Fight Aging! Newsletter, February 9th 2015

FIGHT AGING! NEWSLETTER
February 9th 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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CONTENTS

  • Working on Making New Organs Available as Needed
  • The Nutraceutical Strategy in Attempts to Slow Aging
  • A Slow Evaporation of Skepticism Regarding Radical Life Extension
  • From the 2014 International Conference on Aging and Disease
  • Are Actuaries in Fact Paragons of Rationality When It Comes to the Prospects for Radical Life Extension?
  • Latest Headlines from Fight Aging!
    • A Demonstration of Tissue Engineering Nerve Grafts
    • Social Contact Not As Correlated to Life Expectancy as Thought
    • On Clonal Expansion of Mitochondrial Mutations in Aging
    • Exploring Laser Treatment for Macular Degeneration
    • Proposing the Term "Chondrosenescence"
    • Ever More Cancers Until Cancer and Its Causes are Defeated
    • Examining the Brains of Those With Exceptional Memory Function in Old Age
    • A Study on Exercise Levels and Mortality Showing that More is Not Necessarily Better
    • Considering Dietary AGEs and Alzheimer's Disease
    • Mifepristone Extends Life in Flies, and Studies Using It as a Tool Must Be Reevaluated

WORKING ON MAKING NEW ORGANS AVAILABLE AS NEEDED
https://www.fightaging.org/archives/2015/02/working-on-making-new-organs-available-as-needed.php

There are three principal problems with the current state of organ transplantation, from which all of the other well-known issues arise. Firstly the existing regulatory systems surrounding organ donation actively discourage donors by both restricting possible compensation and making the process far slower and more baroque than it has to be. This is often the case wherever bureaucrats and politicians become involved in medical matters: a donor really has to work hard as well as suffer surgery in order to give an organ, and there will be nothing but thanks for it. There is little fairness and little incentive to be found. For all that it gets most of the attention, this isn't really the important issue, however: it is a symptom. The medical community only makes an effort to reuse organs because of the second problem, the vital and central problem, which is that we do not yet have the biotechnologies needed to manufacture replacement organs to order, from scratch, reliably and safely, and at a mass-market price.

The third problem is that it requires major surgery with a significant risk of death and serious complications in order to transplant an organ. No-one really wants major surgery if they can possibly avoid it, and the risks escalate considerably in later life, at the time when you are most likely to actually need a replacement organ. Thus the ultimate goal of regenerative medicine and tissue engineering is most likely to regrow and repair existing organs in situ in the body. No surgery, just very sophisticated control over cellular behavior alongside equally sophisticated methods of repairing forms of accumulated cellular and molecular damage that cause degradation of organ function.

That grail of medicine lies a way in the future for most applications, however, so for now let us return to the second problem, the current inability to grow organs for transplantation on demand, ideally from the patient's own cells so as to eliminate the possibility of rejection. I think it uncontroversial to suggest that this challenge will be solved in the near future, this technology developed. Indeed comparatively simple and successful attempts have been taking place in limited trials for most of the past decade: tracheas, bladders, and so forth. A recent article on this topic, quoted below, pays attention to the New Organ initiative and its surrounding ecosystem of companies and non-profits involved in advancing the state of the art in regenerative medicine. More attention of this nature is always good to see. These and related efforts are spurring the research and development community to move more rapidly towards viable organ engineering, and the more support they gather the better:

How We'll Finally Put An End To Organ Donation Shortages

Looking at kidneys alone, about 25,000 people die each year waiting for a donation. And as New Organ founder Dave Gobel told io9, there are approximately two million estimated individuals in Europe, North America, and in the British Commonwealth who need replacement organs but don't show up anywhere on waiting lists because they're "deemed by the medical establishment to be 'not a transplant candidate' due to reasons such as having or having had cancer, being too old, and other triage-based disqualifiers."

At the same time, 95% of Americans support organ donation, but only 40% are registered organ donors. There's also the issue of how organs are procured today. "For someone needing a heart/lung transplant, someone must die for them," says Gobel "Imagine being in a situation where you must hope someone dies so you can live." Compounding the problem is that even for the fortunate few who do receive an organ donation (aside from those who receive a kidney), there are severe constraints on the quality of life after an operation. Many face a lifetime filled with the need to take auto-immune suppression drugs to stave off organ rejection, while the same drugs also lower their overall immune competence. "If all of that works out, they will still be facing the fact that transplant organs will often need to be replaced within 10 years of implant," says Gobel. "A ticking time bomb of life. Better than death for sure, but wow, what a life."

New Organ, a collective initiative hosted by Methuselah Foundation (a biomedical charity) and managed by the Institute of Competition Sciences, is currently raising awareness and facilitating research initiatives to help alleviate the shortages, including the New Organ Liver Prize - a large award to the first team "that creates a regenerative or bioengineered solution that keeps a large animal alive for 90 days without native liver function." The organization is currently working on a number of other related initiatives, including a shared roadmap, a prize portfolio to stimulate key breakthroughs, and a growing network of partners.

Indeed, as the biotechnology revolution takes shape, a number of solutions are emerging, including the ability to regenerate whole organs using stem cells, bioprinting tissue, and developing artificial and assistive organs. What's more, we'll soon be able to reliably preserve these bioengineered organs for when they're needed, such as in an emergency. (This prospect is being catalyzed by the Organ Preservation Alliance, a founding partner of New Organ.) Taken together, these advances will do much to meet the growing demand for replacement organs.

THE NUTRACEUTICAL STRATEGY IN ATTEMPTS TO SLOW AGING
https://www.fightaging.org/archives/2015/02/the-nutraceutical-strategy-in-attempts-to-slow-aging.php

There is a greater fool at the end of many paths of research and development, the wallet or collection of wallets that indirectly bankrolls the work. Early for-profit investment occurs because investors believe they can sell their stake at a higher price down the line. Other reasons exist, such as the desire to do good in the world, but are entirely secondary. Most investors, and certainly the wealthier ones, have a fiduciary duty to turn away from world-saving in favor of making money. The market for early for-profit investment in turn indirectly steers research interests and the ability to raise funds from other sources: whatever is presently hot is much more likely to receive grants and philanthropic sponsorship. The state of the market at the end of the development process thus reaches back to influence every part of the long chain of research and development. The predicted inclinations of the greater fool are the tail that wags the dog.

The greater fool of interest for this post is the one indirectly funding the ongoing construction of a grand catalog of human metabolism, an exhaustive accounting of the fine details of how our cellular biochemistry operates and ages. This is understood in outline, but beneath that outline lies an enormous unexplored space of protein interactions, causes and consequences, and the relationship of various states in the system to health at every level. The greater fool is told by various parties that the goal is to enhance healthy longevity, but that isn't really happening via these explorations of metabolism, and in truth doesn't have much of a hope of happening via this research strategy. Look at the past fifteen years of sirtuin research in connection with the calorie restriction response, wherein the greater fool was - collectively - the GlaxoSmithKline shareholder community following the Sirtris acquisition. Well-managed hype sputtered out quite quickly after that liquidity event into nothing more than a slightly greater understanding of a few very narrow areas of mammalian biochemistry. This process happens over and again for each new potential calorie restriction mimetic, or other methodology claimed to slow the progress of aging by altering the operation of metabolism. Yet there is always a greater fool willing to buy.

Even if a drug was developed to completely mimic the beneficial effects of calorie restriction, so what? That is a convenience device, no more. Those practicing calorie restriction have somewhat better health and somewhat less age-related disease, and might live as many as five years longer. It's a larger effect than any currently available medical technology can provide. Nonetheless, the large majority of those people do not and will not live to see 90 years of age in the environment of today's medical technology. They still live the last years of their lives in frailty and pain. Why spend billions on striving to create a convenience device to recreate some of this marginal effect, tiny in the grand scheme of things? Because some people can get rich doing it.

The recent history of medical development related to slowing aging is that some folk have found they can do very well thank you by promising the prospect of enhanced longevity, while delivering nothing of value beyond scientific knowledge. In different circumstances I might be inclined to praise this as a great hack on investment community culture: direct more funding into life science research rather than cat pictures on the internet, and take a deserved cut as the individual who manages to make that happen. There are certainly far worse things for the greater fool to be talked into doing with his or her money.

Today, however, this business of making hay while the sun shines, based on ways to slightly slow aging largely emerged from calorie restriction research, is a distraction from the prospect of real progress. Messing with metabolism in this way cannot even in principle produce meaningful rejuvenation: aging is damage, and slowing down the damage does nothing for people who are already old and damaged. Yet there are other research strategies that can achieve this goal: the better approach is to repair the damage that causes aging, following the existing detailed research plans that aim to produce new rejuvenation biotechnologies. These can in principle restore youthful function for the old, extend healthy life indefinitely, and should not be any more expensive to explore and develop than a continued future of whatever the next replacement for sirtuin research might be. If billions are spent, then let it be in the pursuit of technologies that do offer the possibility for everyone to live to 90, and in good health, lacking frailty, pain, and disease.

It's a fight to make this case. It shouldn't be, but it is. Attention continues to be soaked up by marginal, ultimately pointless efforts such as the one noted in the article below. It won't let you live to be 90 in confidence, it won't create rejuvenation in the old, and no foreseeable evolution of this strategy can in fact provide those benefits. It is just more of the same search for the greater fool to retroactively bankroll the continuing mapping of metabolism.

The Anti-Aging Pill

An anti-aging startup hopes to elude the U.S. Food and Drug Administration and death at the same time. The company, Elysium Health, says it will be turning chemicals that lengthen the lives of mice and worms in the laboratory into over-the-counter vitamin pills that people can take to combat aging. The startup is being founded by Leonard Guarente, an MIT biologist who is 62 ("unfortunately," he says) and who's convinced that the process of aging can be slowed by tweaking the body's metabolism.

The problem, Guarente says, is that it's nearly impossible to prove, in any reasonable time frame, that drugs that extend the lifespan of animals can do the same in people; such an experiment could take decades. That's why Guarente says he decided to take the unconventional route of packaging cutting-edge lab research as so-called nutraceuticals, which don't require clinical trials or approval by the FDA.

This means there's no guarantee that Elysium's first product will actually keep you young. The product contains a chemical precursor to nicotinamide adenine dinucleotide, or NAD, a compound that cells use to carry out metabolic reactions like releasing energy from glucose. The compound is believed to cause some effects similar to a diet that is severely short on calories - a proven way to make a mouse live longer.

Elysium's approach to the anti-aging market represents a change of strategy for Guarente. He was previously involved with Sirtris Pharmaceuticals, a high-profile biotechnology startup that studied resveratrol, an anti-aging compound found in red wine that it hoped would help patients with diabetes. That company was bought by drug giant GlaxoSmithKline, but early trials failed to pan out. This time, Guarente says, the idea is to market anti-aging molecules as a dietary supplement and follow up with clients over time with surveys and post-marketing studies.

A SLOW EVAPORATION OF SKEPTICISM REGARDING RADICAL LIFE EXTENSION
https://www.fightaging.org/archives/2015/02/a-slow-evaporation-of-skepticism-regarding-radical-life-extension.php

Radical life extension is a term showing its years these days: it sounds so very 90s. It can be applied to any goal of adding decades or centuries to healthy human life spans, though as Aubrey de Grey pointed out more than ten years ago in this environment of progress in biotechnology there is little difference between adding a few decades and adding a few centuries. A very binary divide lies ahead of us: either you live long enough to see medical science start to add additional years of life faster than aging can take it away, or you don't. If you do, then your life span is thereafter only bounded by accidents, which given present mortality rates means you will probably live for a thousand years or so, in excellent health and with a youthful physique periodically repaired by ever more advanced therapies.

At present life expectancy for older adults is increasing at perhaps a year every decade, but this is entirely accidental, a side-effect of growing wealth and improvements in medicine. To a first approximation no-one has been trying all that hard to intervene in the aging process: all of the real effort has gone to trying to clean up the consequences, a task that is ultimately futile if you never deal with the root causes. In the years ahead this state of affairs will change, and since there is usually a big difference in outcomes between trying and not trying, we'll no doubt see a great upward discontinuity in the trend of life expectancy as a result. When researchers are actively trying to treat aging as a medical condition, then there will be an appropriate level progress.

The real question is how soon will the fruits of this labor arrive? Trying to spur more rapid progress, and thus a greater likelihood of effective treatments developed before we age to death ourselves, is why there must be advocacy and fundraising. It is why there must be disruption in aging research in which inefficient lines of research are replaced with better ones. The status quo of the recent past is about to be replaced with a new set of research projects for the decades ahead, and if those of us in middle age now want a shot at rejuvenation treatments, then this next crop of research strategies had better be good ones. We have every motivation to help out and fund the research we think best.

Science must be accompanied by advocacy, as at the large scale the only research to receive significant funding is that with widespread public support. Think of the cancer research community and the attitudes of the average fellow in the street with regard to curing cancer. We still stand a long way removed from that sort of support for eliminating all age-related disease and greatly extending healthy life. The public is somewhere between indifferent, hostile, and confused with regard to life extension. People support research on well-known diseases that are caused by aging, but at the same oppose work on greater longevity or eliminating aging, and yet are fearful and saddened by the costs of growing old and that deaths and suffering of those around them.

Still, the past decade of advocacy has led to great changes in attitudes in the research community and in segments of the public. This continues. There is a steady evaporation of skepticism with regard to radical life extension, accelerating of late with the advent of several large and public initiatives in aging research. Where the writers and the speakers go, so too will others follow in the fullness of time:

Living to 150

The Treasurer of Australia, the Hon Joe Hockey MP, recently received widespread attention with the statement: "It's kind of remarkable that somewhere in the world today, it's highly probable that a child has been born who will live to be 150." Hockey made the claim while discussing some of the problems Australia faces as a result of an ageing population. While his statement was ridiculed by cartoonists and political rivals, he received support from some in the medical community. The Dean of Medicine at the University of New South Wales, Peter Smith, described Mr Hockey's claim as a "reasonable assumption". Professor Smith noted that life expectancy for Australians has been climbing dramatically over the past 100 years.

Scientists have long been able to manipulate ageing in other animals. However it has so far proved much harder to extend the lifespan of our own species. Humans have already evolved to have a long lifespan, due mainly to an unusually long post-reproductive phase of life. The same mechanisms used to increase lifespan in short-lived species have little impact on human lifespan, or that of other primates. Hence the fact that we can extend the lifespan of other animals only partially supports the claim that we will soon be able to manipulate human ageing and extend lifespan to 150 years. Significant research effort will be required to reach this milestone.

The most significant consideration favouring lifespans of 150 in the near future term, then, is the fact that there is now a lot of interest in life extension research, both within academia and from well-funded corporations. In late 2013 one of the world's largest companies, Google, established a subsidiary called Calico, with the sole focus of investigating ways to combat human ageing. Similarly Craig Venter, whose company Celera Genomics was the first to sequence the human genome, recently established Human Longevity Inc, a new company with a focus on enhancing human lifespan. One research direction these companies are likely to explore involves incorporating nanotechnologies into our cells. Many gerontologists believe that ageing consists solely of a small number of cellular changes, which are potentially preventable and reversible. Once we develop technologies capable of preventing and reversing these changes, we can prevent and reverse ageing.

FROM THE 2014 INTERNATIONAL CONFERENCE ON AGING AND DISEASE
https://www.fightaging.org/archives/2015/02/from-the-2014-international-conference-on-aging-and-disease.php

A sweeping cultural change in the aging research community has taken place over the past fifteen years. It was a culture in which talking in public about the prospects for the treatment of aging and extension of healthy life was a good way to sabotage your career, and that certainly suppressed progress at a time when new technologies allowed the exploration of extending healthy life spans in laboratory animals. Now, however, many researchers freely raise funding, speak out about treating aging as a disease, and work towards that goal. This sea change didn't happen by accident: it required hard work and advocacy on the part of many groups both within and outside the scientific community to break the old barriers and bring the perception of legitimacy to longevity science. The reward for all of that work is that those formerly opposed now pretend that they agreed all along that it is a great idea to work on helping people to live much longer healthy lives through medical science.

One result of this change in attitudes and speech is that scientific conference series are becoming just as open about the goal of developing therapies for the causes of degenerative aging. A recent addition to the conference circuit was the 2014 International Conference on Aging and Disease, held in Beijing last November. Here are some very readable open access position papers resulting from the event:

Stop Aging Disease! ICAD 2014

The primary stated goal of the International Society on Aging and Disease is "to improve the quality of lives through stimulating research into the association between aging and aged-related disease". The society's concise motto is simply: "Stop Aging Disease!" The conference made yet another step in advancing this goal by "fostering communication among researchers and practitioners working in a wide variety of scientific areas with a common interest in fighting aging and aged-related disease."

The importance of those goals cannot be overestimated, and this importance was further emphasized in the conference resolution and in the position paper issued by the ISOAD following the conference. As the resolution and the position paper state, the degenerative aging processes and related diseases are the gravest challenge to global public health. They cause the largest proportion of disability and mortality worldwide, and should be addressed with the urgency and effort corresponding to the severity of the problem. The weight of the problem of aging-related degeneration and the urgent need for solutions was acknowledged by the conference participants. Yet, beyond the description of the problem, the conference presented a wide array of strategies to tackle it. It emphasized the paramount strategy of connecting the study of aging and aging-related diseases, no longer just exclusively addressing individual diseases and symptoms, but relating them to their unifying determinative factors - the degenerative processes of ageing.

The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population

Over the past decades, the average life expectancy has increased globally. Currently, while the longest life expectancies are still found in the "developed" countries, the fastest and largest increase has been recorded in the "developing" world. Considering the demographics of the world population, between 2000 and 2050 the proportion of people over 60 years will double from about 11% to 22%, which, in absolute terms, means an increase from 605 million to 2 billion people. Although the increasing life expectancy generally reflects positive human development, new challenges are arising. They stem from the fact that growing older is still inherently associated with biological and cognitive degeneration, although the severity and speed of cognitive decline, physical frailty and psychological impairment can vary between individuals.

Nonetheless, degenerative aging processes are the major underlying cause for non-communicable diseases (NCDs), including cancer, ischemic heart disease, stroke, type 2 diabetes, Alzheimer's disease and others. Mental health deterioration due to chronic neurodegenerative diseases represents the largest cause of disability in the world, responsible for over 20% of years lived with disability. Hence, major efforts must be directed toward their alleviation.

New directions in research and development take a more holistic approach for tackling the degenerative processes and negative biological effects of human aging, addressing several major fundamental causes of aging and aging-related diseases at once and in an interrelated manner. For example, at the 2013 US National Institutes of Health (NIH) Geroscience Summit, the following priority research areas have been identified: Adaptation to Stress, Epigenetics, Inflammation, Macromolecular Damage, Metabolism, Proteostasis, and Stem Cells/Regeneration, but there are several other examples of similar approaches, prioritizing research of major sets of aging processes. Instead of targeting single age-related diseases, the mechanisms of the aging process itself are being analyzed with the goal of finding ways for intervention and prevention. Such approaches are very promising, for the following reasons:

1) They are already supported by scientific proofs of concept, involving the evidential increase in healthy lifespan in animal models and the emerging technological capabilities to intervene into fundamental aging processes.

2) They can provide solutions to a number of non-communicable, age-related diseases, insofar as such diseases are strongly determined by degenerative aging processes (such as chronic inflammation, cross-linkage of macromolecules, somatic mutations, loss of stem cell populations, and others). Moreover, they are likely to decrease susceptibility of the elderly also to communicable diseases due to improvements in immunity.

3) The innovative, applied results of such research and development will lead to sustainable solutions for a large array of age-related medical and social challenges that may be globally applicable.

4) Such research and development should be supported on ethical grounds, to provide equal health care chances for the elderly as for the young.

Therefore it is the societal duty, especially of the professionals in biology, medicine, health care, economy and socio-political organizations to strongly recommend greater investments in research and development dealing with the understanding of mechanisms associated with the human biological aging process and translating these insights into safe, affordable and universally available applied technologies and treatments.

ARE ACTUARIES IN FACT PARAGONS OF RATIONALITY WHEN IT COMES TO THE PROSPECTS FOR RADICAL LIFE EXTENSION?
https://www.fightaging.org/archives/2015/02/are-actuaries-in-fact-paragons-of-rationality-when-it-comes-to-the-prospects-for-radical-life-extension.php

The output of the actuarial community often demonstrates its members to be ahead of the curve when it comes to the near future of medicine and great uncertainty over coming trends in life expectancy. This is a time of very rapid progress in the underlying biotechnologies applicable to medical research, and also a time in which both the aging research community and broader medical community are beginning a sweep change in their approach to age-related disease. There is every reason to expect that the near future of human adult life expectancy will look nothing like the past fifty years of slow and fairly steady growth: once the research community begins to actually try to address the causes of aging through medicine, then all bets are off. A likely outcome, indeed the outcome I'd expect if repair-based strategies like the SENS research projects gain large-scale funding and support, is a large upward leap in life span with comparatively little advance warning.

Actuaries are, in theory at least, aware of all of this: it is their job to take account of uncertainty in their projections. Enormous sums of money flow through life insurance companies, pension funds, and other areas of business related to life span. There is thus an equally enormous incentive for these organizations and their allies to understand the state of progress in medicine. Having a solid grasp of the uncertainty of the future is necessary to these businesses, and for many years the actuarial community has been sounding the alarm on rising uncertainty in their projections. This is a direct result of the uncertainty inherent in medical development during a time of rapid progress and strategic upheaval in the research community. Comparatively small differences in funding or happenstance collaboration today could dramatically shift the timing of the future advent of practical rejuvenation treatments.

We all know that the average person in the street is surprisingly disinterested in living longer in good health, and perhaps even hostile to the concept. This is one of the challenges we face as advocates seeking greater support for research to bring an end to the suffering and frailty that presently accompanies old age. Are actuaries any more bold than the rest of the public when it comes to radical life extension through progress in medicine? Possibly not:

Longevity expectations in the pension fund, insurance, and employee benefits industries

Considerable progress has been made in many areas of biomedical science since the 1960s, suggesting likely increases in life expectancy and decreases in morbidity and mortality in the adult population. These changes may pose substantial risks to the pensions and benefits industries. While there is no significant statistical evidence demonstrating rapid decreases in mortality rates, there are conflicting opinions among demographers and biogerontologists on the biological limits of the human lifespan and trends in life expectancy.

We administered a survey of the International Employee Benefits Association (IEBA), a large, international industry group. Industry professionals employed by consulting (35%), insurance (24%), pension (14%), and other (27%) companies responded to 32 questions. Respondents showed reasonably conservative views on the future of longevity and retirement, including that for women. The respondents formed their personal longevity expectations based on their family history and, to a lesser degree, on the actuarial life tables. Most of the sample expressed no desire to life past age 100 years, even if the enabling technologies required to maintain a healthy youthful state were available, and only a few respondents in the sample expressed a desire to live for the maximum period (at least) offered by the survey question. The majority of the respondents would not undergo any invasive procedures, and only 56% of the respondents would opt for noninvasive therapies to extend their healthy lifespans to 150 years of age if these were available.

The results of this study strengthen the argument that the captains of these industries may not use the recent advances in biomedical sciences when forming their personal longevity expectations and engaging in corporate financial planning. Moreover, most of these decision makers do not even appear to show much interest in significantly extending their own longevity should such technologies become available. Considering the recent advances in all areas of biomedical science, the rapid convergence of information technology with biomedicine, and the propagation of these technologies into mainstream clinical and consumer markets, this appears shortsighted, if only from a business perspective. Quite simply, one could lose a lot of money - to the level of affecting the future of the global financial system - by failing to predict these trends correctly. All stakeholders, including pension fund providers, insurance companies, governments, and individuals, may benefit from accelerating biomedical advances and investing in projects that increase productive longevity, or at least from taking such research and development work into account when projecting mortality rates into the future.

LATEST HEADLINES FROM FIGHT AGING!

A DEMONSTRATION OF TISSUE ENGINEERING NERVE GRAFTS
Monday, February 2, 2015
https://www.fightaging.org/archives/2015/02/a-demonstration-of-tissue-engineering-nerve-grafts.php

Researchers in the field of tissue engineering are making steady progress towards repair of larger sections of nerve damage caused by injury, here demonstrating a little restoration of function in pigs:

Nerve cells or neurons work by growing axons, long fibrous projections that connect neurons and form the body's signal transmission and communication structure. Although new neurons are born, the long axon cables that connect them do not regenerate effectively over long distances, yet they are necessary for normal function. Researchers have been working for decades to coax damaged axons to regenerate, with little success in getting enough axons to grow to the right places.

There are currently no commercially available nerve grafts capable of consistently facilitating axon regeneration across major nerve lesions, generally considered to be a loss of a nerve segment five centimeters or longer. Researchers have now demonstrated the success of tissue-engineered nerve grafts (TENGs) in driving axon regeneration across five centimeter nerve lesions in the legs of pigs (in 10 out of 10 subjects). TENGs are lab-grown nervous tissue comprised of long axonal tracts spanning neurons. The ability to generate TENGs is based upon a mechanism of axon "stretch growth". These tissues are not only similar in structure to endogenous nerves, but suitable for transplantation upon removal from custom bioreactors.

The living TENGs were surgically attached to bridge a missing segment of nerve and were shown to accelerate the regeneration of axons, allowing a population of axons to cross the graft within five weeks. At three months, the bulk of axons had crossed the graft into the existing nerve structures opposite the lesion. Target muscle reinnervation was confirmed via an evoked hoof twitch as early as seven months following TENG repair, and over nine to eleven months post-repair there were steady increases in muscle electrical activity and muscle force generation. Microscopic examination of the regenerated nerves revealed a high density of regrown axons bridging the lesion zone and progressing the length of the repaired nerve to innervate target muscle.

SOCIAL CONTACT NOT AS CORRELATED TO LIFE EXPECTANCY AS THOUGHT
Monday, February 2, 2015
https://www.fightaging.org/archives/2015/02/social-contact-not-as-correlated-to-life-expectancy-as-thought.php

In this analysis of many independent studies, the authors suggest that more social contact, on its own and independent of all of the other items associated with it, is not as meaningfully associated with greater life expectancy as was thought. It isn't hard to speculate on the outcomes that are associated with more gregarious individuals, such as greater wealth, and on how these outcomes impact lifestyle choices and use of medical resources. There is a strong web of correlations between wealth, intelligence, education, and life expectancy. It is interesting, but like all examinations of natural variations in human longevity at the present time, it is a distraction from efforts that aim to make everyone live far longer in good health. Given the means to repair the causes of aging and prevent age-related disease, all of the small things that presently shift life expectancy a little in one direction or the other will no longer matter in the slightest.

Social contact frequency is a well-defined and relatively objective measure of social relationships, which according to many studies is closely associated with health and longevity. However, no previous meta-analysis has isolated this measure; existing reviews instead aggregate social contact with other diverse measures of social support, leaving unexplored the unique contribution of social contact to mortality. Furthermore, no study has sufficiently explored the factors that may moderate the relationship between contact frequency and mortality.

We conducted meta-analyses and meta-regressions to examine 187 all-cause mortality risk estimates from 91 publications, providing data on about 400,000 persons. The mean hazard ratio (HR) for mortality among those with lower levels of social contact frequency was 1.13 among multivariate-adjusted HRs. However, sub-group meta-analyses show that there is no significant relationship between contact and mortality for male individuals and that contact with family members does not have a significant effect. The moderate effect sizes and the lack of association for some subgroups suggest that mere social contact frequency may not be as beneficial to one's health as previously thought.

ON CLONAL EXPANSION OF MITOCHONDRIAL MUTATIONS IN AGING
Tuesday, February 3, 2015
https://www.fightaging.org/archives/2015/02/on-clonal-expansion-of-mitochondrial-mutations-in-aging.php

Mitochondria are the power plants of the cell. Each cell has a herd of them that reproduce like bacteria and have their own DNA, separate from that of the nucleus. One of the causes of aging is progressive mitochondrial dysfunction caused by forms of DNA damage that (a) deprive mitochondria of necessary proteins for correct function, but also (b) allow the damaged mitochondria a survival advantage during replication. Thus a fraction of cells become overtaken by damaged mitochondria, and this causes them to export damaging reactive molecules into surrounding tissues. That contributes to, for example, the formation of damaged lipids involved in the progression of atherosclerosis.

This paper looks at the process of clonal expansion whereby damaged mitochondria overtake a cell. The authors focus on point mutations, however. While point mutations will be carried along in damaged DNA that provides a survival advantage, I think that the existence of mitochondrial mutator mice that have a very high load of point mutations but no premature aging as a result shows that point mutations are not all that important in this process. It is probably deletions and other more serious forms of damage that are significant.

Mitochondrial DNA (mtDNA) mutations have been shown to accumulate with age in a number of human stem cell populations and cause mitochondrial dysfunction within individual cells resulting in a cellular energy deficit. The dynamics by which mtDNA mutations occur and accumulate within individual cells (known as clonal expansion) is poorly understood. In particular we do not know when in the life-course these mtDNA mutations occur.

Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (earlier than 20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age.

We show that, by 17 years of age, there is a substantial mtDNA point mutation burden. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

EXPLORING LASER TREATMENT FOR MACULAR DEGENERATION
Tuesday, February 3, 2015
https://www.fightaging.org/archives/2015/02/exploring-laser-treatment-for-macular-degeneration.php

Researchers here demonstrate that they can use very short bursts of laser light to somewhat reduce levels of extracellular waste deposits known as drusen present in the aged retina. The mechanisms of action remain to be explored in greater depth, however:

Age-related macular degeneration (AMD) is a leading cause of vision loss, characterized by drusen deposits and thickened Bruch's membrane (BM). This study details the capacity of nanosecond laser treatment to reduce drusen and thin BM while maintaining retinal structure. Fifty patients with AMD had a single nanosecond laser treatment session and after 2 years, change in drusen area was compared with an untreated cohort of patients. The retinal effect of the laser was determined in human and mouse eyes using immunohistochemistry and compared with untreated eyes. In a mouse model with thickened BM, the effect of laser treatment was quantified using electron microscopy and quantitative PCR.

In patients with AMD, nanosecond laser treatment reduced drusen load at 2 years. Retinal structure was not compromised in human and mouse retina after laser treatment, with only a discrete retinal pigment epithelium (RPE) injury, and limited mononuclear cell response observed. BM was thinned in the mouse model 3 months after treatment, with the expression of matrix metalloproteinase-2 and -3 increased. Nanosecond laser resolved drusen independent of retinal damage and improved BM structure, suggesting this treatment has the potential to reduce AMD progression.

PROPOSING THE TERM "CHONDROSENESCENCE"
Wednesday, February 4, 2015
https://www.fightaging.org/archives/2015/02/proposing-the-term-chondrosenescence.php

In this open access paper, researchers look at some of the interacting effects of aging on the maintenance of cartilage tissues:

Aging and inflammation are major contributing factors to the development and progression of arthritic and musculoskeletal diseases. "Inflammaging" refers to low-grade inflammation that occurs during physiological aging. In this paper we review the published literature on cartilage aging and propose the term "chondrosenescence" to define the age-dependent deterioration of chondrocyte function and how it undermines cartilage function in osteoarthritis. We propose the concept that a small number of senescent chondrocytes may be able to take advantage of the inflammatory tissue microenvironment and the inflammaging and immunosenescence that is concurrently occurring in the arthritic joint, further contributing to the age-related degradation of articular cartilage, subchondral bone, synovium and other tissues.

In this new framework "chondrosenescence" is intimately linked with inflammaging and the disturbed interplay between autophagy and inflammasomes, thus contributing to the age-related increase in the prevalence of osteoarthritis and a decrease in the efficacy of articular cartilage repair. A better understanding of the basic mechanisms underlying chondrosenescence and its modification by drugs, weight loss, improved nutrition and physical exercise could lead to the development of new therapeutic and preventive strategies for osteoarthritis and a range of other age-related inflammatory joint diseases.

EVER MORE CANCERS UNTIL CANCER AND ITS CAUSES ARE DEFEATED
Wednesday, February 4, 2015
https://www.fightaging.org/archives/2015/02/ever-more-cancers-until-cancer-and-its-causes-are-defeated.php

Cancer research is perhaps the field of medical science with the greatest level of funding and public support. The next generation of therapies presently under development are a great leap ahead in comparison to the present staples of chemotherapy and radiation therapy, making use of new tools in cellular biotechnology and promising accurate targeting of cancer cells for destruction with few side-effects. This is just as well, as life spans are lengthening now, and will continue to lengthen at an increasingly rapid pace in the future. That additional time brings with it the standard risk of suffering cancer at some point, which is large at this time since more people are living longer in a period of life that has high cancer risk due to the damage of aging.

Overall we should expect incidence of cancer to increase with the present trend towards longer life spans until better medical technologies become widely available, either rejuvenation treatments that repair cellular damage and restore tissue environments to a much lower, youthful risk of cancer, or which can control cancer sufficiently well so that the higher risk doesn't matter. The latter will probably emerge first. Either way, robust and reliable ways to control the risks of cancer are a very necessary part of any near future toolkit for rejuvenation and healthy life extension:

One in two people will develop cancer at some point in their lives, according to the most accurate forecast to date from Cancer Research UK. Thanks to research, the UK's cancer survival has doubled over the last 40 years and around half of patients now survive the disease for more than 10 years. But, as more people benefit from improved healthcare and longer life expectancy, the number of cancer cases is expected to rise. This new estimate replaces the previous figure, calculated using a different method, which predicted that more than 1 in 3 people would develop cancer at some point in their lives.

Age is the biggest risk factor for most cancers, and the increase in lifetime risk is primarily because more people are surviving into old age, when cancer is more common. "Cancer is primarily a disease of old age, with more than 60 per cent of all cases diagnosed in people aged over 65. If people live long enough then most will get cancer at some point. But there's a lot we can do to make it less likely - like giving up smoking, being more active, drinking less alcohol and maintaining a healthy weight. More than four in ten cancers diagnosed each year in the UK could be prevented by changes in lifestyle - that's something we can all aim for personally so that we can stack the odds in our favour. If we want to reduce the risk of developing the disease we must redouble our efforts and take action now to better prevent the disease for future generations."

EXAMINING THE BRAINS OF THOSE WITH EXCEPTIONAL MEMORY FUNCTION IN OLD AGE
Thursday, February 5, 2015
https://www.fightaging.org/archives/2015/02/examining-the-brains-of-those-with-exceptional-memory-function-in-old-age.php

Some people have exceptional memory function in old age, showing far less deterioration than their peers. Researchers here look for differences in the brains of these individuals. The most actionable of the items discovered so far is the level of metabolic waste in the form of neurofibillary tangles. A range of research groups are presently working on ways to clear these tangles in connection with Alzheimer's disease and other neurodegenerative conditions, but any resulting practical treatment should clearly be applied to everyone on a regular basis:

SuperAgers, aged 80 and above, have distinctly different looking brains than those of normal older people. SuperAgers have memories that are as sharp as those of healthy persons decades younger. An analysis of the SuperAger brains after death show the following brain signature:

1) MRI imaging showed the anterior cingulate cortex of SuperAgers (31 subjects) was not only significantly thicker than the same area in aged individuals with normal cognitive performance (21 subjects), but also larger than the same area in a group of much younger, middle-aged individuals (ages 50 to 60, 18 subjects). This region is indirectly related to memory through its influence on related functions such as cognitive control, executive function, conflict resolution, motivation and perseverance.

2) Analysis of the brains of five SuperAgers showed the anterior cingulate cortex had approximately 87 percent less tangles than age-matched controls and 92 percent less tangles than individuals with mild cognitive impairment. The neurofibrillary brain tangles, twisted fibers consisting of the protein tau, strangle and eventually kill neurons.

3) The number of von Economo neurons was approximately three to five times higher in the anterior cingulate of SuperAgers compared with age-matched controls and individuals with mild cognitive impairment. "It's thought that these von Economo neurons play a critical role in the rapid transmission of behaviorally relevant information related to social interactions, which is how they may relate to better memory capacity."

A STUDY ON EXERCISE LEVELS AND MORTALITY SHOWING THAT MORE IS NOT NECESSARILY BETTER
Thursday, February 5, 2015
https://www.fightaging.org/archives/2015/02/a-study-on-exercise-levels-and-mortality-showing-that-more-is-not-necessarily-better.php

Past epidemiological studies have found little or very mixed evidence that more or different types of exercise are better. There is clearly a big difference between no exercise and regular moderate exercise, but adding more exercise on top of that doesn't seem to have any reliably greater association with long-term health and lower mortality rates. On the other hand there are studies to show that elite athletes live significantly longer than the general population, but there it may be the case that a successful career in athletics selects for those who are more robust and more likely to live longer anyway. Here is a study demonstrating an interesting pattern of association between levels of exercise and mortality:

People who are physically active have at least a 30% lower risk of death during follow-up compared with those who are inactive. However, the ideal dose of exercise for improving longevity is uncertain. The aim of this study was to investigate the association between jogging and long-term, all-cause mortality by focusing specifically on the effects of pace, quantity, and frequency of jogging. As part of the Copenhagen City Heart Study, 1,098 healthy joggers and 3,950 healthy nonjoggers have been prospectively followed up since 2001. Cox proportional hazards regression analysis was performed with age as the underlying time scale and delayed entry.

Compared with sedentary nonjoggers, 1 to 2.4 hours of jogging per week was associated with the lowest mortality (multivariable hazard ratio [HR]: 0.29). The optimal frequency of jogging was 2 to 3 times per week (HR: 0.32) or ≤1 time per week (HR: 0.29). The optimal pace was slow (HR: 0.51) or average (HR: 0.38). The joggers were divided into light, moderate, and strenuous joggers. The lowest HR for mortality was found in light joggers (HR: 0.22), followed by moderate joggers (HR: 0.66) and strenuous joggers (HR: 1.97). The findings suggest a U-shaped association between all-cause mortality and dose of jogging as calibrated by pace, quantity, and frequency of jogging. Light and moderate joggers have lower mortality than sedentary nonjoggers, whereas strenuous joggers have a mortality rate not statistically different from that of the sedentary group.

CONSIDERING DIETARY AGES AND ALZHEIMER'S DISEASE
Friday, February 6, 2015
https://www.fightaging.org/archives/2015/02/considering-dietary-ages-and-alzheimers-disease.php

Advanced glycation end-products (AGEs) are involved in aging, as they can form cross-links that damage tissue structure, and trigger chronic inflammation via the receptor for AGEs. There are are many types of AGE and their influence is not all the same. Some can be broken down rapidly by our biochemistry, and some cannot. They can be manufactured in the body as a form of metabolic waste and also ingested in the diet, so there are two very different characteristics of AGE presence, one class that builds up slowly over time, and another that varies according to intake and ongoing clearance. Further, the types of AGE involved in the pathology of aging in shorter lived animals such as mice are very different to the important types in we longer-lived humans, something that sabotaged early efforts to build treatments that clear the AGEs that damage tissue. More recent initiatives focus on glucosepane as the important source of cross-links in human tissues.

The degree to which dietary AGEs are significant in aging is a topic for debate. On the whole it looks to be the case that the inflammatory consequences of short-lived AGEs are the more important set of mechanisms for that source:

Advanced glycation end products (AGEs) are a group of compounds that are combinations of sugars and proteins and other large molecules. They can be formed in the body, and there is a large body of literature on AGEs and Alzheimer's disease. However, AGEs are also formed when food is cooked at high temperatures or aged for a long time such as in hard cheese. AGEs increase the risk of various chronic diseases through several mechanisms including increased inflammation and oxidative stress. They can also bind to the receptor for AGEs (RAGE). RAGE transports beta-amyloid proteins across the blood-brain barrier and contributes to the development of Alzheimer's disease.

This study looked at the content of AGEs in national diets and clinical studies and compared total AGEs to Alzheimer's disease rates. For this purpose, the values for AGE for many types of food were taken from a study in which researchers cooked 549 foods by different methods and measured the AGE content of the cooked food. They found that the higher the cooking temperature, the higher the AGE content. For example, 100 grams of raw beef had 707 kU of AGEs, but 100 grams of roast beef had 6071 kU. In typical national diets, we found that meat made the highest contribution of AGEs, followed by vegetable oils, cheese, and fish. Foods such as cereals/grains, eggs, fruit, legumes, milk, nuts, starchy roots, and vegetables generally make low contributions to the total amount of AGEs in a diet, either because they are generally prepared at low temperatures or since they comprise smaller portions of diets.

"This epidemiological study supports our previous findings in animals and humans of an important role for dietary AGEs in Alzheimer's disease. We found that mice kept on a diet high in AGEs, similar to Western diet, had high levels of AGEs in their brains together with deposits of amyloid-β, a component of the plaques characteristic of Alzheimer's disease, while at the same time developed declines in cognitive and motor abilities. The mice fed a low AGE diet remained free of these conditions. In addition, clinical studies have shown that subjects with higher blood AGE levels, in turn resulting from high AGE diets, are more likely to develop cognitive decline on follow up."

MIFEPRISTONE EXTENDS LIFE IN FLIES, AND STUDIES USING IT AS A TOOL MUST BE REEVALUATED
Friday, February 6, 2015
https://www.fightaging.org/archives/2015/02/mifepristone-extends-life-in-flies-and-studies-using-it-as-a-tool-must-be-reevaluated.php

In aging research inadvertent calorie restriction has been the usual confounding factor in life span studies carried out with short-lived animals. If the treatment under study happened to cause animals to eat less then there was indeed an extension of life, but due to reduced calorie intake rather than the treatment. The calorie restriction response is large compared to the results of most interventions under study, and many studies were contaminated because there was no control for calorie intake. There are any number of other ways in which life span studies can be compromised, however. For example solvents extend life in nematodes, which is a problem for all experiments using them, a list that includes a range of genetic studies of longevity carried out prior to the solvent discovery. Here researchers find a similar problem in fly studies, wherein a part of the methodology of genetic engineering is shown to extend life:

Some studies on the genetic roots of aging will need a second look after the discovery that a common lab chemical can extend the life span of female fruit flies by 68 percent. For years, scientists have engineered fruit flies whose genes can be turned on and off by a synthetic hormone, allowing detailed studies of the effects of single genes on life span. Many of the genes have close relatives in humans. Unfortunately, the hormone used to perform the studies turns out to be anything but neutral.

Researchers grew suspicious of the hormone that they and others were using to activate the genes - mifepristone, a synthetic chemical known to terminate pregnancy in humans. Many studies have shown that reproduction shortens lifespan in flies and other organisms. Researchers wondered if the hormone they were using could be affecting reproduction in flies, and in turn their life span. They discovered that flies exposed to the hormone laid only half the usual amount of eggs - and lived 68 percent longer, from a median age of 56 to 94 days. The mifepristone had little or no effect on the life expectancy of female flies that had not mated, which had an even better overall survival rate and maximum lifespan.

"This opens up a new line of inquiry for longevity studies, and identifies candidate genes and mechanisms for regulating the trade-off between reproduction and lifespan that may be shared with humans. It does, however, mean that our earlier longevity studies that relied on mifepristone as a gene switch will need to be reevaluated."

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