Fight Aging! Newsletter, August 15th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Crowdfunding a Universal Cancer Treatment: Only a Few Days Left in the Fundraiser
  • Considering the Mechanisms and Treatment of Inflammaging
  • The Damage Done to Health and Life Span: Obesity and Inactivity are by Some Measures Worse than Smoking
  • A Journalist Once Again Fails to Mention SENS and Rejuvenation when Writing About the State of Longevity Science
  • A Failure for GDF11 to Extend Lifespan, but is it a Meaningful Failure?
  • Latest Headlines from Fight Aging!
    • Recent Research on Mechanisms of Limb Regeneration
    • Examining the Relationship Between Hypertension and Cognitive Decline
    • Using CRISPR to Attack Cytomegalovirus
    • CryoSuisse and the 1st International Cryonics Conference this November
    • The Popular Press on the Goal of Slightly Slowing Aging
    • Nampt Overexpression Reduces Age-Related Loss of Exercise Capacity in Mice
    • Evidence for Senescent Cells to Contribute to Osteoarthritis
    • The Anti-Inflammatory Approach to Treating Alzheimer's Disease
    • Greenland Sharks Live for Centuries
    • Radical Life Extension is the Right Idea

Crowdfunding a Universal Cancer Treatment: Only a Few Days Left in the Fundraiser

This year's SENS rejuvenation research crowdfunding event puts the spotlight on the SENS Research Foundation's cancer program. So far more than 300 people have donated, and more than 26,000 has been raised; with ten days left to go, it won't take that much more of an effort to reach the same number of donors and the same level of support given to last year's fundraiser, and which led to the success in that research program. As for all of the SENS research initiatives in the science of aging, the SENS Research Foundation's work on cancer aims to support a big, bold goal in medicine: to build a single type of therapy that can be used to effectively treat all forms of cancer. When achieved, that will greatly increase the pace of progress towards control of cancer, the goal of finally ending cancer as a threat to health. At present the cancer research community spends much of its time and funding on approaches that are highly specific to only one or only a few of the hundred of subtypes of cancer. That is no way to win any time soon, as even with the vast funding devoted to cancer research, there are just too many forms of cancer and too few researchers. What is needed is to change the strategy, to focus on approaches to the treatment of cancer that are no more expensive to develop, but that far more patients can benefit from.

The most promising approach to a universal cancer therapy is to block telomere lengthening in cancerous tissues. Telomeres are a part of the mechanism that limits cell division in all human cells other than stem cells, repeating DNA sequences at the ends of chromosomes that shorten every time a cell divides. In order to achieve unfettered growth all cancers must bypass this limit by continually lengthening their telomeres, a goal that is achieved through mutations that allow cancer cells to use telomerase or the alternative lengthening of telomeres (ALT) processes. If both telomerase and ALT can be blocked in cancer tissue, then the cancer will wither; this is such a fundamental piece of cellular machinery that there is no expectation that cancer cells could find a way around it. Block only one of these two methods of telomere lengthening, however, and the cancer will probably switch to use the other. This has been observed in mice.

Thus it is very important that the research community deploy both telomerase and ALT blockades as a part of a prospective universal cancer therapy. Unfortunately while a number of groups are working on telomerase interdiction, and telomerase is very well studied these days, ALT is still poorly characterized, at the frontiers of what is known of cell biology. ALT doesn't occur in normal cells, and thus despite the fact that 10% of cancers make use of it, only recently have the necessary tools been developed to work towards understanding and intervention. The SENS Research Foundation is picking up the slack in this overlooked area of development, and with our support is working towards ensuring that the first universal cancer therapies can in fact target both telomerase and ALT, and therefore succeed.

The existence of cancer therapies that are both effective and cost-effective is going to become increasingly important as other rejuvenation therapies arrive in the clinic over the next few decades. Senescent cell clearance is under development in startup companies, for example, and a few other lines of research aimed at repairing the damage that causes aging are probably only a few years away from the same point. Certainly the 2020s are going to see multiple competing approaches to clearing out the damage of aging, and the first impact on age-related disease and mortality will occur in the public at large. None of these therapies are going to do much to reverse the random mutational damage in nuclear DNA that drives cancer, however, though they may well help to halt the decline of the immune system's ability to destroy cancerous cells before they become established. Fixing random DNA damage is a hard problem, and viable solutions will probably arrive very late in the progression of rejuvenation biotechnology. In the transitional world in which a lot of older people are living for longer and in better health, but with a high burden of mutational damage, it will be ever more necessary to control cancer through medicine.

Looking at the big picture, then, supporting the SENS approach to cancer makes sense: it is a great way for people like you and I to do our part to help build the sort of future that we want to live in.

Considering the Mechanisms and Treatment of Inflammaging

Today I'll link to an open access review paper on the topic of inflammaging: what it is, what is known of its mechanisms, and approaches to building treatments. The view on treatments is very mainstream and unambitious, in that it doesn't go beyond supplementation, calorie restriction mimetics, and other drugs with marginal effects, such as metformin. This is driven by a strategic approach that ignores the search for root causes in favor of evaluating the dysfunctional system as a whole and seeking to alter its operation, to force it into a mode of operation that resembles that of youth and health. This view of research and development is precisely why the mainstream is struggling to make much of an impact in the treatment of aging, and why they see the control of aging as a distant goal: trying to make a damaged machine run well without repairing the damage is a very challenging task. If we are to see progress in the treatment if aging, it will come from those researchers who aim to repair the low-level biological damage that causes aging, not merely paper over it.

That said, you may find the rest of the paper to be an interesting view of the way in which the immune system runs awry in later life. The authors here differentiate between inflammaging and immunosenescence, though I'm not convinced that these are really distinct enough to be considered two separate things given the present understanding of immune dysfunction in aging. Inflammaging is very focused on chronic inflammation, as you might imagine, while immunosenescence is focused on the declining effectiveness of the immune response. I see these as two perspectives on the same very complex phenomenon. Chronic inflammation increases with age, and contributes to all of the common age-related conditions. Becoming overweight, and thus carrying around excess visceral fat tissue, is one way to produce greater inflammation. Even if you stay in shape, however, the immune system becomes increasingly disarrayed in ways that provoke inflammation. The molecular damage of aging and a lifetime of exposure to pathogens produces an aged immune system that is both overactive and ineffective at the same time. Inflammation is a necessary part of the immune response, but if the switch is jammed in the on position, that inflammation produces a growing burden of damage to tissues and organs.

What to do about all of this? Well, not the items on the list provided in this paper, that is certain. For my money, the same general approaches to immune aging advocated in the SENS view of rejuvenation therapies should put a dent into inflammaging. These include: selectively removing immune cells that have become uselessly specialized to herpesviruses and do nothing but take up space; restoring youthful function in the thymus to increase the rate at which new immune cells are generated; supplying periodic infusions of immune cells created from the patient's own cells; and beyond that the standard SENS plan of repairing all known cell and tissue damage. Senescent cells cause inflammation, for example, and their removal is on the SENS agenda. Since senescent cell destruction is a going concern in the laboratory we should have a good view of its impact on inflammation in aging a few years from now. In the view of aging as an accumulation of damage, problems in old people that can be traced to signaling issues - differences in levels of specific proteins - are reactions to the presence of rising levels of molecular damage. Remove all of the damage and the signaling should revert to that of a young individual. This is more or less the opposite view on strategy from the systems biology perspective put forward in this paper.

An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment

A main feature of the aging process is a chronic progressive increase in the proinflammatory status, which was originally called "inflamm-aging". Inflamm-aging is the expansion of the network theory of aging and the remodeling theory of aging. The network theory of aging posits that aging is indirectly controlled by the network of cellular and molecular defense mechanisms. The remodeling theory, which was put forward to explain immunosenescence, is the gradually adaptive net result of the process of the body fighting malignant damage and is a dynamic process of optimization of the trade-off in immunity. In the process of aging, some researchers pointed out that the phenomenon where adaptive immunity declines is called immunosenescence, while the phenomenon where innate immunity is activated, coupled with the rise of proinflammation, is called inflamm-aging. Some regard the chronic inflammatory process with age as inflamm-aging, while others proposed the oxidation-inflammation theory of aging. Despite the lack of agreement on definitions and terminology, there is consensus that the primary feature of inflamm-aging is an increase in the body's proinflammatory status with advancing age.

The inflammation during inflamm-aging is not in a controlled inflammatory state. Inflammation is a series of complex response events which are caused by the host system facing a pathogen infection or various types of tissue injury. These response events are characterized by interactions between the cells and factors in the microenvironment and by regulation of the balance between physiological and pathological signaling networks. In common conditions, inflammatory responses disappear when proinflammatory factors in infection and tissue injuries are eliminated and then change into a highly active and well regulated balanced state, which is called resolving inflammation. However, in the presence of some as yet uncertain factors, such as persistent and low intensity stimulation and long-term and excessive response in target tissues, inflammation fails to move into a steady state of anti-infection and tissue injury repair; instead the inflammation continues and moves to a nonresolving inflammation state.

Inflamm-aging is a determinant of the speed of the aging process and of lifespan and is highly related to Alzheimer's disease, Parkinson's disease, acute lateral sclerosis, multiple sclerosis, atherosclerosis, heart disease, age-related macular degeneration, type II diabetes, osteoporosis and insulin resistance, cancer, and other diseases. Inflamm-aging also increases morbidity and mortality, significantly harming the health of patients, and causes a decline in the quality of life of patients. Chronic, subclinical inflammation and immune disorders coexist in the process of inflamm-aging. Epidemiological studies show that with age there is an imbalance in the loss of old bone and the formation of new bone. Inflamm-aging may be one of the contributing factors to the imbalance and to the subsequent excessive loss of bone.

Based on the essential effects and our understanding of inflammatory cytokine pathways in the process of inflamm-aging, we can begin to explore the inflammatory cytokine network and perform a quantitative evaluation of inflamm-aging. Inflammatory cytokines, including interleukins, tumor necrosis factor, and interferon, mediate their effects by binding to their receptors and competing in a complex cell-cell network. These cytokines act in both paracrine and autocrine ways to exert direct effects on the microenvironment. This plays an important regulatory role by activating inflammatory and immune cells and by releasing cytokines. Inflammatory cytokines form a complex network which extends in all directions and throughout the whole body. The inflammatory cytokine network can be divided into the proinflammatory cytokine network and anti-inflammatory cytokine network. As with the immune reaction, the inflammatory reaction is also a normal defense function. A moderate inflammatory reaction is advantageous to the body, whereas a high reaction is harmful and the outcome of these reactions is determined by changes in the inflammatory cytokine network. The dynamic balance between the proinflammatory cytokine network and the anti-inflammatory cytokine network maintains the normal function of inflammation in body. Once the balance is broken, pathological inflammation occurs. Therefore, we infer that the cause of inflamm-aging is an imbalance in the proinflammatory cytokine and anti-inflammatory cytokine networks, which leads to a proinflammatory status with increasing age. This may be the mechanism of inflamm-aging.

In summary, inflamm-aging and the inflammatory cytokine network are both classical systems biology issues. The inflammatory cytokine network is involved in the process of inflammation and senescence and may be the ideal breakthrough point of research into inflamm-aging. Omics, such as genomics, transcriptomics, proteomics, and metabolomics, are excellent methods to solve systemic biology problems. Therefore, under the guidance of systems biology, it would be novel strategy to conduct basic research into inflamm-aging using omics methods to identify characteristic inflammatory cytokine genes in the process of aging and to uncover new mechanisms to regulate inflammatory cytokines during inflamm-aging. This will also illustrate the mechanism of inflamm-aging and provide new ways to assess inflamm-aging.

The Damage Done to Health and Life Span: Obesity and Inactivity are by Some Measures Worse than Smoking

From the perspective of health and longevity, the three most damaging things that people commonly do to themselves are (a) take up smoking, (b) lead a sedentary lifestyle, and (c) become obese. A sizable percentage of the population in the wealthier regions of the world falls into at least one of those buckets. The result for near all such people is higher lifetime medical expenses, greater ill health, and a shorter life. The damage done scales by the degree to which an individual smokes, fails to exercise, or puts on weight: there is plenty of evidence to show that even a little additional weight is harmful in the long term, for example. I think that by now the consequences of smoking are widely appreciated, but awareness that choosing to lead a sedentary lifestyle or to carry a lot of excess fat tissue is just as bad? That has yet to spread to the same degree. The open access paper I'll point out today is one of those that finds the losses of life or health caused by obesity and inactivity to be greater than the losses caused by smoking.

How do these choices produce damage that looks a lot like accelerated aging, increasing the incidence of age-related disease, and causing higher mortality rates? I shouldn't have to dwell on the results of smoking for this audience: greatly increased inflammation; particulate matter in the lungs; increased risk of cancers, fibrosis, and cardiovascular disease; and so on. How is it that inactivity and obesity can achieve the same level of harm? In the case of obesity, visceral fat tissue is the driver of damage. It is a very active tissue, producing significant changes in the operation of metabolism and the organs it wraps: metabolic syndrome, type 2 diabetes, and so forth. Visceral fat tissue also produces higher levels of chronic inflammation throughout the body through its interaction with immune cells, and inflammation speeds the development of cardiovascular disease, dementia, and most of the other ultimately fatal age-related diseases. In the case of a sedentary lifestyle, it is easier to look through the literature to find the gains produced by exercise rather than searching for the losses produced by a lack of exercise. Exercise slows the stiffening of blood vessels that leads to cardiovascular disease, increases cellular maintenance activities, improves the immune system by culling unwanted cells, and much more. Like calorie restriction, exercise changes almost every measure of metabolism for the better.

Thus we have this paper, which like so many others catalogs the damage that people inflict upon themselves through poor choices. One day, probably later in this century, none of this will much matter, because medical science will be able to rescue everyone from the consequences of such poor choices - and then add decades of additional healthy life on top of that, by addressing the root causes of aging. We are not there yet, however, and in a world in which progress is rapid, every additional few years of expected life span might make the difference between dying too soon and living to benefit from the first effective rejuvenation therapies. Far and away the most reliable way to add those years today is to take better care of your long-term health.

Smoking, physical inactivity and obesity as predictors of healthy and disease-free life expectancy between ages 50 and 75: a multicohort study

A study based on data from 11 European countries estimated that 60% of deaths from all causes could be attributed to behaviour-related risk factors. Furthermore, the importance of health behaviours for the prevention of chronic diseases, such as type 2 diabetes, coronary heart disease and cancer, is widely acknowledged. Smoking, physical inactivity and obesity are among the top 10 behaviour-related risk factors for burden of diseases in developed countries, and they have also been shown to be associated with shorter health expectancy and life expectancy (LE). The cumulative impact of multiple behaviour-related risk factors on health expectancy is of interest because studies show that people who engage in multiple risk behaviours have higher mortality, increased risk of chronic diseases and poor cognitive and lower physical functioning compared with people who have no or only one behaviour-related risk factor.

Previous studies have estimated healthy years and disability-free years separately for smoking and obesity. In addition, there are at least two large studies that used information on past trends or current levels of obesity and smoking to estimate the combined effect of obesity and smoking on quality-adjusted LE and disability-free LE. Of the two risk factors, obesity appeared to be the main driver for shortened disability-free LE. However, neither of these studies considered low physical activity among the risk factors. This is a limitation, as regular physical activity is known to be associated with reduced risk of several chronic diseases, better physical and cognitive functioning in old age and higher longevity. To address some of these limitations, we examined the extent to which the co-occurrence of three modifiable behaviour-related risk factors, namely smoking, physical inactivity and obesity, predicted healthy LE and chronic disease-free LE in a large dataset of older men and women in England, Finland, France and Sweden. In addition, we estimated the associations of individual risk factors with these outcomes.

Compared with men and women with at least two of the smoking, physical inactivity and obesity risk factors, people with no risk factors could expect to live on average 8 years longer in good health and 6 years longer free of chronic diseases between the ages of 50 and 75 years. The reduction in healthy and chronic disease-free LE was greater for those with multiple behaviour-related risk factors than those with a single risk factor, a finding observed in all four cohorts. Of the individual behaviour-related risk factors, physical inactivity was associated with the greatest reduction in healthy years and obesity with greatest reduction in chronic disease-free years. In all cohorts of this study, healthy LE was longer than chronic disease-free LE. This has also been observed in other studies using multiple types of health indicators to calculate health expectancy. This is expected because suboptimal self-rated health is a holistic measure and it captures a wider range of health-related phenomena beyond chronic disease. Therefore, individuals with chronic diseases may consider their health good if the disease does not hamper everyday life.

A Journalist Once Again Fails to Mention SENS and Rejuvenation when Writing About the State of Longevity Science

The article on longevity science that I'll point out today continues a frustrating recent trend of failing to note one of the most important portions of the aging research field: SENS rejuvenation research. This is a puzzling omission, especially now that senescent cell clearance as a rejuvenation therapy is proven and heading for the clinic - a goal that SENS supporters have been advocating for fifteen years or so. For most journalists, there is no way to quickly and easily distinguish between any of the possible approaches to intervene in the aging process and thus extend healthy life. Being journalists, they are in the business of page views and rapid production of articles, not accuracy. So the typical approach here is to pull a half dozen of the options from the list and talk about them, giving them all equal weight. This is unfortunate, as the various lines of research leading to treatments for aging are far from equal in their challenges and their potential outcomes.

We can broadly divide the aging research situation into two camps. One the one side are ways to modestly slow aging, which is to say slow the rate at which molecular damage accumulates to cause dysfunction, disease, and death. Researchers investigate the operation of metabolism and try to alter it safely and beneficially. These research initiatives typically look like very traditional molecular biology and drug development programs, often pulling drugs from the existing stockpile because they might marginally impact the pace of aging. Attempts to recreate some of the health and life expectancy benefits of calorie restriction or exercise are a common theme, which if completely successful would add perhaps five to ten years to life span, if such a therapy was used throughout life. None have come even close to a fraction of that goal so far: the field is littered with expensive failures.

On the other side of the fence are ways to repair the molecular damage that causes aging, and here there are few limits to the years of additional healthy life that can be added. A repair can be carried out many times, after all. These therapies are as well defined as they can be in advance of their construction, or in the early stages of development in some cases: a mix of small molecule and other drug development to clear metabolic waste, gene therapies of a few varieties, and cell therapies to round out the mix. If repair of damage is complete and comprehensive, and carried out every few years, a person would have an indefinite life span - he or she would never get old, and if already old that burden could be reversed. The first prototype damage repair therapies will be far from complete or comprehensive, of course, but single treatments should produce outcomes that are large in comparison to lengthy periods of a treatment that merely slows aging. The more damage that is repaired, the better the result. Repairing the damage means actual rejuvenation: turning back the clock, trying to defeat aging, not just adjust the downward spiral a little.

For advocates who are trying to ensure that the research community adopts damage repair as the dominant strategy, it is frustrating to have the press telling the public that slowing aging is all there is, or painting specific efforts to slow aging (capable of extending life only a little) as being equivalent to specific efforts to reverse aging (capable of extending life greatly). The article linked here is a particularly egregious example of this sort of thing. It starts out and ends with quotes from people long involved in advocating and funding SENS rejuvenation research, and then completely fails to mention the SENS Research Foundation or the SENS approaches to repairing the damage that causes aging. The author wanders off on a tour of ways to slow aging as though that is the sum of the field. While I recognize that journalists, in their haste to fill the news hole, do this and worse to every topic under the sun, that doesn't stop it from being very annoying when it is a familiar, even important topic. It is vital to our future that repair of molecular damage becomes the mainstream of aging research as soon as possible, as that means the difference between living for a very long time in good health, or not achieving that goal. Unfortunately, for now and the foreseeable future that involves a reliance on philanthropic funding, as the mainstream of aging research is still set on slowing aging only. To the extent that journalists get everyone hyped up about lines of research - metformin, parabiosis, rapamycin, and so on - that cannot possibly produce large effects in humans, that damages the cause by producing cycles of hype and disappointment, an outcome that emerges precisely because people are not backing the right horse. Large effects are out there to be claimed, but not by merely slowing aging.

Adding ages: The fight to cheat death is hotting up

Michael Rae eats 1,900 calories a day, 600 fewer than recommended. He has been constraining his diet this way for 15 years. In some animals calorie restriction (CR) of this kind seems to lessen the risk of cancer and heart disease, to slow the degeneration of nerves and to lengthen life. Mr Rae, who works at an anti-ageing foundation in California, thinks that if what holds for rodents holds for humans CR could offer him an extra seven to 15 years of healthy life. No clinical trials have yet proved this to be the case. But Mr Rae says CR dieters have the blood pressure of ten-year-olds and arteries that are clean as a whistle. But his diet, and the life extension he thinks it might bring, are also a means to an end. Mr Rae, who is 45, thinks radical medical advances that might not merely slow but stop, or reverse, ageing will be available in the not-too-distant future. If CR gets him far enough to benefit from these marvels then a few decades of deprivation might translate into additional centuries of life. He might even reach what Dave Gobel, boss of the Methuselah Foundation, an ageing-research charity, calls "longevity escape velocity", the point where life expectancy increases by more than a year every year. This, he thinks, is the way to immortality, or a reasonable approximation thereof.

That all remains wildly speculative. But CR is more than just an as-yet-unproven road to longer human life. Its effects in animals, along with evidence from genetics and pharmacology, suggest that ageing may not be simply an accumulation of defects but a phenomenon in its own right. In a state of nature this phenomenon would be under the control of genes and the environment. But in a scientific world it might in principle be manipulated, either through changes to the environment (which is what CR amounts to) or by getting in among those genes, and the metabolic pathways that they are responsible for, with drugs. A treatment based on such manipulation might improve the prospects of longer and healthier life in ways that drugs aimed at specific diseases cannot match. Something which slowed ageing down across the board might fit the bill. And if it delays the onset of a range of diseases it might also go some way to reducing the disability that comes with age. An ongoing long-term study at Newcastle University has been looking at the health and ageing of nearly 1,000 subjects now aged 85. At this point they have an average of four to five health problems. None of them is free from disease. Most researchers in the field scoff at talk of escape velocities and immortality. But they take seriously the prospect of healthier 85 year olds and lifespans lengthened by a decade or so, and that is boon enough.

Before discovering whether anti-ageing drugs might be able to deliver such things, though, researchers need to solve a daunting regulatory conundrum. At the moment the agencies that allow drugs to be sold do not consider ageing per se to be an "indication" that merits therapy. It is, after all, something that happens to everyone, which makes it hard to think of as a disease in search of a cure, or even a condition in need of treatment. Unless ageing is treated as an indication, anti-ageing drugs can't get regulatory approval. And there's little incentive to work on drugs you can't sell. If regulators were to change their stance, though, the interest would be immense. A condition that affects everyone is as big a potential market as can be imagined. And there are hints that the stance may indeed be changing. Two existing drugs approved for other purposes - metformin, widely used and well tolerated as a treatment for diabetes, and rapamycin, which reduces the risk of organ transplants being rejected - look to some researchers as though they might have broad anti-ageing effects not unlike those claimed for CR.

The extent to which any of this technology will help will depend on how old those it is used on are when it comes into its own. The scope for radically changing the lifespan of a 65-year-old is much smaller than that of a 20-year-old, let alone an embryo. But the amount that is lost by getting things wrong goes up in exactly the same way. The idea that radical biotechnology can lead to longer lifespans than that of Jeanne Calment, a French woman whose recorded lifespan of 122 years has never been bettered, seems at best a plausible speculation. To say - as Aubrey de Grey, a noted cheerleader for immortality, has done - that the first person to live to 1,000 has probably already been born seems utterly outlandish. But thinking through Calment's life might give you pause. When she was born, in 1875, the germ theory of disease was still a novelty and no one had ever uttered the word "gene". When she died in 1997 the human genome was almost sequenced. All of modern medicine and psychiatry, barring general-purpose anaesthesia, was developed during her lifetime. If a little girl born today were to live as long - and why should she not? - she would see the world of 2138. The capabilities of medicine at that point will surely still be limited. But no one can guess what those limits will be.

It should go without saying, but sadly doesn't, that the scope for radically changing the lifespan of a 65-year-old is dependent on the degree to which the damage of aging can be repaired. Slowing the pace of aging is of no use to the old, those people who are already heavily damaged and failing, suffering and with a high mortality rate. If you want to rescue the old, and prevent people from becoming old and frail and in pain, then the only strategy that can deliver that result is repair of cell and tissue damage. This exactly describes the therapies laid out in the SENS vision, and which are presently under development in a few laboratories and companies. If we want a future of longevity and health, this seed must grow.

A Failure for GDF11 to Extend Lifespan, but is it a Meaningful Failure?

The protein growth differentiation factor 11 (GDF11) has been in the news over the past couple of years. In the course of conducting parabiosis research, in which the circulatory systems of old and young mice are linked, researchers established that levels of GDF11 decline with age in that species. Restoring youthful levels of GDF11 has been shown in some studies to improve numerous measures of age-related decline, perhaps largely through signaling that instructs stem cells to increase their tissue maintenance activities. Not all of the evidence is positive, however. There is an ongoing debate over whether or not studies were correctly interpreted, as GDF11 is similar enough to myostatin to confound some tools, a range of other objections and opposing evidence, and a first pass at obtaining human data suggests that GDF11 doesn't decline with age in our species in the way it does in old mice.

Does raising the level of GDF11 in humans have any sort of future as the basis for a therapy? In theory anything that can put stem cells back to work, reversing some of the characteristic age-related decline in stem cell function, is worth chasing to the same extent that stem cell therapies are worth chasing. The likely best outcomes are in the same ballpark, and work through similar mechanisms. This doesn't fix any of a range of important cell and tissue damage that causes age-related disease, but benefits are benefits. The question is whether or not GDF11 research is on the right track. At this point the balance of evidence for and against, coupled with questions about the methodology in some of the studies, suggests it is too early to tell - and at the very least there are a number of points that need clarification.

The study linked below falls on the negative side of the fence, showing no benefit to life span resulting from increased levels of GDF11 in a lineage of mice engineered to suffer accelerated aging. Evaluating results in accelerated aging models is a challenge, however. It all depends on the fine details of what exactly is involved in that accelerated aging - which is never actually accelerated aging, but rather some form of runaway biological damage that doesn't play a significant role in normal aging. That is good enough for some investigations, in which the precise nature of the damage isn't all that important, because the age-related condition of interest is very similar despite the very different nature of the low-level cell and tissue damage. Still, it has to be said that for every study in which the use of an accelerated aging lineage produced clear and unambiguously useful results, as was the case for senescent cell clearance back in 2011, there are half a dozen more in which the waters remain muddy. The researchers are trying hard to prove relevance in this paper, but I have to say that it still looks pretty muddy to me; there are any number of ways we might connect the particular approach to accelerated aging and GDF11 activities.

GDF11 administration does not extend lifespan in a mouse model of premature aging

The existence of "rejuvenating" factors in young blood capable of improving the function of aging stem cells was first demonstrated in 2005. A decade after this seminal contribution, the new wave of studies has been on the search for those circulating regulatory molecules that can restore the regenerative function of old stem cells and reverse aging. Among several cell-extrinsic factors and metabolites identified to date, GDF11 has been found to be one of the most powerful anti-aging candidates. Thus, it has been shown that GDF11 levels in blood decline with age, and that its supplementation to reach young physiological range in old mice improved the features and function of a number of age-deteriorated tissues, including heart, skeletal muscle and brain. However, recent reports have shown contradictory data questioning the capacity of GDF11 to reverse age-related tissue dysfunction. The availability of the Zmpste24-/- mouse model of accelerated aging, which shares most of the features occurring in physiological aging, gives us an excellent opportunity to test in vivo therapies aimed at extending lifespan both in pathological and normal aging. On this basis, we wondered whether the proposed anti-aging functions of GDF11 would have an overall effect on longevity.

We first determined whether GDF11 levels decline in our mouse model of premature aging in the same manner as it has been reported in physiological aging. We performed western-blot analyses with plasma samples obtained from the same wild-type and Zmpste24-/- mice at the age of 1.5 months and 3 months, to monitor a possible decline over time, considering that average lifespan of these mutant mice is 4 months and that accelerated aging symptoms start to manifest around the age of 2 months. We used the same commercial antibody as the one previously reported in the original study in which GDF11 was first identified as an anti-aging factor. We observed a marked decrease in GDF11 plasma levels in Zmpste24-/- mice compared with wild-type littermates at the age of 3 months.

To test our hypothesis about a possible role for GDF11 on lifespan extension, we did use the same commercial recombinant GDF11 (rGDF11) protein that has been used in those studies describing its anti-aging properties, and at a dosage capable of raising its levels in Zmpste24-/- plasma samples. However, rGDF11 daily treatment did not extend the lifespan of progeroid mice compared with vehicle-treated Zmpste24-/- littermates. It has been suggested that some of the original conclusions about GDF11 cardioprotective effects could be due to the decrease in body weight observed as a secondary effect of rGDF11 daily administration. Our results showed that rGDF11 treatment only caused a slightly reduction in the body weight of female Zmpste24-/- mice compared with vehicle-treated littermates during the first days of the experiment, whereas no significant differences were observed in the male cohort. In conclusion, our results demonstrate that circulating GDF11 levels are reduced in our mouse model of premature aging, which shares most of the symptoms that occur in normal aging. However, GDF11 protein administration is not sufficient to extend longevity in these progeroid mice. Although accelerated-aging mouse models can serve as powerful tools to test and develop anti-aging therapies common to both physiological and pathological aging, the existence of certain differences between the two processes implies that further investigation is still required to determine whether long-term GDF11 administration has a pro-survival effect on normal aged animals.

Latest Headlines from Fight Aging!

Recent Research on Mechanisms of Limb Regeneration

A number of research groups are engaging in mapping the biochemistry of limb and organ regeneration in species capable of such regrowth, such as salamanders and zebrafish. The hope is that the underlying systems of regeneration are merely inactive in mammals, not missing entirely, and therefore somewhere in all of this lies the basis for a therapy to provoke regrowth of missing tissues in adult humans. Whether or not this is the case is yet to be determined, though some of the evidence is promising: scarless healing of minor wounds present in MRL mice; the same outcome induced via inhibition of Cxcr4; the ability to selectively block zebrafish regeneration with the human ARF gene; and others. There are also the evolutionary arguments, such as those put forward by the researchers here. The more that researchers find very similar mechanisms of regeneration in widely diverse species, the more likely it is that those mechanisms also exist to be accessed in mammals.

Many lower organisms retain the miraculous ability to regenerate form and function of almost any tissue after injury. Humans share many of our genes with these organisms, but our capacity for regeneration is limited. Until the advent of sophisticated tools for genetic and computational analysis, scientists had no way of studying the genetic machinery that enables regeneration. Using such tools, scientists have identified common genetic regulators governing regeneration in three regenerative species: the zebrafish, a common aquarium fish originally from India; the axolotl, a salamander native to the lakes of Mexico; and the bichir, a ray-finned fish from Africa. The discovery of genetic mechanisms common to all three of these species, which diverged on the evolutionary tree about 420 million years ago, suggests that these mechanisms aren't specific to individual species, but have been conserved by nature through evolution.

The discovery of the common genetic regulators is expected to serve as a platform to inform new hypotheses about the genetic mechanisms underlying limb regeneration. The discovery also represents a major advance in understanding why many tissues in humans, including limb tissue, regenerate poorly - and in being able to possibly manipulate those mechanisms with drug therapies. "Limb regeneration in humans may sound like science fiction, but it's within the realm of possibility. The fact that we've identified a genetic signature for limb regeneration in three different species with three different types of appendages suggests that nature has created a common genetic instruction manual governing regeneration that may be shared by all forms of animal life, including humans."

In particular, the scientists studied the formation of a mass of cells called a blastema that serves as a reservoir for regenerating tissues. The formation of a blastema is the critical first step in the regeneration process. Using sophisticated genetic sequencing technology, researchers identified a common set of genes that are controlled by a shared network of genetic regulators known as microRNAs. The study also has implications for wound healing, which, because it also requires the replacement of lost or damaged tissues, involves similar genetic mechanisms. With a greater understanding of these mechanisms, treatments could potentially be developed to speed wound healing, thus reducing pain, decreasing risk of infection and getting patients back on their feet more quickly.

Examining the Relationship Between Hypertension and Cognitive Decline

Blood pressure increases with age, driven by loss of elasticity in blood vessels, among other things, leading to the medical condition of hypertension. Here, researchers examine the complex associations between higher blood pressure and greater loss of cognitive function in later life; while it is well known that hypertension damages the physical structure of the brain, to pick one example, when it comes to the end result of cognitive decline a full catalog of the contributing factors and how these processes interact in detail has yet to be established. That said, it is certainly possible to accelerate the progression of higher blood pressure by leading a sedentary lifestyle or becoming overweight, and both of those line items correlate well with greater cognitive decline. While that much is under our control, there is unfortunately all too little that can be done about stiffening of blood vessels at the present time. Real progress on that front will require implementation of some of the SENS rejuvenation therapies, such as a way to break down the cross-links that build up in the extracellular matrix of blood vessel walls.

Despite strong evidence for a positive association between midlife hypertension and late-life cognitive impairment, the relationship between late-life hypertension and cognitive function remains unclear. Observed inconsistencies between studies partly reflect variations in study design and populations. Another likely factor is unmeasured heterogeneity, within populations, as regard the timing and duration of exposure to hypertension, which in turn could influence its effects and potential modifiability. Such investigations would benefit from a proxy measure representing the duration of exposure to hypertension. A potential proxy or surrogate measure is pulse pressure (PP), partly reflecting arterial stiffness, measured as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). PP is potentially a better measure of the chronic effects of hypertension than blood pressure itself. PP increases with age and is associated with a number of cardiovascular risk factors and outcomes. Arterial stiffness appears related to Alzheimer's disease (AD) pathology, providing a potential vascular marker that is more closely related to AD than other cardiovascular measures. However, evidence remains conflicted as to the association of cognitive performance with arterial stiffness, whether measured as PP or through ultrasound determined pulse wave velocity.

Here, we explored the relationships between longitudinal change in PP and cognitive performance in multiple cognitive domains over 5 years and how these relationships were influenced by initial (baseline) blood pressure (BP). As an increase in PP typically reflects significant vascular remodeling and stiffening, we hypothesized that those with increasing PP over time would have a greater decline in cognition. When evaluating distinct longitudinal profiles of PP change over the same time period and accounting for attrition, we identified differences in cognitive change that (1) varied by trajectory of PP change, (2) varied by cognitive domain, (3) varied by age, between the youngest-old and oldest-old, and (4) was significantly influenced by baseline SBP. Importantly, we found that an increasing or persistently high PP was associated with less cognitive decline than in those with low, stable PP but only if baseline SBP was below the median. However, in those starting with higher baseline SBP, it was age, rather than PP group, that influenced cognitive decline the most, with increasing age being associated with greater decline. These findings underscore the importance of identifying the sources of heterogeneity within a population to understand the complex relationships between late life vascular health and cognitive decline and possibly help explain some of the discrepancies in the literature.

The four PP trajectory groups that we identified appear to capture the major categories along a spectrum of possible patterns (stable high or low and increasing or decreasing). They also suggest that different pathways to a specific PP level, rather than the PP itself, have distinct implications for cognition. We can only speculate about the potential mechanisms underlying the noted associations between PP and cognition. These results might indicate that with advancing age, which is also associated with an age-related arterial stiffening, that cognitive function, particularly executive function, becomes increasingly reliant on an additional mechanisms such as adequate cardiac output. However, with advancing age and chronic exposure to higher PP this eventually becomes detrimental, as was supported by the findings in those starting with higher SBP. This was supported by a recent study showing that those with previously elevated SBP were at greatest risk for having evidence of regional white matter changes that support executive cognitive function. In the groups with slowly and rapidly increasingly PP, there was a general pattern of less decline in cognitive function that was most pronounced in those starting at lower SBP. Our findings support speculation that an initial elevation in PP might in fact provide some protection against the effects of hypoperfusion on cognition, particularly in the oldest-old.

Using CRISPR to Attack Cytomegalovirus

Here, researchers discuss the use of the gene editing technology CRISPR to combat persistent herpesviruses such as cytomegalovirus (CMV). This is of interest as CMV is implicated in the age-related decline of the immune system, a large part of the frailty of old age. Near all people are infected by CMV by the time they reach old age, and ever more immune cells in the limited number that can be maintained become uselessly specialized to combat CMV, unavailable for other work. These growing efforts are futile, however, as CMV like all herpesviruses cannot be cleared by our immune systems.

What to do about this? Since CMV doesn't actually cause any harm in most people beyond this slow corruption of the immune system, the most straightforward approach is to clear out the unwanted immune cells, a goal that is becoming very plausible in this age of multiple approaches to targeted cell destruction. Clearing out CMV will only be helpful if it is done early enough, however, and the utility of that depends on the pace at which the damage is done. If, like many aspects of aging, damage occurs at a slow pace throughout much of life but accelerates dramatically after age 60 or so, then a therapy to remove CMV may be worth the effort if carried out early enough. If a patient's immune system is already greatly disordered by CMV, then removing the virus from the body won't make a great deal of difference. It won't put things back to the way they were before.

So far, treatment for herpesviruses has been incapable of fully eliminating the virus from its host, meaning the latent infection is lifelong. The virus continues to replicate, which results in flare-ups of disease symptoms in the host. Current treatment for herpesviruses simply mutes the disease symptoms during these flare-ups, but fails to fully eliminate the infection, which will remain latent throughout the life course. Researchers posited that the precision of CRISPR gene editing technology could break the DNA of a herpesvirus, thereby interrupting viral replication. Next, if CRISPR could reach and destroy all existing copies of the virus while also halting replication, then the infection itself could be eliminated.

The researchers tested their theory in three different strains of herpesviruses: Epstein-Barr virus (EBV), Herpes simplex viruses (HSV-1) and (HSV-2), and human cytomegalovirus (HCMV). The results indicate that CRISPR can be used to eliminate replication in all three strains of the virus, but that the technology was so far only successful in actually eradicating EBV. Researchers think this may be because the EBV genome is located in in dividing cells that are easily accessible to CRISPR. Comparatively, the HSV-1 genome targeted by CRISPR is located in closed-off, non-replicating neurons, which makes reaching the genome much more challenging.

"We first need to explore whether these potent anti-viral activities hold up in animal studies, and eventually humans before they may be applied as a future therapy. The first stop is to perform in vivo studies in animal models for these viruses. If these are successful, testing in humans may be the next step. However, there are several hurdles that need to be taken. I think the direct applications to treat EBV and HCMV infections may be challenging, as infected cells can travel to many sites in the body and are hence difficult to reach. For HSV-1, HSV-2, or VZV, delivery may be more straight-forward, as here the viruses reside in limited numbers of neurons at defined areas in the human body, such as the trigeminal ganglia. These sites may be reached by e.g. local administration of neurotropic viral delivery vectors. We envision that delivery of anti-viral CRISPR/Cas9 to latently infected cells may destroy the virus invader, curing the cell in question and preventing future outbreaks. Or, alternatively when we cannot remove the latent genome, pre-load the cell with an anti-viral mechanism that can target newly generated virus once the latent virus become activated. Hence, hopefully we can cure infected individuals, or prevent serious damage upon reactivation of these viruses."

CryoSuisse and the 1st International Cryonics Conference this November

At present there are only a few active cryonics providers, organizations that can cryopreserve an individual at death in order to maintain the structure of the mind indefinitely, waiting on a future in which the technology exists to allow restoration to active life. Cryonics offers the only shot at a longer life in the future for those who will age to death prior to the advent of working rejuvenation therapies. The odds are unknown, but certainly infinitely better than those associated with any of the other available options at the end of life. Most cryonics providers and their support organizations are in the US, and the oldest have been in business since the 1970s. Another more recently established provider operates in Russia. That leaves much of the world without any easy access to cryonics as a service, though volunteer organizations in a number of countries are working towards the establishment of providers at varying speeds and with varying degrees of success. One of the more recent of these is the European CryoSuisse, whose principals will be hosting the 1st International Cryonics Conference this coming November:

Cryonics is an experimental medical procedure to save human lives. Very low temperatures are used to effectively halt the time - for decades or centuries, until the day when the medicine of the future is capable of reviving the patient and cure his illnesses. Cryonics is based on the most recent insights of cryobiology and medicine. Already today, human embryos are routinely cryopreserved at low temperatures and re-animated later. Even for individual organs, cryonic techniques are already in use. A good cryopreservation of patients which today's medicine can no longer help is already possible. CryoSuisse, the Swiss Society for Cryonics, advocates the promotion, further advancement and practical application of cryonics - in order to give as many people as possible the chance to continue their lives in the future.

How does it work?

Nowadays, many serious illnesses can be cured which had been fatal as recently as one century ago (e.g., tuberculosis, smallpox or kidney failure). One can expect that medicine will proceed just as fast during the centuries to come. The cryonicist waits until the illness he suffered from can be cured. In other words, cryonics is an ambulance service through time.

Are the body tissues not destroyed by the cold?

At temperatures below 0 °C, water freezes into ice crystals. With their sharp edges, ice crystals destroy individual cells and tear tissues apart. Therefore, cryonics does not freeze the body, but vitrifies it. To this end, the bodily fluids of the human are replaced by cryoprotectants which protect the cells and prevent the formation of ice crystals. In this way, the body is transformed into a glass-like state where cells and tissues retain their original structures.

But can this glass also be converted into a fluid again?

Yes it can, this is scientifically proven. For example, researchers have thawed a kidney which had been vitrified at -130 °C and successfully transplanted it into a rabbit. The transplanted kidney recovered quickly to its normal function.

Then why is it that there are no reports about humans who were revived from this state?

Although some individual organs can already be cryopreserved, it has not been possible so far to cryopreserve a living being and revive it thereafter. There are several research programs to improve the technique though. Nevertheless, cryonics already makes sense: The fact that patients cannot be revived using today's techniques does not mean that it's not possible in future.

The Popular Press on the Goal of Slightly Slowing Aging

The popular press here covers the ambition of the scientific mainstream to modestly slow aging. Many researchers don't even want to talk about extending life, but only a small expansion of healthspan. This lack of ambition, and refusal to engage with the large body of evidence that suggests we can do far better, is why we need organizations like the SENS Research Foundation. It is possible and plausible to extend healthy life and overall lifespan indefinitely by implementing the approach of repairing the cell and tissue damage that causes aging. Yet all too much of the rhetoric and effort in the scientific community still goes towards tinkering with the operation of metabolism to slightly slow the pace at which damage accumulates - a clearly far inferior approach, that can at best produce only marginal outcomes.

With all of that, it is still a little odd to see senescent cell clearance, a part of the SENS repair strategy, showing up in articles like this, and given no greater weight than, say, treating people with metformin, which can't possibly have anywhere near as beneficial effect. Journalists typically don't distinguish between the potential value and outcome of different approaches to aging - it is all the same to them, just a flat list. That's something of a problem when the differences are enormously important and the expected outcomes are night and day. If there is to be significant progress towards healthy life extension in our lifetimes, the better strategies, those involving damage repair, must gain far greater support.

Imagine a day in the not-too-distant future. You're in your late 40s, and it's time for a special doctor's visit. The physician reviews your lifestyle, sleep habits and health history and orders some blood work to compare certain biomarkers with baseline measures taken when you were in your 20s. Then she gives you a personalized prescription for change that includes a diet that mimics the effects of fasting and a drug that helps your cells clear out malfunctioning proteins. The goal? To make you age more slowly and lengthen your "healthspan." If it sounds like science fiction, you're right - for now. But researchers in the field of geroscience, which explores the relationship between aging and diseases like cancer, heart disease and Alzheimer's, see that day coming. They are marshalling evidence that the same cellular processes that drive aging also result in those diseases, and that it's possible to slow the damage down. "The idea is that if you can treat the underlying causes of aging, you can delay all of these things as a group.That's a whole different way of thinking about medicine." The goal is not to extend lifespan, though that may indeed happen. Instead it's to extend the length of time you're healthy and active.

Working with a range of organisms from yeast to worms to rodents, scientists have homed in on several interrelated processes they suspect drive aging. Proteostasis, for one, is a fancy name for the quality-control system at work in your cells. Like a factory, a cell has ways to ensure the proteins it makes are up to snuff. If they're not, the malfunctioning proteins are supposed to be broken down and used to build new proteins or as energy. Researchers are looking for interventions, whether lifestyle or drugs, that might repair this age-related quality-control decline. Another area of exploration is inflammation. Low-grade, chronic systemic inflammation in the absence of an infection is a factor in most age-related diseases; it's even known as "inflammaging." The sources of it aren't well known, but scientists are investigating possible contributors, including a state called cellular senescence. Researchers wondered what would happen if senescent cells were removed. In mice, they've shown that certain drugs called senolytics can do just that - and slow the progression of age-related changes and even partially reverse them. Other drugs, too, are being eyed for their potential. A top contender, which has increased both lifespan and healthspan in mice by targeting a protein that controls key cellular functions, is rapamycin, used in people to prevent rejection of transplanted organs. Researchers now studying whether rapamycin has a similar effect in pet dogs, which might be great models for aging research because they share an environment with humans and are genetically varied.

Nampt Overexpression Reduces Age-Related Loss of Exercise Capacity in Mice

NAD, nicotinamide adenine dinucleotide, plays a central role in energy metabolism, and of late has attracted more attention from researchers who aim to modestly slow aging by adjusting the operation of metabolism. Tinkering with NAD levels though any number of different ways appears to produce some benefits in mice, but these are not sizable outcomes. Essentially this looks only incrementally better for normal animals than the marginal results produced for many forms of dietary supplementation in mouse studies.

Researchers examined the role of NAD precursor molecules on mitochondria by specifically disrupting the "NAD salvage pathway," in mouse skeletal muscle. This pathway consists of a series of enzymes that recycles building block molecules to make fresh NAD to power reactions throughout the cell, and especially within the mitochondria, the cell component that makes energy for the body from ingested food. Chemical reactions involving NAD are fundamental to metabolizing all fats and carbohydrates, yet NAD is degraded in response to such physiological stresses as DNA damage, and its concentration declines in several tissues over the natural course of aging.

The team generated mice in which they could restrict the amount of NAD in specific tissues in order to simulate this aspect of normal aging in otherwise healthy mice. Surprisingly, young knockout mice were found to tolerate an 85 percent decline in intramuscular NAD content without losing spontaneous activity or treadmill endurance. However, when these same mice hit early adulthood (three to seven months of age), their muscles progressively weakened and their muscle fibers atrophied. "Their muscle tissue looked like that of Duchenne muscular dystrophy [DMD] patients. The genes that were turned on and the presence of inflammatory immune cells in the muscles lacking NAD looked very similar to what we see in DMD." The team next sought to test whether a dietary NAD precursor might remedy the muscle pathology in the mice. The muscle decline was completely reversed by feeding the mice a form of vitamin B3, called nicotinamide riboside (NR).

Additionally, the team found that induced lifelong overexpression of Nampt, an enzyme important in making NAD, prevented the natural decline in NAD and partially preserved exercise capacity in aged mice. "This was supporting evidence that strategies to enhance muscle NAD synthesis might help to combat age-associated frailty." Researchers plan to follow up on the unexpected muscular dystrophy finding, asking if NAD is also depleted in some forms of dystrophy and if restoring NAD might help ameliorate certain features of the disease. Though the researchers previously found that enhanced NAD synthesis does not benefit muscle performance in young mice, these new findings suggest that it may be useful for combating age-related declines in muscle function.

Evidence for Senescent Cells to Contribute to Osteoarthritis

One way to demonstrate that senescent cells, whose numbers grow with age, do in fact contribute meaningfully to age-related disease despite making up only a small proportion of tissues, is to add more of them to an animal model via a cell transplant and then see what happens. Researchers here take that approach to show that senescent cells are one of the contributing causes of osteoarthritis. Various studies place the proportion of senescent cells in different tissues in older individuals of different species in a large range from 1% to as much as 20%, with lower numbers being more common. These cells secrete a mix of signals that cause inflammation and changes in the operation of surrounding cells and the structure of the nearby extracellular matrix. At present a couple of startup companies are working on the clinical development of means to clear senescent cells from the body, one of the first forms of rejuvenation therapy to reverse a root cause of aging, so we'll be seeing more of this sort of research in the next few years.

Researchers have reported a causal link between senescent cells - cells that accumulate with age and contribute to frailty and disease - and osteoarthritis in mice. "Osteoarthritis has previously been associated with the accumulation of senescent cells in or near the joints, however, this is the first time there has been evidence of a causal link. Additionally, we have developed a new senescent cell transplantation model that allows us to test whether clearing senescent cells alleviates or delays osteoarthritis."

Using the new model, researchers injected small numbers of senescent and non-senescent cells from ear cartilage into the knee joint area of mice. After tracking the injected cells in the mice for more than 10 days using bioluminescence and fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, they found that the injection of the senescent cells into the knee region caused leg pain, impaired mobility and characteristics of osteoarthritis, including damage to surrounding cartilage, X-ray changes, increased pain and impaired function. "We believe that targeting senescent cells could be a promising way to prevent or alleviate age-related osteoarthritis. While there is more work to be done, these findings are a critical step toward that goal."

The Anti-Inflammatory Approach to Treating Alzheimer's Disease

Inflammation in the brain contributes to the progression of Alzheimer's disease. This has been known for some time, but there has been surprisingly little progress in building anti-inflammatory treatments. Some years ago, one approach using existing anti-inflammatory drugs failed in clinical trials, for example. This might be explained by the fact that the immune cells of the brain are quite different from those of the rest of the body, and neuroinflammation is consequently different in its details when compared with inflammation in other tissues. Here, researchers are working on a similar approach that might have more success, but given the history to date optimism may be misplaced. Certainly moving towards rapid testing in humans for any results of this nature in mice that were obtained using existing drugs seems to be a sensible approach:

In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug (NSAID), and 10 mice were treated in the same way with a placebo. The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month. Memory loss was completely reversed back to the levels seen in mice without the disease.

"There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse. Our research shows for the first time that mefenamic acid can target an important inflammatory pathway called the NLRP3 inflammasome, which damages brain cells. Until now, no drug has been available to target this pathway, so we are very excited by this result. However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease. Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs. We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans."

Greenland Sharks Live for Centuries

There are many species for which maximum or even average life span is a question mark. This is a combination of too many species and too few researchers, especially when it comes to marine life, and the fact that for some negligibly senescent species there is no good way to measure age. Their vital statistics and biochemistry change so slowly over time that any estimate may be half a life span removed from the reality. This was the case for lobsters until quite recently, for example. In the research noted here, scientists attempt an new method of age estimation for Greenland sharks, another case in which determining the age of individuals - and thus the species life span - is both quite difficult and little worked on:

A large, almost-blind shark that lives in the freezing waters of the North Atlantic and Arctic oceans is officially the world's longest-living vertebrate. The Greenland shark (Somniosus microcephalus) has a lifespan of at least 272 years, and might live as long as 500 years1. That is older than the 211-year lifespan of the bowhead whale (Balaena mysticetus), the previous record-holder in the scientific literature. It also beats the popular - but unconfirmed - tale of a famous female Koi carp called Hanako, who supposedly lived to 226 years old. Marine scientists already knew that the Greenland shark was long-lived. The fish are enormous but grow slowly, suggesting a long lifespan. Adult Greenland sharks have been measured at more than 6 metres long - and researchers think that they could grow even longer. One 1963 study estimated that the species grows at less than 1 centimetre per year. Getting a definitive measure of the shark's age, however, has proved tricky. Conventionally, researchers count layers of calcified tissue that grow on a fish's fin scales or other bony structures - rather like counting tree rings. But Greenland sharks have small, spineless fins, and their vertebrae are too soft for countable layers to be deposited.

To assess age, the team decided to measure levels of radioactive carbon-14 in fibres in the centre of the shark's eye lens. Such measurements reflect levels of radiocarbon in the ocean when the lens was first formed. Measurements of 28 female Greenland sharks, made during surveys in 2010-13, suggested that the largest of them (at 5.02 metres long) must have been between 272 and 512 years old at the time. The shark's longevity probably arises because it expends very little energy, owing to its cold body temperature and enormous size. Not all cold, large species live to such an exceptional age, so it would be intriguing to know whether the shark has any particular quirks or molecular tricks that contribute to its long lifespan. The study also shows that Greenland shark females don't reach sexual maturity until around 150 years old - suggesting that a century of heavy fishing could wipe out the entire species.

Radical Life Extension is the Right Idea

Here I'll point out an article of mixed quality - there's plenty to complain about, regardless of your views - but let me direct your attention to the core point being made, rather than the wrapping of that point, which is that working to end aging and greatly extend life is the most rational response to the situation we all find ourselves in. Radical life extension is the name given to the goal of postponing the degeneration, medical conditions, and death due to aging for decades or more, living far longer in good health. This outcome will require rejuvenation therapies that can repair the known forms of cell and tissue damage that cause aging. The first of these therapies are presently in development, the rest at various early stages in the laboratory. This should be a cause for celebration, massive funding, and accelerated development, but sadly not everyone considers it obvious that we should be heading down this road. The response from the average person in the street is usually that of course he or she doesn't want to live any longer than his or her parents, that of course this person wants to age and die on schedule. Yet that very same person will take full advantage of medical science now and in their old age. That striving to put an end to the suffering and death of aging is widely considered fringe or outlandish, that we have to advance arguments and advocacy to make progress towards this goal, is another sign that we humans are just not particularly rational.

Peter Thiel has plenty of crazy ideas, but his commitment to radical life extension isn't one of them. He has invested millions in the Methuselah Foundation and SENS Research Foundation, research organizations dedicated to extending the human lifespan by advancing tissue engineering, genomics, and regenerative medicine. Now, while much of the mainstream media will try to discredit the tech mogul on this seemingly outlandish issue, I'm not one of them. On this point, the man is right on target. Death is awful, and we need to get rid of it sooner rather than later. We also need to lose this idea that not wanting to die is somehow crazy or deviant. Not wanting to die is actually one of the most rational beliefs a person can have.

Thiel is not alone in his desire to stave off death. Inspired by advances in genetics, regenerative medicine, cellular biology, and cybernetics, an increasing number of people are calling for an end to aging and mortality. Aging, these self-proclaimed immortalists claim, is a disease that can and should be stopped. They argue that it's not an inexorable process, and that the human body, like any other machine, can be modified and restored to a former glory. And indeed, the science is starting to bear this out. There are things we can do to dramatically slow down aging, from the use of advanced "senolytic drugs" and the destruction of worn-out cells, through to mitochondrial and blood rejuvenation therapies. And by studying supercentenarians, we're learning about the genetic prerequisites for a long and healthy life.

Armed with these and other tools, doctors of the future will matter-of-factly prescribe these therapies to extend the lifespans of their patients. To do otherwise would be a violation of that famous oath they all take upon graduation. Organs worn out? Perhaps it's time to grow some new ones. Cells not reproducing properly? Let's replenish them with younger versions. Brain cells failing? Get yourself some synthetic replacements. Indeed, this tired idea that we'll eventually come up with some sort of magical longevity pill is nonsense; radical life extension will come in the form of multiple interventions and procedures, and few will question it.


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