Fight Aging! Newsletter, April 27th 2015

April 27th 2015

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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  • Supercentenarians Awards: a Million for the First 123-Year-Old
  • The Dearth of Altruism, the Calculation of Self-Interest
  • Calorie Restriction Makes Old Muscle Metabolism More Youthful
  • Rejuvenation Biotechnology Update for Q2 2015
  • Telomerase Therapies and Cancer Risk
  • Latest Headlines from Fight Aging!
    • A Possible Path to Prevent Scarring in Mammals
    • A Possible Cause Identified for the Decline in Natural Killer Cells in Old Mice
    • On Targeting Secretase in Alzheimer's Disease
    • Nebulous Opposition to the Defeat of Aging
    • An Interview with Aubrey de Grey
    • Economic Level and Human Longevity
    • Aging as Neither Failure nor Achievement of Natural Selection
    • Towards a Platform for Cost-Effective Personalized Cancer Immunotherapy, Tailored to the Patient and Tumor
    • DNA Damage and Interferon in Aging
    • Even Perception of Food Scarcity Modifies Metabolism in Short-Lived Species


Dmitry Kaminskiy of Deep Knowledge Ventures is one of a small group of technology entrepreneurs turned venture investors with a strong interest in bringing aging under medical control. I think the size of this group will grow in the future: many of the wealthy individuals you see in the press today talking about longevity science, such as Kaminskiy, Peter Thiel, Paul Glenn, and those steering Google Venture's Calico initiative, have been involved less vocally for years behind the scenes. Thiel has funded SENS rejuvenation research for the past decade, while Kaminskiy has been a trustee of the Biogerontology Research Foundation for some years, for example. Glenn was far ahead of both of them, but has never seemed particularly interested in making a big splash of the work of his foundation outside the scientific community: he continues to establish and reinforce funding for aging research labs year after year.

One of the big shifts in longevity science and its perception over the past couple of years has been the move from quiet support to vocal support, with a corresponding rise in accompanying press attention and public statements of intent from influential individuals. This is all to the good. It grants greater legitimacy to the field in the eyes of those who care more about opinion than fact, which sadly includes the controllers of most sources of large-scale funding. Other quiet supporters are more likely to speak out themselves. This all makes it easier for researchers in the field to raise funding. It also makes it easier for grassroots efforts to gather more supporters and raise more money for the cause. This change in the environment is a necessary step towards taking the defeat of aging, and the prospect for real, working rejuvenation treatments, from something that the average fellow in the street laughs at to something that is as widely supported as cancer research is today.

This leads me to note Kaminskiy's latest advocacy and awareness initiative, a one million prize to be awarded to the first individual verified to reach 123 years of age, beating the record set by Jeanne Calment almost twenty years ago now:

Supercentenarians Awards

Dmitry Kaminskiy will present a one million prize to the first man or woman to reach the age of 123. The current longevity record is held by Jeanne Calment, who lived for 122 years and 164 days. Those with the highest odds of besting Calmant's record can be found among today's elderly population with proof of age recorded by either the Gerontology Research Group, Max Plank Institute for Demographic Research, or Guinness World Records.

The goals of this prize are to raise awareness of issues related to longevity and encourage people to take measures to extend their own lives and youth, encourage progress by drawing the attention of the scientific community to longevity issues, and stimulate business activity and institutions in the fields of health and gerontology.

As advocacy goes, this seems a fairly shrewd approach if kept fresh and well publicized. Nothing of this ilk has been tried before in the longevity science community for all the obvious reasons: people who might reach a new record longevity in the next decade will likely do so in isolation of any relevant modern efforts in the scientific and medical community. Rewarding long-lived individuals is very distant from any focus on research and medical development relevant to rejuvenation, especially if talking about how long someone presently older than 110 might live. Nonetheless, I think you'll agree that this could be a great source of recurring press and public attention if well managed.

Further, the initiative seems unlikely to cost Kaminskiy the one million prize at any point in the near future, which is always an important consideration when thinking about whether or not such an education and awareness effort is worthwhile. By a peculiarity of fate, Jeanne Calment's lifespan was a good three years longer than that of Sarah Knauss, the second longest lived individual with verified records to prove it. In turn, Knauss herself lived for a year and a half out beyond the life spans of the next few record individuals. Anywhere past 110 years of age the mortality rate month by month is enormous, never mind year by year. For people this frail and damaged by age, balanced on a knife-edge of chance and fragility, it seems unlikely that any of the initial implementations of prospective treatments for aging, those currently under development or in the laboratory, could be safely applied any time soon. There is a world of difference between trying to apply stem cell treatments or infusions or medical nanotechnology in a 70-year-old versus a 110-year-old: the latter will be much, much harder.

So, all things considered, I'll watch this prize effort with interest. It is one of many signs of the times, that the early days of the change years are upon us, in which treating aging so as to prevent degeneration and greatly extend healthy life span will move from fringe concern in the scientific community to mainstream research goal, widely supported and appreciated, and massively funded. There is a way to go yet, but this is the time for it. The first seeds are growing.


The latest edition of Rejuvenation Research is assembled online. I thought I'd direct your attention to this thought for the day paraphrased from Aubrey de Grey's editorial:

Let's start with Pasteur. Few would deny that the adoption of rigorous sterility in medical practice, arising from Pasteur's germ theory, saved an absolutely astronomical number of lives. However, any reasonable estimate of the lives Pasteur himself saved must take into account an estimate of how soon his successor would have come along. It wasn't a matter of whether lives would be saved, but when.

So it is with today's progress against aging, but more so, because we have an additional dimension of uncertainty. Pasteur's advance did not require development time: as soon anyone wanted to be more hygienic in their medical practice, they could be. In the matter of aging we are today faced with a very large research agenda that must be completed before we can deliver actual therapies, and, as is the nature of research, we do not remotely know how long it will take. Pasteur's insight led to saved lives starting almost at once, but no amount of additional effort injected today into anti-aging research will save any lives at all for quite some years. And additionally, the date at which such an effort would start saving lives is highly uncertain.

Which brings me back to funding. Time and again I encounter people (high net worth and otherwise) who are provisionally interested in funding anti-aging research, but whose interest, when push comes to check-writing shove, is somehow contingent on being (with substantial probability, anyway) beneficiaries of its success. How crazy is that?

Altruism is rare in comparison to self-interest, and people want silver bullets now. As illustrated, even a vague hope of the existence of a silver bullet, somewhere, perhaps soon, will cause people to pass over the best of present opportunities, things that require work and are no sure thing. Everything worthwhile requires work in this life, and I've certainly never seen a sure thing in any of my endeavors. That is the way most people think, however.

Those who choose not to support de Grey's vision for rejuvenation biotechnology, the work organized by the SENS Research Foundation, are indeed passing on the best shot at accelerating progress towards the medical control of aging. No other coordinated program is anywhere near as promising. True enough, the stem cell and cancer research communities are making some progress on their slices of the overall rejuvenation toolkit, largely as a side-effect of being very large and very well funded, but much of the interest in intervention in aging research remains focused on classes of potential treatment that cannot plausibly do more than slightly slow down the aging progress. Even achieving that modest goal will be painfully expensive, slow, and uncertain because it requires safely reengineering the operation of our metabolism so as to slow down damage accumulation. Metabolism is fantastically complex and decades of work yet remain to make even a dent in the vast unknown areas yet to be mapped. In comparison, SENS focuses on damage repair without metabolic alteration, and far more is known about the damage that causes aging. Thus the best approach is for the damage of aging to be repaired, not merely slowed, yet all too few organizations other than the SENS Research Foundation are trying to make that a focus.

We live in a world full of individuals who would write checks to further rejuvenation research and the development of treatments for aging if they could see it was a sure thing, if they could be certain that they would benefit. This is some subset of the majority of people who would certainly choose to buy rejuvenation treatments if they were widely available today. Unfortunately the size of bank accounts tends to scale with age: the majority of individuals wealthy enough to fund significant chunks of a research program are unlikely to benefit personally from supporting medical research into methods of rejuvenation. They don't have the time to wait for the results and the cycles of development and the clinical translation of research and so forth. So they choose to do other things with their funds. Progress depends, as ever, on the unreasonable minority possessed of altruism enough to care more about the rest of the world than themselves, or given drive and fortune that made them wealthy enough while still young enough to think that they might benefit.


The rudiments of rejuvenation treatments that will emerge in the 2020s and 2030s are presently under development at an early stage in the laboratory, largely with very limited funding and attention. It is true that those portions of the rejuvenation toolkit envisaged by the SENS Research Foundation that involve stem cells are far ahead of the pack in terms of the pace of development and the availability of first generation treatments. For the rest of it, however, all of the other varied technologies needed to repair the causes of degenerative aging, even where there are real and exciting signs of progress, as is the case for clearance of senescent cells, it will be years yet before the first reliable, partially effective treatments are available even via medical tourism.

It is a strange thing indeed for a basically healthy individual to stand in the midst of revolutionary progress in biotechnology, at a time when the research community is finally turning its attention to treating aging as a medical condition, and yet have few new tools available now to improve the odds of living a longer, healthy life. Today's middle-aged individuals can get stem cell treatments for their joints and have easy access to much more reliable data on the benefits of exercise and calorie restriction, but other than that they aren't all that much better off in comparison to their counterparts of half a century past. All of the diffuse advantages of fifty years of progress in medicine has provided perhaps five years of additional remaining life expectancy in middle age. When it comes to what you can choose to do here and now to make a difference in your long-term health the biggest tangible gains still emerge from regular moderate exercise and the practice of calorie restriction.

Calorie restriction has been shown to extend life in near all species examined, and in those where it is most examined, such as in mice, it has been demonstrated to slow near all measures of degenerative aging. Undertaking calorie restriction clearly doesn't have the same effect on maximum life span in humans as it does in mice - we'd have noticed centuries ago if restricting calories while maintaining good nutrition could reliably add decades to life spans. It does, however, improve all of the short term measures of health in humans to much the same considerable degree it does in shorter-lived species, provides resistance to age-related disease, and improves long-term health to a greater degree than any presently widely available medical technology. Will it give you good odds to living to see 90? No. Even today, three-quarters of the healthiest people die before reaching 90. What calorie restriction will do, however, is give you a better chance of living to benefit from the rejuvenation treatments of the future. In an age of rapid progress in medicine a year gained here or a year gained there can be a big deal.

Here is an example of the sort of benefits provided by calorie restriction, in this case with a focus on the metabolism of muscle tissues and the way in which it changes with age. Like many other studies, it demonstrates that it is never too late to start trying calorie restriction. You'll most likely be better off than if you chose not to:

Caloric Restriction: A Fountain of Youth for Aging Muscles?

Calorie restriction is thought to have a protective effect on muscle cells and may help cells better use antioxidants, avoid damage caused by free radicals and function better. While studies that observed the effects of lifelong calorie restriction have shown mixed results in animals of different ages, recent studies have suggested that age may play a role in how CR affects individual animals. The research team hypothesized that because CR can help reprogram metabolism, the most benefit can be reaped from aging muscles in which cellular metabolism is impaired.

Researchers focused on two pathways that produce energy in muscles, glycolysis (sugar metabolism) and mitochondrial oxidative phosphorylation (OXPHOS) in both young and middle-aged rats that were fed a normal diet or a calorie-restricted diet. In the 14-week study, rats on the calorie-restricted diet received 10 percent calorie restriction in the first week, 25 percent restriction in the second and 40 percent restriction for the remaining 12 weeks. The control rats received no calorie restriction. After 14 weeks, the researchers studied changes in the rats' muscles.

"We investigated whether CR reprogrammed muscle metabolism and whether this improvement was associated with the observed increase in muscle mass. In addition, we examined whether the CR-induced changes were age-dependent." Not surprisingly, the middle-aged rats had less muscle mass than the young rats did. However, while 14 weeks of calorie restriction did not significantly affect the middle-aged rats, it reduced muscle mass in the young rats. Calorie restriction slowed the glycolytic rate in the muscles and increased the cells' dependency for OXPHOS versus glycolysis in older rats, which was linked to improvement of normalized muscle mass. The team also found that "14 weeks of CR reprogrammed cellular metabolism, where the relative contribution of OXPHOS and glycolysis in muscles of middle-aged rats with CR was similar to that in muscles of young rats."

Late-onset Caloric Restriction Alters Skeletal Muscle Metabolism by Modulating Pyruvate Metabolism

Caloric restriction (CR) attenuates age-related muscle loss. However, the underlying mechanism responsible for this attenuation is not fully understood. This study evaluated the role of energy metabolism in the CR-induced attenuation of muscle loss. The aims of this study were two-fold: (1) to evaluate the effect of CR on energy metabolism and determine its relationship with muscle mass, and (2) to determine whether the effects of CR are age-dependent.

Young and middle-aged rats were randomized into either 40% CR or ad libitum (AL) diet groups for 14 weeks. Major energy-producing pathways in muscles, i.e., glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), were examined. We found that the effects of CR were age-dependent. CR improved muscle metabolism and normalized muscle mass in middle-aged animals but not young animals. CR decreased glycolysis and increased the cellular dependency for OXPHOS versus glycolysis in muscles of middle-aged rats, which was associated with the improvement of normalized muscle mass.

The metabolic re-programming induced by CR was related to modulation of pyruvate metabolism and increased mitochondrial biogenesis. Compared to animals fed AL, middle-aged animals with CR had lower lactate dehydrogenase A content and greater mitochondrial pyruvate carrier content. In conclusion, 14 weeks of CR improved muscle metabolism and preserved muscle mass in middle-aged animals but not in young, developing animals. CR-attenuated age-related muscle loss is associated with reprogramming of the metabolic pathway from glycolysis to OXPHOS.


The Methuselah Foundation and SENS Research Foundation collaborate to put out a quarterly newsletter for members of the 300, people who pledge to donate to research and development aimed at extending healthy life spans. The 300 are the individuals that kick-started the Methuselah Foundation more than a decade ago, when it was just a few determined individuals setting out to change the aging research community from the outside, back before SENS research programs were any more than a vision statement, and when talking about extending healthy life spans was frowned upon by gerontologists. A great deal has changed since then. The tenor of the research community is very different today, many scientists and philanthropists talk openly about tackling aging as a medical condition, and a great deal of early stage progress has been made in the laboratory. Something approaching thirty million has been raised by the Methuselah Foundation and SENS Research Foundation since the early days and invested in SENS, organ engineering, and diverse other initiatives in longevity science.

The quarterly Rejuvenation Biotechnology Update is aimed at keeping people in the loop, those who support the end goal but who don't keep up with research news on a week to week basis. It is good to show that progress is underway, that the funding provided to the Methuselah Foundation and SENS Research Foundation is not just used well in the immediate sense, but that it is also inspiring greater funding and progress on the part of other organizations and research groups. There are more than enough resources and researchers in the world to defeat aging within our lifetimes via repair strategies such as SENS if people put their minds to it, if a grand scientific endeavor of a size comparable to the stem cell or cancer research fields is formed soon enough. The real challenge at this stage lies in persuasion, spurring the will and the choice to seek greater healthy longevity and the defeat of aging.

Rejuvenation Biotechnology Update, April 2015 (PDF)

The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs

As organisms age, cells begin to accumulate that display a specific phenotype termed "senescence." Senescent cells do not divide, but they also do not carry out their normal function, and do not die. This may not be much of a problem in and of itself, except that these cells are not just passive bystanders, harmlessly "hanging around." Rather, they secrete hormones and cytokines that influence the surrounding tissue and the organism as a whole, and may increase inflammation and make the organism more prone to the development of cancers and other diseases. Specific examples of cell types that can become problematic senescent cells include those in human fat, skin, and connective tissue throughout the body. One goal of SENS Research Foundation is the development of ways to remove senescent cells.

In this study, researchers tested two drugs, quercetin and dasatinib, and found that they killed senescent cells, first in cell culture, then in mice who had a high burden of senescent cells because of being chronologically aged, exposed to radiation, or carrying a genetic mutation. More importantly, the killing and removal of senescent cells by these drugs in the mice led to functional improvements, such as better cardiovascular function, improved limb strength, and an increase in their "healthspan," or healthy life.

This finding is exciting. The two drugs tested in this study, quercetin and dasatinib, each had different "profiles" of which senescent cell types they were most effective at killing. They were tested in the mice in combination, but it is also conceivable that each might be effective individually. We are eager to see future studies reveal additional compounds that can eliminate other specific types of senescent cells. New drugs could then be combined with the two tested here for an even more powerful drug regimen that "covers all the bases" in getting rid of many types of senescent cells. Alternately, the drugs could be used individually in a personalized medicine approach, depending on what type of senescent cells are most problematic for the human patient. The ability to remove senescent cells in humans could be expected to affect tissues such as skin, fat tissue, and connective tissue, and may reduce body-wide inflammation, thereby potentially improving inflammatory conditions.

New α- and γ-Synuclein Immunopathological Lesions in Human Brain

Several degenerative brain disorders (sometimes collectively referred to as "synucleinopathies") are defined by the presence of clumps of a protein called α-synuclein. Recent evidence has surfaced (for a detailed summary, see "Bold Leaps Forward for α-Synuclein Immunotherapy") indicating that α-synuclein aggregates are not only involved in diseases which feature Lewy Bodies, but also in functional impairments in humans who have not yet developed these diseases. There are two vaccines currently in human clinical trials, aimed at clearing α-synuclein aggregates, which will hopefully lead to restoration of function. This is an area of particular interest for SENS Research Foundation, since one of the main strategies in the SENS platform is the cleanup of "intracellular junk," such as protein aggregates like α-synuclein and β-amyloid. This strategy follows from the general principle that underlies all SENS strategies: identify aging damage in the body, and repair the damage once it is present.

This study suggests that in addition to α-synuclein, γ-synuclein or hybrid α-/ γ-synuclein aggregates could be targeted for cleanup to treat synucleinopathies, or even restore the integrity of the brain in aging people who can't be formally diagnosed with these diseases. It remains to be seen whether doing so would be able to restore normal function to the brain in cases where an overt disease like Parkinson's has developed, but results from studies where vaccines were used to induce the organism's immune system to clear α-synuclein aggregates from the brain suggest cause for cautious optimism.

Whole Genome Sequencing of the World's Oldest People

In this study, researchers sequenced the genomes of 17 people who were over the age of 100. These individuals' ages were validated by documents such as birth certificates, marriage certificates, or current passports (an important step; it can be difficult to verify the ages of very old individuals because analog records are easily lost over time or contain erroneous information). They compared their genomic sequences, looking for any genetic variants that changed the structure of a protein and were found among the cohort of supercentenarians, but not in a control group who did not live over 100 years. The authors did not find any such genetic variants.

Although the authors did not find a specific gene variant associated with extreme longevity, their findings could be interpreted in a very hopeful way: this study provides evidence that it is not necessary to have been lucky enough to be born with some specific genetic variant in order to become a supercentenarian. We don't know what genetics confer the best chance of a long life, but at least we haven't yet found any gene that rules us out from having the chance to become a supercentenarian if we lack it.


To date progress in the development of stem cell treatments has been accompanied by a markedly lower risk of cancer than was expected at the outset. The characteristic decline in stem cell activity with age is believed to be an evolutionary adaptation that reduces cancer risk: there is a balance between on the one hand the risk of cancer due to over-active damaged cells, and on the other hand the failure of tissues and organs due to loss of maintenance activities on the part of stem cells. It is the responsibility of stem cells to deliver supplies of fresh, fit cells as needed to replace those that have become damaged, worn, or have reached the inherent limits imposed on replication of somatic cells. That supply tapers off in old age, however, as stem cells gather damage and spend ever more time quiescent rather than active.

Despite the comparative lack of cancer resulting from stem cell therapies, there is still every reason to expect that caution should attend the development of any therapy that spurs greater regeneration in old tissues. The cells in those tissues have a higher load of nuclear DNA damage, and thus a greater cancer risk attends their activity. Yet in practice it isn't working out to be as great a risk as expected, or at least not so far based on the data gathered to date. Why this is the case is an interesting question with no solid answer at this time.

The replication limits of somatic cells depend in part on telomere shortening. Telomeres are repeated lengths of DNA at the ends of chromosomes. A little of that length is lost with each cell division, and very short telomeres trigger cellular senescence or programmed cell death. In comparison stem cells retain long telomeres, and thus the ability to continually create new daughter somatic cells with long telomeres to deliver into the tissues they support. This maintenance of telomere length in stem cells is achieved through the activity of telomerase, an enzyme that adds repeated DNA sequences to the ends of chromosomes.

Based on all of the above, it is not unreasonable to expect that more telomerase activity in more cells would mean a greater risk of cancer. It would mean cells being more active, and older, more damaged cells being more active. In mice, however, this is not what happens. The risk of cancer actually falls, even as life span is lengthened: researchers believe there is increased stem cell activity and tissue maintenance, but not enough time in even the extended mouse life span for the other shoe to drop and cancer risk to catch up. A firm and comprehensive analysis of what exactly is going on inside these mice is probably still a few years away, however. Nonetheless, the picture painted above suggests that we should be cautious about extrapolating a beneficial balance of time and cellular activity in mice to indicate that telomerase treatments would be similarly great for humans. The span of time is different, our telomere biology is different, and the balance of aging and cell activity is different.

On the other hand, the medical community seems to be doing pretty well with stem cell treatments that are just another way of spurring increased cell activity and tissue maintenance in old, damaged tissues. Enhanced telomerase activity seems worthy of further investigation for all the same reasons that stem cell therapies were worthy of clinical development. I don't see telomerase therapies as a treatment for aging per se, however. The approach of increased telomerase activity doesn't address the underlying issues that cause stem cell decline, but instead forces damaged cells to get back to work by overriding the normal reactions of an aged biochemistry. In the view of aging as accumulated cellular damage, stem cell failure with age is an evolved reaction to an increasingly damaged tissue environment. The best way forward is to repair that environment, not override the signals. As first generation stem cell treatments have shown, however, it is possible to achieve beneficial results by taking this path, even while failing to address the root causes of aging. Benefits are good, but we shouldn't let them distract us from the end goal.

Telomerase does Not Cause Cancer

I am one of a growing minority of life extension scientists who believe that telomerase may be our most promising, near-term path to a major boost in the human life span. Notably, almost all the scientists who specialize in telomere biology have come to this opinion. But research investment in this strategy has been limited and the main obstacle has been fear of cancer. Back in 1990, a young Carol Greider was the first to float the idea that the reason that man and most other mammals have evolved with short telomeres is to help protect against cancer. Independently in 1991, senior geneticist Ruth Sager proposed the same hypothesis with more detail, citing circumstantial evidence. Inference of evolutionary purpose is of necessity indirect.

The idea that lengthening telomeres poses a danger of cancer took a life of its own, based on marginal experimental data and firm grounding in a theory that is fundamentally flawed. It is now taken for granted in publications, and only token documentation and no reasoning is provided when this view is asserted. I believe that this concern is misplaced, that activating telomerase will actually reduce net cancer risk, and that the fear of cancer is damping the enthusiasm that telomere science so richly deserves.

I have written a technical article on this subject. There are forces at work here in opposite directions:

(Bad #1) Once a cell becomes cancerous, it can only continue to grow if it has telomerase. So giving the cell telomerase removes one barrier to malignancy.

(Bad #2) Secondary to its role in growing telomeres, the telomerase component hTERT also functions as a kind of growth hormone, that can promote malignancy.

(Good #1) The body's primary defense against cancer is the immune system. As we get older, our blood stem cells slow down because their telomeres are too short. Telomerase rejuvenates the immune system, and helps the body fight cancer before it gets started.

(Good #2) When telomeres in a cell get too short, the cell goes into a "senescent" state, in which it spits out hormones (called "cytokines") that raise inflammation throughout the body and damage cells nearby. Telomerase protects against this.

(Good #3) When telomeres in a cell get too short, the cell's chromosomes can become fragmented and unstable, and this can lead to cancer. Telomerase protects against this.

I believe that the three "goods" far outweigh the risk from the two "bads". In animal experiments this seems to be the case, and I think that the "theoretical" reasons for concern are based on discredited theory. Of course, we won't know for sure until we have more experience with humans.

It's a modestly long post, and worth reading. Bear in mind the author is coming at this from a programmed aging point of view, however. In this perspective, aging is not an accumulation of cell and tissue damage that leads to dysfunction, but is rather an evolved program of dysfunction that causes cell and tissue damage. In the programmed aging view, the right approach to treating aging is to alter levels of proteins to make the cellular environment more youthful in appearance, at which point damage will be repaired. In the aging as damage viewpoint, tinkering with the cellular environment has only limited utility and the right approach is to repair damage. Given sufficiently good repair, the reactions to damage will cease and the tissue environment will become more youthful in operation and appearance.


Monday, April 20, 2015

Scarring occurs in mammals but not in highly regenerative species such as salamanders. Some research results from past years suggest that scar formation isn't an essential part of the mammalian healing process, such as the ability of MRL mice to heal minor wounds without scars. Here researchers report on initial progress towards a potential means of suppressing scar formation:

Scars are comprised mainly of collagen, a fibrous protein secreted by a type of cell found in the skin called a fibroblast. Collagen is one of the main components of the extracellular matrix - a three-dimensional web that supports and stabilizes the cells in the skin. "The biomedical burden of scarring is enormous. About 80 million incisions a year in this country heal with a scar, and that's just on the skin alone. Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack."

In late 2013, a study showed that fibroblasts in the skin of mice arise as two distinct lineages. One, in the lower layer of the skin, mediates the initial steps of repair in response to wounding. Researchers wondered whether this fibroblast type, which expresses a protein called engrailed, could be responsible for the collagen deposition that leads to scarring. They generated genetically engineered mice in which the cells, called EPF cells for "engrailed-positive fibroblasts," were labeled with green fluorescent protein to allow tracking of the cells' location during the animals' development. The cells were also engineered to carry a "kill switch" that could be activated by the presence of diphtheria toxin, which would allow the researchers to assess how wounds healed in the absence of EPF cells.

The researchers found that the proportion of EPF cells, compared to the overall number of fibroblasts in the skin on the backs of the animals, increased dramatically from less than 1 percent in 10-day-old embryos to about 75 percent in mice that were 1 month old. The researchers also found evidence pointing to a major role for EPF cells in scarring. After diphtheria toxin was applied to wounds on the backs of mice, the wounds healed with less scarring. "The EPF cells are clearly responsible for the vast majority of scarring." Complete healing in the diphtheria-toxin-treated wounds required an additional six days compared to controls, but much of the repaired skin looked and appeared to function normally. In contrast, scarred skin is frequently less flexible and weaker than uninjured skin.

When the researchers analyzed the EPF cells more closely, they found that they express a protein called CD26 on their surface. CD26 activity has been implicated in the metabolism of many hormones, including insulin, and the human version of the protein is a target for inhibitors such as sitagliptin and vildagliptin that are marketed for treating low blood sugar levels in people with type-2 diabetes. The researchers found that a small molecule that blocks the activity of CD26 also reduced the amount of scarring in a manner similar to that seen when EPF cells were eliminated. In particular, scars that formed on wounds treated with the CD26-inhibitor covered an area of only about 5 percent of the original wound. In contrast, untreated skin formed scars that covered over 30 percent of the original wound area.

Monday, April 20, 2015

The aging immune system becomes dysfunctional and inefficient for a number of reasons, such as too many cells in its limited repertoire becoming specialized memory cells, leaving too little capacity for the killer T cells responsible for destroying pathogens. That is a problem of the adaptive immune system, but the innate immune system has its own distinct issues. The innate immune cells analogous to killer T cells are known as natural killer (NK) cells; their numbers and functionality decline with aging, making the innate immune response ever less effective. In the research quoted below researchers are coming close enough to root causes for natural killer cell dysfunction to begin attempting interventions aimed at specific cellular mechanisms, though as yet without success:

While it is now well established that in mice and humans NK cells become dysfunctional with age, the whole scope of the dysfunctions and the underlying mechanisms remain unknown. Here, we characterized the impairment of NK cells of aged mice to a greater extent than before, demonstrated that the origin of the defect is in the stroma of the bone marrow. We have previously reported a decreased number of total NK cells in the blood and spleen and reduced frequencies of mature NK cells in the blood, spleen, lymph nodes, and bone marrow of aged mice. Here, we expanded this finding by demonstrating that immature NK cells in the aged mice proliferate poorly, have additional characteristics of immature cells including decreased KLRG1 and increased CXCR3 expression, and dysregulated expression of Eomes and several inhibitory and activating receptors. Expression of activating and inhibitory receptors was also altered with aging, but the reason and functional consequences of these changes remain to be elucidated.

Our analysis of mixed bone marrow chimeras showed that the deficiencies of the NK cells in aged mice are not due to intrinsic defects of the hematopoietic precursors but due to an inadequate stroma. A characteristic of aging is the decline of lymphopoiesis and an increase in myelopoiesis. The main mesenchymal cell types in the bone marrow that regulate hematopoiesis are osteoblasts and adipocytes. Osteoblasts are essential for lymphopoiesis, while bone marrow adipocytes are known to suppress lymphopoiesis and promote myelopoiesis. Moreover, a deficit in osteoblasts results in decreased numbers of hematopoietic stem cells in the bone marrow. Increased bone marrow adipogenesis and decreased proliferation and maintenance of osteoblasts are characteristics of aging.

Our data show that developmental defects in NK cells of the aged are due to deficiencies in the mesenchymal stromal cells of bone marrow but not due to the hematopoietic stem cells. These defects are the consequence of deficient maturational cues provided by bone marrow stromal cells. Notably, the mesenchymal stromal cells are responsible for the production of type I and type IV collagen in the bone marrow. Our data showed that NK cells in aged mice have low expression of α2β1 (CD49b CD29) integrin, receptor for type I collagen with reciprocal increases in expression of α1β1 (CD49a CD29) integrin, and receptor for type IV collagen. Whether these findings are causally related and whether the interaction of developing NK cells with collagen in the bone marrow is required for proper NK cell maturation need to be further explored.

Tuesday, April 21, 2015

The slow progress towards viable therapies for Alzheimer's disease based on clearance of β-amyloid, such as via immunotherapy, has led to a broadening of approaches. Many research groups are looking at other theories on causative mechanisms and other targets for the development of treatments:

Alzheimer's disease (AD) is the most common form of dementia in the elderly and its prevalence is set to increase rapidly in coming decades. However, there are as yet no available drugs that can halt or even stabilize disease progression. One of the main pathological features of AD is the presence in the brain of senile plaques mainly composed of aggregated β amyloid (Aβ), a derivative of the longer amyloid precursor protein (APP). The amyloid hypothesis proposes that the accumulation of Aβ within neural tissue is the initial event that triggers the disease. Here we review research efforts that have attempted to inhibit the generation of the Aβ peptide through modulation of the activity of the proteolytic secretases that act on APP and discuss whether this is a viable therapeutic strategy for treating AD.

From the information reviewed here it remains far from certain whether targeting the secretases involved in APP processing will yield the ground breaking therapeutic that is urgently required to treat AD. The number of high-profile failures in recent years has severely impacted the confidence of large pharmaceutical companies in the continuation of research and development programs in the neuroscience area and a number of companies have scaled back their risk in this field. Further high profile clinical failures could potentially result in the withdrawal of major pharmaceutical companies from the funding of anti-Aβ clinical trials.

The amyloid hypothesis has now been the mainstay of therapeutic research in Alzheimer's disease for over two decades, but a number of issues have plagued the amyloid hypothesis since its inception. First, the level of Aβ burden does not often correlate with clinical manifestation of the disease. Second, the difficulty in isolating the specific neurotoxic species of Aβ and characterizing its effects makes research problematic. Further criticism of the evidence underpinning the amyloid hypothesis revolves around the current transgenic mouse models of AD, which do not fully recapitulate the disease. Despite increased Aβ deposition in these models, there appears to be a lack of coincidental neuronal loss. This is thought to be due mainly to species differences in neuronal susceptibility to Aβ accumulation, a lack of the human tau protein in mice, as well as the lack of a human-like inflammatory response which also plays a pivotal role in the progression of the disease.

Tuesday, April 21, 2015

What is so terrible about the prospect of failing to suffer years of hideous pain, disfigurement, and disability that it forces people to wax lyrical and beat their breasts and say, woe is me, we might have the chance to not suffer and not be diseased and not be forced into a painful death not of our choice? I believe near everyone you can find to ask is generally in favor of cancer research. That's absolutely about preventing all of the above. But the prospect of treating the medical condition we call aging and removing its consequences? Suddenly everyone is a poet, inclined to the morbid, building nebulous castles of fancy and feeling in praise of suffering and death:

I've got some bad news: You're going to die. Well, probably; thanks to the new wave of immortality innovation, you might not. So what happens if we ditch our biological bodies for technological ones that don't face the limitations of organic DNA and death? Technological evolution has the potential to decouple us from death and other basic biological constraints, which would allow us to move forward with the group instead of waiting to become obsolete and, well, dead. This is probably a good thing, but also a potentially terrible thing too.

If you have offspring, that offspring isn't you. They have some of your DNA and some of your partner's in a new combination that adds variation to the population at large. This is how evolution works - it acts on the population, not the person. I think this is the greatest tragedy of evolution. It doesn't happen to each of us; it happens to all of us. And the only way for the whole to progress is for you, me, and everyone else to eventually be left behind.

We may be able to prevent ourselves from dying by linking ourselves to technology rather than biology, but in doing so have we inadvertently killed meaningful progress in other ways? Or are we capable of evolving ourselves mentally to not get mired in the morality and wrongheadedness of the past and let society, ideas, and ourselves progress even without the fear of death? While there are lots of advantages to multi-generational societies, at some point it's better for the gander if the older geese get gone. If everyone hung around forever, the genetics of the population would stagnate, never able to move in any new direction. And in evolution, stagnation often leads to extinction.

Wednesday, April 22, 2015

A recent interview with Aubrey de Grey of the SENS Research Foundation, one of the few groups with a focus on accelerating progress towards the medical control of degenerative aging:

C: For those who are not familiar with you, let us know more about your project. What is the core concept of "Ending Aging"? What would you like to achieve through your project?

AG: At SENS Research Foundation we are focused on developing rejuvenation biotechnologies, which means medicines that can not just slow down aging but actually reverse it. We want to take people who are already in middle age or older and restore their physical and mental function to that of a young adult. We aim to do that by repairing the molecular and cellular damage that the body does to itself throughout life as side-effects of its normal operation.

C: What drives you to pursue your mission, spending lots of time and capital?

AG: I've always been driven by humanitarian motives, so I want to work on problems that cause human suffering. Aging undoubtedly causes far more human suffering than anything else. The strange thing is that there are so few people who think that way: lots of people claim to be humanitarian, but hardly anyone thinks aging is really important.

C: How did you get interested in science, gerontology, and aging?

AG: I got interested when I discovered how few other people are interested - even biologists. Until I was about 30, I had totally assumed that everyone understood how serious a problem aging is and that lots of experts were working hard to defeat it. After I married a senior biologist and discovered that that wasn't true, it was an easy decision to switch from my previous career as a computer scientist.

C: How does your experience in computer science help you understand aging and come up with solutions for that?

AG: It was extremely helpful. The first reason is just that computer science is a very different field; quite often in science people have made important breakthroughs after switching fields, because they are not blinkered by the new field's "conventional wisdom". Second, computer science is a very goal-directed, technological field, whereas pretty much everyone else in gerontology back then was much more of a basic scientist - great at testing hypotheses so as to understand nature better, but not so good at seeing how to use existing knowledge to manipulate nature.

C: In order to raise capital for visionary projects and ideas, what are important things for entrepreneurs, scientists, and futurists to remember?

AG: I sometimes give a talk on that topic, called "How to be a successful heretic". The main messages are that one can rise above the crowd only by having a compelling technical basis for one's idea, a clear vision for its benefit to humanity (and, in the case of investments, to the investor) and a comprehensive set of succinct answers to all the concerns that people may have about whether the idea is as valuable as one is claiming.

Wednesday, April 22, 2015

This study from China makes use of the large economic variation between regions of the country and economic growth over much of the past century to investigate correlations between wealth and longevity. Their results favor the present view of natural variations in aging and longevity as being much more determined by lifestyle choices and environmental circumstances such as access to medical technologies until reaching later old age, whereupon the role of genetics becomes an increasingly important determinant:

We show the variation of longevity indicators in China during the past 60 years and its correlation patterns with per capita GDP (GDPpc) both at provincial and inner-provincial level. Population data from six national population censuses in China (1953-2010) at provincial level and in several typical provinces in 2010 at county-level were selected. Four main longevity indicators were calculated.

The results show that Guangxi and Hainan Provinces maintain relatively high long-lived population (population over the age of 90) across various population censuses. The distributions of the population over the age of 80 and life expectancy are significantly affected by both contemporaneous and historical GDPpc at provincial level. However, areas of high long-lived population (over the age of 90) exhibit continuously stable features that lack any significant correlation with GDPpc both at provincial and inner-provincial level.

Our results indicate a mixed distribution pattern of several longevity indexes and different relation to GDPpc, that is, economic conditions may have limited influence on human longevity, especially for those who live longer than 90 years old. This study suggests that the economic development may favor the local residents to have access to live as old as 80 years old, but it is still difficult for most residents to reach the level of centenarians.

Thursday, April 23, 2015

There exist ageless or near-ageless species, such as hydra. There also exist species that do age and die, but show very little sign of functional degeneration until very close to the end, such as naked mole-rats. Why, then, do near all species age with considerable degeneration along the way? Answering that question is the challenge for evolutionary theories of aging: is aging a matter of accumulated damage produced as a side-effect of mechanisms that evolved to succeed in youthful reproduction, and thus the result of limited selection pressure operating on post-reproductive late life history, or is aging a genetic program that causes damage sufficient to attain a life history that is somehow optimal for species survival? This isn't an academic question, as the answer steers how researchers might try to treat and reverse aging - and these efforts will be largely fruitless if they take the wrong path. The paper linked here takes the more or less mainstream position on the evolution of aging:

In contraposition to the view of aging as a stochastic time-dependent accumulation of damage, phenoptotic theories of aging postulate that senescence may provide supra-individual advantages, and therefore it might have been promoted by natural selection. We reason that although programmed aging theories are subjectively appealing because they convey a cure for aging, they also raise a number of objections that need to be dealt with, before we may be entitled to contemplate aging as an adaptive function evolved through natural selection.

As an alternative view, we present metabolism as an endless source of by-products and errors causing cellular damage. Although this damage accumulation event is a spontaneous entropy-driven process, its kinetics can be genetically and environmentally modulated, giving place to the wide range of lifespans we observe. Mild forms of damage may be accumulating during a long enough period of time to allow reproduction before the fatal failure happens. Hence, aging would be a stochastic process out of the reach of natural selection. However, those genetic pathways influencing the rate of aging and consequently determining longevity may be targets of natural selection and may contribute to shaping the optimal strategy according to the ecological context. In this sense, short- and long-lived organisms represent two extreme strategies that, in terms of biological fitness, can perform equally well, each within its own niche.

Thursday, April 23, 2015

If you live long enough, you will get cancer. It's just a matter of time and odds, and thus any future rejuvenation toolkit must include robust medical technology capable of curing cancer. The principal challenge of cancer research is that every tumor has a different biochemistry, different enough to cause great variation in the effectiveness any one narrow strategy based on targeting a single protein or cellular process. Ways around this issue include (a) focusing on one of the few mechanisms that are the same in all cancers, such as the need to lengthen telomeres, and (b) developing some means to cost-effectively target a different set of proteins and mechanisms in every cancer patient. This early-stage research takes the second approach:

A tailored immunotherapy approach that could be used as a "universally applicable blueprint" was found to be effective in three independent tumour mouse models, a new study reports. Tumour-specific mutations represent ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognised by the body's immune system. However, systematic targeting by vaccine approaches have been hampered by each patient's tumour possessing a unique set of mutations - the mutanome - that must be identified first.

In the current study, researchers established a process by which mutations identified by exome sequencing could be selected as vaccine targets through bioinformation prioritisation based on both expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production. The team undertook work on three separate mouse models of lung, skin, and colon cancer. The investigators generated vaccines that delivered customised synthetic mRNA sequences which encouraged CD4 T cells to attack the target mutations, and showed improved survival in mice treated with the vaccines compared to untreated mice. Finally, they demonstrated an abundance of mutations predicted to bind to MHC class II in human cancers by employing the same predictive algorithm on corresponding human cancer types.

"The tailored immune-therapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time.'"

Friday, April 24, 2015

Researchers here identify one of the mechanisms linking severe forms of DNA damage and cellular senescence. DNA damage accumulates with age, and so too do senescent cells: falling into a senescent state is an evolved response to damage or potentially damaging tissue environments, and at least initially reduces cancer risk by preventing these cells from dividing. Senescent cells are not idle, however: they release all sorts of harmful signals that alter the behavior of surrounding cells, promote inflammation, remodel tissue structure, and otherwise harm tissue function. Too many senescent cells actually promote cancer formation via these mechanisms even as they degrade the normal operation of tissues.

The researchers have found that they can block some of these consequences of DNA damage, preventing cells from reacting by becoming senescent. The risk here would be a greater incidence of cancer and other issues due to very damaged cells remaining active, but in mice altered to have a greatly accelerated rate of DNA damage the outcome of reducing the growth in senescent cells in this way is a net benefit. It remains to be seen whether the same is true in normal mice, however:

Human DNA accumulates damage over time, and older people's bodies can't repair it as well. Many scientists believe a build up of damage can cause cells to enter an irreversible dormant state known as senescence. Cellular senescence is believed to be responsible for some of the telltale signs of aging, such as weakened bones, less resilient skin and slow-downs in organ function. Researchers have now pinpointed a molecular link between DNA damage, cellular senescence and premature aging. Finding the key players could lead to therapeutic targets for counteracting some of the negative effects of progerias and perhaps even forestalling the effects of natural aging.

The study took a closer look at the chemical messenger interferon, a molecule that is naturally produced by the body in response to invading pathogens such as viruses. The team found that interferon signaling ramps up in response to double-stranded DNA breaks and that this signaling prompts cells to enter senescence. One of the reasons senescence is believed to lead to the characteristic changes of aging is that it affects stem cells, which normally serve to replenish populations of healthy cells. Earlier studies had shown that mice lacking the Terc gene, which is key to DNA repair, have lower stem cell function and age prematurely, losing fertility and developing scaly skin, gray fur and shrunken, hunched bodies. These mice also have abnormalities in their intestinal tissues, a site known to be greatly affected by stem cell failure.

The researchers bred Terc-deficient mice to animals also lacking an interferon receptor. These animals had reduced signs of premature aging; they were more fertile, had less gray hair, were larger and lived longer on average than mice lacking only Terc. "We could rescue the majority of these phenotypes by abolishing interferon signaling, showing that there is a substantial role of interferon in aging that is caused by persistent DNA damage." For people who suffer from the effects of accelerated aging after undergoing treatments such as radiation that damage DNA or who suffer from acute radiation poisoning these findings hint at novel therapies. While the current study doesn't pertain directly to normal aging in healthy individuals, future studies could shed light on ways to mitigate its negative effects. "Since natural aging is connected with the DNA damage we accumulate over our lifetime and with decline in the stem cell functions, our skin is not repairing as well, our bones are not holding as well as they used to. There is rationale for the future studies on the role of interferon in normal aging."

Friday, April 24, 2015

Calorie restriction has a powerful effect on longevity in short-lived species such as worms, flies, and mice, and produces impressive health benefits in humans. In at least some species it appears that the mechanisms involved include perception of food scarcity, and that this can be manipulated independently of calorie intake and dietary content. Numerous different effects can be produced, not just lengthening of life. It remains unclear as to what degree these observations in flies have any parallel in mammals, however:

Chemosensation is a potent modulator of organismal physiology and longevity. In Drosophila, loss of recognition of diverse tastants has significant and bidirectional life-span effects. Recently published results revealed that when flies were unable to taste water, they increased its internal generation, which may have subsequently altered life span. To determine whether similar adaptive responses occur in other contexts, we explored the impact of sensory deficiency of other metabolically important molecules.

Trehalose is a major circulating carbohydrate in the fly that is recognized by the gustatory receptor Gr5a. Gr5a mutant flies are short lived, and we found that they specifically increased whole-body and circulating levels of trehalose, but not other carbohydrates, likely through upregulation of de novo synthesis. dILP2 transcript levels were increased in Gr5a mutants, a possible response intended to reduce hypertrehalosemia, and likely a contributing factor to their reduced life span.

Together, these data suggest that compensatory physiological responses to perceived environmental scarcity, which are designed to alleviate the ostensive shortage, may be a common outcome of sensory manipulation. We suggest that future investigations into the mechanisms underlying sensory modulation of aging may benefit by focusing on direct or indirect consequences of physiological changes that are designed to correct perceived disparity with the environment.


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