/news/new-2016/mutation-protects-against-heart-disease/

Average telomere length is presently measured in white blood cells from a blood sample. Telomeres, the caps of repeating DNA sequences that protect the ends of chromosomes, tend to become shorter on average with age, but also with illness: this is probably largely a reflection of stem cell activity (delivering new cells with longer telomeres) and cell division rates (telomere length reduces with each division) in the immune system, which in turn reflects some of the present state of health and age-related decline. This is a statistical observation, however, and it is has more than enough individual variation to be a pretty terrible measure of aging for any practical use. So it isn't unexpected to see observations like this one, in which average telomere length in immune cells is shown to have little to no relationship to a specific outcome in aging:

There is great interest in developing new biomarkers of cardiovascular risk that allow a more accurate risk predication than classical risk factors such as high cholesterol, smoking, physical inactivity, and high blood pressure. An estimated half of cardiovascular disease (CVD) patients do not have a high risk profile based on classical risk factors. Moreover, many individuals who score high for these risk factors do not develop the disease. There is therefore a clear need to find new biomarkers to enable the early identification of individuals who do not yet show disease symptoms but are at high risk of developing atherosclerosis and suffering a heart attack or stroke. One possible biomarker is telomere length, but a new study suggests that leukocyte telomere length (LTL) in circulating blood does not effectively predict CVD risk in individuals without disease symptoms. "These results are rather like taking a snapshot at a single point in a person's lifetime, and we still need to determine if atherosclerosis progresses faster in people who start with shorter leukocyte telomeres, have a higher proportion of very short telomeres, or in whom telomeres shorten at a faster rate during the aging process."

Numerous studies have demonstrated that telomere DNA shortens progressively as we age, leading to genomic instability and eventually cell death, especially when the telomeres become "critically" short. Telomere DNA shortening has come to be viewed as a marker not only of aging, but also of an individual's general state of health, and this has generated great interest in the possibility that telomere length in circulating white blood cells might predict the risk of CVD. This idea is supported by epidemiological studies demonstrating shorter LTL in patients suffering coronary artery disease, heart attack, or stroke. However, the results obtained to date are inconclusive, especially in relation to subclinical atherosclerosis. Moreover, there is a lack of information about the possible association of CVD with a high proportion of very short telomeres.

The new study included 1459 volunteers participating in the PESA (Progression of Early Subclinical Atherosclerosis) clinical trial. In the study, the research team explored whether mean LTL and the proportion of critically short telomeres show an association with the presence and extent of subclinical atherosclerosis. In line with previous studies, the results show an association between increasing age and a lower mean LTL and a higher proportion of short telomeres (defined arbitrarily as those measuring less than 3 kilobases). However, none of these parameters showed any association with the presence or extent of subclinical atherosclerosis in the PESA cohort.

Link: http://www.eurekalert.org/pub_releases/2016-05/cndi-tli052316.php

For many years now, since the first batch of single gene mutations that enhance longevity in short-lived laboratory species were discovered, the cellular maintenance processes of autophagy have occupied a central role in considerations of aging. The open access paper I'll link to today is focused on autophagy in the heart, and provides a good example of the reasons why autophagy is of interest to many of the researchers who search for ways to slow the progression of aging.

Aging is at root a process of damage accumulation. We are machines and we wear and break. Unlike the much simpler mechanical and electrical devices that surround us these days, however, our machinery has a great capacity for self-repair. The overwhelming majority of molecular damage and disarray that arises constantly in all of our cells is repaired very quickly. This makes the progression of damage over time a much more complicated and layered process than is the case in a car or a computer. You can look at the Fight Aging! FAQ for a high level summary, but that does no justice to the poorly understood intricacy of the ways in which the many forms of damage interact over time, and the way in which the diminished capacities or dysfunctions of specific organs and systems in the body feed into one another. Aging is perhaps as much a failure of repair systems as it is an accumulation of damage that cannot be repaired at all - though that certainly does exist in the form of cross-links that cannot be broken down, even in youth, to pick one example.

Autophagy is an important set of cellular repair systems, responsible for breaking down and recycling damaged structures, as well as some large molecules and metabolic wastes. It is a complicated arrangement of signals, detection of damage, markers for damage, processes for moving things around the cell, and specialized organelles that actually perform the dismantling. More autophagy is better for the obvious reason that it means there is less damage at any given point in time, so less of a chance for that damage to cause further issues. Many of the methods of extending life in laboratory species are associated with a higher level of autophagy in at least some tissue types. Calorie restriction, for example, the most well studied of all of the methods of somewhat slowing aging, appears to depend on autophagy for most of its benefits. Disable autophagy, and life is no longer extended by a diet lower in calories. One thing that has become very apparent from the past two decades of making various animals live modestly longer lives is that evolution has not selected for the optimal level of autophagy - or at least, longevity doesn't seem to be high on the list of factors determining that optimal level.

Thus many researchers are interested in producing some kind of therapy that can upregulate autophagy in humans, and for all the same reasons that many researchers want to build drugs that can mimic calorie restriction or mimic exercise. The idea is to modestly slow aging, as even a small gain would would produce enormous economic benefits when spread across the whole population. For me, this is thinking too small, and people should focus on repair and rejuvenation that can add decades for the same cost, but this SENS view of rejuvenation research is still fighting its way to the mainstream. Most researchers focus on slightly slowing aging as a goal, where they are interested in treating aging at all. Oddly, despite many years of working towards drug candidates that might induce greater autophagy, and a stream of research that always looks on the verge of going somewhere, there has been very little progress towards the clinic. The tone of the paper quoted below is very similar to work written ten or fifteen years ago, and yet the therapies are not here yet:

Aging and Autophagy in the Heart

Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by the accumulation of misfolded proteins and dysfunctional organelles. On the contrary, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart.

Because autophagy is downregulated with age and downregulation of autophagy promotes senescence of the heart, interventions to increase the level of autophagy may prevent or slow the progression of aging in the heart. Furthermore, considering the fact that cardiac aging is accompanied by the accumulation of insoluble polymeric materials, such as lipofuscin, and damaged organelles, it would seem to be advantageous to have a degradation mechanism with a large capacity. Interestingly, both calorie restriction (CR) and suppression of mTOR, interventions that alleviate the adverse effects of aging and increase lifespan, promote autophagy in many cell types and organs, even when autophagy is suppressed by aging. Importantly, CR has been shown to reduce age-related pathologies and diseases in animals. However, whether the beneficial effects of these interventions are mediated primarily through activation of autophagy in the heart requires further study.

Many other questions remain unanswered. First, it is unclear when the level of autophagy becomes significantly altered during the course of aging in the human heart. Currently, evaluating the level of autophagy and autophagic flux is challenging in the human heart in vivo. Developing convenient and reliable methods to accurately evaluate cardiac autophagy is essential. Second, more investigation is needed to elucidate the molecular mechanism by which autophagy or mitochondrial autophagy is regulated during the course of aging in the heart. Autophagy is regulated not only at the level of autophagosome formation but also at the levels of autophagosome-lysosome fusion and lysosomal degradation. In particular, how the function of lysosomes is affected by aging requires further investigation. Third, more investigation is needed to clarify the functional role of autophagy or mitophagy during cardiac aging. Currently, none of the available molecular interventions allow purely specific modification of either autophagy or mitophagy in mammalian cells. Currently, none of the available molecular interventions allow purely specific modification of either autophagy or mitophagy in mammalian cells. Whether protein aggregates, such as accumulated lipofuscin, are causatively involved in cardiac aging has not been formally addressed. Development of a more selective intervention or improvement of the selectivity by combining multiple interventions seems essential

Fourth, it is important to clarify the molecular mechanisms by which autophagy or mitophagy regulates cardiac aging. Although autophagy is generally thought to be a nonspecific mechanism of protein degradation, there is increasing evidence that some proteins may be specifically degraded. Fifth, most of the investigations reported to date focused only on autophagy in cardiomyocytes during aging. It is important to determine whether autophagy in other cell types, such as inflammatory cells, also affects cardiac aging and, if so, how these cells communicate with cardiomyocytes. Finally, it is essential to develop more convenient and specific interventions to normalize the level of autophagy in the heart during aging. Autophagy mediates many lifespan-extending and antisenescence mechanisms. Together with the recent advancement in understanding the molecular mechanisms of autophagy, investigating the role of autophagy/mitophagy during cardiac aging should eventually lead to the development of more efficient and specific interventions to slow senescence and increase stress resistance in the heart.

Researchers have recently started to catalog the symbiotic microbes found in the intestines of extremely old human individuals, aiming to gain an understanding of the degree to which differences in microbial populations between individuals can influence the odds of survival in later life. The microbial environment of the gut has been shown to influence aging in various species to a great enough degree to be worthy of investigation by those scientists who seek a full understanding of how aging progresses. From a high level perspective, consider that calorie intake is one of the most influential of environmental factors when it comes to pace of aging, and the activities of microbial populations in the gut help to determine how the amount of calories consumed maps to amounts of specific molecular constituents of food passed on to the rest of the body. There are also interactions between gut microbes and the immune system that may be important, and no doubt a range of other mechanisms to consider as well.

The study of the extreme limits of human lifespan may allow a better understanding of how human beings can escape, delay, or survive the most frequent age-related causes of morbidity, a peculiarity shown by long-living individuals. Longevity is a complex trait in which genetics, environment, and stochasticity concur to determine the chance to reach 100 or more years of age. Because of its impact on human metabolism and immunology, the gut microbiome has been proposed as a possible determinant of healthy aging. Indeed, the preservation of host-microbes homeostasis can counteract inflammaging, intestinal permeability, and decline in bone and cognitive health.

Aiming at deepening our knowledge on the relationship between the gut microbiota and a long-living host, we provide for the first time the phylogenetic microbiota analysis of semi-supercentenarians, i.e., 105-109 years old, in comparison to adults, elderly, and centenarians, thus reconstructing the longest available human microbiota trajectory along aging. We highlighted the presence of a core microbiota of highly occurring, symbiotic bacterial taxa (mostly belonging to the dominant Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families), with a cumulative abundance decreasing along with age. Aging is characterized by an increasing abundance of subdominant species, as well as a rearrangement in their co-occurrence network. These features are maintained in longevity and extreme longevity, but peculiarities emerged, especially in semi-supercentenarians, describing changes that, even accommodating opportunistic and allochthonous bacteria, might possibly support health maintenance during aging, such as an enrichment and/or higher prevalence of health-associated groups (e.g., Akkermansia, Bifidobacterium, and Christensenellaceae).

Link: http://dx.doi.org/10.1016/j.cub.2016.04.016

In recent years researchers have noted that a small proportion of cells in males lose their Y chromosome over the course of aging. This appears to correlate with mortality and cancer risk, among other things, though there is no good picture of why this is the case at the present time. Aging is a global phenomenon, occurring in all tissues and organs, and so most aspects of aging correlate with one another, making it challenging to pick out cause and effect. Here, researchers find a correlation between Y chromosome loss and risk of suffering Alzheimer's disease:

"Most genetic research today is focused on inherited gene variants - mutations that are inherited by the offspring, but what we're looking at are postzygotic mutations that are acquired during life. Using new tools to analyze genetic variations that accumulate with age, we can help explain how sporadic diseases like cancer or Alzheimer's manifest." One such postzygotic mutation found in the cells of biological males is the loss of the Y chromosome in a degree of blood cells. Loss of Y occurs in up to 17 percent of men and is more likely to be found in older men and men who smoke. This study expands on the idea that loss of Y, already a known risk factor for cancer, could be a predictive biomarker for a wider range of poor health outcomes, specifically Alzheimer's. Why loss of Y can be linked to an increased risk for disease remains unclear, but the authors speculate it has to do with reduced immune system performance.

The researchers looked at over 3,000 men to ascertain whether there was any predictive association between loss of Y in blood cells and Alzheimer's disease. The participants came from three long-term studies that could provide regular blood samples: the European Alzheimer's Disease Initiative, the Uppsala Longitudinal Study of Adult Men, and the Prospective Investigation of the Vasculature in Uppsala Seniors. Across the datasets, those with the highest fraction of blood cells without a Y chromosome were consistently more likely to be diagnosed with Alzheimer's. "Having loss of Y is not 100 percent predictive that you will have either cancer or Alzheimer's, as there were men in the study who had the mutation and lived with no symptoms well into their 90s. But in the future, loss of Y in blood cells can become a new biomarker for disease risk and perhaps evaluation can make a difference in detecting and treating problems early." The researchers will next investigate the effect of loss of Y in larger cohorts and explore in greater detail how it confers risk for specific types of cancers and disease. They also plan to look at the cellular changes caused by loss of Y and how it affects different types of blood cells.

Link: http://www.eurekalert.org/pub_releases/2016-05/cp-loy051816.php

At a recent conference, Bill Andrews of Sierra Sciences announced a forthcoming collaboration with BioViva, currently pushing regulatory boundaries to develop gene therapies as treatments for aging. A new company will be formed, BioViva Fiji, to offer gene therapies that can compensate for some of the aspects of degenerative aging via medical tourism in Fiji. The principle focus, given that this is Sierra Sciences we are talking about here, is telomerase gene therapy, but BioViva is also working on a follistatin gene therapy, and it is worth bearing in mind that in this age of CRISPR rolling out any single target gene therapy that has some background work in the research community isn't the huge technical undertaking it would have been in past years. All of the time and cost goes into a reasonable level of testing, and the only real hurdle left from a technical point of view is proving that a therapy can reliably introduce genes into a large enough number of cells to produce benefits. We're going to see a lot of work on gene therapies in the next few years - this is just the start and the tip of the iceberg.

Fiji, like many countries in the Asia-Pacific region, has been taking steps in recent years to make itself attractive as a destination for medical tourism, and thereby encourage the growth of high-end local industries that benefit from the wealth of larger and more prosperous countries. It makes a lot of sense as a long-term plan, and competition between regions for medical tourism will hopefully prevent these countries from falling into the overregulated repression of medical development found in the US and Europe, a state of affairs that slows development and that gave rise to medical tourism in the first place. Fiji is the destination for this particular effort, but it could equally have been any of a number of other choices.

"Sierra Sciences and BioViva - Liz Parrish - have now joined forces. We have started a new company, called BioViva Fiji, on Fiji island, and we are now building a large-scale production facility and a clinic to soon be able to provide a gene therapy approach towards curing aging."

Bill Andrews is, as many of you will recall, an enthusiast for telomerase and telomere length as a key to aging, and he is in full sales mode above. The goal of Sierra Sciences before the company floundered was to build a viable treatment along these lines, but they ran out of funding and then turned to selling herbal nonsense. That was a sad end for a group that was at the outset working on interesting science. Interesting, yes, but from where I stand age-related reduction in average telomere length is a marker of aging, not a cause of aging. Telomerase gene therapies most likely extend life in mice through increased stem cell activity, counteracting some of the decline in stem cell populations that occurs with advancing age. It was surprising to find that this doesn't raise the risk of cancer, as those stem cell populations become damaged by age, and their decline is generally through to be an evolved defense against cancer in later life. It may be that the general enhancement of cell activity extends to the immune system, and better immune surveillance and clearance of cancerous cells is enough to offset that raised risk due to pushing damaged cells back to work. This or any other thesis is far from proven at this point, and telomerase gene therapies in humans still seem overly risky on this count to my eyes.

I believe based on the evidence to date that telomerase gene therapy should be classed as a compensatory treatment. It is pushing a damaged engine to do more, and it may well be the case that in humans as well as mice the balance of factors brings a net improvement in the same way as do stem cell therapies, another field associated with a prospering medical tourism industry, but that is yet to be nailed down and proven. Follistatin or myostatin gene therapies are similarly compensatory. They do not address the damage that causes aging, but they compensate partially for one its effects, in this case by adding extra muscle tissue to offset that lost over time to the mechanisms of aging. Is this all useful? Yes - if you think that stem cell therapies are worth it, then you should also think that this sort of gene therapy is worth it. I'm pleased to see Bill Andrews working on something that doesn't make me sad for the waste of potential it signifies, as was the case for the end of Sierra Sciences as a legitimate scientific venture.

We should not forget, however, that telomerase therapies cannot cure aging. A lot of people would like to think that they do, but it simply isn't the case. They don't treat the causes of aging, they instead adjust a lot of factors to paper over those causes just a little bit better than the papering over that the present mainstream of medicine can achieve. Undergo a telomerase gene therapy and you may benefit in a very similar way to a stem cell treatment, but in both cases you are still aging and still damaged. You still have mitochondrial DNA damage, lipofusin in your long-lived cells, cross-links stiffening your arteries, and so on and so forth, and all those things are still killing you.

The data presented by these researchers is a compelling argument for the importance of hypertension in cardiovascular aging. Hypertension as a result of intrinsic aging processes is probably largely caused by stiffening of blood vessels, but narrowing of vessels due to atherosclerosis and other more general consequences of metabolic dysfunctions, such as those that result from being overweight, also play a part. The cardiovascular system remodels in response to hypertension, and is damaged, producing a variety of forms of cardiovascular disease. In addition, a faster pace of rupture of tiny vessels in the brain due to stiffening and increased pressure leads to dementia. All of these are good reasons to work at maintaining a lower blood pressure throughout later life, and more importantly to support the development of therapies capable of reversing the causes of blood vessel stiffening, such as glucosepane cross-link breakers.

Intensive therapies to reduce high blood pressure can cut the risk of heart disease in older adults without increasing the risk for falls. In the United States, 75 percent of people over age 75 have hypertension, which can lead to cardiovascular disease, a leading cause of disability, morbidity and death. Current guidelines have provided inconsistent recommendations regarding the optimal systolic blood pressure (SBP) treatment target in geriatric populations. The latest findings from the Systolic Blood Pressure Intervention Trial (SPRINT), which focused on ambulatory adults 75 or older, showed that adjusting the amount or type of blood pressure medication to achieve a target systolic pressure of 120 millimeters of mercury (mm Hg) reduced rates of cardiovascular events - heart attack, heart failure and stroke - by almost a third and the risk of death by almost a quarter, as compared to a target systolic pressure of 140 mm Hg.

The 2,636 participants were randomized to an intensive target systolic blood pressure (SBP) treatment target of 120mmHg or the standard target of SBP of 140 mmHg. People with diabetes or heart failure were not included in the trial. At the beginning of the study, people underwent blood pressure measurement three times in a quiet room, completed a walking test to determine gait speed, and responded to a questionnaire to categorize their level of frailty. Blood pressure was rechecked every three months and medication adjusted as needed. Both groups also were checked for eight potential complications of lower blood pressure, such as hospitalizations, falls, acute kidney injury and fainting. The researchers found no difference between the two groups in these areas. On average, persons in the lower blood pressure goal group required one additional medication to reach goal.

"These findings have substantial implications for the future of high blood pressure therapy in older adults because of its high prevalence in this age group, and because of the devastating consequences high blood pressure complications can have on the independent function of older people. Most of the medications used in SPRINT were generic, so this is a fairly inexpensive way to help prolong the time that people can live independently in their homes and avoid those common conditions that often cause a person to have to move to higher level of care or an institution."

Link: http://www.wakehealth.edu/News-Releases/2016/Lowering_Blood_Pressure_Reduces_Risk_of_Heart_Disease_in_Older_Adults_Without_Increasing_Risk_of_Falls.htm

Here one of the long-standing core members of the Gerontology Research Group (GRG) is interviewed. This volunteer organization maintains and validates records of supercentenarians, those rare individuals who live past 110, and also runs one of the few online watering holes for the aging research community. Unfortunately, the interviewer is overly flippant on the topic of aging and longevity, but that can be skipped in favor of the more interesting portions of the interview:

What's the goal of the GRG? Do you want to live forever?

So basically at the moment it has two main departments. One is run by the successor of Dr. Stephen Coles, who founded the GRG in 1990 and passed away in 2014 at the age of - unfortunately - only 73. The goal was for other scientists to get together and discuss the aging process and discuss potential treatments for the aging process. The idea at the time was that Western medicine was too focused on treating the symptoms of aging and not focused on treating the causes of aging. The idea was that if you put a bunch of bright minds together, you would get good results.

What's the history of age validation?

It started in the 1800s with life insurance policies. Actuaries were trying to figure out how long people lived to calculate rate for those policies. Except for the small niche field of actuarial research, very little research was done into supercentenarians. There was no database when the GRG decided to start keeping track in 1998. About 1 in 5 million people in the US are 110 and older, and before the internet came along there was no way to assemble someone that rare into data groups. But when the internet came along, we could get information from all over the world, and it became viable to study them as a population group. Things have changed so fast since the GRG went online in 1995, almost 21 years ago. Smart phones came around 2007, 2008. Go back to 2004 and ancestry.com only had 20 percent of the US census data online. Go back to 2000 and if you wanted to find a document on an extremely old person, you had to use the old hand-crank newsreel. Wow. It could take hours upon hours to look on every line of every page.

I feel like there's a story every month about the world's oldest person dying.

So here's the thing. There's a misconception that the world's oldest person dies all the time. Not true. Since Guinness started keeping track in 1955, the average length of reign has been about 1.6 years. Part of the problem though is that we do have unverified claims of people saying they're older than the oldest person and that gets reported by the media. You also get what's called the longevity myth, which is where people's imaginations exceed reality. So if you don't have a record of when you're born and you're gonna guesstimate your age, and after the age of 80, people begin to inflate their age.

Give it to me straight. What is the longest I could possibly live?

Scientifically speaking, the odds of living to 127 at the moment are one in a trillion, which means it's not happening. Living to anywhere between 115 and 120, you have what I call "probable impossible," I'd say there's about a 1 percent chance, but there's still a possibility. Between 120 and 127, the odds of surviving really begin to disappear totally. When we look at the statistics, we have currently 2,500 cases of people 110 plus. Of those, by the age of 118, only two. When you're going from 2,500 to two in just eight years, to me that's scary. Humans seem to have a warranty period of about 100 years. The average cell divides every two years. Cells divide about 50 times. To get to 115, you'd have to age about 15 percent slower than normal. Basically, Jeanne Calment, who lived to be 122, was called the Michael Jordan of aging. The point was that all the practice in the world isn't gonna make you play basketball like Michael Jordan. OK? On the other hand, if Michael Jordan never practiced, he wouldn't be as good as he was. So you have to fulfill your potential by trying to do the best you can do, but at the same time, you can't make yourself a longevity star.

Do you get the sense that it's even worth living that long? Is there any quality of life at 115?

I've probably met over 50 who are 110 plus. It can vary. One of the things that's clear to me is that you can't put them all in one category. We had one woman who was 116 who lived in her own home, she could walk with a walker, she ate Wendy's, she watched TV, she could do an interview. That's the ultimate extreme case of living well and hanging out with the great, great grandkids. On the other hand, we had a woman who was confined to bed for 21 hours a day, awake for only three, unable to get up. That's a sad situation where maybe it's not worth it. Most people are somewhere in the middle. One more thing I wanna say is that the people who live the oldest are in the best shape. So almost everybody that lives to be 115 was living on their own at 100. So we need to get rid of this idea of, "I'm gonna be 30 years in a nursing home." It's not like that.

Link: http://www.vice.com/read/we-spoke-with-the-scientist-studying-how-to-live-as-long-as-possible

The Dog Aging Project launched last year, and is lavished with attention in this long press article. The initiative is a combined advocacy and research program intended to trial in pet dogs the small range of drug candidates - such as rapamycin - that have good data in mice to support both safety and the ability to modestly slow aging. In addition to the scientific side of things, this is a way to pull in more interest for the development of treatments for aging, and to gather greater support for moving to human studies. In that the goals of the Dog Aging Project are much the same as the human trial of metformin as a treatment to slow aging that is presently in the works. The bottom line is that we - the research and advocacy community - still have a long way to go when it comes to persuading the public, large funding institutions, and regulators that living longer through medical science is possible, plausible, and desirable.

Given the subject, the article here is narrowly focused on one particular view of aging and how to treat it. The scope is (a) traditional drug discovery and development, (b) slightly slowing the progression of aging by altering the operation of cellular metabolism, and (c) the prospect of a long, expensive slog to very marginal gains at some point in the decades ahead. This is a vision of the future in which humans gain a couple of years of additional healthy life sometime around 2030 because they can take a drug derived from or of a similar class to rapamycin. So on the one hand I think it is great that we now see more lengthy articles from the journalistic community that sensibly discuss both the treatment of aging and specific initiatives in aging research. It is also great that researchers are creating these innovative ways to both accomplish the science and attract more attention to the field. But at the same time, this particular approach of drug development and metabolic tinkering is an expensive and slow road to nowhere special. If it were the only path ahead, then fine, but it isn't. There is an entirely separate approach to treating aging based on targeted repair of cellular and molecular damage that could, if funded well, produce far greater gains in healthy life span for the same investment in money and time, as well achieving rejuvenation in the old.

You don't have to look far to see striking comparisons. Billions have been spent on trying to make drugs to slow aging out of sirtuins for example, and that collection of initiatives is an exemplar of the metabolic tinkering approach, hyped in its day. Yet the only concrete result has been to gain knowledge of a small slice of metabolism and its response to calorie restriction - no gain in health life or method to achieve that end has emerged. Meanwhile, for a tiny fraction of that sum, and in half the span of years, researchers taking the damage repair approach of clearing senescent cells in old tissues have already demonstrated robust benefits to health and life span in rodent studies. The pace of progress, the cost of progress, and the potential gains are night and day when comparing these two strategies. The type of longevity research that is carried out over the next few years matters greatly - our lives depend on the outcome.

Dogs Test Drug Aimed at Humans' Biggest Killer: Age

Ever since last summer, when Lynn Gemmell's dog, Bela, was inducted into the trial of a drug that has been shown to significantly lengthen the lives of laboratory mice, she has been the object of intense scrutiny among dog park regulars. The trial represents a new frontier in testing a proposition for improving human health: Rather than only seeking treatments for the individual maladies that come with age, we might do better to target the biology that underlies aging itself. While the diseases that now kill most people in developed nations - heart disease, stroke, Alzheimer's, diabetes, cancer - have different immediate causes, age is the major risk factor for all of them. That means that even treatment breakthroughs in these areas, no matter how vital to individuals, would yield on average four or five more years of life, epidemiologists say, and some of them likely shadowed by illness. A drug that slows aging, the logic goes, might instead serve to delay the onset of several major diseases at once.

But scientists who champion the study of aging's basic biology - they call it "geroscience" - say their field has received short shrift from the biomedical establishment. And it was not lost on researchers that exposing dog lovers to the idea that aging could be delayed might generate popular support in addition to new data. "Many of us in the biology of aging field feel like it is underfunded relative to the potential impact on human health this could have," said Dr. Matt Kaeberlein, who helped pay for the study with funds he received from the university for turning down a competing job offer. "If the average pet owner sees there's a way to significantly delay aging in their pet, maybe it will begin to impact policy decisions."

"I would resist the idea that we should shift funds away from cancer and diabetes and Alzheimer's, where there are clear drug targets, and say, 'We're going to work on this hypothesis,' " NIH Director Dr. Francis Collins said. "If you had a lot of money for geroscience right now, it's not clear what you would do with it that would be scientifically credible." Researchers in the field, in turn, say they might have more to show for themselves if they could better explain to Congress and the public why basic research on aging could be useful. "People understand 'my relative died of a heart attack, so I'm going to give money to that,' " said Dr. James L. Kirkland, a Mayo Clinic researcher. "It's harder to grasp 'my relative was older, that predisposes them to have a heart attack, so I should give money to research on aging.'"

Some companies have embraced the quest for drugs that delay aging. Google created Calico (for California Life Company) in 2013 with the goal of defeating aging. A start-up called UNITY has said it will develop drugs based on new research on aging mice suggesting that purging certain cells can extend a healthy life span. And a group of academic researchers is trying to persuade the FDA to recognize aging as a disease for which a drug can be marketed, which they hope will draw more interest from pharmaceutical firms. The agency recently greenlighted its proposed trial of a widely used diabetes drug, metformin, to see if it can delay the onset of other age-related diseases in older adults who have received a diagnosis of at least one, as one study suggests it might. But the group has yet to secure funding. One reason, the researchers say, is that the notion that aging is immutable is so deeply entrenched. "When I go out and try to raise money for this, the first thing people will say to me is, 'Eh, we're all getting older,' " said Steven Austad, a researcher at the University of Alabama.

I'm very pleased to report that that the SENS Research Foundation project on mitochondrial allotopic expression (MitoSENS) that was crowdfunded at Lifespan.io this time last year has achieved success. The two target mitochondrial genes have been moved to the cell nucleus, and suitably altered so that the proteins produced return to the mitochondria. This means that cells so treated are immune to age-related damage to those two genes in the mitochondrial genome: they will still construct and make normal use of the proteins encoded in those genes as though nothing happened. Given that mitochondrial DNA damage is an important contribution to the aging process, progress on this front is very welcome.

The crowdfunded work was the final sprint at the end of a years-long project conducted with minimal funding, and it is great to see success. Congratulations are due to the researchers involved. There are thirteen mitochondrial proteins in total that are thought to be all that is needed to move into the nucleus. Allotopic expression of one other mitochondrial gene is solidly complete, and is the basis for the therapies under development at Gensight. Another two genes are somewhere in the middle of the process in the SENS Research Foundation network of researchers. This leaves a further eight genes to go. As ever, this is work that is in search of much greater funding: the researchers are always ready to go, and the more that we can do to help deliver that funding, the sooner we'll see rejuvenation therapies in the clinic.

Note that you may need to click the updates tab on the fundraiser page in order for the updates to load:

Hi everyone, it's been an amazing few months. In short, we have been tremendously successful in our efforts to rescue a mutation in the mitochondrial genome! Essentially we've shown that we can relocate both ATP6 and ATP8 to the nucleus and target the proteins to the mitochondria. We can show that the proteins incorporate into the correct protein complex (the ATPase) and that they improve function resulting in more ATP production. Finally, we show that the rescued cells can survive and grow under conditions which require mitochondrial energy production while the mutant cells all die.

We have finished writing up our results and submitted them for review and publication. It may take a while for our results to be published (the peer review process can be lengthy) but as soon as it is I'll post an update here so you can see the full paper. We have also started the project that you helped us get to our stretch goal on. We have made all the combinations of mitochondrial targeting sequences with ATP6 that we proposed and are now working on testing them. I'll let you know when we know more. Thank you so much for your support!

Link: https://www.lifespan.io/campaigns/sens-mitochondrial-repair-project/#updates

The authors of the open access paper linked here are training neural networks on large numbers of blood samples in an effort to produce biomarkers of aging. This is an interesting approach, primarily because it should in theory answer the question of whether a given data set - such as the data from blood tests - has any useful correlation with age. Biomarkers of biological age, how damaged an individual happens to be, are a necessary development in the field of aging research. At present the only reliable way to see how well a possible rejuvenation therapy works is to wait and see, which is slow and expensive in mice and out of the question in humans. What is needed is a quick measurement that accurately reflects biological age and thus remaining life expectancy. Given that, many more potential approaches to treating aging could be assessed and compared for a given level of funding and time, as the need to wait and see could be eliminated.

One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. To make this deep network ensemble available to the public, we placed our system online (at www.aging.ai), allowing any patient with blood test data to predict their age and sex.

The best performing DNN in the ensemble demonstrated 6.07 years mean absolute error in predicting chronological age within a 10 year frame, while the entire ensemble achieved 5.55 years mean absolute error. The analysis of relative feature importance within the DNNs helped deduce the most important features that may shed light on the contribution of these systems to the aging process, ranked in the following order: metabolic, liver, renal system and respiratory function. The five markers related to these functions were previously associated with aging and used to predict human biological age. Another interesting finding was the extraordinarily high importance of albumin, which primarily controls the oncotic pressure of blood. Albumin declines during aging and is associated with sarcopenia. The second marker by relative importance is glucose, which is directly linked to metabolic health. Cardiovascular diseases associated with diabetes mellitus are major causes of death within the general population. Current and future directions of this work include adding other sources of features including transcriptomic and metabolomics markers from blood, urine, individual organ biopsies and even imaging data as well as testing the system using data from patients with accelerated aging syndromes, multiple diseases and performing gender-specific analysis.

Link: http://www.impactaging.com/papers/v8/n5/full/100968.html

Today I'll link to a few unrelated studies of advanced glycation end-products (AGEs) and their role in aging and the pathology of specific age-related diseases. AGEs are both generated in the body as a side-effect of metabolic operation, but can also be found in the diet. There are numerous different classes of AGE, some more common than others. As a general rule the common AGEs are easily broken down and removed in healthy individuals, while the rare ones are persistent and in some cases cannot be broken down at all by our evolved molecular toolkit. The common AGEs play more of a role in metabolic disease: the dysregulated diabetic metabolism suffers from high levels of circulating AGEs, for example. These AGEs interact with the receptor for advanced glycation end-products, RAGE, to promote chronic inflammation and other bad behavior on the part of cells. As regular readers will know, high levels of inflammation contribute to the progression of damage and disease in aging, and this is one of the ways in which metabolic diseases, such as the varieties of diabetes, shorten life span and raise the risk of suffering age-related conditions.

Long-lasting persistent AGEs are perhaps more dangerous, however. For one they are far less well studied. The predominant form of persistent AGE in humans is glucosepane, and a quick PubMed search will show you that next to no-one is publishing papers on the subject in comparison to other forms of AGE. Glucosepane forms an ever-increasing number of cross-links between macromolecules in the extracellular matrix, and this cross-linking that degrade its structural properties - particularly elasticity in skin and blood vessels. Wrinkled skin we can live with, but blood vessel stiffening produces hypertension, structural failure of tiny vessels in the brain, detrimental remodeling of heart and blood vessel structures, cardiovascular disease, and death. Given all of this it is nothing short of amazing that it remains a struggle to find funding to advance the development of glucosepane cross-link breaker drugs. A single effective drug candidate could largely remove this sizable contribution to the aging process. As a topic this has been discussed in some depth in past posts, so I'll skip that story for the present. Just note that glucosepane isn't a fact of life written in stone; it would take very little investment today to produce drug candidates a few years from now. On that topic, this first paper focuses on AGEs in type 1 diabetes, not the age-related variety, but is unusual for actually including glucosepane in its analysis:

Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes

We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies and the long-term progression of microvascular disease in in diabetes, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC), change of carotid intima-media thickness (IMT), and cardiac MRI outcomes.

Correlations showed furosine (early glycation) was associated with future mean CAC. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change. Left ventricular (LV) mass correlated with MG-H1, and inversely with pepsin solubility, while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1, and highly with carboxymethyl-lysine (CML). In multivariate analysis only furosine was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane.

In type 1 diabetes, multiple AGEs are associated with IMT progression implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.

Biological Effects Induced by Specific Advanced Glycation End Products in the Reconstructed Skin Model of Aging

The aging human skin is characterized by decreased elasticity and accumulation of insoluble collagen and impaired wound healing. These changes are worsened in sun-exposed skin in which proinflammatory changes further help remodel the collagen-rich matrix. Two components are expected to participate in the latter process. The first involves a chemical process in which advanced glycation end products (AGEs) are produced from glucose and oxoaldehydes, thereby inflicting damage to the extracellular matrix, which includes protein crosslinking, insolubilization, and loss of elasticity. The second involves interactions between the modified AGE-rich dermal matrix and dermal cells leading to cell activation via AGE receptors (RAGE) and other receptors, eventually resulting in growth factor and cytokine release that profoundly remodel the extracellular matrix. Many of these changes have been observed in two-dimensional models in which cells are grown onto modified matrix. For several years now, our interest has been to evaluate the role of the aging extracellular matrix in three-dimensional models, that is, the reconstructed skin model in which fibroblasts are embedded in a three-dimensional collagen matrix and establish cross-talk with keratinocytes grown on the dermal matrix. Using such system, we were able to demonstrate that the glycated matrix mimicked a phenotype that shared many similarities with the aging skin. In particular, we showed that when AGE-rich glycated matrix formed by the reaction of D-ribose with bovine collagen was used, an aging-like phenotype developed.

Advanced Glycation End Products: Association with the Pathogenesis of Diseases and the Current Therapeutic Advances

Advanced glycation end products (AGE) have been imparted in the development and worsening of complications of diabetes. They are also involved in atherosclerosis, normal aging process, arthritis, cancer and progression of age-related neurodegenerative diseases like Alzheimer's disease. Endogenously, they formed by nonenzymatic glycation by aldoses/ketoses to form intermediates precursor that were slowly converted into AGE. A positive correlation was observed with the level of AGEs formation and progression of the diseases. Exogenously, they formed in foods when they were cooked at very high temperature.

AGEs can interact with the cell surface receptors of AGE (RAGE) to release cytokines, free radicals as well as directly modify the extracellular matrix and action of hormones. Hence, the mechanism of AGE association with pathogenesis of diseases can be ascribed mainly to the generated cytokines and free radicals. Second type of receptors such as AGE receptor-1, 2 and 3 were more specific and involved in their detoxification and clearance. Therapeutic agents were used to inhibit AGEs formation, traps the reactive carbonyl intermediate precursors, interfering with Amadori's products, cross-link breaker and low molecular weight inhibitors of RAGE had been described as well. Despite the several therapeutic agents described so far, none of them have proved to be recommended for clinical use. Furthermore, no methods or standard units were accepted universally to measure AGEs are existing. This review discusses AGEs formation, association with diseases and therapeutic agents to alleviate them.

Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies

Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies.

Cellular Mechanisms and Consequences of Glycation in Atherosclerosis and Obesity

Post-translational modification of proteins imparts diversity to protein functions. The process of glycation represents a complex set of pathways that mediates advanced glycation endproduct (AGE) formation, detoxification, intracellular disposition, extracellular release, and induction of signal transduction. These processes modulate the response to hyperglycemia, obesity, aging, inflammation, and renal failure, in which AGE formation and accumulation is facilitated. It has been shown that endogenous anti-AGE protective mechanisms are thwarted in chronic disease, thereby amplifying accumulation and detrimental cellular actions of these species. Atop these considerations, receptor for advanced glycation endproducts (RAGE)-mediated pathways downregulate expression and activity of the key anti-AGE detoxification enzyme, glyoxalase-1 (GLO1), thereby setting in motion an interminable feed-forward loop in which AGE-mediated cellular perturbation is not readily extinguished. In this review, we consider recent work in the field highlighting roles for glycation in obesity and atherosclerosis and discuss emerging strategies to block the adverse consequences of AGEs.

Relationship between advanced glycation end-product accumulation and low skeletal muscle mass in Japanese men and women.

The present study aimed to investigate the relationship between advanced glycation end-product accumulation and skeletal muscle mass among middle-aged and older Japanese men and women. A total of 132 participants enrolled in this cross-sectional study. Skin autofluorescence was assessed as a measure of advanced glycation-end products. Participants were divided into two groups (low skeletal muscle index and normal skeletal muscle index) using the Asian Working Group for Sarcopenia's skeletal muscle index criteria for diagnosing sarcopenia.

Participants consisted of 70 men (mean age 57 ± 10 years) and 62 women (mean age 60 ± 11 years). There were 31 and 101 participants in the low and normal skeletal muscle index groups, respectively. Skin autofluorescence was significantly higher in the low skeletal muscle index group compared with the normal skeletal muscle index group. Skin autofluorescence was a significant independent factor associated with low skeletal muscle index based on multivariate logistic regression analysis.

There is a contingent of cryonics supporters who want more iron-clad evidence beyond that which already exists to demonstrate that the process of vitrification of tissue does work to preserve the fine structure of the brain, and thus the data of the mind. Everyone has a different threshold of comfort for proof, and some people have the luxury of time when it comes to watching the evidence accumulate over the years. There will always be those who will be uncomfortable with all uncertainty and wish to wait until the first preserved individual is revived, for example, but that is distant in time and technology; many decades, or possibly longer. Decisions on whether to sign up and whether to be preserved must be made before that point arrives for most of us.

There is also a contingent of cryonics supporters who see the ultimate destination for a preserved individual as scanning in order to run a mind in emulation in software. The original tissue would be discarded, and some folk are just fine with that. This is not appealing to me, and I see the primary purpose of preservation as being to offer the chance of restoration of the original - a copy of you is not you. Identity is not just a pattern, but also bound up in the particular matter that encodes that pattern. Restoration of vitrified brain tissue to a living, repaired status in a new body will probably be a more challenging task than scanning and emulation for the technology of the late 21st century, even though reversible vitrification of organs other than the brain is fairly close to realization as a practical technology for use in the organ transplant industry. Still, it is the only option if you, yourself, the original individual, wish a chance at a renewed life in the future.

Though no frozen humans have yet been revived, cryonics has been an industry for over fifty years. In that time, focus has shifted slightly. Lately, the emphasis has been more on brain emulation: mental maintenance as opposed to physical resurrection. The body and the self have been, in a sense, decoupled. Michael Cerullo, a neuroimaging specialist, moonlights as a cryonics pioneer. He spends a lot of time working with the Brain Preservation Foundation, an organization devoted to pushing cryonics toward the mainstream or, barring that, the mainstream towards cryonics. Because he's a doctor, Cerullo thinks of the freezing procedure as fundamentally medical in nature. More specifically, he and the BPF consider it an issue of brain health, which is why they awarded scientist Robert McIntyre a prize in February for his pioneering work with Aldehyde Stabilized Cryopreservation. McIntyre's technique allowed him to preserve a rabbit's connectome for, in theory, thousands of years. Cerullo says this is the sort of procedure he hopes will someday happen in hospitals.

What makes Cerullo a particularly compelling advocate for cryonics is that he's not a true believer - not exactly. He's an associate member of Alcor, the most recognizable name in the field, but he hasn't signed up to be preserved: evidence is lacking that current technology actually works. He's a man who wants proof and, more specifically, he's a man who wants proof that his identity can be preserved. He's open to experimentation with machine-neuron interfaces and emulation, but if he comes back, he wants to come back as himself. And that's the rub. We can't know if self-identity can be preserved until the technology starts working. Cerullo gives it twenty years, but points out that current dead bodies are stored as donated organs. If they still contain selves, we'll need to seriously reconsider our relationships with the frozen and the passed on.

If the brain turns off, are we the same people when it turns back on? That's the challenging question. Right away there are two schools of thought. A lot of the cryonics people want to be brought back biologically. They're hoping for a technique that they can be thawed out and continue in the same brain and same body. The challenge with that, though, is that a lot of the procedures, like the Aldehyde Cryopreservation, are not reversible. The first step is infusing the brain with glutaraldehyde, which is about the deadliest substance known. So you're never going to be able to revive that. What you're hoping is that, since you've got all the information there, with improvements in large-scale scanning techniques, you could get all the information uploaded. Let's say you do something like this new procedure, where there's no hope of biological revival. Then you upload the brain. There are still a couple of options: there's destructive and nondestructive uploading. One possibility would be that you could noninvasively scan the brain and get all the information. More likely, it would be destructive uploading, where you slice the brain in billions and billions of little nanometer thick slices, and map the whole connectome. Let's say you do that. Then, you emulate it in a computer in fifty, a hundred years, when the technology is there.

Does identity continue? Ultimately, we don't know the answer. No one has the full answer. A lot of people, though, assume that, you know, 'Okay, well this is just a simulation or a copy, and so of course it's not you.' I think that's the default answer. That seems to be the safe answer, because it doesn't really challenge a lot of things. But, what I think is more interesting, though, is that either way you answer that question - whether you say yes, the person is the same, or no, it's just a copy - either way there are a lot more implications than people realize. Either way, consciousness is a lot more complicated than we think. I don't think there's any easy answer. Either answer you take leads to paradoxes and just bizarre consequences that we really don't have great answers to. A lot of the scientists that I talk to are very gung-ho: 'Yes, this preserves the pattern, the information, and that's all we are.' I have a lot of sympathy for that view, but I think there are still a lot of deep questions that you really need to think about. But, I think that's the strongest answer, because the more we learn about the brain, and the more neuroscience advances, there really doesn't seem to be anything left out. The brain is the neurons and the information, and if that pattern's still there, then the person is still there.

Link: https://www.inverse.com/article/15728-can-cryonics-save-the-brain-and-the-self-a-doctor-holds-out-hope

A number of different research groups are working on ways to restore function of the thymus in old individuals, with methods ranging from the introduction of cells with youthful characteristics to the engineering of thymus tissue for transplantation. Promising results have been produced in mice. The thymus is where the immune cells known as T cells mature, and it atrophies fairly early in adult life, reducing the supply of new immune cells to a trickle. That the supply of new cells is so small across most of the life span is one of the factors contributing to the age-related decline of the immune system, and so opening the floodgates to a much larger supply should help to diminish and reverse some of the characteristic failures of an old immune system. Dysfunction of the immune response is a considerable portion of age-related frailty, and it isn't just a matter of failure to deal with invading pathogens. The immune system is also responsible for destroying damaged and potentially threatening cells, such as senescent cells and cancerous cells, and failing that task has equally serious consequences.

The thymus is mainly composed of two types of epithelial cells, medullary thymic epithelial cells and cortex thymic epithelial cells (mTECs and cTECs). The tissue structure and mechanism for T cell development are complicated, with generation of the thymus regulated by complex molecular and cellular interactions of the thymic microenvironment during embryogenesis. Since the development of organ regeneration techniques became available, complete in vitro regeneration of the thymus has been attempted. Steric induction systems are thought to be optimal for tissue regeneration, but three-dimensional (3-D) induction of TECs from induced pluripotent stem cells (iPSCs) has not yet been reported.

Here, we demonstrate the induction of functional TECs from iPSCs by a 3-D spheroid culture system with recruitment of robust numbers of T cells into the peripheral blood. Purified iPSC-derived TECs showed a sufficient expression level of FoxN1 comparable to TECs, and phenotypic analysis revealed that iPSC-derived TECs were expressing K5. Moreover, transplants of cell aggregations into recipient mice were not rejected and there was normal support of T cell development. Functional analysis revealed that T cells showed immune tolerance to both donor and recipient major histocompatibility complexes and could reject an allogeneic third party's skin graft without tumorigenesis. Taken together, these findings raised the possibility of using iPSC-derived TECs induced by 3-D spheroid culture in future regenerative therapy for patients with immunodeficiency.

Link: http://dx.doi.org/10.1089/cell.2015.0006

Today I'll point out a few recent studies on exercise and age-related disease in human populations. Animal studies show that regular exercise improves health and extends healthspan, the period of life free from age-related conditions. Human studies, which use statistical methods on large sets of population data, tend to show correlations only, but these correlations match what is seen in animal studies. It is not unreasonable to believe based on the evidence that exercise is good for you over the long term, and that maintaining fitness as you age reduces the risk of suffering all of the common age-related diseases - that this is causation, not just correlation. In an age of rapid progress in biotechnology, postponing aspects of the inevitable decline of old age, even for just few years, increases the odds of being around and in good shape to benefit from the rejuvenation therapies that are envisaged, in development, but yet to be realized.

In the long run, yes, only progress in medical science can save us from aging to death. As we grow older and ever more damaged, the span of life remaining is increasingly determined by the capabilities of the medical community and how rapidly those capabilities are improving. So in a sense we'll all need to be rescued by that progress - you can't exercise your way to agelessness. But why sabotage yourself and reduce your odds living to benefit from greatly improved medicine when that much of your fate at least is absolutely under your control? Being sedentary and unfit has a cost, both additional lifetime medical expenditure and lost years of life expectancy. You can always choose not to pay that cost, to be healthier.

Being fit may slow lung function decline as we age

"While everyone's lung function declines with age, the actual trajectory of this decline varies among individuals. What is less known is, beyond smoking, what factors affect this rate of decline. Even though the majority of people will not develop lung disease in their lifetime, declining lung function is known to increase overall morbidity and mortality even in the absence of overt pulmonary disease." Researchers analyzed data from the CARDIA (Coronary Risk Development in Young Adults) Study, which began in 1985-86 with 5,115 healthy black and white men and women, aged 18-30. The study has measured participant's cardiopulmonary fitness periodically over 20 years using a graded treadmill test. At the beginning of the study and at each follow-up assessment, pulmonary function (PF) was also assessed by measuring forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). After adjusting for age, smoking, body mass index and change in BMI, the association between fitness and lung function remained statistically significant.

Researchers found that participants in the top quartile of baseline fitness experienced the least annual decline in PF. Participants with the greatest decline in fitness experienced the greatest decline in FEV1 and PF over 20 years. Participants with sustained or improved fitness experienced the least decline in PF over 20 years.

Study: Regular exercise at any age might stave off Alzheimer's

Recent research suggests that exercise might provide some measure of protection from Alzheimer's disease and other dementias. Thirty men and women ages 59-69 were put through treadmill fitness assessments and ultrasounds of the heart. Then they received brain scans to look for blood flow to certain areas of the brain. "We set out to characterize the relationship between heart function, fitness, and cerebral blood flow, which no other study had explored to date. In other words, if you're in good physical shape, does that improve blood flow to critical areas of the brain? And does that improved blood flow provide some form of protection from dementia?"

The results showed blood flow to critical areas of the brain - and so the supply of oxygen and vital nutrients - was higher in those who were more physically fit. "Can we prove irrefutably that increased fitness will prevent Alzheimer's disease? Not at this point. But this is an important first step towards demonstrating that being physically active improves blood flow to the brain and confers some protection from dementia, and conversely that people who live sedentary lifestyles, especially those who are genetically predisposed to Alzheimer's, might be more susceptible." Since people who exercise frequently often have reduced arterial stiffness, researchers postulate that regular physical activity - regardless of age - maintains the integrity of the "pipes" that carry blood to the brain. "In the mid-late 20th century, much of the research into dementias like Alzheimer's focused on vascular contributions to disease, but the discovery of amyloid plaques and tangles took prevailing research in a different direction. Research like this heralds a return to the exploration of the ways the vascular system contributes to the disease process."

Physical Activity Associated with Lower Risk for Many Cancers

Higher levels of leisure-time physical activity were associated with lower risks for 13 types of cancers, according to a new study. Physical inactivity is common, with an estimated 51 percent of people in the United States and 31 percent of people worldwide not meeting recommended physical activity levels. Researchers pooled data from 12 U.S. and European cohorts (groups of study participants) with self-reported physical activity (1987-2004). They analyzed associations of physical activity with the incidence of 26 kinds of cancer. The study included 1.4 million participants and 186,932 cancers were identified during a median of 11 years of follow-up. The authors report that higher levels of physical activity compared to lower levels were associated with lower risks of 13 of 26 cancers. Most of the associations remained regardless of body size or smoking history, according to the article. Overall, a higher level of physical activity was associated with a 7 percent lower risk of total cancer.

Given a robust algorithm for assessing how youthful someone appears to be, and there are a few of those floating around the research community in various stages of development, it comes possible to look for correlations between a youthful appearance and various genetic variations. It isn't clear that this will lead to any practical outcome, but that is true of most fundamental research at the time it is undertaken. Possibly the most interesting aspect of the study noted here is that the correlation they found is present in multiple populations, which is a fairly rare occurrence in research into genetics and longevity.

Looking young for one's age has been a desire since time immemorial. This desire is attributable to the belief that appearance reflects health and fecundity. Indeed, perceived age predicts survival and associates with molecular markers of aging such as telomere length. Understanding the underlying molecular biology of perceived age is vital for identifying new aging therapies among other purposes, but studies are lacking thus far. As a first attempt, we performed genome-wide association studies (GWASs) of perceived facial age and wrinkling estimated from digital facial images by analyzing over eight million single-nucleotide polymorphism (SNPs) in 2,693 elderly Dutch Europeans from the Rotterdam Study. The strongest genetic associations with perceived facial age were found for multiple SNPs in the MC1R gene. This effect was enhanced for a compound heterozygosity marker constructed from four pre-selected functional MC1R SNPs, which was replicated in 599 Dutch Europeans from the Leiden Longevity Study and in 1,173 Europeans of the TwinsUK Study.

Individuals carrying the homozygote MC1R risk haplotype looked on average up to 2 years older than non-carriers. This association was independent of age, sex, skin color, and sun damage (wrinkling, pigmented spots) and persisted through different sun-exposure levels. Hence, a role for MC1R in youthful looks independent of its known melanin synthesis function is suggested. Our study uncovers the first genetic evidence explaining why some people look older for their age and provides new leads for further investigating the biological basis of how old or young people look.

Link: http://dx.doi.org/10.1016/j.cub.2016.03.008

Oct4 is one of the factors used in reprogramming recipes that convert ordinary somatic cells into induced pluripotent stem cells, similar to embryonic stem cells and capable of generating any tissue type given the right environment and further programming. Given this, it is not entirely unexpected for Oct4 to show up in mechanisms relevant to aging and regeneration, as is the case here. Researchers have found Oct4 to have a protective role in the development of atherosclerosis, stabilizing the plaques that form in blood vessels over the course of that condition. As a target for therapy this leaves a lot to be desired - it is very far down the line of disease progression, and stable plaques still grow and narrow blood vessels, producing high blood pressure, remodeling of the vascular system, and other aspects of cardiovascular disease. It would be far better to note this research as interesting and focus instead on better ways to remove plaques and prevent their existence in the first place.

The gene, Oct4, plays a key role in the development of all living organisms, but scientists have, until now, thought it was permanently inactivated after embryonic development. Some controversial studies have suggested it might have another function later in life, but a new study is the first to provide conclusive evidence of that. The gene plays a critical protective role during the formation of atherosclerotic plaques inside blood vessels. The rupturing of these plaques is the underlying cause of many heart attacks and strokes. The researchers found that Oct4 controls the movement of smooth muscle cells into protective fibrous "caps" inside the plaques - caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques. This is exciting, because studies suggest that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. "Our findings have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques." One surprising finding: when the researchers blocked the effect of Oct4 in mice, they thought the atherosclerotic plaques might become smaller, because of the reduced number of smooth muscle cells inside. Instead, the plaques grew larger, less stable and more dangerous, stuffed with lipids, dead cells and other damaging components.

Researchers believe the gene could also prove critical to the field of regenerative medicine, which investigates the growth and replacement of tissues and organs. The researchers believe that Oct4 and its family of target genes are activated in other somatic cells - the non-reproductive cells in the body - and play a key role in the cells' ability to repair damage and heal wounds. Studies to test this are under way. Researchers suspect that at least some of the detrimental effects of aging, including the increased possibility of a plaque rupture, stem from a decrease in the body's ability to reactivate Oct4. "Finding a way to reactivate this pathway may have profound implications for health and aging. We think this is just the tip of the iceberg for controlling plasticity of somatic cells, and this could impact many human diseases and the field of regenerative medicine."

Link: http://www.eurekalert.org/pub_releases/2016-05/uovh-ghp051616.php

Here I'll point out a long discussion with Aubrey de Grey of the SENS Research Foundation that is packaged and sold as a book. This is a most interesting, and I think worthwhile, way for an author or journalist to approach the long-form interview process. Like many other new approaches this wouldn't have been financially viable a few decades ago, and is in and of itself a small example of the sort of freedom, choice, and innovation that can occur when costs fall and barriers to entry crumble. At the present time, we can hope that the same things that have already happened to the publishing industry will also come to pass for the edifice of medical research and development: an explosion of greater participation, experimentation, and creation. These two areas of human endeavor couldn't be more different in their details, but in both cases the costs of participation are falling dramatically.

Aubrey de Grey needs little introduction for the long-time readers here. Something more than fifteen years ago he took it upon himself, as an outsider to the field at the time, to alternately kick and persuade the aging research community into working towards the treatment of aging. When he surveyed the field, he saw plenty of evidence to show that aging is caused by a small variety of forms of cell and tissue damage. Yet that evidence was largely ignored in the formulation of research strategy, while scientific discussion the treatment of aging in public was a threat to career and funding, and the vast majority of aging research was nothing more than a process of gathering data. Fast forward to today, however, and this situation has been turned around. Arguments among scientists are now over how exactly aging should be treated in order to prevent disease and extend healthy life, and researchers can speak in public and publish their thoughts on that goal without any fear of losing their ability to raise funding or advance their careers.

This was achieved through considerable effort by a network of advocates within and beyond the research community, and few would argue that de Grey was anything other than one of the most important of these figures. He now leads the scientific and funding efforts of the SENS Research Foundation, an organization that, along with its parent non-profit the Methuselah Foundation, has accomplished a great deal in moving the vision of rejuvenation therapies closer to reality. Clearing senescent cells as a way to treat aging, for example, was dismissed by many in the research community a decade ago despite the strong evidence for its role in age-related degeneration. Today, however, therapies to clear senescent cells from old tissues have been demonstrated to improve health and extend life in rodent studies, the research non-profit Major Mouse Testing Program is crowdfunding further studies, and two startup companies, Oisin Biotechnologies and UNITY Biotechnology, are working on bringing these treatments to the clinic. The world is changing, and we shouldn't lose sight of those who worked hard to make this the case.

Advancing Conversations is a line of interview books documenting conversations with artists, authors, philosophers, economists, scientists, and activists whose works are aimed at the future and at progress. The biogerontologist Aubrey de Grey, as the world's pre-eminent longevity advocate, is nothing if not future oriented. De Grey is the founder of the SENS Research Foundation, an organization developing medical interventions to repair the damage the body does to itself over time. Stated more directly, Aubrey de Grey and his organization aim to defeat aging.

Douglas Lain: I thought I'd start our conversation with a joke from Louis CK. Louis says that when you're forty and you go to the doctor, they don't try to fix anything anymore. Once you get over forty they don't try to fix you, they just say "Yeah, that starts to happen." Is this really a general attitude that people have, that there is any truth to this joke?

Aubrey de Grey: Yes. There is an enormous amount of truth in it. And I think we need to distinguish here a little bit between the medical progression - doctors and other people in the medical world - as against the rest of the world. The medical progression have the enormous problem, which we need to sympathize with, that they have a certain range of tools to work with, to help people to be healthier and to restore people to health, but those tools are very limited in their efficacy. In particular they're extremely limited with regard to what they can do for people who are getting old. Ultimately, your average doctor just has to work with what they have, and a lot of that involves management of expectations. That's really all the Louis CK is saying there. Right?

Of course, that doesn't say anything about what might happen in the future. What might be possible in terms of maintenance or restoration of youthful good health with medicines that haven't yet been developed. But, that is not what doctors are supposed to be interested in. Doctors are all about doing their best with the tools that are already available.

Now contrast that with the situation that the general public has. The general public are not providing care, they are the recipient of medical care. And they are the people who should be thinking about the potential improvement in that medical care that might arise from further advances, from progress in the laboratory. It's kind of beholden on the public and therefore policy makers and opinion formers and so on ... to actually drive this, to actually deliver the funding and general resources that are required to allow people like SENS Research Foundation to move forward and create therapies that don't yet exist. Once those therapies do exist, of course they enter the universe of tools that your doctor can actually prescribe, can actually administer. But until that time, it's not the problem of the doctors. It's not their fault.

This open access review paper looks over what is known of the role of the immune system in bone regeneration. A variety of immune cells play important roles in tissue regeneration, but these activities are not yet fully cataloged and understood, and are different in different tissues. Since the immune system declines with age, along with the stem cell populations that provide signals and a supply of new cells for tissue maintenance, it is likely that this is one of the causes of failing regeneration in older individuals.

Bone fractures are among the most common orthopedic problems that require medical intervention, particularly in the elderly. Almost half of fractures are related to osteoporosis, especially in individuals over the age of 55. Bone injury leads to the production of pro-inflammatory cytokines and chemokines and to systemic recruitment of macrophage precursors to the injury site. Bone healing is a complex process and there appears to be a deficiency in our understanding of the interactions between macrophages and mesenchymal stem cells (MSCs) in bone healing, especially in the elderly population. Specifically, aging may alter these interactions and thereby play an important role in the elderly patient's ability for regeneration of musculoskeletal tissues.

As such, it is important to understand the different macrophage populations that play a role in bone repair. Though they exist within a spectrum, macrophages can be broadly described as uncommitted M0, pro-inflammatory M1, and anti-inflammatory M2 populations. In actuality, both in humans and mice, there probably exists a spectrum of polarization phenotypes, with a general preponderance of pro- versus anti-inflammatory properties. With these multiple phenotypes, macrophages play several roles within the bone-healing process, depending on their polarization status and environmental cues.

Although it is apparent that macrophages have altered activities with age, it is unclear as to what these specific changes entail and the mechanisms that drive such changes in musculoskeletal tissues. Several studies point to intrinsic factors that alter macrophage polarization, function, and survival. It was found that aged muscle had higher levels of M2a polarized macrophages, muscle fibrosis, and collagen accumulation. The increased frequency of M2a macrophages and fibrosis was attributable to the aging of myeloid lineage cells, as demonstrated by rescue of aged muscle with infusion of young bone marrow cells. In addition to intrinsic changes of aging, macrophages are modulated by their aging microenvironment and a poorly described number of external factors. When challenging young macrophages with aged serum, studies found reduced macrophage secretion of TNFα and increased basal levels of IL-6. In a study comparing phagocytosis by young and aged peritoneal macrophages and bone marrow-derived macrophages, it was demonstrated that older peritoneal macrophages have significantly impaired phagocytosis compared with younger macrophages.

Aging is also associated with elevated levels of secreted inflammatory cytokines beyond the previously described functional and environmental changes. Much of the literature describes aged macrophage hypersensitivity and increased responsiveness to inflammatory signals. These findings suggest that aged macrophages remain in a pre-activated resting state that enhances their response to exposure of pro-inflammatory stimuli. However, with increased production of reactive oxygen species, aged macrophages are susceptible to oxidative damage. Although there is increased responsiveness to pro-inflammatory signals, aged macrophages also have impaired function with reduced phagocytic activity, reduced nitrite burst capacity, and reduced autophagy.

Given current knowledge, it is apparent that aging-associated changes in the macrophage population are normal events but can also be potential sources for pathological states. With aging, the proliferative and functional abilities of macrophages and MSCs are impaired because of a combination of intrinsic and environmental factors. As proper bone healing requires an inflammatory phase, the increased survival of anti-inflammatory M2 macrophages and reduced secretion of pro-inflammatory factors with age may jeopardize timely bone regeneration. At the same time, aging negatively impacts MSC proliferation and differentiation, further impeding the bone-healing process. It would appear that, taken together, both macrophages and MSCs, cells critical for regeneration of musculoskeletal tissues, are adversely affected by aging. This scenario provides new opportunities for modulation of cellular events in order to optimize the healing of mesenchymally derived tissues, including bone.

Link: http://dx.doi.org/10.1186/s13287-016-0300-9

Mutational damage to nuclear DNA increases with age, and this is one of the reasons as to why cancer is predominantly an age-related disease. The more damage there is, the more likely that some of that damage causes a cell to run wild as the seed of a cancer. Beyond this, there is some debate over whether or not nuclear DNA damage produces a significant contribution to aging by dysregulation of cellular behavior, though the mainstream consensus at this point - in advance of any definite study proving the point - is that it probably does. To a large degree this is based on the observation that any breakdown of the extremely efficient DNA repair mechanisms present in our cells produces a range of conditions, many of which appear superficially similar to aging. The point is subtle, however: if aging is damage, there are many ways to generate cell and tissue damage in a living organism that have no particular relevance to aging, even though they also result in disability and death.

Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent damage. DNA carries the inheritable genetic information for all living organisms. However, DNA receives endogenous and exogenous insults every minute and the lesions (approximately 10^4-10^5 per cell per day) are extremely deleterious to cells. These lesions, if not correctly repaired, will interrupt genome replication and transcription and cause wide-scale chromosomal aberrations that trigger malignant transformation or cell death. Therefore, effective sensing and repair systems are developed during evolution to eliminate the DNA lesions and to maintain genome integrity. Dysregulation of DDR and repair is closely associated with human diseases such as cancers, cardiovascular disease, neurodegenerative disorders and aging.

Aging is defined as a progressive decline of body function and a decrease of physiological response to stress that ultimately results in death. Because the insufficiency of repair will cause the accumulation of DNA damage which leads to cell death or functional defect, it is reasonable to hypothesize that DDR and repair is closely associated with aging. Indeed, mice defective in DNA repair exhibit features of premature aging. Human genetic diseases with DNA repair defects such as Huchinson-Gilford Progeria all show premature aging. However, not all DNA damage and repair cause aging. Defects in mismatch repair (MMR) may result in cancer formation but not directly correlate with aging. Interestingly, an accumulation of DNA damage or defect in DNA repair also promotes cellular senescence and apoptosis. This raises the question whether senescence induced by physiological or pathological alterations may be involved in aging.

Many previous studies addressing the senescence mechanism were done in single cells, especially in fibroblasts. An obvious question is how cellular senescence caused by deficient DNA repair finally affects the aging of a living organism. We propose three potential mechanisms to explain the systemic effect. First, senescence depletes the supplemental pool of stem cells or progenitor cells that leads to the continuous decline of tissue homeostasis and accelerates organ aging. Secondly, senescence causes tissue degeneration. As evidenced in human diseases, defects in DNA repair induce senescence and degeneration of nervous and endocrine/exocrine tissues. Dysfunction of the nervous system would decrease the activity of innervated tissues and dysfunction of the endocrine/exocrine system would disturb hormone homeostasis and nutrient balance which ultimately causes organ aging. Thirdly, senescence induces chronic inflammation. One well-known characteristic of senescent cells is the production of pro-inflammatory and matrix-degrading molecules, known as the senescence-associated secretory phenotype (SASP). Higher serum levels of pro-inflammatory factors such as interleukin-6 and tumor necrosis factor are found in aged mice. A similar observation is also confirmed in aged individuals. Chronic inflammation triggered by these pro-inflammatory factors changes the immune response and vascular system and finally disrupts the physiological function of many tissues to promote the aging process.

Link: http://www.mdpi.com/1422-0067/17/5/685/htm

By way of following on from today's AMA over at /r/futurology, I recently had the chance to ask a few questions of the Major Mouse Testing Program (MMTP) volunteers, a mix of scientists and advocates who aim to do their part to speed up progress towards effective treatments for the causes of aging. The group formed six months ago or so, and are presently seeking funds for their first mouse studies through crowdfunding with the Lifespan.io organization. The initial focus is on senolytic treatments capable of removing senescent cells from old tissues. I encourage you all to take a look at the details of their research proposal.

Growth in the number of dysfunctional, senescent cells is a contributing cause of degenerative aging, involved in the progression and pathology of all of the common age-related diseases. A growing body of evidence supports the outright removal approach as a way to minimize or eliminate this portion of the aging process. Unfortunately there is - as ever in the aging research field - a paucity of funding and always the need for more and better animal data in order to pull in other players with deep pockets. At this stage in the progression from laboratory to clinic, prior to the involvement of any large institutions or companies, all such efforts are important work. I'm pleased to have been able to contribute to this Major Mouse Testing Program fundraiser, and hope to see great things from this group in the future.

How did the Major Mouse Testing Program come about? How did you meet and what made you decide to undertake this particular project?

Elena: I have been collaborating with the International Longevity Alliance (ILA) for about 3 years. It is an international non-for-profit organization with the head office in Paris, our goal is to support innovative biomedical technologies to address aging. At the beginning, the core team had a lot of discussions with other pro-longevity organizations and with the scientific community to identify the bottlenecks that impede the development of the technologies to slow down, postpone and reverse age-related damage to health. And we learned that one of the barriers was the deficiency in robust animal trials for a long list of promising interventions. Then one of the Founding Board Members, Edouard Debonneuil, came in with the idea that the ILA could start its own fundraising project to support this kind of research. This is how MMTP was started.

Steve: I learned about the MMTP project via the International Longevity Alliance. They had a number of projects ranging from lobbying, advocacy to research, for me the research appealed as I wanted to get my hands dirty and get as close to the frontline as possible. MMTP is a mixture of advocacy and actual research so for me it was a good combination. The research is focused on speeding up progress in rejuvenation medicine so I felt it was important to get involved with this kind of project.

Paul: I learned about the MMTP project from Steve. He had just started working on the project, We knew each other quite well and had a good rapport, and he thought I'd be a good fit for the group. I wasn't initially keen to join the group, I didn't appreciate the work that animal researchers do, like a lot of people I guess I didn't appreciate why animal data is so important for developing new drugs and therapies. The more I learned about the project, the more I realised how vital the work was! My skillset seemed to fit the needs of the group so I decided to commit to the group.

The world would be a better place if everyone pitched in to move research forward. Why don't they? What are the challenges in doing this?

Elena: You would be surprised but there is a lot of studies in sociology that answer this question. As I am going to make my PhD in this field, I read a lot and I combine my own experience in longevity promotion with scientific evidence. So far, we know, that if you ask a person to choose a desirable lifespan, he or she will only add about 10 years to the mean life expectancy in any given country. But if you ask, if people would like to live longer while also remaining youthful and healthy, at least 30% will consent to live much longer or even indefinitely. Many people show more interest after being provided with the data from animal studies - which look fantastic today, with mice lifespan extended twofold.

Another important thing to keep in mind is that the perception of the innovation depends very much on its end use. People are keener to support a new and even experimental treatment for a severe disease, but often refuse to accept it in case it is used for life extension. Which basically means, that before promoting life extension technologies, we have to explain that aging is a root cause of severe age-related diseases, that aging itself is very similar to a disease, even if we don't call it so. If people can see how deteriorating aging processes are for their health, they will understand that it is only right to develop the means to protect people from its consequences. Cancer and diabetes are two of the most horrible consequences of aging, and I have not yet met someone who would say no to the development of a cure against cancer or diabetes. This is how powerful the admission of a serious problem can be.

Last but not least, we should not avoid talking about the prejudices and concerns that people have towards personal and social implications of longevity technologies. It is only reasonable that they want to make informed decisions. In our case, to be properly informed means to have some information outside the field of medicine. So we should share evidence-based data and expert foresight in demography, economy, ethics, ecology, law and other sciences on request, as in our case this is what can significantly influence public perception - and will also influence adherence to longevity therapies in the future. So, to get more supporters we seem to have a lot of educating to do.

Paul: Yes it would be truly amazing if more folk who declared an interest in this kind of research, actually played an active role in ensuring that it manifests itself as something people can go to a clinic and receive, rather than just daydreaming about it! But people are inclined to be either overly optimistic, or the complete opposite. Some don't believe this will ever amount to anything, so they see no value in joining the fight, and that is what this is. The other extreme, believe that it will happen whether they do anything or not, so why bother? They just sit around complaining about the lack of progress, while looking at exponential technology graphs, occasionally muttering "Are we there yet?" So the main challenge is to make people realise that this will not happen, if it is not made to happen. And if folks want this soon, it is in their best interests to pitch in and help get the job done.

You've been gearing up for your first fundraiser for a few months now; now that you're launched, what are the details?

Steve: We launched our fundraising campaign on lifespan.io with an ideal goal of $60,000 in order to initiate a robust scientific study. We will scale the experiment based on the funds we raise so no matter what, we will be making progress.

Elena: It is important to mention, that if we raise a little more, we will be able to do even more tests and so improve our data on health changes in our mice.

Once you have the funds in hand and are embarked on making mice live longer, what is next for the Major Mouse team?

Steve: Given the expertise of our researcher, we are very interested in moving into stem cell therapy for longevity. This could be very exciting as we plan to potentially combine senolytics with stem cell therapy. Imagine, first we remove the bad cells from the body, second - we stimulate the regeneration and replenish lost stem cells. This is one reason why our current study not only focuses on lifespan but our secondary goal is to closely examine the effect of senolytics on resident stem cell populations, this information will guide how we approach combining the two therapies.

Where do you see this field of rejuvenation research going over the next few years?

Steve: Stem cells are certainly shaping up to be a big player, CRISPR and gene therapy likewise. Senolytics has attracted a great deal of interest of late too though we need to robustly test this to ensure it is a viable path to longevity. There are a number of "camps" in the research community, the bulk seem to favour tinkering with the metabolism far downstream of the problems, another is the engineering strategy of SENS and the third is the hotly debated telomerase camp.

I think the most important thing at this point is to get the research underway, start answering the unanswered questions and work out what the best approaches are. Personally I see little value in messing with metabolism far downstream but which of the other two camps is right could be some of column A and some of column B. I am not married to either idea which is why we will test these things robustly and find out what works. It would be very poor science indeed if we made a conclusion and then cherry picked our results to support them, no we will research thoroughly and we will go where the data leads!

Elena: If anyone is expecting a universal pill against aging in the next 10 years, I don't believe this is going to happen. If you look at animal data, combine what they are treated with, then you can imagine, what a complex of anti-aging interventions is today. So far the approach to slow down and reverse aging includes drugs, senolytics, vaccines, cell therapies, gene therapies, organ regeneration in situ and of course lifestyle measures. In future, we will learn to combine several types of interventions in one procedure, and maybe we will wear a rechargeable bracelet able to inject a mix of longevity drugs directly into our bodies on demand, maybe several times a month. To repair a damaged organ we will have to undergo an injection of stem cells into that organ, which would supplant some of the more invasive interventions. By the way, this is what is already happening: an ongoing study in Melbourne, Australia, shows amazing results in joint repair in situ, on humans, using stem cell therapy.

Paul: Now that's a question! Things are moving so fast, every week there seem to be announcements, news about CRISPR and stem cells. These are two of the fastest moving areas of research. Those two and Senolytics, this is another rapidly accelerating area of research. Senolytics should help clear the senescent cells, and that will set the stage for recovery or rejuvenation. This is where things like stem cells come in. I know we would like to take our research into combination therapies, either combinations of the same therapies, involving multiple senolytics for example, or combinations of complementary therapies such as Senolytics and stem cells.

Funding is, obviously, ever the battle in the sciences, and especially aging. How can we change this for the better?

Elena: There are several ways for a scientific group to get funded. There is already settled state funding for the research - in this case, our goal is to make a state research institution more interested in investigating aging and longevity. There is an additional source - the grants. This is what most of gerontologists try to obtain, but this form of support has its own limitations: the paperwork can take too much time, there are some inconvenient regulations of spendings timeline, we hear many groups complaining about that.

Crowdfunding is much more attractive in this regards. We don't ask for excessive amount of papers, only a decent experiment protocol and a reasonable estimate, making clear the amount of such expenditures as the substances to test, the mice and their housing, and everything necessary to obtain the data on health changes. The contract between the ILA and the research institution guarantees the observation of the study design and volume. Apart from that, we let the scientific groups do their work without unnecessary distraction. Luckily, the cost of such experiments is from 60 to 100 thousand, so it can be acquired by crowdfunding. And while it is not so easy to influence state funds allocation, in MMTP we let general public influence the progress in biomedical sciences directly.

Paul: I think we need to educate interested parties at all levels, about the need to get this work done. About the potential, not only in terms of human lives and suffering that can be saved, but the enormous cost savings that could be potentially had too, by investing in preventative and rejuvenation therapies. Health providing organisations worldwide are creaking under the financial burden of established medicine, a model that offers increasing periods of decrepitude, in exchange for ever increasing amounts of money. This faustian bargain offers a very poor return on investment and simply cannot continue much longer. So advocacy and education are two of our biggest weapons going forward. We also need to foster a change in governmental policies worldwide! The ILA has already made a start, by approaching bodies like the World Health Organization (WHO), which themselves see a need for change. By the way, WHO recently held a Consultation on Global Strategy and Action Plan on Ageing and Health, where the need for more research on aging and longevity was discussed.

About the Team Members

Steve: Project lead for MMTP and a longevity advocate, whose energy and devotion is inspiring the team.

Elena: Project coordinator and fundraiser, Elena is involved in project management and community outreach to donors.

Paul: Social media manager and writer, Paul is an important part of our promotion team.

The researchers and advocates of the Major Mouse Testing Program will be answering your questions in an /r/futurology AMA ("Ask Me Anything") event today. The organization is presently raising funds via crowdfunding in order to run the first in a set of animal life span studies of senolytic drugs as a means to reduce the number of senescent cells in old tissues. The presence of such cells is one of the causes of aging, and a range of initiatives aimed at treatments are presently in the early stages of development. This is a still a very poorly funded area of research in comparison to its potential, however, which is why our continuing support is absolutely necessary if there is to be significant progress in the next few years:

The Major Mouse Testing Program (MMTP) is an ambitious project of the International Longevity Alliance (ILA), featuring an international team of scientists and advocates testing therapies against aging decline. This experiment is is lead by world class stem cell researcher Dr. Alexandra Stolzing and was inspired by our scientific advisor and colleague Dr. Aubrey de Grey.

The Major Mouse Testing Program is seeking to speed up scientific progress in the field of regenerative medicine and biogerontology. After ILA experts conducted an analysis of delays preventing the development of life extension technologies, it was shown that a serious problem was the lack of robust animal data for the potential of different compounds to promote health and extend maximum lifespan. Without this data promising interventions cannot enter clinical trials and become available to the general public. The MMTP is currently running a crowdfunding campaign to raise funds to address this issue.

For the first experiment we are testing a new class of drugs known as senolytics, these drugs have been shown to help seek out and destroy toxic senescent cells that accumulate with age and improve various aspects of health. We wish to see if senolytics can increase maximum lifespan in addition to healthspan. We have big plans for the future with combination testing of senolytics, stem cells and more to help speed up scientific progress. So go ahead and ask us anything!

Link: https://www.reddit.com/r/Futurology/comments/4jgty0/mmtp_ama_senolytics_seek_and_destroy/

Researchers here report on the details of pacemaker cell decline in aging. These cells drive the heartbeat, but as is the case for all tissues, they and their environment become damaged and dysfunctional in later life. Signaling mechanisms attempt to compensate, but that compensation is imperfect, and itself subject to the effects of damage:

Healthy heart beating intervals (BIs) are not strictly constant, but rather exhibit beat-to-beat variations, imparting complexity to the heart rhythm. Beating Interval Variability (BIV) reduction is a predictor of heart diseases and an increased mortality rate. Although the average basal BI remains constant with advancing age, the basal BIV is found to be reduced. In contrast to the preservation of the average basal BI, the average intrinsic BI, that is, in the absence of autonomic neural input, is found to be prolonged with advanced age. Whether and how the intrinsic BIV is altered in advanced age and the identities of mechanisms that underlie the changes in the BI-BIV relationship that accompany advancing age have not been well characterized.

Two main mechanisms regulate the average BI and BIV: (i) stimulation of extrinsic autonomic receptors on pacemaker cells (i.e. β-adrenergic receptors or cholinergic receptors) within the sinoatrial node (SAN) controlled by the balance between sympathetic and parasympathetic neural impulses to the heart and (ii) constitutive signaling intrinsic to pacemaker cell via Ca2+-calmodulin adenylyl cyclase (AC) types 1 and 8, which, in the absence of autonomic receptor stimulation, drives many of the same cell mechanisms that are modulated by autonomic receptor stimulation. Both neural input to pacemaker cells and mechanisms intrinsic to pacemaker cells deteriorate with advancing age.

We hypothesized that age-associated changes in average BI and BIV result from the alteration in both intrinsic and neural input signaling. We analyzed BI dynamics in mice of varying ages: (i) in vivo, when the autonomic input to the sinoatrial node is intact; (ii) during autonomic denervation in vivo; and (iii) ex vivo, in the intact isolated SAN tissue (i.e. in which the autonomic neural input is absent). BIV was quantified and although the average basal BI did not significantly change with age under intrinsic conditions in vivo and in the intact isolated pacemaker tissue, the average BI was prolonged in advanced age. In vivo basal BIV indices were found to be reduced with age, but this reduction diminished in the intrinsic state. However, in pacemaker tissue BIV indices increased in advanced age vs. adults. In the isolated pacemaker tissue, the sensitivity of the average BI and BIV in response to autonomic receptor stimulation or activation of mechanisms intrinsic to pacemaker cells by broad-spectrum phosphodiesterase inhibition declined in advanced age. Thus, changes in mechanisms intrinsic to pacemaker cells increase the average BIs and BIV in the mice of advanced age. Autonomic neural input to pacemaker tissue compensates for failure of molecular intrinsic mechanisms to preserve average BI. But this compensation reduces the BIV due to both the imbalance of autonomic neural input to the pacemaker cells and altered pacemaker cell responses to neural input.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12483/

The popular science article I'll point out here is written from a programmed aging point of view, in which - to simplify greatly - epigenetic change is considered to be the root cause of aging, changing the operation of cellular metabolism so as to generate damage, dysfunction, and death. One of the authors maintains a blog, and you'll find much more on his take on programmed aging there. I consider the opposite view to be more plausible, that the root cause of aging is accumulated damage, produced as a side-effect of the normal operation of metabolism, and that where we observe epigenetic changes in aging, they are a response to rising levels of damage. Placing this crucial difference to one side for one moment, the article below does makes an entirely valid point, which is that the enormous evolved variation in life histories in the natural world - in the pace and character of aging and species longevity - indicates that it is in principle possible to engineer a radically different human metabolism in order to create individuals who undergo slower aging, and down the line that sort of approach could be used to produce negligibly senescent or even ageless branches of humanity.

Why Aging Isn't Inevitable

Humans age gradually, but some animals do all their aging in a rush at the end of life, while others don't age at all, and a few can even age backward. The variety of aging patterns in nature should be a caution sign to anyone inclined to generalize - particularly the generalization that aging is inevitable. Life spans range from Methuselans great and small to genetic kamikazes that die of a spring afternoon. Submerged dragonflies live four months, adult mayflies half an hour. We live some 70-odd years; but the meristem of the ginkgo may be millions of years old. This range becomes all the more impressive when we realize that the genetic basis for aging is widely shared across different species, from yeast cells on up to whales. Somehow, the same genetic machinery, inherited from our common ancestors at the dawn of life on Earth, has been molded to generate life spans ranging from hours (yeast cells) to thousands of years (sequoia trees and quaking aspen).

And it is not only the length of life but the pattern of deterioration within that time that varies widely. Aging can occur at a steady pace through the course of an entire lifetime (most lizards and birds), or there can be no aging at all for decades at a time, followed by sudden death (cicadas and century plants). Our own "inner assassin" works with stealth, like an evil empress gradually poisoning her husband; but other species have inner killers that do their deed far more quickly, and still others appear to have no genetic death programs at all. Such variety is a sure signal for a feature molded by active natural selection, not an immutable law of entropy. The great variety of aging styles among plants and animals suggests it can be controlled.

Suppose we were to remove length of life completely from consideration and compare different species based on the shape rather than the duration of their life histories. However long or short the life span, we display it in the same size box for comparison. Rather than asking how long they live, ask instead whether their populations tend to die out gradually, or if many die in infancy and fewer later on, or if all the deaths bunch up at the end of the life cycle. The strange bedfellows that appear as neighbors on the chart are utterly unexpected. For example, at the top of the chart, with low mortality that rises suddenly at the end of life, humans are joined by lab worms and tropical fish (guppies)! In fact, in terms of aging profiles, we humans look more like the lab worm than the chimpanzee.

Styles of aging in nature are just about as diverse as they can be, which suggests that nature is able to turn aging on and off at will. With this in mind, we may be forgiven for regarding theories that explain why aging must exist with extreme skepticism. Whatever our theory of aging turns out to be, it had better make room for plasticity, diversity, and exceptions.

I do not believe that building a variant of human biochemistry to produce negligibly senescent individuals is a near term project in any way, shape, or form. It is certainly possible, and may well be accomplished, but in the same sense as building out human habitats in high Jupiter orbit is possible, and may well be accomplished. Both are projects that could be eclipsed and rendered retro-futures by any number of advances over the decades ahead: why invest in building a negligibly senescent human biochemistry in a world in which we can discard our biology to merge with the machinery of a mature molecular nanotechnology industry, becoming ageless, durable, and repairable, for example? Or why do it if by the time it is plausible the medical community can already comprehensively repair the biological damage that causes aging?

At the present time we stand at least decades from even a comprehensive map of healthy, normal metabolism. Applications of that knowledge will require longer to arrive, and based on existing experience that work will be painfully challenging. Over the past fifteen years, it has required scores of researchers and a few billion dollars to somewhat improve the state of knowledge for one small set of genes and processes involved in calorie restriction, a very well-studied altered state of metabolism that modestly increases health and longevity. The research community is nowhere near a full accounting of how calorie restriction works, or any way to turn it on safely all the time, or even good ways to recreate some of its effects using the standard panoply of drugs and gene therapies. All of that effort could be repeated ten times over between now and 2030 and researchers would still be only a little further along in the process of figuring out how it all works in detail. The molecular biology of life is fantastically complex.

I point this out, as usual, to illustrate why the SENS approach of repairing damage is really the only viable way forward to radical life extension in our lifetimes. The cell and tissue damage that causes aging - that is the signature difference between old and young tissues - is well cataloged, agreed upon in many diverse fields of medical research, and there are plausible ways to repair it either under development or that are planned out in some detail. Given the vast costs and length of time needed to get to the point of being able to defeat aging by creating a new human metabolism, it is vitally important that we have an alternative approach to rejuvenation and agelessness that requires little to none of that effort in order to progress. It really is as simple as periodically fixing the damage and observing the results, a process that is taking place for senescent cell clearance in mice right now, today. This and other similar efforts in the years ahead will help map cause and effect and relative contributions to specific age-related diseases, but much more importantly will also produce the basis for rejuvenation therapies - and produce them soon enough to matter to people alive today.

Gaining more years of healthy life through progress in medicine is a change with no downside, to my eyes. That many people strive to find problems, and that many more people seem disinterested in gaining more years, disinterested in eliminating age-related suffering and frailty, is a mystery to me:

The greatest benefit of life extension is the continued existence of the individual who remains alive. Each individual - apart from the worst criminals - has incalculable moral value and is a universe of ideas, experiences, emotions, and memories. When a person dies, that entire universe is extinguished, and, to the person who dies, everything is lost and not even a memory remains. It is as if the individual never existed at all. This is the greatest possible loss and should be averted if at all possible. The rest of us, of course, also lose the possible benefits and opportunities of interacting with that individual.

People would be able to accomplish far more with longer lifespans. They could pursue multiple careers and multi-year personal projects and could reliably accumulate enough resources to sustainably enjoy life. They could develop their intellectual, physical, and relational capabilities to the fullest. Furthermore, they would exhibit longer-term orientations, since they could expect to remain to live with the consequences of decisions many decades and centuries from now. I expect that a world of longer-lived individuals would involve far less pollution, corruption, fraud, hierarchical oppression, destruction of other species, and short-term exploitation of other humans. Prudence, foresight, and pursuit of respectful, symbiotic interactions would prevail. People would tend to live in more reflective, measured, and temperate ways instead of seeking to haphazardly cram enjoyment and activity into the tiny slivers of life they have now. At the same time, they would also be more open to experimentation with new projects and ideas, since they would have more time to devote to such exploratory behaviors.

Major savings to health-care systems, both private and governmental, would result if the largest expenses - which occur in the last years of life today, in the attempt to fight a losing battle against the diseases of old age - are replaced by periodic and relatively inexpensive rejuvenation and maintenance treatments to forestall the advent of biological senescence altogether. Health care could truly become about the pursuit of sustainable good health instead of a last-ditch effort against the onslaught of diseases that accompanies old age today. Furthermore, the strain on public pensions would be alleviated as advanced age would cease to be a barrier to work.

I do not see true drawbacks to life extension. Certainly, the world and all human societies would change significantly, and there would be some upheaval as old business models and ways of living are replaced by new ones. However, this has happened with every major technological advance in history, and in the end the benefits far outweigh any transitional costs. For the people who remain alive, the avoidance of the greatest loss of all will be well worth it, and the human capacity for adaptation and growth in the face of new circumstances is and has always been remarkable. Furthermore, the continued presence of individuals from older generations would render this transition far more humane than any other throughout history. After all, entire generations would no longer be swept away by the ravages of time. They could persist and preserve their knowledge and experience as anchors during times of change.

Every day, approximately 150,000 people die, and approximately 100,000 of them die from causes related to senescence. If those deaths can be averted and the advent of indefinite life extension accelerated by even a few days, hundreds of thousands of irreplaceable individual universes would be preserved. This is worth paying even substantial costs in my view, but, fortunately, I think the other - economic and societal - effects that accompany life extension would be overwhelmingly positive as well.

Link: http://www.rationalargumentator.com/index/blog/2016/04/impacts-of-indefinite-life-extension/

If researchers can shut down metastasis by targeting a fundamental mechanism common to all or even many cancers, then cancer becomes much more manageable and much less threatening. That is why it is worth paying attention to research that might produce useful results along those lines. This link between metastasis and the cellular maintenance process of autophagy is intriguing:

Researchers have shown that inhibiting autophagy, a self-devouring process used by cells to degrade large intra-cellular cargo, effectively blocks tumor cell migration and breast cancer metastasis in tumor models. "Using genetic and chemical means, we showed that autophagy is required for the motility and invasion of highly metastatic tumor cells. Our work suggests that inhibiting autophagy in the clinical setting may be an effective approach to block metastatic dissemination."

Metastasis is responsible for 90 percent of cancer deaths. Rapidly growing tumor cells are tightly packed. They quickly exhaust their available supplies of oxygen and nutrients. By breaking away from the original tumor, migrating cancer cells have a chance to escape starvation and wind up in a less crowded environment with more nutrients. "We began by asking, what would happen if we shut down autophagy in metastatic cancer cells." The researchers noticed that when they placed metastatic breast cancer cells on a dish and monitored them with time-lapse microscopy, the control cells were "active, constantly moving around the dish." But cancer cells that the team had altered, by knocking down autophagy-related genes Atg5 and Atg7, "didn't move at all. They appeared to be stuck."

When they injected these gene-altered cancer cells into the mammary fat pad of female mice, the cells multiplied, forming large primary breast tumors, but these cancer cells were unable to metastasize to the usual distant sites, the lungs, liver or bone. A closer look showed that these cells were morphologically very different. Their focal adhesions, large structures at the edge of the cell that are crucial for cell movement, were more numerous and abnormally large. As the cell travels forward, focal adhesions form at the front of the cell and establish dynamic connections to the extracellular matrix. As the cell passes over them, these adhesions drift back to the trailing edge of the cell. Then autophagy intervenes, disassembling the focal adhesion, breaking down its contents and allowing the back edge of the cell to disengage from the extracellular matrix and be pulled forward by traction from the front end. The researchers have now shown that if autophagy is inhibited, these metastatic tumor cells cannot move. Adhesions that don't get turned over grow larger and larger. They anchor the cell in place. "They literally just get stuck. Through the microscope, you can see the cell wobbling, trying to move, to put out new protrusions, to migrate. But it can't, because it is stuck, unable to dissolve the adhesions at the back end of the cell."

Link: http://www.eurekalert.org/pub_releases/2016-05/uocm-sci050916.php

There are a lot of people who have both a medical condition and a lot of wealth - tens of millions of dollars or more. In this day and age, a fraction of that wealth is enough to produce a prototype treatment from scratch for many classes of condition, if you are willing to wait the decade or two that low-cost basic science takes to run its course. Alternatively, for a faster result in the five year range, that much money is enough to take a couple of promising potential therapies with initial animal studies and move them to prototype status. Not all conditions are amenable to this sort of approach, but many are. When you have a prototype, you license it freely to maximize the odds that it will be picked up and improved upon, and meanwhile pay a reputable clinic in one of the less regulated portions of the world to set it up for your own use. This is all very possible for a wide range of medical conditions. Why is it that so few wealthy, sick people take this path?

In the longevity science community we tend to ponder a very narrow facet of this question, which is ask why, with very few exceptions, the wealthy of the world are not funding rejuvenation research. They are all aging to death, just like the rest of us. Why are they walking off the cliff when they have a good shot at preventing that outcome? Yet the broader question is also of interest: not just aging research, but all medical research. I was pondering this after donating to the present crowdfunding initiative for DRACO, a universal basis for cheaply creating effective treatments for any and all viral infections, such as those that are poorly controlled and afflicting large numbers of people today. How many individuals are there with both resistant viral hepatitis and enough money to take DRACO to what its inventor considers the finish line of readiness for human trials? The cost of that is a few million dollars at this point. I can think of a couple of individuals from the last celebrity generation alone who are in this demographic. But of course it isn't happening, these people are not jumping in to make waves and build out a prototype therapy that could cure or control their infections. So it seems to me that perhaps our first problem with regard to funding rejuvenation research isn't in fact a matter of convincing the world that treating aging is a viable goal in medicine. That is a challenge, and has to be accomplished, but it isn't the first issue in line. That first problem is that next to no-one with the wealth to have a fair shot at solving their own medical problems through funding research thinks that they can in fact achieve that goal.

We can debate as to just why this is the case. For example, firstly there is simple ignorance of the possibilities. Some people and their supporting networks don't have the framework of ideas that lights the way. I think it isn't unfair to say that most people don't have any great insight into medicine as a system that can be changed and improved. I certainly didn't for half of my life. Engaging with doctors and learning about a specific condition because you happen to have developed it may or may not provide that insight - it strongly depends on the individual. The state of medicine and even the state of waiting for better medicine can be taken as set in stone. You can be good enough at what you do to become very wealthy, and yet lack the ability or patience or drive - or that framework of ideas - to learn the science behind the medicine, see that this science can be influenced, and understand the economics and connections well enough to see how to influence it. That is a tall order for someone who has invested decades in the minutiae of their own business and profession, a hard right turn in life, and a significant investment in time and will.

Secondly, there is a poster child effect here. Consider Michael J. Fox as one example, someone who has given large sums to Parkinson's disease research over the past two decades. Unfortunately, this is a condition in which it will take a long time and enormous funding to establish effective treatments, as is the case for most neurodegenerative diseases at this time. Conditions for which this is true tend to get a lot of the press, since there is more work taking place, and also more philanthropy. Secondly, the span of Fox's philanthropy crosses from a time in which life science work was very expensive and time-consuming into the present in which it is much cheaper and faster. Medical research is very much easier today than it was at the turn of the century: all of the tools are greatly improved, as is knowledge of cellular biochemistry. But people think of this, and similar cases, and see decades of expense and no resulting cure. Subtleties such as the considerable progress achieved in both understanding the condition and building a foundation for treatments yet to come are somewhat lost on the world at large.

Thirdly, it is enormously expensive to move from prototype therapy to clinical availability through the regulatory gauntlet. That is well understood, and it is why most people think of medical research as fantastically expensive. But it is not. Building prototypes is cheap. Early stage research and investigation can be so cheap that it can be crowdfunded by ordinary people like you and I. It is the testing required to prove reasonable safety for clinical translation of a prototype therapy that is merely ordinarily expensive. Then it is the over the top regulatory compliance that is par for the course in the US and Europe that drives the cost through the roof, restricts all meaningful clinical development inside the system to the entrenched Big Pharma interests, and ensures that all too many lines of research are never developed, and never even fully researched, as they cannot be cost-effective.

This is why I point out the strategy of open licensing and medical tourism. Build the prototype, then give it away and undergo the treatment yourself. We live in a world in which the BioViva CEO can be (probably) the first human to undergo a particular gene therapy with good animal data, and get that done for a low six figure cost or less. Regulation and its tremendous costs are not needed to produce a treatment that can be judged safe enough to risk - and that choice of safety should be up to the individual in any case. Again, however, near all of the people with the money to do this sort of thing from scratch, and with a condition that might be treated, don't see things this way. Wealth doesn't magically grant knowledge or wisdom. They, like most people, view medicine as an enormously expensive undertaking, far beyond their ability to move the needle, where they think of it as something that can be influenced at all.

This open access paper is quite representative of attitudes in much of the aging research community. Scientists are excited by the obvious burst of progress and possibilities, and changing attitudes in the research community let them openly express the desire to intervene in the aging process without risk to their careers - a concern that significantly suppressed dialog on treating aging as recently as a decade ago. Yet at the same time, very few people look past the established approach of drug development to tinker with metabolism in the hope of slightly slowing the aging process, and that is certainly the case here. The SENS rejuvenation research approach of repairing the cell and tissue damage that causes aging in order to reverse the aging process still has a long way to go in order to capture even a sizable fraction of the mainstream and its funding. This is why advocacy and philanthropic fundraising remain very important.

We are at a tipping point in the biology of aging-from lifespan extension per se to maintaining and extending health in late life. Since the early 1980s, there have been serious efforts to use genetic approaches to extend lifespan in model systems such as Caenorhabditis elegans, Drosophila, and, increasingly, mice. Collectively, such efforts fall under the catch-all term "geroscience", which describes interdisciplinary efforts to better understand the biology of aging with a view towards improving healthcare in the elderly. Recently, the tried and true genetic approaches of the 1990s and early 2000s in geroscience research have been increasingly giving way to a plethora of pharmacological approaches to extend lifespan. This has been in conjunction with efforts to simultaneously increase healthspan, thereby providing a preclinical rationale for similar studies in human beings.

It has been reported that lifespan and healthspan can be extended in invertebrates using a variety of pharmacological approaches, including single antioxidants through small molecule screens and natural compounds as well as some anticonvulsants. Not to be outdone, there are also supporting data for lifespan/healthspan extension in mice using repurposed US Food and Drug Administration (FDA)-approved drugs, novel chemical compounds, and biologicals. Before examining key concepts in geroscience that drive a lot of the excitement in the pharmacology of lifespan/healthspan extension, it is necessary to first of all define what we mean by aging and healthspan. This is particularly germane in the model systems most commonly used in the biology of aging. By no means is the definition of such terms straightforward, and eminent figures in the field have spent considerable effort clarifying such apparently simple concepts. For the purposes of this article, the term "aging" refers to post-reproductive changes that adversely affect lifespan. However, to define healthspan in the context of geroscience is perhaps even more difficult.

Healthspan is commonly interpreted to mean "maintenance of functional health with increasing age". By necessity, this means one has to understand what it is to be healthy for multiple different systems and tissues. In human beings, this is perhaps non-controversial-one can access high-quality data collected from many thousands of individuals of both sexes as well as differing ethnicities while controlling for multiple lifestyles. One can then establish age-dependent measures for many different aspects of human biology. These include measures of cardiovascular and cognitive function, movement (walking speed), renal function, and hemodynamic function, to name a few. Typically, such functional measures peak in early adulthood, then decline at different trajectories as the individual ages. There are many factors that can modulate the slope of such a functional decline with age, including exercise, diet, and lifestyle. Maintaining function and independence with age using selective and specific interventions is arguably the single biggest challenge currently facing geroscience. For the model systems commonly employed in the study of aging biology, identifying functional measures that are relevant to human healthspan is quite difficult. In nearly all model systems used in the biology of aging, healthspan measures have been collected from aging animals not necessarily because of their relevance to human aging but because methods exist that allow one to measure the metric in question over time. Amongst these metrics, there is one clear measure that is very well established as being a robust biomarker of healthspan in human aging, and that is the measurement of movement with age. A sound argument can be made for measuring this parameter in model systems of aging to ensure potential translational relevance.

Here, researchers report on a recent study of the ability of mitochondrially targeted antioxidants to modestly increase healthy life span in lower animals such as the flies used here. Mitochondria are important in the progression of aging for a number of reasons, all of which seem to be very connected to the reactive oxygen species (ROS) they produce in the course of generating chemical energy stores to power the cell. ROS can damage mitochondrial structures, and that can lead to mutant mitochondria that take over and cripple cells, causing harm to surrounding tissues. ROS are also used as signals in many fundamental cellular processes, such as the response to exercise and triggering of cellular maintenance in response to stresses. Thus antioxidants targeted specifically to the interior of mitochondria have the ability to influence these processes, where other types of antioxidant cannot:

Mitochondria play an important role in aging. Strongly reduced function of the mitochondria shortens life span, whereas moderate reduction prolongs life span, with reactive oxygen species production being the major factor contributing to life span changes. Previously, picomolar concentrations of the mitochondria-targeted antioxidant SkQ1 were shown to increase the life span of Drosophila by approximately 10%. In this article, we demonstrate that SkQ1 elevates locomotion, which is often considered a marker of health and age. We also show that mating frequency and fecundity may be slightly increased in SkQ1-treated flies. These results indicate that SkQ1 not only prolongs life span but also improves health and vigor.

An important property of any potential therapeutic is the stability of its effects in an uncontrolled and changing environment as well as on individuals with various genetic constitutions. In this article, we present data on SkQ1 effects on Drosophila longevity in extreme environments (low temperatures and starvation) and on individuals with severe genetic alterations in the mitochondrial systems responsible for production and detoxification of reactive oxygen species. We hypothesize that in vivo SkQ1 is capable of alleviating the probable negative effects of increased mitochondrial reactive oxygen species production on longevity but is not effective when reactive oxygen species production is already reduced by other means.

Link: http://dx.doi.org/10.1093/gerona/glw084

The cadence of SENS rejuvenation research fundraising this year will be a little different from that of past years. There will be more groups involved and more smaller initiatives running through existing crowdfunding sites for a start. The first of these fundraisers for 2016 has launched at crowdfunding site Lifespan.io, and is definitely worthy of our support. The Major Mouse Testing Program is a new non-profit group of researchers and advocates, who have spent the last six months making connections and laying the groundwork to run more animal studies of SENS-relevant prototype therapies focused on health and life span. This is an important gap in the longevity science community as it exists today: consider the painfully slow progress in organizing animal studies in senescent cell clearance over the past five years, for example. Given more enthusiasm and more funding, that could have happened a lot faster. Consider also that the research mainstream - such as the NIA Interventions Testing Program - carries out very few rigorous health and life span studies of potential interventions for aging in mice, and of those almost none are relevant to the SENS approach of damage repair, the only plausible path to radical life extension within our lifetimes.

Animal studies are vital; not just one or two, here or there, but a systematic approach to generating rigorous supporting data, establishing dosage, and uncovering unexpected outcomes. The Major Mouse Testing Program can do a great deal to fill this gap for our community, and has the potential to be an important supporting organization for the SENS Research Foundation, for startups working on SENS technologies such as Oisin Biotechnologies, and for labs involved in SENS research. The more diversity the better. The only thing that the Major Mouse Testing Program lacks today is the initial funding and support that we can provide to give them a good start on their plans for the future. With clever organization, a non-profit organization allied with established labs can carry out solid animal studies at a cost low enough for people like you and I to fund the work via fundraisers, and that is exactly what we should do.

I have stepped up to donate to this first fundraiser for the Major Mouse Testing Program, and I hope that you will too. This is a useful, needed initiative, the people involved are solid members of the community, doing the right thing, and pulling together the right networks, and they deserve our support. This first crowdfunding initiative is focused on expanding animal studies of drug-based senescent cell clearance approaches, in collaboration with existing groups that are working in this field. Remember, however, that this isn't just about setting up one set of experiments. This is the first step in building out an organization that can help greatly in the years to come, as the field of potential rejuvenation treatments expands, and the need grows for the non-profit groups in our community to specialize and diversify. This is one piece of the larger picture of building a network of research and advocacy at all levels that will shape the next few decades of progress towards effective therapies to treat and control the causes of aging.

Testing a new class of compounds, senolytics, on their ability to extend healthy lifespan by clearing out dysfunctional cells in the body.

According to modern science aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair systems. The good news is that the processes that constitute aging are amenable to medical intervention. We can slow down or even reverse some aspects of aging through the application of different therapies, which prevent or block some of these processes. One of these processes of aging is cell senescence. Senescent cells normally self destruct via a process called apoptosis, but unfortunately not all of them do. These "death resistant" senescent cells accumulate in the body with age and secrete toxic signals. This causes inflammation and damage to organs and tissues, increasing risks for cancer and other diseases of old age. This is why these cells are often called "good citizens but bad neighbors". They remain partially functional, but their presence does more harm than good. A new class of drugs known as senolytics have recently demonstrated the ability to remove senescent cells to improve health. However, the potential of senolytics to increase health and lifespan beyond current maximums remains unknown. This is what we at Major Mouse Testing Program want to investigate - with your help!

In our study we have opted to treat already naturally aged mice. These mice will be 16-18 months old (equivalent to a human of approximately 60 years old). This has two advantages: we speed up research, and also demonstrate the feasibility of translating senolytics to already middle aged or older humans. So far senolytics have only been shown to reduce the number of senescent somatic cells, but what effect do they have on stem cells? This has not been closely studied, and is a question we intend to fully answer in addition to the implications this presents for lifespan. It is entirely possible that senolytics taken alone may not extend maximum lifespan, but rather healthspan. Even if this is the case, it is no reason to be discouraged. What we learn in this first phase, paves the way for our next step - combining senolytics with stem cell therapy to encourage tissue regeneration. As part of our commitment to the sharing of scientific research the team plans to publish the results of our research as open access. We believe that knowledge should be shared and this is the level of our contribution to sharing and growing as a community together.

MMTP Campaign Launches to Test New Class of Cell-Clearing Drugs on Healthy Lifespan Extension

As we age our bodies accumulate damage in the form of dysfunctional cells that have entered a state called "senescence", which secrete toxic signals that can lead to chronic inflammation, higher rates of cancer and additional aging-related conditions. Today we proudly announce the launch of a new Lifespan.io campaign to test compounds, already known to remove these harmful cells, on their ability to extend healthy lifespan: the Major Mouse Testing Program (MMTP). This program, supported by the International Longevity Alliance (ILA), aims to expedite the identification of compounds which have the potential to increase healthy lifespan in humans via robust testing in mice. By using cohorts of middle-aged mice, the likelihood of discovering promising compounds will be increased in the short term.

The project will be directed by Dr. Alexandra Stolzing at Leipzig University and will involve three compounds already shown to have "senolytic" (senescent cell clearing) properties: dasatinib, quercetin and venetoclax. As such compounds are already FDA approved to treat various cancers, any positive results obtained through the MMTP study would enable a fast-track towards clinical trials. With your support we can help screen these and many more promising senolytic compounds. By donating to the MMTP campaign, your funds can jump start a pipeline towards developing drugs that enhance our healthy life span well into the future. Please check out the campaign, share with your friends, and keep building grassroots support for life extension research!

In all but the most aged and damaged individuals, the beneficial effects of much of the present generation of stem cell transplant therapies could in principle be produced by stem cell populations already present in the body. These cells just need the right signals and instructions to be put to work. Gaining a sufficient understanding of those signals is a work in progress, and the existing approach of stem cell culturing and transplantation has been an important part of that work to date - a necessary step on the road. It is still the early days in this field when considering the bigger picture, but it is interesting to see that factions within the research and development community are already forging ahead towards a stem cell medicine that doesn't involve transplantation:

OxStem has closed a £16.9 million ($24.4million) fundraising round to design stem cell drugs that treat age-related diseases. The £16.9 million raise - the highest ever for a UK academic spinout - will go toward developing small molecule drugs that can activate repair mechanisms that already exist within the body. The biotech was first founded back in 2014. Building on decades of experience in medicinal chemistry, OxStem will design drugs that can programme resident stem and stem-like cells in situ to treat currently untreatable age-related conditions. This follows in-line with other biotechs looking to "cure old age."

Just last month, U.S. biotechs Ascentage Pharma and Unity Biotechnology signed a research pact to help reverse aging, using preclinical data focusing on senescent cells. Google is also attempting to make a splash in the expanded lifespan field with its upstart Calico, although this very early-stage and the tech giant is a little thin on the details. Others are looking to older meds that may contain previously unknown qualities - the top among which is the off-patent type II diabetes drug metformin. Studies are planned from U.S. academic and government centers in the next year to see if the drug can delay or prevent some of the most devastating diseases of advanced age, from heart ailments to cognitive decline to cancer.

OxStem is focusing on stem cell science, and in essence aims to switch on the body's natural regeneration and repair systems. Current stem cell treatments mostly focus on injection of cells into the body and are available only in hospitals with access to the specialist laboratory facilities needed to harvest, isolate and multiply stem cells. The biotech said it however plans to reprogram stem and stem-like progenitor cells that already exist in the body with no need for cell transplantation procedures. "We will identify small molecule drug candidates, which can programme adult stem and stem-like cells to repair and replace tissues affected by disease or injury. We are tackling many of the worst conditions associated with ageing: dementia, heart failure, cancer and macular degeneration, which is the leading cause of blindness in the developed world."

Link: http://www.fiercebiotech.com/biotech/oxford-university-spin-off-oxstem-gains-record-funding-big-names

This popular science article focuses on the study of negligibly senescent species in the context of work aimed at adjusting the course of human aging. There is at least one negligibly senescent mammal, the naked mole-rat, but it seems to me that attempting to mine benefits from other species and port them to humans is just another way to say we should re-engineer human metabolism to age more slowly. The past twenty years have demonstrated that this is enormously expensive and enormously challenging. Billions have been spent on trying to safely change just a few genes and proteins, and to try to better understand the modestly slowed aging of calorie restriction, with no practical result other than to add thin slices to our knowledge of metabolic processes. We should have similar expectations for the results of trying to obtain benefits from the biochemistry of another species - and going far beyond that in scope to produce a whole new human metabolism is very far from being a plausible project today.

The only way today to make practice, cost-effective progress towards very large gains in human longevity is to follow the SENS model of damage repair. The damage that causes aging is very well understood, and we don't need a full explanation of how exactly at the detail level that damage multiplies and interacts to contribute to every facet of aging. We don't need to adjust those facets or integrate them into a new working model of human biochemistry. All we have to do is periodically repair the damage, maintaining the youthful version of human biochemistry that we know works. It is an engineering approach in which we can bypass our ignorance of the details in order to produce working rejuvenation therapies here and now. Repair of the first form of damage is already in the clinical development pipeline: clearance of senescent cells. Others might follow soon, if there was just more support and funding.

The naked mole rat is the superhero of the animal kingdom. Similarly sized rodents usually live for about five years. The naked mole rat lives for 30. Even into their late 20s, they hardly seem to age, remaining fit and healthy with robust heartbeats, strong bones, sharp minds, and high fertility. They don't seem to feel pain and, unlike other mammals, they almost never get cancer. "It's not a ridiculous exaggeration to suggest we can one day manipulate our own biochemical and metabolic pathways with drugs or gene therapies to emulate those that keep the naked mole rat alive and healthy for so long. In fact, the naked mole rat provides us the perfect model for human aging research across the board, from the way it resists cancer to the way its social systems prolong its life."

Over the centuries a long line of optimists, alchemists, hawkers and pop stars have hunted various methods of postponing death, from drinking elixirs of youth to sleeping in hyperbaric chambers. The one thing those people have in common is that all of them are dead. Still, the anti-aging industry is bigger than ever. In 2013, its global market generated more than $216 billion. By 2018 it will hit $311 billion, thanks mostly to huge investment from Silicon Valley billionaires and Russian oligarchs who've realized the only way they could possibly spend all their money is by living forever. Even Google wants in on the action, with Calico, its $1.5 billion life-extension research center whose brief is to reverse-engineer the biology that makes us old or, as Time magazine put it, to "cure death." It's a snowballing market that some are branding "the internet of healthcare." But on whom are these savvy entrepreneurs placing their bets? After all, the race for immortality has a wide field.

British biomedical gerontologist Aubrey de Grey is enjoying the growing clamor about conquering aging, or "senescence," as he calls it. His charity, the SENS Research Foundation, has enjoyed a bumper few years thanks to a $600,000-a-year investment from Peter Thiel ("Probably the most extreme form of inequality is between people who are alive and people who are dead"). Though he says the foundation's $5.75 million annual budget can still "struggle" to support its growing workload. According to de Grey, the fundamental knowledge needed to develop effective anti-aging therapies already exists. He argues that the seven biochemical processes that cause the damage which accumulates during old age have been discovered, and if we can counter them we can, in theory, halt the ageing process. He says traditional medicines won't wind back the hands of our body clocks - we need to manipulate our makeup on a cellular level, like using bacterial enzymes to flush out molecular "garbage" that accumulates in the body, or tinkering with our genetic coding to prevent the growth of cancers, or any other disease. "If you look at the maths it is very straightforward. All we are saying here is that it's quite likely that within the next 20 or 30 years, we will develop medicines that can rejuvenate people faster than time is passing. It's not perfect yet, but soon we'll take someone aged 60 and fix them up well enough that they won't be 60 again, biologically, for another 30 years. In that period, therapies will improve such that we'll be able to rejuvenate them again so they won't be 60 for a third time until they are chronologically 150, and so on. If we can stay one step ahead of the problem, people won't die of aging anymore."

Of course, the naked mole rat isn't the only animal scientists are probing to pick the lock of long life. With a heart rate of 1,000 beats a minute, the tiny hummingbird should be riddled with rogue free radicals, the oxygen-based chemicals that contribute to aging by gradually destroying DNA, proteins, and fat molecules... but it's not. Then there are pearl mussel larvae that live in the gills of Atlantic salmon and mop up free radicals, and lobsters, which seem to have evolved to have more of a protein which repairs the tips of DNA, allowing for more cell divisions than most animals are capable of. And we mustn't forget the 2mm-long C. elegans roundworm. Within these 2mm-long nematodes are genetic mechanisms that can be picked apart like cogs and springs in an attempt to better understand the causes of aging and ultimately death.

Link: http://www.vice.com/en_ca/read/quest-for-immortality-what-will-win-tech-animals

A new crowdfunding effort is running to gather funds and support to push forward with DRACO antiviral technology. DRACO stands for double-stranded RNA activated caspase oligomerizer, a class of designer molecules that can selectively destroy cells that are hosting viruses. Viruses hijack cellular machinery in order to replicate, and that process has a distinctive signature: all known viruses produce double-stranded RNA during replication, and that double-stranded RNA is not not otherwise found in our cells. Thus any cell containing these molecules is fair game. Since DRACO therapies don't target any of the other highly varied molecular machinery of the virus itself, but rather prevent the virus from effectively multiplying its numbers, they can be used against near any target virus without much need for specialization or adjustment. It has proven effective against a score of very different viruses in tests in past years.

DRACO is a big deal, a real, potentially truly disruptive medical technology with solid evidence in animal studies to back up the claims. It might be used to up-end the entire field of antiviral therapies, and in principle can effectively treat and defeat near all viruses in near all of the species we care about. Needless to say even in our own species there are plenty of serious viral infections for which there is presently no effective treatment. DRACO could fill all of those gaps. The early development of DRACO is a shining example of how searching for commonalities in an otherwise highly complex field can find ways to turn a very expensive process of addressing thousands of targets individually into a process of addressing one target - a solid, cheap, effective, single path forward.

But of course all good ideas have to be forced on the world. No radical improvement or beneficial departure from the status quo goes unopposed. Just as in our community we are faced with the need to persuade people that we can and should use medical technology to address the root causes of aging and thereby live longer in good health, and we scramble to try to find meaningful levels of funding for rejuvenation research, so too DRACO is stuck in the funding gap that often follows great initial results in animal studies. It is a measure of the madness of the world we live in that such promising technologies can languish for years, or simply never be adopted, and that it requires scores of people to advocate and persuade to keep the work moving forward. Fortunately in this day and age ordinary folk like you can I can band together and do something about this: we can support fundraisers and help to persuade those we know of the value of DRACO. The world is full of people who have presently incurable viral infections, and once we include cytomegalovirus in that list, a cause of age-related immune system degeneration, that is pretty much all of us by the time we are old. People should be beating a path to the door of DRACO's inventor, not living an uncomfortable life without even knowing that this technology exists.

So, quite separately and aside from the usual focus here on aging research and furthering human longevity, I am happy to be able to put my money where my mouth is for DRACO and contribute to this latest fundraiser. I did so today. I hope that you will consider doing so too.

IndieGoGo: DRACOs May Be An Effective Cure For Viral Diseases

We are now raising funds to test and optimize DRACOs against the herpesvirus family, which contains many major clinical viruses such as Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), Cytomegalovirus (CMV), Varicella Zoster Virus (VZV, chickenpox and shingles virus), Epstein-Barr Virus (EBV), and Kaposi's Sarcoma Herpesvirus (KSHV). If we can raise enough funding, we also hope to test and optimize DRACOs against the family of retroviruses, which includes Human Immunodeficiency Virus (HIV) and Human T-Lymphotropic Virus (HTLV). In principle, the DRACO approach should be effective against virtually all known viruses, or potentially even against new viruses that may appear.

DRACOs could potentially revolutionize the treatment and prevention of viral infections, just as the development of antibiotics revolutionized the treatment and prevention of bacterial infections in the mid-20th century. With your help, we hope that DRACOs may ultimately end suffering and save lives of those struggling with any number of viruses. By the process of efficiently eliminating only virus-infected cells, DRACOs may be able to permanently cure viral infections that can currently only be controlled but not cured by existing antiviral therapeutics. When tested in human and animal cells, DRACOs have been nontoxic and effective against 18 different viruses, including rhinovirus (the common cold) and dengue hemorrhagic fever. For more information on the results of previous DRACO experiments, see the article published in PLOS ONE.

The drug approval process is unfortunately long and complicated. What we know is that 4 years (or potentially less depending on funding and results) should be enough time to test and collect enough data on clinically relevant herpes viruses that should persuade partners to help advance DRACOs toward human clinical trials. We are committed to testing and optimizing DRACOs against clinically relevant viruses as rapidly and as thoroughly as funding will permit, and we hope to see DRACOs advance to human trials as soon as possible. The greatest challenge has been securing funding to help DRACO research progress. It is also important to note that while DRACO is based on sound scientific principles and has yielded promising experimental results thus far, biological systems are very complex and we can offer no guarantee that DRACO research will end with a pill in a bottle for everyone. Without your help, though, we may never find out. If successful, the results of those experiments should persuade pharmaceutical companies and other major sponsors to commit their own resources to advance DRACOs through large-scale animal trials and hopefully human trials. Without your assistance, DRACOs may never progress further, and their potential to revolutionize the treatment of viral infections may remain unfulfilled.

Lower calorie intake, while still obtaining required levels of micronutrients, has long been demonstrated to improve near all measures of health, leads to better quality of life, and modestly slows aging. A higher calorie intake leads to visceral fat deposition, metabolic syndrome, type 2 diabetes, fatty liver disease, and a shorter, less healthy life. Separately, fasting appears to have similar influences on health and aging to those produced by a lower calorie intake, but to some degree independently of overall calorie level - though it is worth noting that the body of research here is much smaller than that for calorie restriction without fasting. Since just about every aspect of metabolism is altered by calorie intake, both in the short term and over the long term, researchers attempting to understand how it all works at the detail level have an enormous task ahead of them. They are breaking off pieces of the puzzle one protein at a time, as in the research noted here, and will be doing so for a long time yet:

The growing number of overweight people has long been one of modern society's pressing issues. In particular the resulting metabolic diseases such as type 2 diabetes and corresponding secondary conditions can have serious consequences for health. A reduced intake of calories, such as in the framework of an intermittent fasting diet, can help to whip the metabolism back into shape - but why does this happen? Once we understand how fasting influences our metabolism we can attempt to bring about this effect therapeutically."

In the current study, the scientists looked for liver cell genetic activity differences that were caused by fasting. With the help of transcript arrays, they were able to show that especially the gene for the protein GADD45β was often read differently depending on the diet: the greater the hunger, the more frequently the cells produced the molecule, whose name stands for 'Growth Arrest and DNA Damage-inducible'. As the name says, the molecule was previously associated with the repair of damage to the genetic information and the cell cycle, rather than with metabolic biology. Subsequent simulation tests showed that GADD45β is responsible for controlling the absorption of fatty acids in the liver. Mice who lacked the corresponding gene were more likely to develop fatty liver disease. However when the protein was restored, the fat content of the liver normalized and also sugar metabolism improved.

The scientists were able to confirm the result also in humans: a low GADD45β level was accompanied by increased fat accumulation in the liver and an elevated blood sugar level. "The stress on the liver cells caused by fasting consequently appears to stimulate GADD45β production, which then adjusts the metabolism to the low food intake." The researchers now want to use the new findings for therapeutic intervention in the fat and sugar metabolism so that the positive effects of food deprivation might be translated for treatment.

Link: https://www.helmholtz-muenchen.de/en/news/latest-news/press-information-news/article/34525/index.html

The present vocal but minority view in the aging research mainstream is that aging is an evolved program with a strong epigenetic component. In this view, epigenetic changes are keyed to age, occur first, and cause the cell and tissue damage associated with aging. In the majority view of aging as a consequence of damage accumulation, the damage occurs first, and epigenetic changes are then a reaction to this damage, causing secondary and later issues. There is so much work yet to do in mapping out the detailed molecular biology of the progression of aging, and the blank spots on the map so large, that these two entirely opposing viewpoints, each with many variations, can continue to theorize and thrive.

For the damage accumulation view of aging, we fortunately don't need the full map of the molecular details of aging, an explanation of exactly how damage causes each and every age-related disease, in order to make solid progress towards the defeat of aging. All researchers need to do is to repair the root causes of aging, the forms of fundamental damage that distinguish old and young tissues, and these are well known and well cataloged. The fastest way to figure out what they are linked to in terms age-relate decline is to fix them and see what happens - which is also the fastest path to meaningful therapies. So, for example, life extension in mice has been robustly demonstrated in the case of clearing senescent cells, and clearance therapies are on their way to the clinic despite the vast amount of data yet to be gathered on how exactly aging progresses without this contribution.

The programmed aging school does need the molecular map of aging for significant progress, however. In this view, researchers should be working to list and revert epigenetic changes, and that should then either stop further damage or allow damage to be repaired by natural processes. Some such initial reversions, such as increased GDF11 levels, have been shown to produce benefits by restoring stem cell activity in old individuals - but is entirely possible for an epigenetic alteration to produce some level of benefits even if aging is caused by damage, and without addressing underlying damage, by reducing secondary issues or by forcing systems into action where they are normally in decline as a reaction to damage. Perhaps there will be consequences, such as a raised risk of cancer, but so far in the case of stem cells it is all working out better than expected. These results have boosted the confidence of the programmed aging side of the field, but I think they still overstate their case given the varying weights of evidence.

For readers who know me less well, I should introduce my perspective: I believe that aging is an evolved epigenetic program. When we are young and growing, particular genes are turned on and off with exquisite timing to determine the growth and development of bones, muscles, and organs. When we are old, the program continues, more slowly and more diffusely, but inexorably nonetheless. Genes are turned on that destroy us with inflammation and cell senescence and auto-immunity and programmed cell death, while the systems that protect us from pathogens and from free radical damage are gradually shut down. Evolution has left nothing to chance. Epigenetics is a new science in the 21st century. All the cells in one body have the same DNA (pretty much), but different genes are "expressed" (translated into proteins) in different tissues and at different times, and this is what controls the body's metabolism. In fact, only 2% of our DNA is genes, and 98% determines how the DNA is folded and spooled, opened and closed at particular times and places, and this in turn controls gene expression. We are 2% genetic and 98% epigenetic. The part of the epigenetic code on which we have the best handle at present is called "methylation of CpG islands". Long stretches of DNA have CGCGCGCG... on one strand, complemented by GCGCGCGC... on the other. Often the C's in this region get an extra methyl group, turning from cytosine to 5-methylcytosine. Then this stretch becomes a "repressor region," a signal to NOT express the adjacent gene.

DNA methylation can be persistent, turning a gene off for decades at a time. When a cell divides and its DNA is copied, the methylation pattern can be copied with it. This accounts for some of the persistence of epigenetics, and the way gene expression can be inherited across generations. DNA methylation has been appreciated for 30 years, but two recent developments make the subject attractive and accessible to research. (1) There is now a simple lab/computer technique for reading the methylation pattern from DNA. It relies on commercially available, automated machinery for PCR to sequence a full genome before and after chemical modification of the methylated C's. (2) There is now a simple lab/computer technique for changing the methylation state of any chosen target site in the DNA. It is based on CRISPR technology that is taking genetics labs by storm the last two years.

The correlation between aging and epigenetic status is established beyond dispute. But what does it mean? This is the big question. Most researchers think of the body as programmed by evolution to be as strong and healthy as possible. So, when different genes are expressed in old age, they find it natural to assume that the body is protecting itself in response to damage that it has suffered over the years. We express different genes when we are older because we need different genes when we are older. The other possible interpretation is my own, and it has become common among those who are closest to the field of epigenetics. It is that epigenetic changes with age are means of self-destruction. The body is programmed to die, and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes. This idea flies in the face of traditional evolutionary theory. (How could natural selection prefer a genome that destroys itself and cuts off its own reproduction?) Nevertheless, the evidence for this hypothesis is robust. The genes that are turned on don't protect the body - quite the opposite. Genes for inflammation are dialed up. Genes for the body's defense against free radicals are dialed down. Cell turnover is dialed down. DNA repair is dialed down. The mechanisms of programmed cell death (apoptosis) are strengthened in healthy cells, at the same time that they are perversely weakened in cells that are a threat to the body, like infected cells and cancer cells.

In my opinion, the existing evidence heavily favors the hypothesis that aging is caused by epigenetic changes, rather than the other way around. When we look at the kinds of changes that occur, they seem to be pouring fuel on the fire, not putting it out. Protective genes are turned off and inflammatory genes are turned up. I also think that parabiosis experiments provide a strong clue. Three research groups have shown that injecting blood plasma from a young mouse into an old mouse makes the old mouse healthier, and relieves some problems associated with age. The blood plasma contains no cells - only signal molecules that are the product of gene expression. This is powerful evidence that youthful gene expression is supporting a strong and youthful body, and (conversely) that the kind of gene expression that characterizes old age is not doing the body any good. But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating effect.

Link: http://joshmitteldorf.scienceblog.com/2016/05/09/epigenetics-of-aging-and-prospects-for-rejuvenation/

In the long sweep of human history, there has never been an age in which advocacy could have made as big a difference as advocacy for aging research can make today. The scientific community stands at the gates of rejuvenation, of the effective medical control over the causes of aging. The forms of cell and tissue damage that distinguish old tissues from young tissues are cataloged. The consensus position in the research community is that accumulation of this damage causes aging. Rejuvenation therapies capable of repairing, preventing, or working around the damage of aging are not in the clinic yet, but are at various stages of development, from early clinical trials and development in startup companies, all the way back down the chain to research in progress with years of work left to accomplish. The wave is building up, but despite the promise, despite the goal of controlling the medical condition of aging, a condition that kills more than 100,000 people every day, there is very little interest and very little funding for this branch of medical science.

This is why we live in an age in which advocacy has such power. The science of aging and the plans to build effective treatments stand far, far ahead of the public perception, the funding, and the will to treat aging as a medical condition. Aging is natural, people say - but so is cancer, cancer is caused by aging, and you'd be hard pressed to find someone who thinks that cancer research should be halted. The choice to defeat cancer rather than treating it as set in stone, a part of life not subject to change, is the very same choice that our culture has yet to make regarding aging. Until the average person in the street, when asked about preventing aging so as to live longer in good health, has exactly the same response as is presently the case for cancer research, then progress towards the control of aging will remain slow and uncertain. If the aging research community had the same support and funding as stem cell science or cancer research, both energetic fields as a result of that support, then we would be solidly on our way towards an end to frailty, pain, and suffering in old age - an end to all age-related disease.

This has yet to happen, but it is only a matter of persuasion. The research, the scientists, the biotechnology industry are ready to productively use high levels of funding to finalize prototype rejuvenation therapies and take the results into clinics around the world. That funding and the support it requires are all that is missing. Thus advocacy - simple persuasion - can today change the world, change the very nature of the human condition, can save billions of lives, can rescue the frail and the sick, and prevent the healthy from becoming frail and sick. Progress in the medicine of rejuvenation is limited by funding, and fixing that problem requires nothing more than widespread agreement that these goals are worthwhile and desirable. At the large scale and over the long term of decades research priorities follow the will of the masses, the zeitgeist of the age. We need to change ours for the better.

At present a growing faction within our advocacy community believes that engaging with government and international bodies such as the World Health Organization (WHO) is an effective path to this end. The goal is to sway standards and regulatory bodies to declare aging to be a disease, and thus amplify the views of this community through the megaphones of these large agencies:

If Aging Could Be Stopped, Should It Be? The Need for Accelerated Development of Scientific Methods to Extend Lifespan

100,000 people die every day from age-related diseases - i.e. those deadly diseases (cardiovascular disease, cancer, diabetes, Alzheimer's disease), the risk of which increases with age in geometric progression due to a number of already known biological processes, which are collectively called "aging". Aging transforms active citizens from people who are benefiting society into people requiring state resources to maintain their ailing health. State budget losses include payments for the treatment of age-related diseases, social costs of care for the disabled, budget shortfalls due to tax losses from tax on personal income, etc. The bulk of the costs of medical care falls on the last years of life, therefore, prolonging the health years of citizens will allow to use available funds to address other socially important tasks. It is also hard to overestimate the social benefits from additional healthy years of life of older people, which they can devote to useful social activities or to education and care for their grandchildren.

The latest developments in medical and biological sciences have led to a paradigm shift where aging is now known to be a combination of pathogenic and harmful processes, the intensity of which increases with age. Moreover, recent discoveries show that these processes can be slowed down or even reversed. For example, caloric restriction alone increased maximum lifespan in mice by 40%; pharmacological interventions achieved an increase in lifespan by almost a third. Almost every year science is finding new animals (in 2016 - more than twenty), that exhibit a so-called "phenomenon of negligible senescence", meaning that the probability of death and age-related diseases of these animals, unlike humans, does not increase with age, providing them with healthy longevity and a much longer life expectancy than those of species closest to them. Moreover, scientists have already discovered dozens of drugs and other interventions that are able to extend healthy life expectancy and maximum lifespan in different animals, delaying the onset of age-related diseases and deaths associated with them. The need for a significant increase in aging research and intervention capacity against it to prevent age-related diseases and increase healthy life expectancy is also recognized by the international scientific community and even formed the basis for the signing of the Open Letter on Aging Research by 57 of the world's leading scientists.

An understanding of aging as a disease is gradually entering into the global health discourse. Today, deep old age (senility) is recognized as a disease by the WHO. However, recognizing the above late-stage manifestations of aging does not resolve the underlying problem of aging. Aging as a set of reversible disease processes begins at a relatively early age and requires specific approaches to combat (control, treat, compensate) from the early stages of its development. Aging is a global phenomenon, and the fight against it requires special medical and biological approaches, as well as government support. This corresponds to subjective factors (the degree of scientific understanding of aging processes and the methods of control and control), and objective factors - both of medical and biological nature and those related to the economy and the sociology of healthcare.

We should begin an open dialog on whether age-related pathologies should be formally classified as a disease - and not just recognized nationally, but also internationally within the framework of WHO's ICD-11, as such classification is a prerequisite for substantially increasing worldwide government funding dedicated to finding successful treatments for age-related pathologies - treatments that would greatly increase healthy lifespans. We can start by engaging our governments on where science is today in its understanding of what biological mechanisms cause age-related diseases and how we can fix them, and then hold public debates on whether there is enough scientific evidence to begin the process of classifying aging as a disease. The next step could be an establishment of a National Strategy for Life Extension and a dedicated task force responsible for the coordination of scientific and practical efforts aimed at increasing longevity and fighting aging. The world already knows successful precedents where some countries are mobilizing the international scientific community for the development of therapies for a variety of diseases.

It is an absolute certainty that eventually humanity will conquer aging, just as it had conquered a host of previously terminal diseases thanks to vaccines and antibiotics. But if we want the victory over aging to happen before it is too late for our loved ones, the time to act is now.

In its later stages atherosclerosis is a vicious cycle in which oxidized lipids and the remains of dead cells build up into deposits in blood vessel walls, growing because these deposits cause nearby healthy cells to signal for help. That produces an inflammatory response and attracts the immune cells called macrophages that try and fail to clean up the mess, adding their own remains to the disaster area. As a result of this process of ever-widening damage, blood vessels weaken, narrow, and are ultimately blocked, causing incapacity and death.

Inflammation in blood vessel walls is an important driver of atherosclerosis in its early stages as well. Levels of preexisting inflammation contribute to determining the tipping point between successful cleanup of a small deposit of oxidatively damaged lipids and failure of that cleanup, producing a persistent area of damage that will grow over time - the seed of atherosclerosis. An increasing level of chronic inflammation throughout the body is a characteristic feature of aging, caused by a combination of immune system dysfunction and various other factors. Here researchers discuss one of the mechanisms by which chronic inflammation contributes to the development of atherosclerosis:

Atherosclerosis in the aging population has well surpassed other age-associated diseases such as susceptibility to infection, chronic lung disease, and cancer as a cause of morbidity and mortality in older people. The strongest independent risk factor for the development of atherosclerosis is aging. This risk is greater than the additive risk of hypertension, hypercholesterolemia, and genetics accrued over time. Despite the ongoing threat of atherosclerosis in older people, our understanding of the mechanisms by which aging enhances atherosclerosis remains unclear and under investigated especially in relevant experimental disease models.

Aging may affect atherosclerosis through several mechanisms in hematopoietic cells, vascular cells, or both. For example, aging induces cellular senescence, which leads to DNA damage and impaired antioxidant responses resulting in vascular inflammation that contributes to atherosclerosis. In addition, studies in disease-free animals have found that vascular aging induces oxidative stress in endothelial cells, and leads to medial vessel wall thickening, increased collagen, and extracellular matrix deposition. Endothelial cells (ECs) and vascular smooth muscle cells (VSMC) from disease-free animals exhibit enhanced secretion of inflammatory mediators with aging. Hence, these studies indicate that vascular aging may predispose to diseases such as atherosclerosis, yet whether such age-related vascular changes occur during atherosclerosis remains unclear.

Monocytes and their macrophage descendants are critical immune cells for atherosclerosis. Monocyte recruitment into aortas is critical during atherogenesis, whereas macrophage proliferation in the tissue enhances atherosclerotic lesion progression. Monocytes can be categorized into 'inflammatory' monocytes and 'patrolling' monocytes. Inflammatory monocytes are typically the initial cells recruited into inflammatory sites of the aorta that develop atherosclerosis. After recruitment, the cells engulf lipid particles, become 'foam cell' macrophages, and accumulate within atherosclerotic lesions. It is not known, however, whether aging enhances monocyte intrinsic function or whether aging impacts monocytes indirectly via the vasculature during chronic inflammatory diseases such as atherosclerosis.

Here, we examined how aging impacts atherosclerosis using Ldlr-/- mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr-/- mice exhibited enhanced atherogenesis within the aorta. Aging also led to increased LDL levels, elevated blood pressure on a low-fat diet, and insulin resistance after a high-fat diet. On a high-fat diet, aging increased a monocytosis in the peripheral blood and enhanced macrophage accumulation within the aorta. When we conducted bone marrow transplant experiments, we found that stromal factors contributed to age-enhanced atherosclerosis. To delineate these stromal factors, we determined that the vasculature exhibited an age-enhanced inflammatory response consisting of elevated production of CCL-2, osteopontin, and IL-6 during atherogenesis. In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells. Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas. Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12488/

Researchers have made use of human mesenchymal stem cells to effectively delay retinal degeneration in rats. In this study the authors demonstrate that, as in many other cases, the methodology of delivery matters just as much as the details of the cells used:

Retinal and macular degenerative diseases affect millions of people worldwide. Similar to other neurodegenerative diseases, there are no effective treatments that can stop retinal degeneration or restore degenerative retina. Recent advances in stem cell technology led to development of novel cell-based therapies, some are already in phase I/II clinical trials. Studies from our group and others suggest that human bone marrow-derived mesenchymal stem cells (hBM-MSC) may be a promising source for retinal cell-based therapy.

Currently, one of the major challenges in stem cell-based therapy is how to safely deliver effective doses of cells to the target posterior eye tissues (retina, retinal pigment epithelium (RPE) and choroid), due to the unique anatomy and physiology of the eye. The current subretinal injection method involves three port pars plana, vitrectomy and insertion of a needle that penetrates the retina and, in doing so, detaches the photoreceptor cell layer from the RPE forming subretinal 'blebs'. Limited volumes can be injected and therapeutic effect is restricted to areas proximal to point of injection. Moreover, the subretinal surgery raises a significant safety issue, as the retinal architecture across the entire retina in age-related macular degeneration (AMD) and retinitis pigmentosa (RP) patients is fragile and the surgery can induce mechanical damage, reactive gliosis, and loss of function.

We have recently developed a new cell delivery system that enabled the transplantation of hBM-MSCs as a thin layer across the extravascular spaces of the choroid. We used this system in Royal College of Surgeons (RCS) rats, a widely used model of dry AMD and retinal degeneration. The graft covered most of the area of the back of the eye via a single injection with no retinal detachment or choroidal hemorrhages. Cell transplantation delayed photoreceptor degeneration throughout the whole retina and rescued retinal function for up to 5 months in RCS rats. By contrast, when hBM-MSCs were injected intravitreally, they formed a large cell clamp in the vitreous cavity and retinal function was rescued for a shorter duration, up to 12 weeks following transplantation. These findings suggested that the delivery method significantly affects therapeutic potential of transplanted cells, and that graft location, distance from the retina and graft surface area may be critical parameters for achieving effective treatment.

Link: http://dx.doi.org/10.1016/j.scr.2015.08.007

The small, forty-year-old cryonics industry offers indefinite low-temperature storage of at least your brain following death. In a well-organized cryopreservation, the medical team is right there when you die, and cooldown and infusion with cryoprotectant solution can begin immediately. The result is vitrification of tissue, especially brain tissue, to preserve the fine structure that stores the data of the mind. Then you wait, suspended, in liquid nitrogen in a dewar vessel, heading for an uncertain future in which the possibility of restoration exists. That possibility is what you are paying for, and it is the single most important difference between cryopreservation and all the other choices you have at the end of life. Those other choices offer only the certainty of oblivion, but for so long as the data of the mind exists, so long as there is continuity of preservation, then sufficiently advanced molecular nanotechnology and biotechnology will one day be capable of restoring you to life. In a world in which a small but growing number of people are striving to build rejuvenation therapies to defeat aging, and the timeline for that defeat is very uncertain, cryonics is the only available backup plan.

Personally, I don't see much uncertainty in the golden future of transcendent technology that lies ahead. It will happen. The uncertainties all lie in the timing of that technological progress, how long continuity of preservation and preservation organizations can be sustained, and most of all in arranging the slings, arrows, and final moments such that the medical team is in fact right there and waiting when you die. That last one is the hardest part, and will remain so until the laws on euthanasia become more civilized in more parts of the world. If we could be allowed to choose our time, then all cryopreservations could be well-run, minimizing tissue damage and cell loss, and be largely free from large and unexpected costs. Sadly that's all too rarely the case. Even people in very late life are surprised by their own final decline, and all too few make the serious effort to ensure that the unexpected is caught, or at least that it is going to happen in a location at which the cryopreservation organization can muster a very quick response. That it is illegal for people to help you in this situation through euthanasia is just the final indignity, a reminder that civilized and compassionate behavior on the part of those in positions of power remains a still-thin veneer.

What I wanted to talk about here is related to all of this, but not really discussed all that much in the cryonics community. I think it might be one of those things that is so taken as read in the core community of supporters that people don't put much thought into it. Cryonics organizations are non-profits with a membership structure: you pay a monthly or annual fee, and have a variety of options when it comes to ensuring funding for your ultimate cryopreservation, an event hopefully still decades away at the very least. Cryopreservation is in effect a form of surgery, plus other items, involving a group of medical and technical folk with specialized tools carrying out a procedure, and so the costs are similar to those of a surgical procedure - which works out to anywhere from $30,000 to $200,000 depending on the organization and the details of the arrangement. Most people opt to pay using life insurance, since a contract for even $200,000 is pretty cheap on a monthly basis if you are healthy and young, and a life insurance policy can be set up so that the mechanisms of payment will go into effect robustly on your death with no need for micromanagement at a time when you are unlikely to be capable of that effort.

However, this isn't a case of a transfer of funds today, where you see you need to pay $200,000, so you set up a policy for $200,000 and you are done. No. The cost of the cryopreservation agreement today is that $200,000, but that amount will rise with inflation. Thus you take out a life insurance policy that also grows with time. There are many varieties of growth policies, all using different models to try to keep up with inflation while still making a profit for the insurance company. Sometimes they will work, sometimes not, but the people involved in setting up these instruments are all pretty motivated by competition to try to adjust to keep up. Still, we are talking about trying to match the future inflated amounts of two very different things half a lifetime or more from now. If you look at the rule of 72, you'll see that even for plausible levels of inflation on the part of a government that more or less achieves the level of debasement of currency that it aims at, costs will double several times between youth and old age: it is not implausible to expect the $200,000 cryopreservation you signed up for to cost $800,000 four decades from now. If the US meanders into another period like the 1970s, the situation could be much worse than that. If rejuvenation biotechnology goes the way I hope it does, then the horizon and the financial uncertainty expands further. Not that you can't adjust along the way, but that is always going to be more expensive than just being right at the start. Given this, the smart thing to do is to make the life insurance policy larger than it has to be at the outset, especially since that choice costs little. Overfunding the policy shifts the odds greatly in your favor when it comes to the life insurance payout being larger than the cost of cryopreservation on the day that bill is due.

This matter of uncertainty in inflation and financial instruments is not the only reason to have a larger life insurance policy than the minimum needed. Consider that there are any number of things that can go wrong at the end of life, greatly increasing the costs incurred by the cryonics organization. Yes, once you and the cryonics technicians are in the same room, everything is practiced and under control, but before that point there are many ways to run off the rails. You could be in an inconvenient location, local government officials or family members could interfere and require legal efforts to deal with, flights might have to be chartered at short notice, and so on and so forth. Any one of these could easily balloon into a few tens of thousands of dollars today. If you look back through the history of cryopreservations in which the details have been made public, such as those published by Alcor, there are many cautionary tales, and more than a few cases in which everyone involved did the right thing and costly problems still occurred. If the hurdles put in place by chance or opponents are too costly for the cryonics organization to overcome, given the funding you have put in place, or that others can supplement at the time, then you won't be preserved. Cryonics providers will make absolutely the best effort possible, and again, if you look at the history there are many cases in which companies and volunteers have gone above and beyond to make a cryopreservation happen, but they won't damage or risk the sustainability of the entire organization for one person. Lines have to be drawn.

So, again, assume the worst, and when sorting out life insurance apply for more than the minimum needed to fund your cryopreservation. Twice the minimum is not unreasonable: nothing in life is certain, and it is better to be safe than sorry when being safe costs little. It is all about swinging the odds more in your favor. If the extra funds turn out not to be needed, then they can be directed to a charity, or to sustaining the cryonics organization, or its research efforts, or another worthy goal. Some people even set up forms of perpetual trust, another experiment with an uncertain chance of success, but which may lead to there being some personal funds to continue with in the case of restoration. Certainly from an immediate and practical point of view, all of the cryonics organizations advise in their materials that you overfund your policy, but they tend to say as much and move on. There's less in the way of accessible discussion out there that goes through the reasons as to why this is the case. Hopefully this small contribution helps.

This very readable paper discusses the possible role for ceramides in the processes of aging relevant to declining fitness and muscle function. This is all some steps removed from the fundamental cell and tissue damage that causes aging, however, and is really a discussion of the details of a small snapshot of later, complicated reactions to that damage. That said, it is very representative of most present research into aging by groups that lean towards producing possible therapies. Interventions are planned for later consequences in aging, without addressing the root causes of observed disruptions and alterations.

Aging is associated with a progressive loss of cardiorespiratory fitness, which in turn leads to an increased risk of morbidity and mortality. Cardiorespiratory fitness is defined as maximal oxygen consumption (VO2 peak) during dynamic exercise and is typically measured during a graded exercise test. Using this operational definition, the decline in fitness starts around the age of thirty and continues at approximately 10% per decade. It accelerates even further toward the end of the lifespan, even in healthy persons. Cardiorespiratory fitness is a critical determinant of physical function in older adults and an accurate indicator of cardiovascular and overall health. Thus, maintaining a good level of fitness is fundamental to delaying mobility difficulty and attaining healthy longevity.

Maximal oxygen consumption is largely explained by cardiovascular adaptations in transporting oxygen to muscle as well as mitochondrial adaptations within muscle, to meet the energy demands of physical activity. Recent evidence suggests that the capacity for vasodilatation in the peripheral vasculature also plays an important role in maximal oxygen uptake. The decline in VO2 peak with aging has been primarily attributed to the reductions in muscle oxygen delivery, due to decreased cardiac output, and to the reductions in skeletal muscle oxidative capacity, mainly due to the mitochondrial dysfunction. However, there is a wide interindividual variability in the rate of decline, which is only partially explained by differences in physical activity. Thus, studies of biological correlates of physical fitness are important because they may provide insight as to why some individuals experience an accelerated decline of aerobic capacity. Further, such correlations may serve as clinically valuable prognostic indicators of cardiovascular health, morbidity, and mortality risk.

Ceramides are a ubiquitous group of lipids that consist of a sphingosine linked to a fatty acid. Ceramides are known for their structural role in plasma membranes and also as important signaling molecules involved in many essential cellular processes including inflammation, immune cell trafficking, vascular and epithelial integrity, apoptosis, autophagy, and stress responses. In the circulation, ceramides are transported primarily in low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). Previous studies suggested that ceramides increase with age and are associated with accelerated aging and age-related chronic conditions, particularly cardiovascular and metabolic diseases. Treatments targeting ceramides may be potentially very effective for preventing or treating these conditions. For example, elevated plasma ceramides cause vascular endothelial dysfunction by promoting endothelial cell growth arrest, oxidative stress, senescence and death, disrupting insulin signaling and increasing inflammation. Perhaps through these same mechanisms, ceramides may contribute to the early stages of atherosclerosis.

Given the evidence linking ceramide to mechanisms fundamental to cardiovascular health in cell culture and animal studies, we examined the relationships between ceramides and indicators of cardiovascular health in older adults. We applied multiple regression models to test the associations between ceramide species and VO2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity. The associations held true for both sexes (with men having a stronger association than women) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long-chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12491/

This open access paper describes data on epigenetic and protein abundance changes with age in the liver and brain in rats. It is a good introduction to just how much data is yet to be cataloged in detail when looking at all tissue and cell types and how their operations change with aging. The sheer complexity of our biochemistry is why shortcuts that enable us to evade waiting on more data are essential to rapid progress towards rejuvenation treatments. At present, for example, the forms of damage that distinguish old tissue from young tissue are well enumerated and well understood. So the research community can work towards repair therapies without needing to fill in any of the blanks regarding exactly how this damage produces the very complex set of alterations and wide range of age-related diseases seen in old tissues.

Here, we present an integrated comparison of gene expression, translation, protein abundance, and phosphorylation in organs from young and old rats. Our work expands the list of proteins that are affected by chronological age in mammals. Although some of the functional modules discussed above were previously identified as hallmarks of aging, we identified hundreds of molecular events underlying these processes that were previously unknown to be affected by age. We thus provide a rich resource that should stimulate the generation of new, experimentally testable hypotheses, leading to a better understanding of aging on the organism level.

The comparison of two organs with different physiology and regenerative capacity enabled us to distinguish organ-specific effects from more systemic effects of aging. Intuitively, our results suggest that organ-specific effects of age are tightly linked to the organ function. For example, in brain, multiple alterations of key signaling mediators are observed. We speculate that these alterations might be part of a progressive functional deterioration that affect the maintenance of neuronal plasticity in old brains and other phenotypes observed the aging brain. Notably, 45 of the changes that we identified in old rat brains are consistent with a previous transcriptomics study of aging human brains, suggesting that age-related changes in the proteome and transcriptome are to some extent conserved from rat to humans.

The systemic impact of chronological age on proteome homeostasis manifests on many levels. In the liver, the majority of age-dependent changes are driven by alteration of transcript abundance (58% of the affected transcripts versus only 25% in brain), suggesting the occurrence of age-related changes in transcriptional regulation. In contrast, the brain appeared to be affected by age largely at the translational level. Our data suggest that an age-associated remodeling of the translation machinery in the brain may ultimately lead to alterations of the translation efficiency of a subset of transcripts in old animals. Specifically, we identified 15% of the brain transcripts to be affected by a change in translation (versus only 2% in liver).

Despite the correlation between translation output and protein abundances, not all the observed changes of protein abundance could be explained by changes in translation output, particularly in brain. This phenomenon strongly indicates a higher degree of post-translational control in the brain as compared to the liver. Indeed, our proteomic analysis revealed that key regulators of protein homeostasis were altered in aged brain, including several components of the ubiquitin-proteasome and autophagy systems. These findings imply that altered protein homeostasis, which has been shown to affect organism longevity under stress-response conditions, also leads to detectable proteomic alterations that occur between young and old animals. The exact consequences and targets of such alterations are likely complex and remain to be explored in detail.

Link: http://dx.doi.org/10.1016/j.cels.2015.08.012

There is a portion of the life science community interested in the longevity of plants, though it is fairly disconnected from research into medicine and aging for the animal half of the planet. We can debate whether or not there is anything useful for medical research to be learned from comparing plant species and gaining a better understanding as to why some are much longer-lived than others. After all, researchers already reach for very difference species when beginning investigations of cellular biology relevant to medicine. In the animal-focused aging research familiar to this audience, a great deal of experimentation and exploration is carried out in studies of yeast, a fungus rather than an animal, and yet possessing so many similarities to mammals in its cellular processes that the data can be very useful. Yeast is a long evolutionary distance from humanity, but it is arguably a bigger leap from yeast to plants than it is from humans to yeast. Plants have chloroplasts, and that's just the start of a long list of differences. Early stage research into cellular biochemistry is always a trade-off: much more can be done for a given amount of funding in yeast, flies, and worms, but many of those results will fail to also prove relevant in mice, let alone in humans. So far the collective wisdom of the life science research community has declared that yeast passes the cost-benefit equation, while anything with a chloroplast does not.

There are of course, always heretics willing to argue the point, but that is the way science progresses. In the research noted here, a stem cell angle is pursued, and this is one of the areas where I could perhaps be persuaded there might be something useful to be learned from plant life science. If investigations of hydra and their continuous regeneration - and how that relates to mammalian stem cell biology - are worthwhile, then so might be research into the continuous regeneration of some plant species. Still, this is about as close to fundamental research as one can get, which means it is a part of the long-term gathering of information, with no presently plausible application to medical science, and we can only speculate as to where any part of it might prove useful in the decades ahead.

Mechanism Behind Extreme Longevity in Some Plants

Compared to humans' century-long life span, some plants - evergreens in particular - have the capacity to live for an exceptionally long time, even millennia. Researchers zeroed in the formation of axillary meristems - stem cells that give rise to branches - in Arabidopsis thaliana and tomato, finding few cell divisions between the apical meristem located at the very top of a plant and the axillary meristems. With such little proliferation comes less opportunity to accumulate potentially deleterious genetic mutations in somatic cells that could kill the organism, the authors reasoned. "Meristem aging is not a problem for perennial plants, in other words. The meristems are the growing units. If they don't senesce, then the plant will keep the capacity to grow and reproduce forever, at least potentially." Instead, structural defects or pathogens most often kill plants.

In tomato, "it turns out all the cells around are making lots of cell divisions to make leaves and stems, but few cells are destined to become the axillary meristem. Those really don't divide." If the same is true in other species, the results suggest that most plants have something akin to the germline in animals. "That is, plants seem to set aside some cells in such a way as to minimise the number of mutations they accumulate."

One project underway in Switzerland could lend empirical data to test the group's hypothesis. The Napoleome project is an effort to sequence the full genome of a 238-year-old oak tree. The team has actually sequenced two genomes, taken from different parts of the tree, to see how many mutations are present and whether these distant sites share any mutations. "This meristem hypothesis is what we're testing basically with our project. No one has an idea of how many somatic mutations are in an old tree that has lived outside for more than 200 years." Whether this mechanism to limit somatic mutations was selected for evolutionarily to increase longevity or protect the germline "remains an open question, and one that would be very tricky to answer."

Patterns of Stem Cell Divisions Contribute to Plant Longevity

The lifespan of plants ranges from a few weeks in annuals to thousands of years in trees. It is hard to explain such extreme longevity considering that DNA replication errors inevitably cause mutations. Without purging through meiotic recombination, the accumulation of somatic mutations will eventually result in mutational meltdown, a phenomenon known as Muller's ratchet. Nevertheless, the lifespan of trees is limited more often by incidental disease or structural damage than by genetic aging. The key determinants of tree architecture are the axillary meristems, which form in the axils of leaves and grow out to form branches. The number of branches is low in annual plants, but in perennial plants iterative branching can result in thousands of terminal branches.

Here, we use stem cell ablation and quantitative cell-lineage analysis to show that axillary meristems are set aside early, analogous to the metazoan germline. While neighboring cells divide vigorously, axillary meristem precursors maintain a quiescent state, with only 7-9 cell divisions occurring between the apical and axillary meristem. During iterative branching, the number of branches increases exponentially, while the number of cell divisions increases linearly. Moreover, computational modeling shows that stem cell arrangement and positioning of axillary meristems distribute somatic mutations around the main shoot, preventing their fixation and maximizing genetic heterogeneity. These features slow down Muller's ratchet and thereby extend lifespan.

Research from the past few years has demonstrated that far better correlations between weight and mortality can be obtained by considering the history of individual weight rather than just taking snapshots of populations at a moment in time. In particular, some studies produced results suggesting that being overweight has a lower mortality rate in older age, but this happened as a result of failing to consider weight changes in the studied populations; following work has fairly comprehensively torn down those results. Consider that, for example, a fair number of thinner old people were overweight when younger but suffer from chronic medical conditions that produce both weight loss and much higher mortality. They distort the data, being completely different from people who were always thinner and are as a result healthier in old age. This is why you can't put all people who are thin at a given moment in time into one statistical bucket and expect sensible data on the other side of the calculations: garbage in, garbage out. The publicity materials linked here cover studies that provide more data along these same lines:

People who are lean for life have the lowest mortality, while those with a heavy body shape from childhood up to middle age have the highest mortality, reveal findings of a large study. Researchers tracked the evolution of body shape and associated mortality among two large cohort studies. In total, 80,266 women and 36,622 men enrolled in the Nurses' Health Study and Health Professionals Follow-up Study, recalled their body shape at ages 5, 10, 20, 30, and 40 years. They also provided body mass index at age 50, and were followed from age 60 over a median of 15-16 years for death. They answered detailed questionnaires on lifestyle and medical information every two years, and on diet every four years.

Among the cohort, five distinct body shapes were identified from age 5 to 50: lean-stable, lean-moderate increase, lean-marked increase, medium-stable/increase, and heavy-stable/increase. Results showed that people who remained stably lean throughout life had the lowest mortality, with a 15-year risk of death being 11.8% in women, and 20.3% in men. Those who reported being heavy as children and who remained heavy or gained further weight, especially during middle age, had the highest mortality, with a 15-year risk of death being 19.7% in women and 24.1% in men. The authors conclude: "our findings provide further scientific rationale for recommendations of weight management, especially avoidance of weight gain in middle life, for long-term health benefit."

In a second study, an international team of researchers confirm that increasing levels of body mass index (BMI) are associated with higher risks of premature death. The BMI is an established way of measuring body fat from the weight and height of a person, but the optimal BMI associated with the lowest mortality risk is not known. It's expected that a higher BMI is associated with a reduced life expectancy, but the largest previous study showed that when compared with normal weight, overweight was associated with reduced mortality, and only high levels obesity were associated with increased mortality.

So researchers in the current study sought to clarify this association by carrying out a large meta-analysis of 230 prospective studies with more than 3.74 million deaths among more than 30.3 million participants. They analysed people who never smoked to rule out the effects of smoking, and the lowest mortality was observed in the BMI range 23-24 among this group. Lowest mortality was found in the BMI range 22-23 among healthy never smokers, excluding people with prevalent diseases. And among people who never smoked, and studied over a longer duration of follow up of more than 20 and 25 years, where the influence of prediagnostic weight loss would be less, the lowest mortality was observed in the BMI range 20-22.

Link: http://www.eurekalert.org/pub_releases/2016-05/b-hbs050416.php

For more than a decade there has been some interest in the research community in developing treatments based on enhancing the cellular maintenance processes of autophagy. Higher levels of autophagy feature in many of the established animal lineages with modestly extended healthy longevity, created through genetic manipulation. Despite this interest, and a growing number of drug candidates, there has been little progress in moving towards trials or clinical translation, however. This paper describes another new drug candidate:

Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies.

Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer's disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.

Link: http://dx.doi.org/10.1080/15548627.2015.1082023

In the open access paper linked below, researchers demonstrate modest life extension in the short-lived killifish and zebrafish species by inhibiting a specific portion of the protein machinery inside mitochondria, the power plants of the cell responsible for - among many other things - producing a supply of the chemical energy store molecule adenosine triphosphate (ATP). Mitochondria swarm in animal cells by the hundred. They are the evolved remnants of symbiotic bacteria, contain their own mitochondrial DNA, separate from the chromosomal DNA in the cell nucleus, and still replicate like bacteria even though they are tightly integrated into the cellular processes of monitoring and damage control. The cell culls the herd on a continual basis, destroying mitochondria that show signs of damage.

Mitochondria are known to be important in aging, but there are a number of different mechanisms involved. For one, there is a robust association between the details of mitochondrial biochemistry and longevity across species. Species with more resilient mitochondria, made up of a mix of lipids that is on average more resistant to oxidative damage, tend to be longer lived. Secondly, if mitochondria become dysfunctional or limited in number due to any sort of damage or change in environment - such as the sweeping changes of aging - then tissues with high energy requirements begin to suffer. The brain is particularly vulnerable from this perspective, and loss of mitochondrial function over time is associated with the progression of neurodegenerative conditions. Thirdly, mitochondrial signaling is involved in all sorts of processes known to be associated with aging and longevity, such as programmed cell death and triggering of cellular recycling and maintenance mechanisms. Many of the long-lived mutant lineages created over the past two decades in the lab are characterized by altered mitochondrial function and greater cellular repair activity. Lastly, and probably most importantly, rare forms of mitochondrial damage, such as large deletions in mitochondrial DNA, can evade quality control mechanisms, causing cells to be taken over by mutant mitochondria and fall into a harmful state. These cells grow in number with age, and export large quantities of reactive molecules out into tissues, contributing to many forms of age-related damage. For example, this increases the presence of the oxidized lipids that are the seed for the development of atherosclerosis in blood vessel walls.

The SENS rejuvenation research approach to mitochondrial damage is genetic engineering to create a backup copy of mitochondrial DNA in the cell nucleus. Thus there is always a supply of the necessary proteins, and mitochondria can't fall into a state in which they are malfunctioning due to DNA damage. Nuclear DNA is much more robustly protected and repaired than mitochondrial DNA. The challenge lies in the changes and additions needed to route the generated proteins from the nucleus back to the mitochondria. So far this has been achieved for only a few of the necessary genes, and it is a time-consuming process. Gensight is trialing this technology for a gene involved in an inherited mitochondrial disorder, for example, but everything they come up with as a technology platform is applicable to the end goal of carrying out this backup gene therapy for all mitochondrial genes, so as to remove this contribution to aging.

Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan

Here, we have used the short-lived killifish N. furzeri to perform a longitudinal study of gene expression during adult life. N. furzeri is the shortest-lived vertebrate that can be cultured in captivity and replicates many of the typical hallmarks of aging. The recent sequencing of its genome, and the establishment of genome-editing techniques makes it a convenient model species for experimental investigations on aging in vertebrates. Here, we report the observation that individual N. furzeri of different lifespans differ in their transcript levels at an early adult age. Further, we observed that genome-wide the rate of age-dependent gene modulation was lowest in the longest-lived individuals, suggesting that they are characterized globally by a slower aging rate.

Intuitively, differences in gene expression between individuals that differ in their aging rate should become larger as age progresses. However, we do not observe this consistently as differences between the longevity groups were larger at 10 weeks than at 20 weeks, and numbers of differentially expressed genes between adjacent age steps showed a U-shape. Our observations in N. furzeri are rather consistent with the results of a large-scale study of human aging in the prefrontal cortex: rates of age-dependent changes in gene expression are high during childhood, decline until age 20 years, rise again after 40 years, and, by the age of 60, exceed those observed during teenage years. The main result of this paper is that conditions favoring longevity are laid out during early adult life when inter-individual differences in gene expression are larger, and this result is consistent with observations in C. elegans where knock down of complex I genes or mitochondrial ribosomal proteins during development is necessary and sufficient for life extension.

Reduced mitochondrial mass and function is among the most conserved hallmarks of aging and is specifically observed also in N. furzeri at the levels of gene expression, mitochondrial mass, and mitochondrial functional parameters. Mitochondrial biogenesis is intimately connected to conserved longevity pathways such as the mTOR- and IGF1-pathways. Improved mitochondrial function is currently considered as a crucial component for the health-promoting action of physical exercise and calorie restriction. However, knock down of complex I genes expression induces life-extension in worms and flies. This contradiction between physiological age-dependent regulation and effects observed after genetic manipulations is also observed for another major longevity pathway: the IGF-I pathway. Genetic dampening of IGF-I signaling is life-extending in several models, yet growth hormone and IGF-I concentrations in blood decline during aging. Also, expression of mitochondrial ribosomal proteins declines during aging, but knock down of these proteins induces life-extension.

Complex I of the respiratory chain can be potently inhibited by small molecules, such as rotenone (ROT). The effects of ROT may also be explained by the mitohormesis hypothesis postulating that life-extending interventions act via a transient burst of free radical oxygen species that induce adaptive stress responses. In C. elegans, life-extending effects of calorie restriction or RNAi of the insulin signaling pathway are blocked by antioxidants, and partial inhibition of complex I by ROT prolongs lifespan, generates a burst of ROS, and antioxidants block the life-extending effects of ROT. Increasing the dosage of ROT, however, is life-shortening in N. furzeri, as it is expected by a hormetic effect. Life-extending effects of metformin on mice may also be mediated by mitohormesis, since this drug can inhibit complex I, and effects of metformin in C. elegans were directly linked to mitohormesis via induction of peroxiredoxin.

We observed that treatment with a dose of ROT three orders of magnitude below the median lethal concentration can revert the transcriptional profile of brain, liver, and skin to patterns characteristic of younger animals. This effect was seen not only in N. furzeri, but was replicated in the zebrafish D. rerio, showing that ROT effects are not linked to the peculiar physiology of this short-lived species. In D. rerio, effects of ROT were dependent of the length of treatment: treatment for 3 weeks had a smaller effect than a treatment of 8 weeks. The median lifespan of D. rerio is in the order of 3 years, therefore 8 weeks represent ∼5% of median lifespan indicating that a relatively short treatment can cause rejuvenation of the transcriptome. In summary, our data suggest complex I as a new potential target for prevention of age-related dysfunctions.

The various heat shock proteins play a role in the hormetic response to damage. When damaged, cells dial up their repair activities for a while, and if the damage is mild and brief, the result is a net gain in quality control. Less damage means less dysfunction, and this is why increased cellular maintenance activities are involved in many of the methods demonstrated to modestly slow aging in animal studies. It is possible to dial up maintenance without using damage as a trigger, through suitable changes to levels of proteins, such as genetic engineering to increase the production of heat shock proteins:

Intrinsic cardiac aging is defined as slowly progressive functional declines and structural changes with age, in the absence of major cardiovascular risks such as hypertension, diabetes, hypercholesterolemia, and smoking. However, intrinsic cardiac aging can increase the vulnerability of the heart to both endogenous and exogenous stressors, ultimately increasing cardiovascular mortality and morbidity in elderly individuals. Therefore, interventions to combat cardiac aging not only will improve the healthspan of the elderly, but also can extend their lifespan by delaying cardiovascular disease-related deaths. Studies indicate that the pathogenesis of cardiac aging involves multiple molecular mechanisms, including oxidative stress, impaired autophagy, metabolic changes, dysregulated calcium homeostasis, and activation of neurohormonal signaling. Indeed, the reactive oxygen species (ROS) content significantly increases in the aged heart, while mitochondrial overexpression of catalase (an important antioxidative enzyme) improves the aging-induced decline in cardiac function and prolongs the lifespan of mice. Intracellular ROS in the aged heart are mainly generated from damaged mitochondria. In normal conditions, damaged mitochondria are selectively degraded through autophagy, a process known as mitophagy. Unfortunately, autophagy is progressively impaired over time.

Heat shock protein 27 (HSP27) is an ubiquitously expressed member of the small heat shock protein subfamily. Studies demonstrated the involvement of HSP27 in various biological functions, including the responses to oxidative stress, heat shock, and hypoxic/ischemia injury. Of particular interest to this study, we and others showed that overexpression of HSP27 protects cardiac function against cardiac injuries induced by ischemia/reperfusion, myocardial infarction, inflammation, and doxorubicin. The mechanisms that contribute to cardioprotection by HSP27 involve the antioxidative capacity, suppression of inflammatory responses, improvement of cardiomyocyte survival, and activation of autophagy and mitochondrial activity. It is possible, therefore, that overexpression of HSP27 protects the heart from aging-induced injury.

In this study, we examined the effects of HSP27 on cardiac aging using transgenic (Tg) mice with cardiac-specific expression of HSP27. We observed an improvement in cardiac function and decreases in the levels of cardiac aging markers in old Tg mice compared with age-matched wild-type (WT) controls. This action of HSP27 involves the antioxidative capacity and activation of mitochondrial autophagy (mitophagy). Our results suggest that management of HSP27 expression may serve as an alternative intervention to alleviate cardiac aging.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821973/

Here researchers investigate how immune cells in the brain work to fix tiny breakages of blood vessels. The link between vascular aging and neurodegeneration is most likely largely driven by breakage of blood vessels in the brain. Increased stiffening of vessels and increased blood pressure causes an ever greater frequency of microbleeds, each a tiny unnoticed stroke in essence, destroying a small piece of brain tissue. Over time that destruction adds up. The ideal treatment is to periodically repair the damage that causes stiffness and other deterioration in blood vessels, such as cross-linking, calcification, and mechanisms of atherosclerosis involving oxidized lipids and macrophage behavior, thus preventing breakages. Enhancing repair of the blood vessels after the fact of breakage is probably also useful, though the damage to neural tissue may be done by that point.

As we age, tiny blood vessels in the brain stiffen and sometimes rupture, causing "microbleeds." This damage has been associated with neurodegenerative diseases and cognitive decline, but whether the brain can naturally repair itself beyond growing new blood-vessel tissue has been unknown. A zebrafish study now describes for the first time how white blood cells called macrophages can grab the broken ends of a blood vessel and stick them back together. "We believe that this macrophage behavior is the major cellular mechanism to repair ruptures of blood vessels and avoid microbleeding in the brain."

To simulate a human brain microbleed, researchers shot lasers into the brains of live zebrafish to rupture small blood vessels, creating a clean split in the tissue with two broken ends. Then, the researchers used a specialized microscope to watch what happened next. The repair process started about a half hour after the laser injury. A macrophage showed up at the damaged blood vessel site and extended two "arms" from its body toward the ends of the broken blood vessel, producing a variety of adhesion molecules to attach itself. Then, it pulled the two broken ends together to mediate their repair. The researchers suspect that adhesion molecules produced by the blood-vessel tissue also play a role in reattachment. Once they were adhered, the macrophage left the scene. The whole process took about three hours. "After we confirmed that the macrophage mediates this repair through direct physical adhesion and generation of mechanical traction forces, we were excited. This is a previously unexpected role of macrophages."

A similar repair process also occurred outside the brain. When the researchers ruptured a blood vessel in the zebrafish fin using a laser, a macrophage arrived at the injury site and extended its protrusions to pull the broken blood vessel back together. The researchers did observe a few quirks in the process. When they used a laser strike to destroy the first macrophage that arrived at a laser-wound site in the brain, no other macrophages came to help repair the breakage (but another macrophage arrived to eat the dead one). Rarely, two macrophages would arrive at the injury on their own, each grab a broken end of the blood vessel, and then simply disengage without fixing the damage. Macrophages aren't the brain's only repair mechanism for small broken blood vessels, though they look to be the fastest and most efficient.

Link: http://www.eurekalert.org/pub_releases/2016-05/cp-wic042716.php

Below find linked an open access paper that looks at what has to be done to reach the goal of engineered patient-matched organs, built as needed for transplantation, and the resulting end to shortages and waiting lists. It is interesting for putting some figures on the table for time and cost for the various lines of development required. From my perspective, over the longer term of the next twenty to fifty years, the interesting race in tissue engineering and regenerative medicine is between as-needed production of patient-matched tissues and organs for transplant on the one hand and in-situ restoration of all damage in existing tissues and organs on the other. If organs can be comprehensively repaired in place through regenerative medicine, a process that would have to incorporate the SENS portfolio of damage repair therapies for the old, and thus be much more than just an evolution of the stem cell approaches in their infancy today, then there would be little need for transplantation. At present the production of tissues for transplant is much more advanced, however, on the verge of producing useful, functioning sections of internal organs for medicine rather than research.

Thus, over the next couple of decades the immediate race is between the varied established approaches to engineering organs to order, between the range of possible ways to improve transplantation procedures, and between the research groups specializing in different organs or methodologies. These methodologies include decellularization of existing donor organs, xenotransplantation of transgenic pig organs, the bioprinting of tissue scaffolds and cells, and force-growing tissues from stem cells, with the latter still having a long way to go yet. Researchers have demonstrated tiny sections of functional tissue for the kidney, liver, intestines, thymus, and various other organs, but at present these are intended to speed up research. They are only a stepping stone. Scaling up beyond a sliver of tissue is a real challenge, as it involves building complex vascular networks to supply the cells, something that has been a roadblock for more than a decade now, and this despite a great deal of funding, ingenuity, and effort. This is why decellularization and xenotransplantation (or both together) have gathered support and funding: they represent a shorter path to expanding the supply of viable organs.

There are other challenges to the near future of organ engineering beyond those involved in building blood vessel networks of tiny capillaries. All will require time and effort to overcome, and while the scientific community devoted to this work has better funding and support than those involved in aging or rejuvenation research, there is never enough funding or support as would be justified given the end results. No society in history has devoted as much to research as would make sense from a purely logical point of view, sad to say. It is human nature to be consumed by what is, and not with what might be. Progress is an afterthought, which is why even in fields with a sizable output of papers and trials, it is still the case that we need the advocacy of groups like the Methuselah Foundation and the New Organ prize series. Research prizes and contests such as the NASA Vascular Tissue Challenge spur progress, and faster progress towards engineered organs is a good thing indeed.

Bioengineering Priorities on a Path to Ending Organ Shortage

There are four main pathways that we will consider at a high level on a path to end organ shortage through bioengineering: (1) bioprinting organs and tissues, (2) recellularization strategies, (3) cellular repair or regeneration, and (4) xenotransplantation.

Bioprinting

3D printing, or layer-by-layer building of organs and tissues, is a process in which cells and intercellular materials are laid out (also referred to as 3D bioprinting, biofabrication, or additive manufacturing) to create a functioning tissue or organ. This living construct would then be implanted into the patient to replace lost organ functionality.

Recellularization Strategies

Through the use of existing tissue scaffolds from other organs or biologic material, new functionality can be provided to patients. These scaffolds must first be cleared of all endogenous cells, and then repopulated with new cells to form a functional bioengineered organ, at which time the newly formed organ would be implanted into the patient. Cells can also be seeded onto/within biodegradable scaffolds that slowly breakdown after implant, leaving only the desired cells and the extracellular matrix they have deposited. One example of promising work in this area is tissue-engineered autologous urethras for patients.

Cellular Repair or Regeneration

In vivo repair/regeneration of damaged organs can be accomplished by delivering small molecules, growth factors, or genetically modified cells into existing organs in a patient. It is expected that the new cells integrating into existing tissues may increase tissue functionality through a paracrine effect, as well as by directly supplementing functional cells. Additionally, growth factors or genome-editing techniques could boost organ functionality or stimulate regeneration. Genome-editing techniques, such as the clustered, regularly interspaced, short palindromic repeat (CRISPR) technology, are showing promise in this area. It is expected that advances in CRISPR and other genetic modification systems could repair tissues that harbor genetic damage as a result of cancer, disease, or trauma, and thereby remove the need for replacement tissues in some patients.

Xenotransplantation

The use of genome-editing of animals to alter immune recognition and prevent organ rejection is another promising area that could help reduce the increasing shortage of donor organs. In principle, suitably modified animal organs could then be transplanted into human patients (xenotransplantation). Much uncertainty remains regarding the appropriate functional and genetic modifications and the necessary safety precautions that would be required for successful xenotransplantation, but some encouraging progress is being made.

Technical Feasibility and Cost to Arrive at Successful Solutions to Bioengineering Challenges and Limitations

We reached out to 35 leaders in the field to delve into each of these challenges and limitations to provide perspectives on the technical feasibility of addressing each of these bioengineering challenges, as well as the estimated cost to arrive at successful solutions for the proposed bioengineering challenges. The majority of those polled (67%) indicated that we have, for the most part, identified the major bioengineering challenges. These cover a wide range of areas, including manufacturing, storage and distribution challenges, regulatory and standards challenges, and technological challenges.

Mapping: 5-10 years, costing $1M-50M

It is important to improve our understanding of the detailed structures and organization of cells within each organ to accurately bioengineer tissues to replace lost functionality. Maps of cell placement, phenotype, function, organization, and interaction have not been created in sufficient detail to reliably provide a blue print to repair or replace the functions of existing organs. The generation of a comprehensive "cellular atlas" for each organ would provide great benefit to reconstruction and repair of organ functionality. This cellular atlas would consist of both genetic and development mapping. In many solution pathways, bioengineered organs will likely not be perfect mimics of native organs, but nonetheless will deliver the functions needed. For example, pancreatic islet transplants delivered into the liver can function, but do not replicate the microenvironmental pancreas map.

Vascularization: 5-15 years, costing $50M-100M

Engineering thick tissues in vivo or ex vivo requires the ability to create an internal vascular system that provides the required nutrients to all cells. This has not yet been achieved for tissues thicker than a few millimeters. In order to engineer thick-tissue organs such as the heart, liver, lung, or kidney, this challenge must be overcome. Some progress has been made toward this goal. For example, co-transplantation of hematopoietic and mesenchymal stem/progenitor cells has been shown to improve vascularization in a bioengineered tissue graft model. Developing strategies such as this to improve vascularization in bioengineered tissues and organs, through the addition of cells, small molecules, biomaterials, or other methods, will aid regenerative mechanisms as well as ensure sufficient diffusion of nutrients and oxygen and removal of waste.

Integration: 5-15 years, costing $100M-1B

The nervous and lymphatic systems are not intentionally reestablished at the time of organ transplant, so it remains unclear if bioengineered tissues and organs will behave in the same manner as their native counterparts, or if they will require additional connections to successfully integrate with the patient's body. A need for innervation and lymphatic drainage may be a complex challenge that varies from one organ to the next. Solutions may also vary with the pathways being pursued. Connecting thick tissues to an existing host's vasculature will require different techniques than integrating new vascularized tissues, or other thin-walled structures. Interesting work has shown nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation. Expanding work such as this to larger tissues, and eventually to bioengineered organs, will be critical to ensure proper organ function.

Immunosuppression: 5-10 years, costing $1M-50M

Immunosuppression has been critical for allowing for graft survival and limiting rejection after organ transplantation. However, the long-term use of immunosuppression carries with it several side-effects, such as progressive renal impairment. When cells or tissues are implanted into new patients, immunosuppression requirements can greatly reduce the quality of life, damage the transplanted organ if left unchecked, and increase the risk of infection, cancer, cardiovascular disease, diabetes mellitus, and others. Immunosuppressive drugs are also expensive. Eliminating the need for immunosuppression would be ideal. This may be addressed by using autologous cell sources, the genetic modification of cells and tissues, and possibly by methods we have not yet conceived to induce tolerance in organ transplantation.

Cell manufacturing and sourcing: 5-10 years, costing $50M-100M

There is great need to create more reliable sources of different types of cells that are required to produce each desired organ function. We do not yet have enough reliable, replicable sources of key cell types that can be provided at economical costs and scale. The purity and quality of existing cell sources must also be improved to better prepare bioengineered tissues and organs. Autologous cell sourcing techniques are preferred to banking of allogeneic sources, as the use of autologous cells would mitigate rejection and minimize the need for immunosuppression requirements; however, allogeneic sources are far more cost-effective.

Envisioned Impact Eliminating Organ Shortage Would Have on Disease and Global Economies

An extensive report on improving organ donation and transplantation was prepared by the RAND Corporation in 2008. This report is comprehensive and interested readers are encouraged to review. The authors provided projections on organ donation and transplantation rates, quality-adjusted life years and life years saved, health risks to patients, living organ donation, cross-border exchange, and health inequalities. Their most favorable scenario projected health benefits including transplanting up to 21,000 more organs annually in the EU, which would save 230,000 life years or gain 219,000 quality-adjusted life years (QALYs). For social impacts, it was predicted that increasing organ transplantation will have a positive effect on quality of life for organ recipients, and will lead to increased participation in both social and working life activities. RAND Europe projects the economic benefits of implementing policies to improve organ donation and transplantation of up to €1.2 billion in potential savings in treatment costs, and productivity gains of up to €5 billion. These calculations are based solely on increasing transplants by 21,000 more organs annually. Imagine the projected savings globally for completely eliminating organ shortage!

In recent years human studies of exercise and life expectancy have pointed to a correlation between time spent sedentary and mortality rate, and this correlation appears to be independent of the level of regular exercise undertaken. Here researchers look to calcification as a possible mechanism to explain this association. Calcification of blood vessels and heart tissue occurs with age, and contributes to the tissue stiffness that leads to hypertension, followed by detrimental remodeling of the heart and vascular system to try to compensate. At the end of that road lies cardiovascular disease and death. It isn't completely clear as to whether calcification will occur to a significant degree even if other forms of cell and tissue damage known to cause vascular aging can be repaired, in other words whether calcification is an entirely secondary process of aging. Given that uncertainty it is probably worth adding it as a target for future regenerative therapies.

Researchers have found that sedentary behavior is associated with increased amounts of calcium deposits in heart arteries, which in turn is associated with a higher risk of heart attack. The researchers had previously shown that excessive sitting is associated with reduced cardiorespiratory fitness and a higher risk of heart disease. The latest research - part of the Dallas Heart Study - points to a likely mechanism by which sitting leads to heart disease. "This is one of the first studies to show that sitting time is associated with early markers of atherosclerosis buildup in the heart. Each additional hour of daily sedentary time is associated with a 12 percent higher likelihood of coronary artery calcification." The researchers concluded that reducing daily "sitting time" by even 1 to 2 hours per day could have a significant and positive impact on future cardiovascular health, and called for additional studies into novel interventions to reduce sedentary behaviors. For the many individuals with a desk job that requires them to sit for large portions of the day, they suggested taking frequent breaks.

In some individuals, cholesterol builds up inside the walls of the arteries supplying blood to the heart in mounds called cholesterol plaques. Over time, calcium accumulates in these plaques. The amount of coronary artery calcium can be measured through CT scanning and directly correlates with the amount of cholesterol plaque, as well as with heart attack risk. In this study, the researchers asked some 2,000 participants in the Dallas Heart Study to wear a device that measured their activity levels for a week. Participants spent an average of 5.1 hours sitting per day and an average of 29 minutes in moderate to vigorous physical activity each day. "We observed a significant association between increased sedentary time and coronary artery calcium. These associations were independent of exercise, traditional cardiovascular disease risk factors such as diabetes and high blood pressure, and socioeconomic factors. This research suggests that increased subclinical atherosclerosis characterized by calcium deposition is one of the mechanisms through which sedentary behavior increases cardiovascular risk and that this risk is distinct from the protective power of exercise."

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/april/sedentary-heart.html

Researchers have published an interesting set of results from one of a number of human studies of moderate calorie restriction that have taken place over the past decade. Reduced calorie intake has a beneficial effect on long-term health, producing outcomes in human and animal studies that no presently available medical technology can match, because no presently available medical technology slows progression of the cell and tissue damage that causes aging to the same breadth and degree. That is all the more reason to put more effort into producing therapies capable of treating these causes of aging, but why not take advantage of benefits that are free while waiting for rejuvenation therapies to arrive? There is some speculation as to the degree to which benefits resulting from calorie restriction are due to carrying around less visceral fat, tissue that contributes to chronic inflammation, but research demonstrates that there is a lot more than that going on. Calorie restriction moves almost all measures of metabolic activity, and among many other things spurs greater cellular housekeeping activities, for example.

A 25 percent calorie restriction over two years by adults who were not obese was linked to better health-related quality of life, according to the results of a randomized clinical trial. Researchers tested the effects of calorie restriction on aspects of quality of life that have been speculated to be negatively affected by calorie restriction, including decreased libido, lower stamina, depressed mood and irritability. Their work extends the literature with a study group of nonobese individuals because beneficial effects of calorie restriction on health span (length of time free of disease) increase the possibility that more people will practice calorie restriction.

In this clinical trial conducted at three academic research institutions, 220 men and women with body mass index of 22 to 28 were enrolled and divided almost 2 to 1 into two groups: the larger group was assigned to two years of 25 percent calorie restriction and the other was an ad libitum (their own preference) control group for comparison. The analysis included 218 participants and self-report questionnaires were used to measure mood, quality of life, sleep and sexual function. Data were collected at baseline, a year and two years. Of the 218 participants, the average age was nearly 38 and 70 percent were women. The calorie restriction group lost an average of 16.7 pounds compared with less than a pound in the control group at year two.

According to the authors, the calorie restriction group, compared with the control group, had improved mood, reduced tension and improved general health and sexual drive and relationship at year two, as well as improved sleep at year one. The bigger weight loss by the calorie restriction participants was associated with increased vigor, less mood disturbance, improved general health and better quality of sleep. "Calorie restriction among primarily overweight and obese persons has been found to improve quality of life, sleep and sexual function, and the results of the present study indicate that two years of calorie restriction is unlikely to negatively affect these factors in healthy adults; rather, CR is likely to provide some improvement."

Link: http://media.jamanetwork.com/news-item/study-links-some-positive-effects-to-calorie-restriction-in-nonobese-adults/

Senolytic therapies are those that cause senescent cells to die while causing minimal side-effects. Developing methods to selectively destroy senescent cells has been on the SENS rejuvenation research agenda for going on fifteen years, based on strong evidence from many fields, but only recently have factions within the broader research community started to pick up on this approach to treating one of the causes of aging. Over the past two years a tipping point of sorts was reached and passed, and now a number of drug candidates are emerging from research groups, and the startup Oisin Biotechnologies has a more selective gene therapy approach to achieve the same aim. The open access paper I'll point out today describes one of these candidates, along with animal data that shows it destroying between a quarter and a half of senescent cells in a few tissues. This is on a par with the performance of some of the other candidates that have produced improved measures of health in mice.

Why destroy senescent cells? Because they help to make us old. Cells become senescent in response to reaching the Hayflick limit to the number of divisions, or when suffering damage, especially DNA damage likely to produce cancerous mutations, or a toxic local environment that seems likely to produce that sort of damage. Senescent cells cease to replicate and most self-destruct via apoptosis, or are targeted by immune cells for destruction. Some linger however, secreting a problematic mix of signals that induce inflammation and remodeling of tissue structures, while also encouraging neighboring cells to become senescent. As the years pass ever greater numbers of these cells cause ever greater disarray, contributing meaningfully to the development and progression of all common age-related diseases, and ultimately the tissue and organ failures that cause death. If all senescent cells were periodically removed, however, never permitted to assemble in large numbers, then this part of the aging process would be eliminated, the span of healthy life extended, and age-related disease pushed off that much further into the future. This has been demonstrated in a life span study in mice, in which continuous senescent cell removal via genetic engineering produced a 25% extension of median life span.

How to destroy senescent cells? In past years, I predicted that targeted therapies like those under development in the cancer research community would be used, combining a smart detector of cell chemistry that delivers a not-so-smart kill mechanism, but only to specific cells. At present immunotherapies are the best of these, but there are also selective viral therapies, and others involving nanoparticles. As it turned out, however, all of the more advanced techniques for destroying senescent cells are not targeted at all, and focus on inducing apoptosis, a path to destruction that these cells are already primed to take in comparison to a normal cell. A gentle nudge to the right cellular pathways, such as by increasing or reducing the levels of proteins relevant to apoptosis, will be ignored by near all cells other than those in a senescent state. There, however, it can be enough to tip them over the edge in large numbers. So a senolytic therapy can be delivered generally without targeting. Interestingly, inducing apoptosis is a long-standing line of work in the cancer research community, so there are already stables of drug candidates to explore for use in destruction of senescent cells. If recent deals are any indication, we'll probably see a lot of cross-pollination between these fields in the next few years. Aside from that, a lot of the recent work on senolytic drugs has focused on bcl-2 inhibitors capable of reducing levels of bcl-2, bcl-xl, and bcl-w, all of which act in various ways to suppress apoptosis. This latest published research is along these lines:

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL

While the mechanisms driving senescence are well studied, understanding of the mechanisms endowing these cells with increased survival capacity is limited. The BCL-2 protein family plays a central role in cell death regulation by diverse mechanisms, including apoptosis and autophagy. This family includes the anti-apoptotic proteins BCL-2, BCL-W, BCL-XL, MCL-1 and A1, and is intensively studied as a target for pharmacological intervention in cancer. We set out to evaluate the individual contributions of each of these BCL-2 family members and their combinations to the viability of senescent cells. We found that the increased presence of BCL-W and BCL-XL underlies senescent cell resistance to apoptosis, and that their combined inhibition leads to senescent cell death. We show that a small-molecule inhibitor targeting the BCL-2, BCL-W and BCL-XL proteins (ABT-737) causes preferential apoptosis of senescent cells, both in vitro and in vivo, and eliminates these cells from tissues, opening the door for targeted elimination of senescent cells.

In light of the consistent upregulation of BCL-W, BCL-XL and BCl-2 observed in all tested types of senescent cells, we examined the effects of their inhibition on cell viability using ABT-737, a potent small-molecule inhibitor of BCL-2, BCL-XL and BCL-W24. Human senescent cells of all three types were significantly more sensitive than control cells to treatment with ABT-737, showing up to 65% death at the highest concentration tested. The same effect was observed following ABT-737 treatment of senescent and control mouse embryonic fibroblasts (MEFs). These findings indicate that BCL-W, BCL-XL and BCL-2 confer resistance of senescent cells to apoptosis, and their inhibition by ABT-737 triggers cell death specifically in these cells.

Our experiments above showed that ABT-737 treatment causes selective elimination of senescent cells in tissue culture, including of cells that were induced to senesce by direct induction of DNA damage. We therefore set out to test the effectiveness of ABT-737 treatment in elimination of DNA-damage-induced senescent cells in vivo. To this end, we induced lung damage and senescence in mice by ionizing radiation, which causes long-lasting accumulation of senescent cells, readily identified by persistent DNA damage, in the lungs. Seven days after irradiation the mice were treated with ABT-737 for 2 days, and 1 day later the lungs were excised and analysed for the expression of senescence markers. SA-β-Gal staining showed a significant decrease in the amount of senescent cells following ABT-737 treatment. This reduction was accompanied by a significant decrease in the numbers of γH2AX-positive lung cells and a decrease in the expression of the senescence markers p53 and p21. The molecular targets of ABT-737, BCL-XL and BCL-W, were expressed in the irradiated lungs and their levels were reduced as a result of the treatment. The reduction in the expression of senescence markers and ABT-737 target proteins was accompanied by increased caspase-3 cleavage, suggesting an increase in apoptosis in the lung following the treatment. These findings establish that ABT-737 treatment leads to the elimination of senescent cells in vivo.

We next tested whether BCL protein family inhibition by ABT-737 could eliminate senescent cells induced by direct activation of p53 in the skin. To this end, we used transgenic mice in which the human p14ARF gene is inducibly expressed in the basal layer of the skin epidermis. Induction of p14ARF in these mice activates p53 and generates senescent epidermal cells that are retained in the tissue for weeks. To generate senescent cells, we activated expression of p14ARF in 3-week-old mice for a period of 4 weeks, and then treated the mice with ABT-737 for 4 consecutive days. The number of senescent cells in the epidermis, determined by SA-β-Gal staining, was dramatically reduced in the ABT-737-treated mice relative to control mice. A similar degree of elimination was observed after ABT-737 treatment of these mice for 2 days. Concomitantly, the percentage of epidermal cells in which the transgenic p14ARF protein could be detected was reduced, indicating preferred elimination of transgene-expressing cells. Increased levels of apoptosis were detected in the epidermis after 2 days of ABT-737 treatment, consistent with increased apoptosis as the mechanism of senescent cell elimination. These findings indicate that the survival signal provided by BCL-family proteins is an essential component of the ability of senescent cells to be retained in the tissue, and in its absence they rapidly die.

The ability to pharmacologically eliminate senescent cells in vivo opens the door to study the roles of senescent cells in a wide range of physiological settings in which they are detected, and to dissect their beneficial and detrimental functions. Importantly, this is an early step towards potential clinical application of senolytic drugs, in such settings as aging-associated diseases. The chemotherapeutic elimination of senescent cells from premalignant lesions and tumours may also prove beneficial, in particular settings in which a pro-tumorigenic function of senescent cells in the tumour or stroma will be proven. Overall, our findings reveal a central molecular mechanism maintaining the viability and retention of senescent cells in tissues, and suggest that the elimination of senescent cells by inhibition of this mechanism represents a promising strategy for targeting senescent cells during tumourigenesis and age-related diseases.

Researchers here make an attempt to extract some insight into causation from longitudinal data on retirement age and subsequent mortality rates. If continuing to work on balance involves undertaking more physical activity than would otherwise be the case, it isn't unreasonable to think that this might be a possible mechanism of causation, given the existing evidence for even low levels of activity such as that involved in cleaning and gardening to make a measurable difference to health and life expectancy in later life. Still, the data in this study isn't particularly compelling in and of itself; it has to be considered in the context of other research.

Researchers examined data collected from 1992 through 2010 through the Health and Retirement Study, a long-term study of U.S. adults. Of the more than 12,000 initial participants in the study, the focus narrowed to 2,956 people who began the study in 1992 and had retired by the end of the study period in 2010. "Most research in this area has focused on the economic impacts of delaying retirement. I thought it might be good to look at the health impacts. People in the U.S. have more flexibility about when they retire compared to other countries, so it made sense to look at data from the U.S."

Poor health is one reason people retire early and also can lead to earlier death, so researchers wanted to find a way to mitigate a potential bias in that regard. To do so, they divided the group into unhealthy retirees, or those who indicated that health was a factor in their decision to retire - and healthy retirees, who indicated health was not a factor. About two-thirds of the group fell into the healthy category, while a third were in the unhealthy category. During the study period, about 12 percent of the healthy and 25.6 percent of the unhealthy retirees died. Healthy retirees who worked a year longer had an 11 percent lower risk of mortality, while unhealthy retirees who worked a year longer had a 9 percent lower mortality risk. Working a year longer had a positive impact on the study participants' mortality rate regardless of their health status.

"The healthy group is generally more advantaged in terms of education, wealth, health behaviors and lifestyle, but taking all of those issues into account, the pattern still remained. The findings seem to indicate that people who remain active and engaged gain a benefit from that. Additional research is needed to better understand the links between work and health, the researchers said. As people get older their physical health and cognitive function are likely to decline, which could affect both their ability to work and their longevity. "This is just the tip of the iceberg. We see the relationship between work and longevity, but we don't know everything about people's lives, health and well-being after retirement that could be influencing their longevity."

Link: http://oregonstate.edu/ua/ncs/archives/2016/apr/working-longer-may-lead-longer-life-new-osu-research-shows

The lysosome is a type of cellular component that serves as a recycling unit, breaking down unwanted proteins and structures into their raw materials. As such they play an important role in cellular housekeeping, the removal of damaged structures, machinery, and waste that will, if left unchecked, harm cells and cellular processes. Unfortunately not all byproducts of metabolism can be broken down, either efficiently or at all, and in long-lived cell populations lysosomes become bloated and dysfunctional, filled with a mix of hardy waste products called lipofusin, and much less able to perform their recycling activities. This contributes to the progression of aging, leading to a sort of runaway garbage catastrophe.

Researchers have demonstrated that improving lysosomal function, even without addressing the issue of liposfusin, can greatly improve measures of organ function in older animals. The SENS rejuvenation research approach to this aspect of aging is to find ways to break down the important constituents of lipofuscin by mining the bacterial world for suitable enzymes capable of digesting it. We know they exist because lipofuscin doesn't build up in the soil of graveyards. At present this work has produced some candidates, and is slowly heading in the direction of initial commercial development - though as for near all lines of research relating to repair of the causes of aging, there is all too little interest and funding.

Lysosomes are found in all animal cell types (except erythrocytes) and represent the cell's main catabolic organelles. The variety of substrates degraded in the lysosomes is wide, ranging from intracellular macromolecules and organelles to surface receptors and pathogens, among others. However, lysosomes are not mere sites for disposal and processing of cellular waste but also act as pivotal regulators of cell homeostasis at different levels. For instance, they are involved in the regulation of cellular responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation, among many others. Thus, lysosomes play a determining role in processes that control cellular and organismal life and death. Concurring with this pleiotropic importance, lysosomal dysfunction is associated to a plethora of disorders. Notably, lysosomal defects disturb the balance between damaged proteins and their proteolytic clearance, ultimately resulting in the accumulation of highly cross-linked aggregates. Accumulation of aggregates in post-mitotic cells appears to be particularly dramatic, since the material cannot be diluted via cell division. Many resulting aggregates of oxidized proteins may further react with cellular components like lipids and metals in different compositions, forming a fluorescent material termed lipofuscin. Indeed, the aging process itself may be fueled by a decrease in lysosomal function.

Mounting evidence suggests that a cell's lifespan is partly determined by lysosomal function. This implies that processes in which lysosomes are generally involved, but which have not been clearly associated to aging yet, might also directly or indirectly modulate longevity. Lysosomal exocytosis, for example, in which lysosomes dock to the cell surface, fuse with the plasma membrane and release their content into the extracellular space, has an important role in membrane repair and may contribute to intracellular regeneration upon cellular senescence. At the same time, lysosomal exocytosis is involved in secretion processes that could interact with aging-related intercellular signals at the tissue and organismal level and/or help alleviate intracellular stress conditions, possibly in cooperation with selective secretion through exosomes. Interestingly, lysosomal exocytosis is modulated by Ca2+ and TFEB, both of which have regulatory functions during aging.

On the other hand, molecular processes known to impact aging may at least partly do so because they affect lysosomal function. Such processes may engage single components of the cellular network that are involved in lifespan control, including mitochondria, the nucleus, or peroxisomes. Intriguingly, lysosomes not only communicate with other organelles in the frame of their autophagic removal. For example, the peroxisome-lysosome interaction does not seem to be restricted to pexophagy. The membranes of both organelles can come in close apposition (without fusion), creating lysosomal-peroxisome membrane contacts (LPMC), which are essential for the cellular trafficking of cholesterol. Interestingly, cholesterol oxide derivatives (oxysterols) are involved in different aging-relevant processes like redox equilibrium and inflammation. In addition, they have been associated to major age-related pathologies like neurodegenerative and cardiovascular diseases. Thus, organelles associated with the generation, transformation and transport of such molecules may strongly influence their impact on aging. The occurrence of membrane tethering sites (microdomains) like LPMCs allows an efficient interplay between organelles. Thus, the establishment of microdomains between lysosomes and other organelles may allow signal exchanges that contribute to a dynamic and orchestrated control of aging. Though some remain speculative in their causality, these lysosome-aging connections exemplify the multilayered mechanisms through which lysosomal function may crucially contribute to aging control. Recognizing this potential opens doors not only to further understand the process of aging but also to improve the ravages of time via lysosomal avenues.

Link: http://www.sciencedirect.com/science/article/pii/S1568163716300666