Fight Aging!

Engineering is in essence the business of producing good, workable solutions in absence of complete knowledge. The Romans could construct excellent bridges with a tiny fraction of the knowledge of materials science, mathematics, and modeling possessed by today's architects. Medical technologies today are in much the same position: we might know about as much of the fine details of biology as the Romans did of the deeper sciences underlying architecture. A vast scope of discovery and cataloging is yet to be accomplished in the life sciences. Yet we can still produce good therapies well in advance of a full understanding of human biochemistry.

Pure science as practiced today is the polar opposite of engineering. The goal is to produce complete understanding, and only then hand over that knowledge to those who will apply it to produce technologies. This is an ideal rather than the reality, of course: at some point in the development process there are always those who will make the last leap to clinical application because it is more cost effective to take a chance than to grind to the very end of the research process. The last stages of medical research are ever a compromise between the ethic of science, full understanding first, and the ethic of engineering, let's just get it done when there's a reasonable chance of success. Building proposed therapies and trying them out is sometimes the best path forward for both learning and application of knowledge.

In aging research the archetype of the engineering approach is the SENS program, scientific projects aimed at moving as rapidly as possible towards practical rejuvenation therapies. The SENS vision for development is explicitly a way to use our present knowledge of forms of cellular and tissue damage that cause aging in order to work around our present lack of knowledge regarding how exactly metabolism and aging interact over time. The damage is comparatively simple, but the details of how that damage spreads and interacts, and how it forms age-related disease, are intricate and poorly understood. We are very complex self-adjusting biochemical factories, so it is a given that even simple malfunctions have complicated outcomes. Because the malfunctions are simple, however, they themselves are the best and most cost-effective point of intervention: the first step towards treatment of aging should be to repair the breakages known to cause it.

The very readable open access paper linked below is a similar argument for engineering (take action now) over science (wait for full understanding), but for less ambitious efforts to intervene in the aging process. These are drug development programs aimed at manipulating the operation of metabolism so as to gently slow the accumulation of damage, and thus slightly slow the pace of degenerative aging. The expected outcome here in terms of additional healthy life delivered per billion dollars invested is not great; you might look at the past decade of sirtuin research to see the median expected outcome, which is to say a lot of data on a tiny slice of metabolism and aging, but no practical therapies. In comparison given a billion dollars and ten years there is a reasonable shot at implementing prototype SENS rejuvenation treatments in mice. The challenge for now is to persuade enough people that this is the best path forward to have a hope of expanding the SENS funding and research community to this scale.

Why Is Aging Conserved and What Can We Do about It?

Aging is something everyone can relate to. From grandparents, to parents, and ultimately our own bodies, we are intimately familiar with the declines in form and function that accompany old age. Yet, we don't all appear to age at the same rate. Many individuals are healthy and active well into their 70s, 80s, or even 90s, while others will suffer from chronic disease and disability by the time they reach their 40s or 50s. Those of us that have companion animals also observe that different animal species or even subspecies, as in the case of dog breeds, age at profoundly different rates. Defining the factors that influence individual rates of aging is a major focus of aging research.

From a biomedical perspective, it is critically important to gain a better understanding of the mechanisms that drive biological aging, as age is the single greatest risk factor for the leading causes of death in developed nations. The fact that aging influences so many different conditions is particularly curious. What is it about aging that creates an environment within our cells, tissues, and organs that is permissive for all of these seemingly disparate pathological states?

In order to understand the biological mechanisms of aging, scientists have turned to laboratory model organisms such as rats and mice, fruit flies, nematodes, and even yeast. While some have questioned the utility of these systems as models for human aging, it is now clear that similar pathways and processes affect longevity in each of these species. These studies have resulted in the identification of interventions that slow aging in taxa spanning broad evolutionary distances. Although it is still unknown whether these interventions will slow human aging, the potential impact on human health, if they do, is enormous.

In general, the known conserved modifiers of longevity tend to mediate the relationship between fundamental environmental and physiological cues (i.e., temperature, nutrient status, and oxygen availability) and the regulation of growth and reproduction. One school of thought holds that this relationship results from the ability of organisms to forgo reproduction and invest in somatic maintenance during times of adversity. In other words, based on the quality of the environment, the organism has evolved to make the appropriate choice between allocating its limited resources toward reproducing rapidly, and hence aging more quickly, versus delaying reproduction and allocating resources toward maintaining the soma, thereby aging more slowly.

Although conserved longevity pathways clearly exist, it has been challenging to identify their primary molecular mechanisms of action or even to definitively determine whether they directly modulate the rate of aging. This is true, in part, because there are no generally accepted molecular markers of aging rate in any organism. In mammals, several phenotypes are known to correlate with chronological age, and a handful have been suggested to have some predictive power for future life expectancy; however, none have been demonstrated convincingly in prospective studies.

In addition to gaining an understanding of the molecular mechanisms of aging, a primary goal of aging research is to identify interventions that will slow aging in people. Advanced age is the primary risk factor for the majority of diseases in developed nations, and there are enormous social and financial pressures associated with demographic shifts toward more elderly populations. Interventions that expand the period of healthy life and reduce the period of chronic disease and disability (referred to as "compression of morbidity") offer the potential to alleviate these pressures while simultaneously increasing individual productivity and quality of life.

In practical terms, it may not be necessary to understand in detail why aging is conserved in order to do something about it. In several cases, components of the insulin signaling / mTOR network, as well as the sirtuins, have been shown to be associated with longevity and age-associated disease risk in people. While it remains unclear how difficult it will be to develop interventions to improve healthy aging in humans, there is reason for optimism that this may not be far off. Drugs that target these pathways, including some already shown to increase life span and health span in rodents, are beginning to be tested for effects on age-associated phenotypes or disease in humans. Unfortunately, because of the glacial pace of human aging when compared to common animal models, it will likely take several decades to determine whether rapamycin or other such compounds generally improve age-associated outcomes in people.

Building and maintaining excess fat tissue, specifically the visceral fat clustered around internal organs, harms long-term health in numerous ways. It raises the risk of suffering from all of the most common age-related medical conditions, and raises lifetime medical expenditures even while lowering life expectancy. A primary mechanism here is thought to be greater levels of chronic inflammation spurred by this fat tissue, but visceral fat is metabolically active and prompts a wide range of changes throughout an individual's body. One of the end results is a greater level of physical damage to brain tissue over time, largely a result of breakage and failure in tiny blood vessels:

Obesity has been associated with microstructural brain tissue damage. Different fat compartments demonstrate different metabolic and endocrine behaviors. The aim was to investigate the individual associations between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and microstructural integrity in the brain. This study comprised 243 subjects aged 65.4 ± 6.7 years. The associations between abdominal VAT and SAT, assessed by CT, and magnetization transfer imaging markers of brain microstructure for gray and white matter were analyzed and adjusted for confounding factors.

Our data indicate that increasing visceral adipose tissue rather than subcutaneous adipose tissue is associated with microstructural brain tissue damage in elderly individuals. This association cannot be accounted for by BMI, which is an easily obtainable clinical measure of obesity but does not discriminate different fat compartments. Awareness of differences in the underlying mechanisms between body fat patterns and brain damage may offer more focused individual advice or treatment than considering BMI only. Further research in a general population with a wider age range is necessary to study whether the relationship between visceral adiposity and microstructural brain tissue damage is merely a result of ageing, or exists independently of age. Furthermore, cognition tests could be of additional value for evaluating the clinical consequences of these findings.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1002/oby.21048/

Predicting human life expectancy in the decades ahead is a big business, as the vast pension and life insurance industries rely upon these forecasts. If the forecasts are dramatically wrong, and they will be just as soon as any significant advances in rejuvenation biotechnology reach the clinic, then financial upheaval lies ahead for all of the counterparties, insurers, and governments who bet against larger than expected increases in human life. The actuarial profession pays attention to the state of medical research aimed at intervention in the aging process, and the more mainstream treatment of age-related disease, and their estimates of life expectancy at a given future date have been rising in past years. This is the most recent example of this process at work:

A new study forecasting how life expectancy will change in England and Wales has predicted people will live longer than current estimates. The researchers say official forecasts underestimate how long people will live in the future, and therefore don't adequately anticipate the need for additional investments in health and social services and pensions for the elderly. Researchers developed statistical models using death records, including data on age, sex, and postcode, from 1981 to 2012 to forecast life expectancy at birth for 375 districts in England and Wales. They predict that life expectancy nationally will increase for men from 79.5 years in 2012 to 85.7 in 2030, and for women from 83.3 in 2012 to 87.6 in 2030. The longevity gap between men and women has been closing for nearly half a century and will continue to get narrower. The forecasts for 2030 are higher than those by the Office of National Statistics, by 2.4 years for men and 1.0 year for women.

People living in the longest-living areas in 2012 - found in southern England and well-off parts of London - are expected to live seven or eight years longer than those in parts of urban northern England, such as Blackpool, Liverpool and Manchester, and South Wales - equivalent to the difference in national life expectancy between the UK and Sri Lanka or Vietnam. By 2030, the gap is projected to grow to more than eight years. "The bigger gains in life expectancy we predict will mean pensions will have larger payouts, and health and social services will have to serve an older population than currently planned. We also forecast rising inequalities, with bigger increases in lifespan for people in affluent areas than those in disadvantaged areas. This means wealthy people will benefit more from health and social services than poor people, and therefore should be prepared to pay its costs through higher taxes."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=152147&CultureCode=en

In the long run, the span of decades and centuries, the only thing that really matters is technological progress. It is how we measure the division of eras, it is what makes the difference between poverty and wealth. It is why we live longer than our immediate ancestors and suffer far less pain and disease. Of all our technologies, the most important at this time are all in the field of medical science. Biotechnology is advancing at a rapid pace, and this is the era in which all of the manifold ills caused by aging will be eliminated. The causes of aging will be treated successfully, and in the fullness of time all age-related disease will be banished as a relic of a barbaric past, alongside smallpox, scurvy, and many other medical conditions that existed only because our knowledge and ability was lacking.

Significant, rapid progress in medical science and its clinical application requires large-scale research, however, and sad to say but medical research is funded at a tiny fraction of the level of investment it merits given the potential benefits. In our societies more funding is devoted to drinks with pretty umbrellas in them, or the lighting of game fields, or the tools of organized murder used upon the members of other tribes. Better medicine is a very low priority, and most people don't give any thought to medical research at all - or at least not until they are ill, which is far too late. Progress in a newly wealthy society full of distractions therefore depends on the unreasonable, the zealots, the motivated, the visionaries, and there are never enough of them to go around.

When we are out there raising funds for early stage research into human rejuvenation that won't pay off for another decade or two, strong motivations and compelling visions are very necessary. We must paint a persuasive picture of the terrible cost of aging today, and show a vision of a near future vastly improved by cures for age-related disease. Most people won't think about this and won't help to make it happen unless it is put in front of them at some point, and that is really all that advocacy is at root; persuading the world to help make things better, one person at a time.

Fighting Death

The most significant event in a person's life is death. It changes everything. More precisely, it takes everything that a person had. If he was in love, he no longer is. If he was aspiring to pleasures, there will be none any longer. The world will be gone for the person. Every single neuron will disappear that was responsible for the wishes, desires, and feelings. We don't realize this, but everything single thing we accomplish, we do so looking in the face of inevitable death. Death takes away the sense of a person's life.

That little human being that you were once, who looked at the world with eyes wide open, got surprised, laughed, sometimes cried, this human being will cease to exist. Will disappear. Forever. Death is the triumph of unfairness. It is bloodcurdling that everybody will die. Kids, olds people, adults, women, men. Every person's life is a tragedy, because it ends badly every time. Death is so horrible that a man denies the very fact of its existence to protect himself. He simply doesn't think he is mortal or comes up with a unproven theory that there is no death whatsoever.

The inevitability of death is defined by the fact that people age. Therefore, the most rational behavior will be to study aging, and to try to slow it down and stop. I am standing in the middle of the hall in the institute where aging will be defeated. When? When there is enough funding. When there are large-scale scientific projects. When a lot of people understand that aging has to be eliminated without proposing any additional requirements.

A Vision of a Future Free of Alzheimer's

It is the year 2025 and it seems like a miracle reminiscent of John F. Kennedy's moonshot. A multi-modality cure for Alzheimer's disease was recently discovered, fast-tracked and approved by the FDA. Not just a prevention (although that came first, back in 2020), but breakthroughs in science and technology have actually caused a reversal of the disease. Just a decade earlier in 2015, the statistics were alarming and held the potential to create a global pandemic of catastrophic proportions. Half of all those over age 85 - the fastest-growing segment of the population - had some form of dementia. People of all ages cited Alzheimer's disease as the scariest of all disabling diseases in later life.

And for good reason. Back then, we didn't even know the cause of the disease let alone how to slow it, prevent it or cure it. And for the sufferers, the progression of the disease got worse over time until memory and judgment faded, followed by vast mood and behavioral changes, and eventually dementia victims had no ability to care for themselves in the most fundamental ways. Yet many often lived up to 20 years after diagnosis ... a life sentence for both the victims and their families. The projections for the future were staggering: By the year 2050, more than 115 million people world-wide could be suffering from Alzheimer's disease and other dementias.

But fast forward to the future when we woke up from that nightmare with a cure that combines advanced stem cell therapeutics, precision pharmaceuticals, trans-cranial direct-current stimulation and a highly specific lifestyle regimen. The results have been phenomenal. Suddenly cognitively impaired older adults who had been either living in long-term-care facilities or at home with around-the-clock caregiving could not only live with dignity but gain back their ability to remember, think, and live active lives again. And, it transformed the way everyone thinks about aging and the potential for the later years of life.

With the end of Alzheimer's disease, the world has changed for us in some very significant ways. More than half of all nursing-home beds have been emptied, saving hundreds of billions of dollars for families and governments world-wide. Tens of millions of caregivers have been unshackled from the burden of providing physical, emotional and financial care to loved ones suffering from the disease. And the health of these caregivers has improved dramatically, giving them a second chance at life. Research dollars aimed at finding a cure for Alzheimer's disease and other dementias can now be funneled into finding a solution for other diseases. Millions of individuals cured of Alzheimer's disease have now come out of the shadows to live independently, be a loving and interdependent part of their families, and find ways to be productive, contributing their wisdom and experience to their communities and society at-large. The fear of living a long life but being struck down by Alzheimer's disease has now been quashed. It has liberated us all to think about the future through the prism of possibilities which could include work, giving back, time with family and friends and the opportunity to stay active, engaged, and productive.

Of course, this isn't yet fact because we're here in 2015, speculating about the future. However, many share the hope and are working hard to turn that hope into a reality: that one of the biggest fears of aging - Alzheimer's disease and other dementias - can be thought of as a thing of the past by the year 2025.

This sort of notice should be expected given that the leadership at Google's Calico venture shows all the signs of intending to set up a very broad research infrastructure for the development of drugs to modestly slow aging. Sooner or later they are going to partner with all of the major laboratories and research groups in the field that share the same interests. This latest news is missing any interesting details on which technologies they might be interested in, but that is par for the course. I point it out to play the connections game in this small research community, noting that the SENS Research Foundation also partners with the Buck Institute on, for example, senescent cell clearance research. Near everything else the Institute does is of little relevance to the SENS approach to development of rejuvenation biotechnology, however - it is more in line with the mainstream approach of manipulation of the operation of metabolism so as to slow aging. This is slowing the accumulation of damage, not trying to repair that damage, and will probably be more challenging and produce far less impressive results.

The future for SENS-like rejuvenation therapies such as senescent cell clearance is to step by step take over the mainstream by consistently producing much better results at much lower costs at each stage of the early development process. So far this is the way things are going for senescent cell clearance, but there are a lot of other technologies making up the rejuvenation toolkit of the future that remain far from that stage of progress.

The Buck Institute for Research on Aging in Novato announced Tuesday that it has entered into a partnership agreement with Calico Life Sciences, a Google-backed life extension company based in South San Francisco. Chris Stewart, chairman and CEO of the North Bay Life Science Alliance, an effort to develop the North Bay into an economic hub for life-science companies, said, "We're very excited. You're seeing for the first time a significant amount of private sector money going into research on aging. I think it is a good marriage between the two organizations."

In September 2014, Calico announced it had entered into a five-year joint venture with AbbVie, a Chicago-based pharmaceutical company, to develop treatments for cancer and Alzheimer's. Both Calico and AbbVie committed to investing $250 million initially with the option to each add another $500 million at an unspecified later date. Since then, Calico has entered into partnership agreements with five different research laboratories, including the Buck Institute, but it has kept the financial terms of those agreements and most other details secret. Stewart said more and more pharmaceutical companies are "outsourcing their research and development by going to universities or institutes like the Buck Institute and partnering with them. Rather than buying companies, Calico is doing some strategic partnerships."

Announcing the deal with the Buck Institute, Calico's president of research and development, Hal Barron, said in a press release, "Given the Buck's exclusive focus on aging, we believe that there's great potential to increase our understanding of the biology of aging and to accelerate the translation of emerging insights into therapies to help patients with age-related diseases." Aside from that, Calico declined all comment. The only details supplied in the press release were that Calico will have the option to obtain exclusive rights to discoveries made under research it supports at the Buck Institute and will establish and maintain "certain" science operations there. One possible reason for Calico's reticence is that it hasn't decided on what areas of age-related illness it wants to focus, and it doesn't want to tip its hand to competitors.

Link: http://www.marinij.com/general-news/20150428/buck-institute-in-novato-partners-with-google-entity-to-search-for-biotech-fountain-of-youth

Researchers have demonstrated a new method of implanting artificial blood vessel structures to guide regrowth of tissue, leading to regeneration of a functional biological blood vessel:

Blocked blood vessels can quickly become dangerous. It is often necessary to replace a blood vessel - either by another vessel taken from the body or even by artificial vascular prostheses. Researchers have developed artificial blood vessels made from a special elastomer material, which has excellent mechanical properties. Over time, these artificial blood vessels are replaced by endogenous material. At the end of this restorative process, a natural, fully functional vessel is once again in place. The most important thing is to find a suitable material. The artificial materials that have been used so far are not ideally compatible with body tissue. The blood vessel can easily become blocked, especially if it is only small in diameter. Researchers have therefore developed new polymers. "These are so-called thermoplastic polyurethanes. By selecting very specific molecular building blocks we have succeeded in synthesizing a polymer with the desired properties."

To produce the vascular prostheses, polymer solutions were spun in an electrical field to form very fine threads and wound onto a spool. The wall of these artificial blood vessels is very similar to that of natural ones. The polymer fabric is slightly porous and so, initially, allows a small amount of blood to permeate through and this enriches the wall with growth factors. This encourages the migration of endogenous cells. The new method has already proved very successful in experiments with rats. "The rats' blood vessels were examined six months after insertion of the vascular prostheses. We did not find any aneurysms, thromboses or inflammation. Endogenous cells had colonized the vascular prostheses and turned the artificial constructs into natural body tissue." In fact, natural body tissue re-grew much faster than expected so that the degradation period of the plastic tubes can be made even shorter.

Link: http://www.meduniwien.ac.at/homepage/1/news-and-topstories/?tx_ttnews%5Btt_news%5D=5625

The brain is enormously complex, and as is true of almost every aspect of metabolism there is far more left to map than is already known. The entirely of the knowledge of human biochemistry is really just a sketch of the starting points for further exploration. The final finished catalog of everything there is to know about how a baseline human functions and ages will be truly vast in comparison to today's databases. Building this catalog will be the work of decades yet, even given the rapid and accelerating pace of progress in biotechnology. This is why many researchers believe that little meaningful progress is possible in the near term towards treating aging and extending healthy life spans. To their eyes the process of development is to first achieve a much greater understanding of how exactly every relevant cellular mechanism changes during aging, and then build ways to alter the operation of aged metabolism based on that new knowledge. This is not a short term vision, and making any meaningful progress will be a slow and expensive undertaking.

This state of affairs is exactly why we need more proactive shortcuts based on an engineering approach to medicine and aging. A great deal is in fact known, proven, and hypothesized with reasonable evidence when it comes to the cellular and molecular damage that causes aging. There is a solid list of the types of damage involved, a list finalized more than twenty years ago with no new additions since then even in this period of great progress in biotechnology. Thus it is reasonable to think it is fairly complete. If researchers develop means to repair that damage, then knowing how exactly the damage interacts and progresses - with great complexity - to cause aging becomes much less important. This is how the engineering approach works: you build using present knowledge where it is cost-effective to bypass the need to gain further knowledge. You won't win all the time, but it is a strategy that should produce far better results in the near term. There is every reason to hurry development of treatments for degenerative aging, given that the cost of delaying a day in the effective treatment of aging is more than 100,000 lives lost.

Here are two examples of the sort of research presently underway into the unmapped areas of brain biochemistry relevant to aging. These are very thin slices of a vast field of science:

Neuropeptides and Aging: Breaking the Signaling Barriers Within the Body

The complexities of the brain are still largely unrevealed. Associations between neuronal decline with age and the onset of disease have been identified, but the specific mechanisms that regulate this decline are still unknown. Between neuron morphological changes, alterations of neuronal signals, and accumulation of protein masses in various brain regions, the realms of research are far and wide. As brain functions are responsible for approximately 20% of the body's energy usage, further understanding of neurological function is essential for ensuring a longer and healthier life.

Neuropeptides are responsible for communicative signals between neurons and other regions of the body. Neuropeptide signaling changes with age, and frequently these changes induce detrimental effects in neurons. They are packaged in large dense core vesicles and cleaved by enzymes at each end to reach their mature forms, which then interact with G protein-coupled receptors to induce signaling. These receptors can be local, but may also be found in other regions of the body, which means that malfunction in a given neuropeptide's production or transport can result in dysfunction in multiple systems.

Interestingly, levels of the neuropeptide oxytocin are decreased in old mice plasma. Furthermore, knocking out oxytocin can diminish the formation of new muscle fibers upon injury induction, providing evidence to the possibility that age-related decreases in oxytocin can cause an age-related inability to regenerate muscle. Another neuropeptide that decreases with age is gonadotropin-releasing hormone (GnRH1), which is linked to inflammation and the stress response. Injection of GnRH1 into the brains of older mice restored neurogenesis in the hippocampus (the memory-forming center of the brain), which is a process known to decrease with age. The effects of altered neuropeptide levels can be profound, as is seen in the example of montane and prairie voles. Differing levels of vasopressin and oxytocin result in drastically differing social patterns, despite similar genetics between the two species. Such subtle differences in the regulation of neuropeptides are just an example of why it's important to understand how alteration in neuropeptide signaling with age can contribute to a potential decline in health.

The Aging Brain: Synaptic Regulation and Aging

Our brain is constantly changing, adjusting to the environment based on input. At the same time, there seems to be mechanisms in place to resist change. At the junctions between neurons and their targets, known as "synapses", there are mechanisms to ensure that the amount of signal sent from neurons and the sensitivity of the target cells are in constant balance. There is increased interest in how this homeostatic mechanism changes with age, as disruption in synaptic homeostasis may be causal to disease. Hence it may be possible to increase lifespan via interventions that restore optimal activity of synapses.

Involvement of TOR in increasing synaptic function is particularly interesting in light of the association of TOR inhibition and longevity. Disruption of the TOR pathway in yeast, nematodes, fruit flies, and mice increases lifespan significantly. Could the benefits of reducing TOR activity in part be explained by TOR's role in increasing synaptic function? There seems to be an overarching theme of disrupted synaptic function in neurodegenerative diseases, but whether this synaptic dysfunction is causal or consequential is still unknown.

I have to think that all too many bioethicists see it as their job to manufacture reasons not to make progress towards better medical technologies capable of preventing more pain, suffering, and death. The more self-evident the potential benefits of new medicine, the more ridiculous these manufactured reasons become, but these individuals are nonetheless striving hard to act as grit in the wheels, a spanner in the works. Some are even proud of it. How is it that we supposedly sensible human beings have created an entire infrastructure with the purpose of draining funding away from real medical research into order to slow it down? This entire field and all of its practitioners should be evicted from the halls of polite society.

Discussions of life extension ethics have focused mainly on whether an extended life would be desirable to have, and on the social consequences of widely available life extension. I want to explore a different range of issues: four ways in which the advent of life extension will change our relationship with death, not only for those who live extended lives, but also for those who cannot or choose not to. Although I believe that, on balance, the reasons in favor of developing life extension outweigh the reasons against doing so (something I won't argue for here), most of these changes probably count as reasons against doing so.

First, the advent of life extension will alter the human condition for those who live extended lives, and not merely by postponing death. Second, it will make death worse for those who lack access to life extension, even if those people live just as long as they do now. Third, for those who have access to life extension but prefer to live a normal lifespan because they think that has advantages, the advent of life extension will somewhat reduce some of those advantages, even if they never use life extension. Fourth, refusing life extension turns out to be a form of suicide, and this will force those who have access to life extension but turn it down to choose between an extended life they don't want and a form of suicide they may (probably mistakenly) consider immoral.

Link: http://dx.doi.org/10.1111/bioe.12161

Your bones are not as static as you might think, and are constantly being remodeled on the small scale by the activities of distinct populations of cells. It is known that a growing imbalance between the activities of osteoblasts, cells responsible for creating bone, and osteoclasts, cells responsible for breaking down bone, is involved in age-related loss of bone mass and strength. Researchers are making some progress towards understanding why inflammation causes more rapid bone loss, and one of the mechanisms turns out to be very similar:

Gum disease affects millions of North Americans each year. In fact, as much as $125B is spent each year in the US in an attempt to tackle periodontitis - considered an "osteoimmune" condition similar to osteoarthritis and osteoporosis - and its attendant complication: bone loss. Osteoinflammation produces larger osteoclasts. These "superosteoclasts" cause damage as they form on the bone surface, and, once attached, spit out enzymes that chew away at the bone - and loosen the teeth in the process. The larger the osteoclasts, the more efficient they are at resorbing bone. The question has always been, though: why does inflammation create larger osteoclasts?

To find the answer, the group looked carefully at the role of cytokines, chemicals released by cells in the body as part of an immune response. The team discovered that the cytokines spurred the production of adseverin, and from there, were able to trace a clear role for the protein through study models. "Adseverin appears to be critical for the generation or formation of super large osteoclasts responsible for the rapid bone loss associated with periodontal disease - and potentially other bone-related diseases such as osteoarthritis and osteoporosis. Adseverin has a very limited distribution in the body and very few cells express this protein at significant levels, which make it easier to target from a pharmacotherapeutic standpoint. It's an exciting drug target."

Link: http://www.eurekalert.org/pub_releases/2015-04/uot--pai042215.php

The Gerontology Research Group is a long-standing point of connection and networking hub for a range of scientists and advocates interested in slowing or reversing degenerative aging. It was set up by the late Stephen Coles of the UCLA faculty back in 1990, right at the dawn of the modern era of scientific interventions in the aging process. A mailing list has been running for about as long as I've been interested in the defeat of aging and extension of healthy life span as a goal, and nowadays there is a linked blog as well.

Of late the GRG volunteer staff have been experimenting with online meetings as a way to expand access to the regular presentations on aging research and related science that have been taking place on at least a monthly basis for more than two decades. A couple of meetings are coming up at the start of May, for example. If interested in listening in, you'll want to click through for connection instructions, which I won't reproduce here:

Gerontology Research Group Online Meetings

Dear GRG Member, Two GRG online meetings are scheduled.

1) Saturday May 2 - 10:00 am Pacific, 1:00 pm ET, 5:00 pm GMT

We will meet with GoToMeeting. A test run will be done the day before, so if you are not familiar with GoToMeeting but would like to join or watch - and make sure it works for you - contact us.

Robert Young, Director of the Supercentenarian Research and Database division will bring us up to date on recent supercentenarian activities. I'll briefly discuss the severe problem that currently exists with pre-clinical testing and solutions involving engineered (lab grown) tissue systems for drug and aging therapy assessment. Here and now there is Organovo's exVive3D™ liver and tissue testing services, and under development other varied systems such as tissue chips and engineered tissue systems for heart, liver, lung, kidney, brain and others.

Then as the main event, Vince Giuliano of Anti-Aging Firewalls will make a presentation on liposome delivered aging intervention therapies in humans: principles, research, and practical experience.

2) Friday May 8 - 10:00 am Pacific, 1:00 pm ET, 5:00 pm GMT

We will meet via NIH's WebEx system. You will receive instructions on how to join before the meeting.

This will be an extension of the tissue chips and engineered tissue systems section of the previous meeting. Our presenter will be Kristen Fabre, Scientific Program Manager, NIH National Center for Advancing Translational Science (NCATS) and Manager of the Tissue Chip for Drug Screening program.

Topic: The Tissue Chip for Drug Screening Initiative. This NIH/DARPA/FDA collaboration aims to develop 3-D human tissue chips that model the structure and function of human organs, such as the lung, liver and heart, and then combine these chips into an integrated system that can mimic complex functions of the human body. Once developed and integrated, researchers can use these models to predict whether a candidate drug, vaccine or biologic agent is safe or toxic in humans in a faster and more cost-effective way than current methods, and how effective a therapeutic candidate would be in clinical studies.

The more conservative end of the aging research community is not in favor of engineering approaches like SENS, which focus on repair of the known causes of aging as a way to evade very slow and expensive investigations of the details of how aging progresses, where understanding is still minimal and the unexplored spaces on the map remain very large. Engineering is a matter of doing the best you can in advance of full understanding, and can be highly effective. The Romans built great bridges without modern materials science and architectural understanding, for example. The conservative scientific viewpoint is to require something much closer to full understanding before progressing any further, however.

In the pure science view the only viable way forward to treat aging is to indeed follow the very slow and expensive process of obtaining full understanding of all the relevant complexity of our metabolism, followed by attempting to manipulate the operation of metabolism so as to slightly slow the aging process. Scientists putting forward this position avoid the claim that adding decades to human life spans is possible within the foreseeable future. Some don't believe it to be the case, others are merely not going to say so in public. The wheels turn slowly enough in the sciences that it has taken the better part of fifteen years to even come to the point of generally agreeing in print that gently slowing down the process of degenerative aging is possible and desirable.

All of this is why we need greater support for engineering approaches to the treatment of aging, such as the SENS research programs carried out by the SENS Research Foundation. If we wait around for the pure science community to catch up to what is plausible and worth trying, we'll all be aged and dead before there is significant progress. It is much better to forge ahead and build proposed rejuvenation therapies based on a reasonable expectation of providing benefits than to continue the slow and steady path. None of the approaches discussed in the paper below are capable in principle of providing more than a fraction of the additional years of healthy life span that a prototype rejuvenation toolkit based on SENS programs could in theory produce. They will further be of very limited use in old people: they don't repair the damage causing degeneration and disease, but only slow down the pace at which it continues to accumulate.

Human aging and age-associated diseases are emerging as among the greatest challenges and financial burdens faced by developed and developing countries. Research related to longevity extension has traditionally been viewed with skepticism and with concerns that it could lead to an increase in the size of the elderly population and the prevalence of diseases associated with aging. However, studies in a wide range of organisms have demonstrated that major lifespan extension is accompanied by reduced or delayed morbidity in most cases.

There was a general consensus among this panel of experts on the following points: (i) aging can be slowed by many interventions; (ii) slowing aging typically delays or prevents a range of chronic diseases of old age; (iii) dietary, nutraceutical, and pharmacologic interventions that modulate relevant intracellular signaling pathways and can be considered for human intervention have been identified. Additional potential targets will continue to emerge as research progresses; and (iv) it is now necessary to cautiously proceed to test these interventions in humans.

The strategies believed to be most promising by the panel of invited experts and authors of this manuscript are as follows: (1) Pharmacological inhibition of the GH/IGF-1 axis, (2) Protein restriction and Fasting Mimicking Diets, (3) Pharmacological inhibition of the TOR-S6K pathway, (4) Pharmacological regulation of certain sirtuin proteins and the use of spermidine and other epigenetic modulators, (5), Pharmacological inhibition of inflammation, (6) Chronic metformin use. These choices were based in part on: (i) consistent evidence for their pro-longevity effects in simple model organisms and rodents; (ii) evidence for their ability to prevent or delay multiple age-related diseases and conditions; and/or (iii) clinical evidence for their safety in small mammals and/or nonhuman primates.

Accumulating scientific evidence from studies conducted in various organisms and species suggests that targeting aging will not just postpone chronic diseases but also prevent multiple age-associated metabolic alterations while extending healthy lifespan. A number of pathways affecting metabolism, growth, inflammation, and epigenetic modifications that alter the rate of aging and incidence of age-related diseases have been identified. Interventions with the potential to target these pathways safely and to induce protective and rejuvenating responses that increase human healthspan are becoming available. We believe that the time has come not only to consider several therapeutic options for the treatment of age-related comorbidities, but to initiate clinical trials with the ultimate goal of increasing the healthspan (and perhaps longevity) of human populations, while respecting the guiding principle of physicians primum non nocere.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12338/

Mitochondria are the power plants of the cell, a host of organelles evolved from symbiotic bacteria. They each carry a small amount of DNA, and this accumulates damage with age. Some sorts of damage can spread rapidly within a cell's mitochondria, causing all of them to become dysfunctional. The cell itself also malfunctions as a result, exporting damaging reactive molecules into surrounding tissues. A small but significant portion of all the cells in the body suffer this fate by the time old age rolls around, and their presence contributes to degenerative aging.

Any comprehensive rejuvenation toolkit developed in the near future must include some way to deal with this issue. One possibility is a form of gene therapy for all cells in the body, delivering fixed and fully functional mitochondrial DNA, coupled with removal of the damaged strains to prevent them from spreading once more. The use of TALENs is showing some promise here, but at this point the research community is focused on inherited mitochondrial diseases rather than aging:

Mutations in mitochondrial DNA (mtDNA) can be specifically targeted and removed by transcription activator-like effector nucleases (TALENs) in murine oocytes, single-celled mouse embryos, and fused human-mouse hybrid cells, providing proof of principle for a method that could one day be used to treat certain hereditary mitochondrial disorders in people.

Between 1,000 and 100,000 mitochondria power each human cell. Often, mitochondria in the same cell have different genomes, or haplotypes, a condition known as heteroplasmy. Certain haplotypes include mutations that impact mitochondrial function and cause disease, particularly in energy-hungry organs such as the brain and heart. Because mitochondria segregate randomly as cells divide, it is impossible to determine early in embryonic development how a mix of wild-type and mutated mitochondria inherited from the mother will affect an organism.

To rid mitochondria of these harmful mutations, researchers have used restriction enzymes as well as zinc-finger nucleases (ZFNs) and TALENs, which can be designed to recognize any DNA sequence, to cut and eliminate mutated mitochondrial genomes from heteroplasmic cells. "Because the cell likes keeping the number of mtDNA molecules constant, after elimination of the faulty ones, the wild-type copy will repopulate the cell."

Now, an international team has used mitochondria-targeting restriction enzymes and TALENs in the mammalian germline and early-stage mouse embryos for the first time. Injecting mRNAs encoding each enzyme into mouse cells with two different wild-type mtDNA haplotypes selectively removed the targeted genome variant, and the edited embryos grew into normal mice. The team did not observe any off-target effects. To determine whether the enzymes could be used to edit human mtDNA, the researchers fused mouse oocytes with fibroblast cells from patients with one of two mitochondrial disorders - Leber's hereditary optic neuropathy or neurogenic muscle weakness, ataxia, and retinitis pigmentosa. Unlike in the mouse experiment, mutant mtDNA was still detectable, albeit at lower levels, after TALEN mRNA injection. Mutated mtDNA usually only causes disease if more than 60 percent to 75 percent of a cell's mitochondria harbor the error, so "the reduction that we observed was more than enough for the phenotype to disappear."

Link: http://www.the-scientist.com/?articles.view/articleNo/42791/title/Erasing-Mitochondrial-Mutations/

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.

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.

Link: http://dx.doi.org/10.1093/gerona/glv039

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."

Link: http://www.eurekalert.org/pub_releases/2015-04/uop-psi042315.php

The Methuselah Foundation and SENS Research Foundation collaborate to put out a quarterly newsletter for members of the 300, people who pledge to donate $25,000 over 25 years 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 $30 million dollars 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.

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.'"

Link: http://ecancer.org/news/7219-mouse-models-show-tailored-immunotherapy-to-be-effective.php

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.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25902459

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.

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.

Link: http://dx.doi.org/10.1016/j.archger.2015.03.004

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.

Link: http://www.creativida.org/#!Aubrey-de-Grey-The-Pioneer-The-craziest-idea-is-often-the-best-idea/cd8q/54db2ea70cf2a1055e454b08

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.

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.

Link: http://motherboard.vice.com/read/the-humanness-of-death

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.

Link: http://www.future-science.com/doi/full/10.4155/fso.15.9

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 $1 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 $1 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 $1 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 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.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12291/

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.

Link: http://med.stanford.edu/news/all-news/2015/04/cell-type-responsible-for-scarring-skin-cancer-growth-identified.html

It's always good to listen to viewpoints that you happen to disagree with. This is why I pay attention to research strategies and researchers informed by programmed aging theories such as the hyperfunction hypothesis that builds on antagonistic pleiotropy. In this view aging is the consequence of various developmental processes running off the rails, colliding, and fighting one another along the way, producing dysregulation and damage. This is programmed in the sense that it is an inevitable consequence of the way in which the many biological systems evolved to perform in early life. Thus evolved programs cause accumulations of cellular and molecular damage, which goes on to create further harm.

This is exactly backwards from the more mainstream view in the research community, and how I myself see the balance of evidence, which is that cellular and molecular damage accumulates through the normal operation of metabolism. That damage causes increasingly large reactions in evolved biological systems, few of them good, as their operating parameters and local environment become ever more dysfunctional. Damage causes more damage, and the process accelerates rapidly in later life, just as in any complicated machine. One of the most fascinating things about aging research at the present time is that biology is so fantastically complex that there is room enough yet to argue over whether damage causes change or change causes damage. There is so much left unknown and fuzzy still at this stage, despite the mountains of knowledge accumulated, that researchers still have great latitude to theorize and rearrange the chunks of what is known.

The end result is a lot of theorizing, as is always the case in any territory where much is left to be mapped. This will continue until enough proof arrives to settle the debate. In the case of the most important debate in aging research, which is between programmed aging and aging as damage, the most rapid and cost-effective way to settle this would be to implement initial prototypes of the SENS proposals for rejuvenation treatments. These are based entirely on the view of aging as damage accumulation, and involve the repair of specific forms of cellular and molecular damage thought to be fundamental, caused by the ordinary operation of metabolism rather than by some other form of damage. If aging is programmed then SENS will not work well at all, producing only fleeting benefits before the programs assert themselves to create more damage. If aging is damage, then SENS prototypes will greatly extend healthy life spans in laboratory animals such as mice. The cost of producing these prototypes is probably in the vicinity of $1-2 billion and 10-20 years, which is less than the cost for a Big Pharma entity to develop a single drug these days.

One of the originators of the hyperfunction theory of aging is very much in favor of manipulating mTOR, mechanistic target of rapamycin as a way to treat aging. He is a prolific author on this topic, and feels that work on rapamycin - and related drug candidates such as everolimus - in recent years goes a long way towards bolstering his case for mTOR as a master regulator of the aging process. If you are an adherent of the programmed aging viewpoint then altering metabolic operation, such as by dialing up or dialing down circulating levels of specific proteins, is exactly the approach that should be taken to treat aging. Restore something that looks more like youthful metabolism and damage will be repaired to at least some degree, depending on how far things have gone. If you follow the aging as damage viewpoint, on the other hand, then altering metabolic operation is a matter of rearranging deckchairs on the Titanic: it fails to address the underlying cause of frailty, degeneration, and disease, and therefore can only produce poor or fleeting benefits.

I think you'll find this an interesting piece, being almost exactly reversed in many of its viewpoints from much of the research I point out. All groups have their triumphalism, and one can appreciate a well conducted expression of that urge even when fairly certain that the author is wrong in his or her big picture view of the science:

Rejuvenating immunity: "anti-aging drug today" eight years later

Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented. Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR (Target of Rapamycin). TOR-centric model predicts that rapamycin (and other rapalogs) can be used in humans to treat aging and prevent diseases. In proper doses and schedules, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans. This theory was ridiculed by opponents and anonymous peer-reviewers. Yet, it was predicted in 2008 that "five years from now, current opponents will take the TOR-centric model for granted". And this prediction has been fulfilled.

Currently, humans and animals (in protected environment) die from age-related diseases, which are manifestation of aging. By slowing aging, rapamycin and calorie restriction can delay age-related diseases including cancer. They extend life span. Yet, the causes of death seem to be the same. Or not? Why is this important? Consider an analogy. 300 years ago in London, 75% of people died from external causes (infections, trauma, starvation) before they reached the age of 26. So only a few died from mTOR-driven aging. Only when most external causes have been eliminated, people now die from mTOR-driven age-related diseases. Similarly, if TOR-driven aging would be eliminated by a rational combination of anti-aging drugs, even then we still would not be immortal. There will be new, currently unknown causes of death. I call this post-aging syndrome. We do not know what it is. But we know that accumulation of molecular damage or telomere shortening (as examples) eventually would cause post-aging syndrome.

Even in the ancient world, when most people died from "external causes", symptoms of mTOR-driven aging were well known. In contrast, we do not know symptoms of post-aging syndrome. Aging is quasi-programmed and is not accidental. Although its rate varies among individuals, the chances to outlive aging and to die from post-aging syndrome are very low. Still, we may identify these symptoms in humans over 110 years old and especially in animals treated with rapamycin (and other anti-aging modalities). Inhibition of mTOR may extend life span, thus revealing post-aging syndrome. How will we know that we observe post-aging syndrome? There are potential criteria: Animals and humans die from either unknown diseases, unusual variants of known-disease and rare diseases. Or at least, the range of age-related diseases is dramatically changed. As discussed in 2006, causes of post-aging syndrome may include accumulation of random molecular damage, telomere shortening, selfish mitochondria and so on.

While gerontologists were studying free radicals and anti-oxidants, the TOR-centric (hyperfunction) theory revealed anti-aging drugs such as rapamycin and metformin. There are several potential anti-aging drugs in clinical use. Combining drugs and modalities, selecting doses and schedules in clinical trial will ensure the maximal lifespan extension. Simultaneously, medical progress improves aging-tolerance. Aging tolerance is the ability to survive despite aging. For example, bypass surgery allows patients with coronary disease to live, despite aging-associated atherosclerosis. Gerontologists do not need to catch the train that has already departed. No need to study rapamycin, which already entered the clinic. This is now a merely medical task. Gerontologists may continue to study free radicals and accumulation of random molecular damage as a potential cause of post-aging syndrome (not aging). It is important to study post-aging syndrome, to be ready to fight it, when medical progress with rapamycin will allow us to reach post-aging age: perhaps 50 years from now.

This is a good example of first generation cell therapies that have been available via medical tourism for quite some time, with enough information available for patients to make an informed decision about use, but are only now working their way through the regulatory system in the US:

Osteoarthritis (OA), a debilitating and painful degenerative disease, strikes an estimated 14 percent of adults 25 years of age and older, a third of adults age 65 and older in the U.S. alone. Those who suffer from OA may one day have a new and effective cell therapy, thanks to a team of Czech researchers who studied the effectiveness of using an OA patient's own adipose (fat) cells in a unique transplant therapy aimed at reducing the symptoms of this prevalent and difficult to treat condition as well as healing some of the damage caused by OA. The study, carried out with 1,114 OA volunteer patients who received autologous (self-donated) fat cell transplants saw their symptoms improved by the therapy.

"Adipose-derived cells have potential application in a wide range of clinical disorders, including myocardial infarction, stroke, Crohn's disease, multiple sclerosis (MS), rheumatoid arthritis, and breast augmentation and reconstruction. In this study we evaluated the safety and efficacy of freshly isolated autologous stromal vascular fraction cells (SVF cells). We hypothesized that the SVF cell treatment might contribute to cartilage healing." The study followed and evaluated 1,114 patients (median age 62, range 19-94 years; 52.8% male) treated with a single dose of SVF cells isolated from lipoaspirate. Patients were followed for between 12 and 54 months with a median of 17.2 months of follow-up. Their evaluations were based on pain, non-steroid analgesic usage, limping, extent of joint movement and stiffness before treatment and at three, six, and 12 months. Hip and knee joints were the most common joints treated and some patients had more than one joint treated.

"No serious side effects, systemic infection or cancer was associated with SVF cell therapy," reported the researchers. "Most patients improved gradually three to 12 months after treatment." The evaluations demonstrated that at least a 75 percent score improvement was noticed in 63 percent of the patients and at least a 50 percent score improvement was documented in 91 percent of the patients after 12 months. Typically patients in the study consumed large amounts of painkillers for their symptoms. Researchers found that painkiller usage declined dramatically after treatment.

Link: http://www.eurekalert.org/pub_releases/2015-04/ctco-pof041615.php

It is always going to be easier to develop treatments for non-vital organs, and in some cases work on cell therapies for those organs can be simpler and less costly for other, unrelated reasons. Thus progress is faster in these areas, and we should expect to see widespread availability of first generation, comparatively simple therapies well in advance of more ambitious goals, such as the regeneration of complex internal organs:

The regenerative medicine company RepliCel Life Sciences is developing potential cures for chronic tendinosis, damaged or aging skin, and pattern baldness by reseeding affected areas with specific cell populations isolated from patients' own healthy hair follicles. RepliCel is picking the low-hanging fruit of regenerative medicine - low technological risk, underserved markets, clear clinical indications. Furthermore, commercial success is not dependent on successful reimbursement negotiations. "On the technical level, we're not asking these cells to do anything other than what they naturally do, or be anything more than they are. These are adult, somatic cells derived from the patient which we simply isolate and grow. We're not differentiating, genetically modifying, or manipulating these cells in any way."

From the scientific and manufacturing perspective, RepliCel is using the hair follicle as the cell source because the cells are simple to collect, grow well in culture, and are both relatively naive and highly functional. On a clinical level, the company is simply addressing a deficit of active cells in the patient by local delivery of cells shown to function in ways needed to solve a human condition such as tendinosis or pattern baldness. "The cells are injected in ways and places that largely eliminate any concerns around in vivo cell migration. [This approach ensures] enough cells stay in situ and viable to affect a sustained effect."

For tendinosis - a disrupted healing cycle of the tendon - nonbulbar dermal sheath (NBDS) fibroblast cells are isolated from a biopsy of hair follicles taken from the back of the scalp. After these cells are replicated, creating populations of millions of cells, they are injected into the wound site to jump-start the disrupted wound repair. In early-stage trials researchers used a similar approach with tendinosis patients who had been failed by other therapies. The NBDS approach returned these patients to painless, near-normal function. In the next 18 months, RepliCel expects to conclude a Phase I/II study at the University of British Columbia involving 28 participants.

Phase II trials to treat baldness - specifically, androgenetic alopecia - will begin this year. For this therapy, dermal sheath cup (DSC) cells are isolated from the base of the hair follicle, replicated into the millions, and injected to the area of thinning hair. "DSC cells are responsible for maintaining the number of dermal papillae cells, which directly corresponds to the hair thickness. We are simply delivering a volume of androgen-insensitive DSC cells into an area where androgen-sensitive DSC cells have disappeared ... to restore the normal hair follicle cycle." In animal studies, this approach grew hair on the feet of mice (which have no hair follicles there). When these cells were injected into their ears, the healthy cells migrated into resident hair follicles, making that hair thicker.

Link: http://www.genengnews.com/gen-articles/cell-therapy-is-hair-raising-in-a-good-way/5469/

The varied approaches to research developed over past decades by the aging research community are driven by two things: firstly that we live for a long time, and secondly the absence of a way to accurately determine an individual's biological age. The only way to measure the effects of potential treatments is to carry out life span studies, and in humans that is impractical to say the least. Thus research into aging and longevity starts with short-lived animals such as nematode worms and flies: exploration and experimentation takes place using these species because life span studies can be carried out in a suitably short period of time to make progress. Promising work moves to mice, where life span studies can last for five years and cost millions. Only later do potential treatments make it to human clinical trials, if at all. This is all much the same as most modern medical research; the process of discovery and development moves incrementally from a state of being far from human biology and cheap to work on to a state of being close to human biology and very expensive to work on.

To a surprising degree the fundamental biology of cells, regulation of metabolism, and mechanisms of aging are similar in even very widely separated species. Aging and many of its interesting epicycles such as the calorie restriction response appeared very early in evolutionary history, a long way down in the tree of life. Thus research in lower animals can still be relevant to human cellular biochemistry, and provide insight into human aging. Nonetheless, worms are not mice and mice are not people. The cost of investigative research that starts with other species is that there is a fair degree of failure when translating promising work over to mammals, and yet more failure when moving from short-lived mammals such as mice to long-lived mammals such as humans. That is acceptable given that the alternative is no research at all, as all studies would be prohibitively expensive to carry out.

Another aspect of research into aging and its associated medical conditions is that genetically altered lineages of laboratory animals are frequently employed. The reasons for this are again economic at root. If you want to study a specific condition, such as old age for example, it is more cost-effective to work with mice that suffer from a DNA repair deficiency that mimics some aspects of accelerated aging than it is to work with normal mice. More research can be carried out more rapidly with accelerated aging mice, even when accounting for the fact that a significantly greater fraction of the results will be irrelevant to normal aging. The same applies to the many different animal models of specific age-related diseases: these are all loose replicas intended to share some characteristics of the disease as it occurs in humans, but under the hood they are not the same thing at all. Animal models are a way to make progress in a cost-effective manner, not an accurate rendition. These things are always worth bearing in mind when reading research results based on animal studies.

Do Model Animals Tell Us Anything about Human Aging?

Using model animals in gerontological studies has yielded an enormous wealth of useful information about the mechanisms of human aging and longevity. Animal models were crucial in identifying the conserved pathways that regulate human aging. Model organisms are fundamental for aging research, because there are serious limitations of using human subjects, such as the length of lifespan, genetic heterogeneity and vast differences in environmental influences. The shape of survival curves represents the health of the organism over time. Model organisms display significantly different lifespans, however the survival curves resemble those of humans quite remarkably.

Yeast S.cerevisiae

Yeasts have been instrumental in identifying the major conserved aging pathways shared among a large variety of species. Despite the fact that yeast is a unicellular organism that has significant differences in its genetic pathways with humans, the advantages of using yeast as an aging model include their fast growth, low cost and easy storage and maintenances of organism strains. Over the years researchers have developed a broad variety of genetic manipulations that make yeast a powerful tool in the hands of an aging biologist.

Nematode C.elegans

The roundworm Caenorhabditis elegans is a powerful model for studying aging due to its short lifespan. It is easy to culture and maintain strains because nematodes can be kept frozen and suffer no apparent damage upon thawing. The animals are optically transparent and can be used in high-throughput automated experiments, which makes them a perfect tool for answering the most pressing questions in biology of aging. However, there are obvious drawbacks of using C. elegans as a model for human aging. They are evolutionary distant from humans, lack tissues like brain, blood, they don't have internal organs and are post-mitotic, meaning that nematodes lack the ability to regenerate their tissues and are limited in serving as a model of aging of highly proliferative tissues.

Fruit fly D.melanogaster

Fruit flies have many advantages as a model system for aging studies. They have a relatively short lifespan of 60-80 days, which is more than that of a nematode, but compared to them drosophila have more distinct tissues and organs including the brain, eyes, kidney, liver and heart. Fruit flies have proliferating stem cell populations in their guts. Flies share about 60% of disease-related genes with humans, which makes them a desirable model also given their low cost and easy handling. However, maintaining a transgenic strain is more costly and labor-heavy, since whole flies cannot be frozen and thawed without damage.

Hydra

Hydra is definitely not the most popular model organism, but it might be overlooked quite groundlessly. Hydras are notorious for their negligible senescence. This very fact makes them a very desirable system to study. In fact, there is no apparent senescence in asexually reproducing hydras, yet the signs of aging can be seen after the organism reproduces sexually. Another overlooked fact is that hydras share 6071 genes with humans, whereas fruit flies have 5696 genes in common with humans, and nematodes - only 4751. Among the known human aging-related genes at least 80% are shared with hydra.

Fish

The most widely used fish model is the zebrafish D.rerio. It lives for about 2-3 years, which is not particularly beneficial, because its lifespan is similar of rodents, but it is more evolutionary distant from humans. Nonetheless, zebrafish has a remarkable ability to regenerate its tissues, which is an advantage for elucidating the mechanisms of tissue regeneration and longevity. Another fish may be a more promising laboratory model for aging - turquoise killifish Nothobranchius furzeri. Killifish is one of the shortest-lived vertebrate with a lifespan of only 13 weeks. Its small size and high fecundity offer a considerable advantage in terms of reducing laboratory costs on housing and maintenance.

Rodents

Mice are invaluable in aging research. There are approximately 99% of human orthologs in mice, which is a significant advantage compared to invertebrate models. Mouse lifespan is approximately 2-3 years depending on the strain, which makes them a more expensive tool in the arsenal of an aging biologist. Inbred mice have been studied very extensively and a large body of knowledge about aging mechanisms, age-related diseases and existing and potential therapies was created using this model. Using inbred lines is a double-edged sword: on one hand, genetic differences between animals are virtually non-existent, however this is not representative of human population and it is not clear to what extent the results can be transferred to humans.

Naked mole rats

Heterocephalus glaber, the naked mole rat, is the most long-lived rodent with a maximum life span of approximately 30 years. Naked mole rat exhibits negligible senescence, virtually no age-related increase in mortality and high reproduction levels until death. They have several signs of age-related pathology similar to humans, such as osteoarthritis and degeneration of the retina. Naked mole rats can provide clues to mechanisms of longevity and potential therapies in humans, and hence are an extremely valuable model animal. There are several disadvantages of using them as laboratory animals, however, including specific housing conditions like low light levels, high temperature and humidity. Very long lifespan poses an obvious limitation on the variety of experiments suitable for this model.

Primates

Rhesus macaques have been used in various types of research, however there are not too many studies of age-related mechanisms in primates. The main reasons for that are their long lifespan, which is more than 30 years, their size and weight, which complicate housing and maintenance and make this model an expensive and hard to handle. However, there are several distinct advantages of using non-human primates for studying age-related pathologies, such as Alzheimer's disease and other neurodegenerative diseases that can't be recapitulated in mouse models.

Aging is accumulated cell and tissue damage, and the slow growth of healthy human life expectancy that has taken place over the past two centuries thus reflects a lesser load of a damage present in individuals of a given age. The old in their 60s and 70s today are on average less damaged and less frail than people of the same chronological age were in the past. This trend is incidental, however, an unintended side-effect of broad improvements in medicine and related technologies that have other immediate goals: control of infectious disease, treatment of specific age-related conditions, and so forth. Things will change in the near future as the focus slowly turns to deliberate efforts to treat aging as a medical condition, as this should produce much faster gains in healthy human life span.

Faster increases in life expectancy do not necessarily produce faster population aging, according to new research. This counterintuitive finding was the result of applying new measures of aging to future population projections for Europe up to the year 2050. "Age can be measured as the time already lived or it can be adjusted taking into account the time left to live. If you don't consider people old just because they reached age 65 but instead take into account how long they have left to live, then the faster the increase in life expectancy, the less aging is actually going on."

Traditional measures of age simply categorize people as "old" at a specific age, often 65. But previous research has shown that the traditional definition puts many people in the category of "old" who have characteristics of much younger people. "What we think of as old has changed over time, and it will need to continue changing in the future as people live longer, healthier lives. Someone who is 60 years old today, I would argue is middle aged. 200 years ago, a 60-year-old would be a very old person. The onset of old age is important because it is often used as an indicator of increased disability and dependence, and decreased labor force participation. Adjusting what we consider to be the onset of old age when we study different countries and time periods is crucial both for the scientific understanding of population aging for the formulation of policies consistent with our current demographic situation."

In the new study the researchers compared the proportion of the population that was categorized as "old" using the conventional measure that assumes that people become "old" at age 65 and the proportion based on their new measure of age, which incorporates changes in life expectancy. The study looked at three scenarios for future population aging in Europe, using three different rates of increase for life expectancy, from no increase to an increase of about 1.4 years per decade. The results show that, as expected, faster increase in life expectancy lead to faster population aging when people are categorized as "old" at age 65 regardless of time or place, but, surprisingly, that they lead to slower population aging when the new measures of age are used.

Link: http://www.eurekalert.org/pub_releases/2015-04/iifa-apa041315.php

The available evidence from animal studies shows that lack of exercise causes poor health and a shorter life expectancy, while moderate regular exercise causes better health and a longer life expectancy. In humans the data can largely only show correlations rather than cause and effect, but the same pattern emerges. So it is reasonable to expect that regular moderate exercise provides improved odds of a healthier, modestly longer life, and that a sedentary lifestyle is harmful in comparison. The next question is whether more exercise is better, and that one is hard to answer based on work to date, but researchers are making inroads:

Exercise has had a Goldilocks problem, with experts debating just how much exercise is too little, too much or just the right amount to improve health and longevity. Two new, impressively large-scale studies provide some clarity, suggesting that the ideal dose of exercise for a long life is a bit more than many of us currently believe we should get, but less than many of us might expect. The studies also found that prolonged or intense exercise is unlikely to be harmful and could add years to people's lives. No one doubts, of course, that any amount of exercise is better than none. Like medicine, exercise is known to reduce risks for many diseases and premature death. But unlike medicine, exercise does not come with dosing instructions. The current broad guidelines from governmental and health organizations call for 150 minutes of moderate exercise per week to build and maintain health and fitness. But whether that amount of exercise represents the least amount that someone should do - the minimum recommended dose - or the ideal amount has not been certain.

In the broader of the two studies, researchers gathered and pooled data about people's exercise habits from six large, ongoing health surveys, winding up with information about more than 661,000 adults, most of them middle-aged. Using this data, the researchers stratified the adults by their weekly exercise time, from those who did not exercise at all to those who worked out for 10 times the current recommendations or more (meaning that the exercised moderately for 25 hours per week or more). Then they compared 14 years' worth of death records for the group. They found that, unsurprisingly, the people who did not exercise at all were at the highest risk of early death. But those who exercised a little, not meeting the recommendations but doing something, lowered their risk of premature death by 20 percent. Those who met the guidelines precisely, completing 150 minutes per week of moderate exercise, enjoyed greater longevity benefits and 31 percent less risk of dying during the 14-year period compared with those who never exercised. The sweet spot for exercise benefits, however, came among those who tripled the recommended level of exercise, working out moderately, mostly by walking, for 450 minutes per week, or a little more than an hour per day. Those people were 39 percent less likely to die prematurely than people who never exercised.

The other new study of exercise and mortality reached a somewhat similar conclusion about intensity. While a few recent studies have intimated that frequent, strenuous exercise might contribute to early mortality, the new study found the reverse. For this study, Australian researchers closely examined health survey data for more than 200,000 Australian adults, determining how much time each person spent exercising and how much of that exercise qualified as vigorous, such as running instead of walking, or playing competitive singles tennis versus a sociable doubles game. Then, as with the other study, they checked death statistics. And as in the other study, they found that meeting the exercise guidelines substantially reduced the risk of early death, even if someone's exercise was moderate, such as walking. But if someone engaged in even occasional vigorous exercise, he or she gained a small but not unimportant additional reduction in mortality. Those who spent up to 30 percent of their weekly exercise time in vigorous activities were 9 percent less likely to die prematurely than people who exercised for the same amount of time but always moderately, while those who spent more than 30 percent of their exercise time in strenuous activities gained an extra 13 percent reduction in early mortality, compared with people who never broke much of a sweat.

Link: http://well.blogs.nytimes.com/2015/04/15/the-right-dose-of-exercise-for-a-longer-life/

Élie Metchnikoff was a noted figure in the first days of modern immunology, with much of his most important work carried out in the closing decades of the 19th century. He is credited with coining the term gerontology for the study of aging, and was the author of The Prolongation of Life: Optimistic Studies - which through the miracles of modern technology one can now read online for free. I strongly recommend perusing the section entitled "Should We Try to Prolong Human Life?" as it shows how little arguments over the use of medicine to enhance human longevity have changed in the past century:

Although the duration of the life of man is one of the longest amongst mammals, men find it too short. From the remotest times the shortness of life has been complained of, and there have been many attempts to prolong it. Ought we to listen to the cry of humanity that life is too short and that it would be well to prolong it? Would it really be for the good of the human race to extend the duration of the life of man beyond its present limits? Already it is complained that the burden of supporting old people is too heavy, and statesmen are perturbed by the enormous expense which will be entailed by State support of the aged.

If the question were merely one of prolonging the life of old people without modifying old age itself, such considerations would be justified. It must be understood, however, that the prolongation of life would be associated with the preservation of intelligence and of the power to work. In the earlier parts of this book I have given many examples which show the possibility of useful work being done by persons of advanced years. When we have reduced or abolished such causes of precocious senility as intemperance and disease, it will no longer be necessary to give pensions at the age of sixty or seventy years. The cost of supporting the old, instead of increasing, will diminish progressively.

If attainment of the normal duration of life, which is much greater than the average life to-day, were to over-populate the earth, a very remote possibility, this could be remedied by lowering the birth-rate. Even at the present time, while the earth is far from being too quickly peopled, artificial limitation of the birth-rate takes place perhaps to an unnecessary extent.

Members of the energetic European grassroots community of longevity advocates propose to celebrate Metchnikoff's anniversary each year, and given his views and his work in medicine rightfully so, I say. That date is May 15th, and this year marks the 170th anniversary of Metchnikoff's birth. This initiative joins many others from past years, such as working to make celebrate the UN International Day of Older Persons as Longevity Day, all of which aim to raise awareness and build support for serious scientific efforts to treat and control degenerative aging.

Good advocacy is made up of many varied initiatives, year after year, for who knows which approach will go on to become a great success. Good advocacy is a matter of continually and inventively striving to deliver our message to ever more listeners, to persuade that next supporter, to raise that next dollar to fund the research that matters. The more that is done the easier it becomes: success attracts success, and every small gain matters.

May 15, 2015 - 170th anniversary of Élie Metchnikoff - the founder of gerontology

There is a tradition to celebrate the anniversaries of great persons (scientists, artists, writers, politicians, generals) to promote the area of their activity and popularize their ideology. It may be hoped that, in this year, the anniversary of Metchnikoff will serve to promote and popularize the science and ideology of healthy life extension, including the state level. The "Metchnikoff Day" can provide an impulse for organizing topical meetings and conferences, a stimulus for research, and publications in the media, dedicated to Metchnikoff's legacy and continuation of his life work - the study of aging and longevity. This may play a positive role not only for the advancement and popularization of research of aging and healthy longevity, but also for the promotion of optimism, peace and cooperation.

In view of the immense significance of degenerative aging processes for the emergence of virtually all diseases, both communicable and non-communicable, and in view of the accelerating development of potential means to intervene into and ameliorate these processes for the sake of achieving healthy longevity, Metchnikoff's pioneering contribution to this field assumes an ever greater global significance. The world is rapidly aging, threatening grave consequences for the global society and economy, while the rapidly developing biomedical science and technology stand in the first line of defense against the potential threat. These two ever increasing forces bring gerontology, describing the challenges of aging while at the same time seeking means to address those challenges, to the central stage of the global scientific, technological and political discourse. At this time, it is necessary to honor Metchnikoff, who stood at the origin of gerontological discourse, not just as a scientific field, but as a social and intellectual movement.

Currently events in honor of the Metchnikoff Day are being planned in Kiev, Ukraine, on behalf of the Kiev Institute of Gerontology of the Ukrainian Academy of Medical Sciences; St. Petersburg, Russia, on behalf of the Gerontological Society of the Russian Academy of Sciences and I.I. Mechnikov North-Western State Medical University; in Moscow on behalf of the National Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation and the Russian Longevity Alliance; Larnaca, Cyprus, on behalf of the ELPIs Foundation and the Cyprus Neuroscience and Technology Institute; Oxford, UK, on behalf of the Oxford University Scientific Society and Biogerontology Research Foundation; in Ramat Gan, Israel, on behalf of the Israeli Longevity Alliance and the International Society on Aging and Disease (Israel). It may be hoped that, following these examples, more events and publications will be held around the world in honor of this day.

We live in an era of very rapid change driven by technological progress. Today's world is enormously different from that of three or four decades past: consider the pervasive effects of the revolution in communications and computing technologies that has taken place over that time. Yet, human nature being what it is, most of the people who lived through this profound shift in capabilities and culture are nonetheless very skeptical of claims that the future will look radically different from today in any important aspect. It is strange.

In particular the concept of actuarial escape velocity leading to thousand year life spans is a very hard sell. People look at the large number that is very different from today's maximum life span and immediately reject it out of hand, no matter the reasonable argument behind it. Any medical technology that produces some rejuvenation in old patients buys extra time to develop better means of rejuvenation. At some point the first pass at rejuvenation treatments will improve such that remaining healthy life expectancy grows at more than a year with each passing year. At that point life spans will become indefinite, limited only by accident or rare medical conditions not yet solved.

It doesn't help that most of the public has very little knowledge of the present state of medical research in any field, never mind the specific details of how aging might be treated and brought under medical control. The only solution to that issue is to keep on talking: educate, advocate, and spread the word.

It is likely the first person who will live to be 1,000 years old is already alive today. This is according to a growing regiment of researchers who believe a biological revolution enabling humans to experience everlasting youthfulness is just around the corner. At the epicentre of the research is Aubrey de Grey, co-founder or the California-based Strategies for Engineered Negligible Senescence (SENS) Research Foundation.

"The first thing I want to do is get rid of the use of this word immortality, because it's enormously damaging, it is not just wrong, it is damaging. It means zero risk of death from any cause - whereas I just work on one particular cause of death, namely ageing." de Grey said his research aims to undo the damage done by the wear and tear of life, as opposed to stopping the ageing process altogether. "If we ask the question: 'Has the person been born who will be able to escape the ill health of old age indefinitely?' Then I would say the chances of that are very high. Probably about 80 per cent."

"The therapies that we are working on at the moment are not going to be perfect. These therapies are going to be good enough to take middle age people, say people aged 60, and rejuvenate them thoroughly enough so they won't be biologically 60 again until they are chronologically 90. That means we have essentially bought 30 years of time to figure out how to re-rejuvenate them when they are chronologically 90 so they won't be biologically 60 for a third time until they are 120 or 150. I believe that 30 years is going to be very easily enough time to do that."

Link: http://www.news.com.au/technology/science/researchers-believe-a-biological-revolution-enabling-humans-to-experience-everlasting-youthfulness-is-coming/story-fnpjxnqt-1227304902553

Age-related macular degeneration has a fairly direct relationship to the accumulation of a mix of metabolic wastes called lipofuscin in long-lived retinal cells. There are other contributing causes, but that is an important one. Cell repair mechanisms are impacted, cells falter and die as a result and are not replaced, and progressive blindness follows the consequent retinal damage. Here researchers show that the overall process of degeneration can be significantly slowed via a stem cell therapy, though it is unclear as to how it affects lipofuscin accumulation versus other mechanisms:

Age-related macular degeneration occurs when the small central portion of the retina, known as the macula, deteriorates. The retina is the light-sensing nerve tissue at the back of the eye. Macular degeneration may also be caused by environmental factors, aging and a genetic predisposition. When animal models with macular degeneration were injected with induced neural progenitor stem cells, which derive from the more commonly known induced pluripotent stem cells, healthy cells began to migrate around the retina and formed a protective layer. This protective layer prevented ongoing degeneration of the vital retinal cells responsible for vision. "This is the first study to show preservation of vision after a single injection of adult-derived human cells into a rat model with age-related macular degeneration." The stem cell injection resulted in 130 days of preserved vision in laboratory rats, which roughly equates to 16 years in humans.

Researchers first converted adult human skin cells into powerful induced pluripotent stem cells (iPSC), which can be expanded indefinitely and then made into any cell of the human body. In this study, these induced pluripotent stem cells were then directed toward a neural progenitor cell fate, known as induced neural progenitor stem cells, or iNPCs. "These induced neural progenitor stem cells are a novel source of adult-derived cells which should have powerful effects on slowing down vision loss associated with macular degeneration. Though additional pre-clinical data is needed, our institute is close to a time when we can offer adult stem cells as a promising source for personalized therapies for this and other human diseases." Next steps include testing the efficacy and safety of the stem cell injection in preclinical animal studies to provide information for applying for an investigational new drug. From there, clinical trials will be designed to test potential benefit in patients with later-stage age-related macular degeneration.

Link: http://www.newswise.com/articles/stem-cell-injection-may-soon-reverse-vision-loss-caused-by-age-related-macular-degeneration

The development of fairly consistent, accurate means to measure biological age - as opposed to chronological age - from a tissue sample is an important thread in aging research. Aging is a process of damage accumulation, and rejuvenation would be achieved through damage repair. Research and development aimed at significant extension of healthy life span can only become cost-effective given good ways to measure damage, however. There must be some reliable means to quickly assess the results of a treatment that claims a degree of rejuvenation through the partial repair of a specific form of cellular or molecular damage. In some cases this might seem easy. Take senescent cell clearance, for example: you run the therapy in mice, and compare a range of measures known to scale by senescent cell count in tissue samples before and after the treatment regimen. However, all that really tells you is how well the therapy clears senescent cells. All aspects of biology interact with one another, and age is a global phenomenon. To determine how aged an individual is and how effective a treatment might be when it comes to the practical outcome of additional healthy life span added there is presently little to be done other than wait and see.

The biggest challenge in the development of life-extending therapies is funding and cost. On the one hand there is far too little funding directed towards finding ways to treat aging. On the other hand effectively evaluating an alleged means of treating aging currently requires life span studies, and even in mice that takes far too long and costs far too much to be done casually. If there were standardized, quick and easy markers of physiological age that could be assessed before and after a treatment, then this research and development might be able to proceed ten times as rapidly, and evaluation of possible therapies would be open to far more research groups. There are many, many more laboratories with the capacity and funding to carry out a speculative $100,000 study versus a speculative $1,000,000 study.

All of this is to explain why there is considerable interest in developing a cheap biomarker of aging that can reliably assess physiological age from a tissue sample. No-one wants to run a five year mouse study if there is a ten minute alternative that produces an answer of about the same accuracy. That ten minute alternative doesn't yet exist, but some lines of research seem promising, such as work on DNA methylation patterns that appear to be fairly consistent between individuals over the course of aging. There is also the suggestion that the approach should be to measure the fundamental forms of damage thought to cause aging - but all of them, not just the one being treated by the therapy under consideration. At the present time that might be more onerous than finding a good set of secondary consequences that are reactions to damage, such as epigenetic changes.

The open access paper linked below covers a fairly wide range of topics. The structures of our cells and tissues are built of proteins, and these proteins are constantly damaged and replaced. Many varied mechanisms toil constantly to remove proteins and cellular components as soon as they show damage or dysfunction. Nonetheless the difference between young tissue and old tissue is that old tissues have far more damage: misfolded proteins, malfunctioning structures inside cells, metabolic waste products such as advanced glycation endproducts (AGEs) gumming together structures in between cells, and on and so forth. The damage leaks through, and even damage repair mechanisms are not invulnerable; they falter with age due to much the same set of issues as causes dysfunction elsewhere. In the future repair technologies, such as those outlined in the SENS proposals, will bring about rejuvenation by reversing these forms of damage. Since these issues are a part of full set of causes of aging they are also potential markers of aging.

Protein modification and maintenance systems as biomarkers of ageing

Changes in the abundance and post-translational modification of proteins and accumulation of some modified proteins have been proposed to represent hallmarks of biological ageing. Non-enzymatic protein glycation is a common post-translational modification of proteins in vivo, resulting from reactions between glucose or its metabolites and amino groups on proteins, this process is termed "Maillard reaction" and leads to the formation of advanced glycation endproducts (AGEs). During normal ageing, there is accumulation of AGEs of long-lived proteins such as collagens and several cartilage proteins. AGEs, either directly or through interactions with their receptors, are involved in the pathophysiology of numerous age-related diseases, such as cardiovascular and renal diseases and neurodegeneration.

Beside protein glycation, it is also well known that levels of oxidised proteins increase with age, due to increased protein damage induced by reactive oxygen species (ROS), decreased elimination of oxidized protein (i.e. repair and degradation), or a combination of both. Since the proteasome is in charge of both general protein turnover and removal of oxidized protein, its fate during ageing has received considerable attention, and evidence has been provided for impairment of the proteasome function with age in different cellular systems. Thus, these protein maintenance systems may also be viewed as potential biomarkers of ageing.

It is expected that a combination of several biomarkers will provide a much better tool to measure biological age than any single biomarker in isolation. For the most part, the markers based on proteins and their modifications that have been chosen are directly related with mechanistic aspects of the ageing process. Indeed, they are relevant to such important physiological features such as protein homeostasis and glycoprotein secretion that have been previously documented as being altered with age. Therefore, it is expected that they may be less influenced by other factors not necessarily related with ageing.

It is known that cellular repair processes are important in the determination of life span. Many of the methods of modestly slowing aging in laboratory species are accompanied by increased rates of cellular housekeeping, the recycling of damaged proteins and cell components. One set of these processes is centered around the proteasome, responsible for breaking down unneeded or damaged proteins, and here researchers demonstrate a correlation between proteasomal activity and species longevity in mammals:

Within the animal kingdom there is extraordinary variation in lifespan. Members of some species only live a few days or weeks, while others live tens, if not hundreds, of years. This large variation in species lifespan found in nature provides a powerful tool for the identification of factors that regulate the rate of aging. There is now a body of evidence to suggest that primary skin-derived fibroblasts can be used to evaluate aspects of cell biology that may differ between long-lived and short-lived species. This approach is not based on any assumption that changes in fibroblast properties would significantly affect organismal lifespan, but rather on the notion that evolutionary changes that produce slow aging might affect multiple cell types, including some that contribute to long-lasting resistance to disease and disability, as well as others, like fibroblasts, that are easy to cultivate and expand under standardized conditions for scores of species in parallel.

Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation. Fibroblasts from long-lived primates also appeared more responsive to IFN-γ than cells from short-lived primate species, and this increase in IFN-γ responsiveness correlated with elevated expression of the IFN-γ receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-α-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species.

Link: http://dx.doi.org/10.1172/JCI80514

Cryonics is the low-temperature preservation of the deceased in order to grant them a chance at a renewed life when technologies for restoration are developed. One of the big outstanding questions is the degree to which cryopreservation successfully preserves the fine structure of the brain and thus the data of the mind. The fact that cold water drowning victims can live again after an hour or more of brain death tells us that memory is encoded in physical structures, with the current consensus suggesting it is located in synaptic connections between neurons. Scanning technologies have been used to show that cryopreservation via vitrification of cryoprotectant-infused tissue does indeed preserve the fine structure of brain cell connections, but there is always the need for more and better proof. At the present time studies involving restoration of vitrified individuals must be carried out in lower animals, as researchers are still far from the point at which they can safely restore vitrified mammals:

Can memory be retained after cryopreservation? Our research has attempted to answer this long-standing question by using the nematode worm Caenorhabditis elegans (C. elegans), a well-known model organism for biological research that has generated revolutionary findings but has not been tested for memory retention after cryopreservation. Our study's goal was to test C. elegans' memory recall after vitrification and reviving.

Using a method of sensory imprinting in the young C. elegans we established that learning acquired through olfactory cues shapes the animal's behavior and the learning is retained at the adult stage after vitrification. Our research method included olfactory imprinting with the chemical benzaldehyde (C6H5CHO) for phase-sense olfactory imprinting at larval stage 1, the fast cooling SafeSpeed method for vitrification at larval stage 2, reviving, and a chemotaxis assay for testing memory retention of learning at the adult stage. Our results in testing memory retention after cryopreservation show that the mechanisms that regulate the odorant imprinting (a form of long-term memory) in C. elegans have not been modified by the process of vitrification or by slow freezing.

Link: http://dx.doi.org/10.1089/rej.2014.1636

There are a lot of theories of aging. Simply outlining the numerous categories of theory and offering a few comments as to which of the better known theories are currently well supported, dead, or disputed is a fairly detailed undertaking. It is hard to avoid delving into the history of the field when explaining how the research community ended up where it is today in terms of the various camps. There are evolutionary theories that seek to explain how aging came about, there are damage accumulation theories of aging, programmed aging theories that see aging as an evolved program of individual self-destruction, and any number of single-mechanism theories based on one or more researchers generalizing their narrow area of familiarity out to the whole body. Usually overgeneralizing, to be truthful: aging is a complex mix of at least initially independent causes, not one single mechanism.

The diversity of theories is really a reflection of just how much yet remains uncertain in the study of human biochemistry. In the sciences you will find theories proliferating wildly wherever there are few definitive answers due to the sheer complexity of the systems under examination. Inventive exploration and theorizing continues until some faction can prove themselves correct and everyone else wrong beyond any reasonable doubt. My expectation is that damage accumulation theories are mostly correct, that the SENS proposals contain a fair digest of which damage is fundamental and important rather than secondary or unimportant, and proof beyond any reasonable doubt will be provided in animal studies that test various SENS or SENS-like implementations of rejuvenation treatments. Large degrees of healthy life extension in the laboratory will prove the point faster and more cost-effectively than any research programs aiming to find and catalog all of the relevant mechanisms involved. This process is well underway for relevant areas in stem cell research, and has of late just begun for the clearance of senescent cells. Repair of other important forms of damage is yet to be earnestly tested: removal of various forms of metabolic waste, for example, such as amyloids and lipofuscin.

It has long been noted in parts of the aging research community that the activity of most of the researchers involved bears some resemblance to the tale of the blind men and the elephant. Each feels but a part of the whole, and that is their conception of the beast. Modern medical life science, even just a small field within the whole, is so complex and vast that researchers specialize in tiny slices of it, having only a superficial familiarity at best with everything else. It is often the case that when these researchers apply their knowledge to aging in isolation, without networking extensively, they propose theories that only cover a fraction of the biochemistry that the broader aging research community has identified as being relevant and involved in aging.

Redox theory of aging

Hundreds of philosophers and scientists have addressed the topics of longevity and aging, and many theories have been advanced. These have been recently reviewed, and I make no attempt to further summarize these important contributions. Rather, the present article provides a conceptual review based upon the emerging concept that redox systems function as a critical interface between the genome and the exposome. Relying extensively upon emerging understanding of redox systems biology, acquired epigenetic memory systems, and deductive reasoning, a simple theory is derived that aging is the decline of the adaptive interface of the functional genome and exposome that occurs due to cell and tissue differentiation and cumulative exposures and responses of an organism. This theory is not limited to redox processes but has a redox-dependent character due to the over-riding importance of electron transfer in energy supply, defense, reproduction and molecular dynamics of protein and cell signaling.

Several years ago, I presented a redox hypothesis of oxidative stress in which I concluded that oxidative stress is predominantly a process involving 2-electron, non-radical reactions rather than commonly considered 1-electron, free radical reactions. The central arguments were that (1) experimental measures showed that non-radical flux substantially exceeds free radical flux under most oxidative stress conditions, (2) radical scavenger trials in humans failed to show health benefits, and (3) normal cell functions involving sulfur switches are readily disrupted by non-radical oxidants. The redox hypothesis is thus founded upon the concept that oxidative stress includes disruption of redox circuitry in addition to the macromolecular damage resulting from an imbalance of prooxidants and antioxidants.

The redox hypothesis of oxidative stress contained four postulates:

1. All biologic systems contain redox elements [e.g., redox-sensitive cysteines], which function in cell signaling, macromolecular trafficking and physiologic regulation.

2. Organization and coordination of the redox activity of these elements occurs through redox circuits dependent upon common control nodes (e.g., thioredoxin, GSH).

3. The redox-sensitive elements are spatially and kinetically insulated so that "gated" redox circuits can be activated by translocation/aggregation and/or catalytic mechanisms.

4. Oxidative stress is a disruption of the function of these redox circuits caused by specific reaction with the redox-sensitive thiol elements, altered pathways of electron transfer, or interruption of the gating mechanisms controlling the flux through these pathways.

The current article represents an extension and development of these concepts into a redox theory of aging. This redox theory is not exclusively limited to redox reactions but rather emphasizes the key role of electron transfer in supporting central energy currencies (ATP, phosphorylation, acetylation, acylation, methylation and ionic gradients across membranes) and providing the free energy to support metabolism, cell structure, biologic defense mechanisms and reproduction. Importantly, improved understanding of the integrated nature of redox control and signaling in complex, multicellular organisms provide a foundation for this generalized theory.

Hsp22 is a heat shock protein in the fly genome. Like other heat shock proteins it is involved in hormesis, wherein cells repair themselves more aggressively in response to heat, toxins, and other forms of stress. If the stress is mild or short-lived then the result is a net reduction in cellular damage. If this persists for long enough then the individual experiences improved health and longevity: increased cellular repair efforts and altered levels of heat shock proteins are observed in many of the approaches shown to slow aging in laboratory species. There is consequently some interest in the development of therapies based on triggering increased cellular housekeeping without the need for the initial stress, and manipulating levels of heat shock proteins seems like a good starting point:

Mitochondria are involved in many key cellular processes and therefore need to rely on good protein quality control (PQC). Three types of mechanisms are in place to insure mitochondrial protein integrity: reactive oxygen species scavenging by anti-oxidant enzymes, protein folding/degradation by molecular chaperones and proteases and clearance of defective mitochondria by mitophagy.

Drosophila melanogaster Hsp22 is part of the molecular chaperone axis of the PQC and is characterized by its intra-mitochondrial localization and preferential expression during aging. As a stress biomarker, the level of its expression during aging has been shown to partially predict the remaining lifespan of flies. Since over-expression of this small heat shock protein increases lifespan and resistance to stress, Hsp22 most likely has a positive effect on mitochondrial integrity. Accordingly, Hsp22 has recently been implicated in the mitochondrial unfolded protein response of flies. This review will summarize the key findings on D. melanogaster Hsp22 and emphasis on its links with the aging process.

Link: http://journal.frontiersin.org/article/10.3389/fgene.2015.00103/full

Here is an interesting study on the association of average telomere length with cancer risk, a relationship that is apparently quite hard to pull from raw epidemiological data:

Telomere shortening is an inevitable, age-related process, but it can also be exacerbated by lifestyle factors such as obesity and smoking. Thus, some previous studies have found an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association found between short telomeres and increased cancer mortality was correlational but other factors (age and lifestyle), not adjusted for in previous studies, were the real causes. Genetic variation in several genes associated with telomere length (TERC, TERT, OBFC1) is independent of age and lifestyle. Thus, a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow the presumably causal association of telomere length and cancer mortality to be studied.

Researchers used data from two prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, including 64,637 individuals followed from 1991-2011. Participants completed a questionnaire and had a physical examination and blood drawn for biochemistry, genotyping, and telomere length assays. For each subject, the authors had information on physical characteristics such as body mass index, blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables. In addition to the measure of telomere length for each subject, three single nucleotide polymorphisms of TERC, TERT, and OBFC1 were used to construct a score for the presence of telomere shortening alleles.

A total of 7607 individuals died during the study, 2420 of cancer. Overall, as expected, decreasing telomere length as measured in leukocytes was associated with age and other variables such as BMI and smoking and with death from all causes, including cancer. Surprisingly, and in contrast, a higher genetic score for telomere shortening was associated specifically with decreased cancer mortality, but not with any other causes of death, suggesting that the slightly shorter telomeres in the cancer patients with the higher genetic score for telomere shortening might be beneficial because the uncontrolled cancer cell replication that leads to tumor progression and death is reduced.

Link: http://www.sciencedaily.com/releases/2015/04/150410165312.htm

Telomeres are repeating DNA sequences of that cap the ends of chromosomes. A little of that length is lost when DNA is copied during cell division, and telomere length is thus a part of the system of linked mechanisms that limits the replicative life span of ordinary somatic cells. The vast majority of cells in the body are somatic cells, and they are subject to this Hayflick limit: they can only divide a few dozen times before self-destructing or lapsing into a senescent state. Tissues consisting of somatic cells are maintained by stem cell populations that deliver a supply of fresh somatic cells with long telomeres: when a stem cell divides one of the daughter cells remains a stem cell while the other differentiates to become a somatic cell of a specific type.

How do stem cells continue to deliver long-telomere descendants if they are consistently dividing? They lengthen their telomeres through the activity of telomerase, an enzyme whose chief identified function is to add more repeating DNA sequences to the ends of telomeres. In our species telomerase is only active in some circumstances, such as in stem cells and cancers, but many other species, including other mammals, have somewhat different telomere dynamics. That is a basic sketch of a very complex system: cells have a countdown mechanism, tissues are largely made of cells that cannot adjust that mechanism, and a small, select group of cells that continually reset their own countdown are responsible for building new cells as the old ones run down and die.

Average telomere length, proportion of very short telomeres, and other similar statistics are usually measured in immune cells present in a blood sample. Average telomere length decreases with advancing age, but also with illness. On a fairly short time frame this measure can move up and down: the erosion over a lifetime is a long slope made up of a lot of oscillation about a mean. A range of research and development over the past decade has focused on restoring telomere length as a potential life-extending treatment, based on the idea that loss of telomere length is a contributing cause of aging. A number of early attempts failed to get anywhere, but a few years ago researchers demonstrated improved health and life extension in mice via artifically increased telomerase activity. The root causes are not yet firmly pinned down, but probably have a lot to do with increased stem cell activity and consequently better tissue and organ maintenance over the course of degenerative aging. That, of course, is not the same thing as merely having longer telomeres on average in somatic cells.

The bulk of the rest of the evidence regarding telomere biology looks very much to me as though average telomere length is a very indirect reflection of the state of our biology as a whole. How damaged are we? How active are our stem cells? What is being measured by average telomere length in white blood cells is some amalgam of the pace of cell replacement by stem cells, state of immune system health, and the level of underlying damage that drives changes in those biological systems. There are counter-arguments to that view, such as the recent discovery that telomeres seem to influence gene expression profiles across the genome differently depending on their length.

Here is an open access paper that looks at some of the recent research into telomere length and its role in our biology, concluding that "recently obtained knowledge shifts the telomere paradigm from a simple clock counting cell divisions to a more complex process recording the history of stress exposure within a cell lineage."

Telomeric aging: mitotic clock or stress indicator?

Telomeres are located at chromosomal ends and allow cells to distinguish chromosome ends from double-strand breaks and protect chromosomes from end-to-end fusion, recombination, and degradation. Telomeres are not linear structures, telomeric DNA is maintained in a loop structure due to many key proteins. This structure serves to protect the ends of chromosomes. Telomeres are subjected to shortening at each cycle of cell division due to incomplete synthesis of the lagging strand during DNA replication owing to the inability of DNA polymerase to completely replicate the ends of chromosome DNA ("end-replication problem"). Therefore, they assume to limit the number of cell cycles and act as a "mitotic clock". Shortened telomeres cause decreased proliferative potential, thus triggering senescence.

Telomere length is highly heterogeneous in somatic cells, but generally decreases with age in proliferating tissues thereby constituting a barrier to tumorigenesis but also contributing to age-related loss of stem cells. Telomerase maintains telomere length by adding telomeric DNA repeats to chromosome ends in prenatal tissues, gametes, stem cells, and cancerous cells. In proliferative somatic cells, it is usually inactive or expressed at levels that are not high enough to maintain the stable telomere length. Repair of critically short ("uncapped") telomeres by telomerase enzyme is limited in somatic cells, and cellular senescence, apoptosis and/or a permanent cell cycle arrest are triggered by a critical accumulation of uncapped telomeres. Shortened telomeres have also been observed in a variety of chronic degenerative diseases, including type 2 diabetes, cardiovascular disease, osteoporosis, and cancer. The specific molecular mechanism by which short telomeres trigger the development of diseases is, however, not yet determined. It has been proposed that telomere shortening per-se might not be a direct signal for cell cycle arrest, but rather the consequence of telomere loss. It can promote a pro-inflammatory secretory phenotype, in turn contributing to a variety of age-related diseases.

Replicative attrition, however, is not the only explanation for age-dependent telomere shortening. Some studies demonstrate that this process can be non-replicative and significantly stress-dependent because of the deficiency of a telomere-specific damage repair. Oxidative stress is one of the most important stress factors causing telomere shortening. Telomeric DNA is known to be more susceptible to oxidative damage than non-telomeric DNA. In human cell lines, telomeres generally shorten by 30-200 base pairs at each round of DNA replication, but only approximately 10 base pairs of this reduction are a consequence of the end-replication problem; the remaining loss is likely owing to oxidative damage.

The complexity of processes underlying age-related telomere erosion came from several longitudinal studies of telomere dynamics in vivo. Traditionally, it was assumed that telomeres are stable structures, which may be changed only in unidirectional way - shortening over the lifetime. Today, however, it has become increasingly clear that telomeres shortening over time in an oscillatory rather than linear fashion and they may be either shortened or lengthened under certain conditions. Several pilot studies indicate that treatment procedures targeting to reduce stress, e.g. meditation, along with the enhanced physical activity and changes in dietary patterns, can slow or even reverse telomere shortening owing to the elevated telomerase activity. The elongation of telomeres may be caused by the telomerase-mediated extension or appear due to the "pseudo-telomeric lengthening." The latest is due to the fact that, since telomere lengths are commonly measured in a mixed leukocyte population, mean telomere length can increase because of a redistribution of cell subpopulations, i.e., change in the percentage of various cell types in the blood samples.

Given data from recent studies, a concept that replicative senescence is a "clocked" and stepwise process seems doubtful, and repeatedly reported reproducibility of both replicative lifespans and rates of telomere shortening could be the result of stochastic rather than programmed events. In other words, it seems that telomeres can be an indicator of stress-induced damage level rather than a mitosis "counter." Moreover, considering the fact that oxidative stress represents a common causative mechanism for both age-related telomere shortening and age-associated disease, there are reasons to believe that relationships between telomere length and morbidity or mortality are non-causal, and telomere length can be an indicator of previous exposure to oxidative stress that may, in turn, cause both greater telomere shortening and higher risk of chronic disease. Thereby, perceived stressful events, though correlated with telomere length, may likely have independent effects on health and longevity. By summarizing recent research findings, it is concluded that recently obtained knowledge "shifts the telomere paradigm from a simple clock counting cell divisions to a more complex process recording the history of stress exposure within a cell lineage." This point of view, based on the accumulated evidence, appears plausible, and requires further investigation.

The cancer research establishment is not a single monolithic entity, but rather consists of many diverse fields and approaches to treatment. Researchers in one area may or may not be paying all that much attention to other areas. This is an important issue in modern scientific development, where there is simply too much information and too much going on for any one person to know everything of relevance to the work at hand. There is need for at least a few scientists in every field to spend much of their careers in synthesis and knowledge exchange, bringing together research groups who would otherwise not know that they might benefit from collaboration:

The prospect of combining genomically targeted therapies with drugs that free the immune system to attack cancer suggests "we are finally poised to deliver curative therapies to cancer patients." While individual researchers and pharmaceutical companies are studying and developing both types of drugs, a major initiative is needed to understand how both drug types might best work together. "Without a major initiative, it will be harder to make progress because the groups focused on genomically targeted therapy and the checkpoint blockade researchers will largely stay in their own camps."

Drugs that hit a specific genomic defect that drives a patient's cancer provoke good initial responses in most patients, the review notes. For example, drugs that target a specific BRAF gene mutation commonly found in melanoma shrink tumors in about half of patients with the mutation. However, resistance almost always develops because tumors harbor multiple genomic defects capable of driving the disease after a targeted drug knocks down one driver. BRAF inhibitors prolonged median survival in clinical trials by about seven months.

Checkpoint blockade is an approach that treats the immune system, rather than the tumor directly, by blocking molecules on T cells that shut those attack cells down, protecting tumors from immune response. Knowing that the immune system is capable of recognizing distinctive features of cancer cells and launching a T cell attack against those tumor antigens, and that checkpoint blockade removes a roadblock to that attack, it's logical that these drugs should work against many tumor types. But the impact varies across cancers.

There's a school of thought that combining multiple genomically targeted therapies might prove effective. However, evidence suggests that tumor genomic diversity might still defeat such combinations, and that it's axiomatic in oncology that side effects increase in number and intensity as more drugs are added to treatment. Targeted therapies might act as effective cancer vaccines, killing tumor cells and releasing new target antigens for T cells to identify and associate with tumors. And they might vary in their ability to enhance or inhibit immune response, because little is known right now about how targeted agents affect the immune system.

Early efforts to combine approaches have yielded interesting results. One phase I trial of an immune checkpoint blockade drug combined with two established targeted therapies yielded 40-50 percent response rates among patients with metastatic kidney cancer. "At this stage, it does not seem a stretch to say that increasing funding to combination therapies will be key to development of new, safe treatments that may prove to be curative for many patients with many types of cancer."

Link: http://www.mdanderson.org/newsroom/news-releases/2015/potential-cancer-immunotherapy-plus-targeted-therapy.html

One of the contributing causes of aging is the accumulation of metabolic waste products that are hard or impossible for our biochemistry to break down. Cells undertake numerous forms of housekeeping, one of which is autophagy: in this process, unwanted or damaged proteins and cellular components are tagged and shuttled to the nearest lysosome where they are broken down for recycling. Waste products that cannot be broken down remain in the lysosome, however, to form a mix of various compounds known as liposfusin. Over time the lysosomes in long-lived cells of the nervous system, such as those of the retina, become bloated and dysfunctional, and the cells begin to malfunction and die as a result.

The SENS rejuvenation research approach to this part of the aging process is the find ways to safely break down lipofuscin constituents, with a starting point of mining the natural world of bacteria to find those capable of consuming lipofuscin. It is well understood in the research community that lipofuscin accumulation is a cause of age-related retinal degeneration and consequent blindness, and so SENS researchers are far from the only people looking for ways to get rid of lipofuscin or blunt its effects. This paper looks into mechanisms involved in the disruption of autophagy caused by lipofusin and suggests one potential form of amelioration:

Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is unclear. In this study, we investigate innate mechanisms that modulate autophagy in the retinal pigment epithelium (RPE), a key site of insult in macular degeneration. High-speed live imaging of polarized adult primary RPE cells and data from a mouse model of early-onset macular degeneration identify a mechanism by which lipofuscin bisretinoids, visual cycle metabolites that progressively accumulate in the RPE, disrupt autophagy.

We demonstrate that bisretinoids trap cholesterol and bis(monoacylglycero)phosphate, an acid sphingomyelinase (ASMase) cofactor, within the RPE. ASMase activation increases cellular ceramide, which promotes tubulin acetylation on stabilized microtubules. Live-imaging data show that autophagosome traffic and autophagic flux are inhibited in RPE with acetylated microtubules. Drugs that remove excess cholesterol or inhibit ASMase reverse this cascade of events and restore autophagosome motility and autophagic flux in the RPE. Because accumulation of lipofuscin bisretinoids and abnormal cholesterol homeostasis are implicated in macular degeneration, our studies suggest that ASMase could be a potential therapeutic target to ensure the efficient autophagy that maintains RPE health.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279221/

The usual model for presently available stem cell therapies is for stem cells to be taken from the patient, often from bone marrow, greatly expanded in number, and reintroduced into target tissues. This has been shown over the past decade to produce a wide range of benefits, with an increasing degree of confidence and reliability as techniques have improved. Stem cell transplants have been demonstrated to suppress inflammation, encourage greater regeneration on the part of native cell populations, and improve various other measures of tissue health. Different approaches and different stem cell types tend to produce a different mix of benefits. At this point some types of cell therapy are definitely more robust than others: stem cell treatments for joint issues and heart disease have a much greater expectation of benefits than, say, trying to treat autoimmune disorders or nerve damage.

Stem cell therapies are still under continued development. It is far from the case that every mechanism involved in the beneficial effects of stem cell transplantation is fully understood. A broad range of work is ongoing in many laboratories with the aim of creating a catalog of the effects of stem cell treatments, all of which feeds back into efforts to build better versions of existing cell therapies and introduce new therapies where none exist. An example of this sort of research is linked below: the researchers show that transplantation of mesenchymal stem cells reduces a few common measures of cellular senescence in rat hearts, both in cell culture and living animals. This may be important from the point of view of aging and age-related decline in tissue function. Senescent cells can no longer divide. They accumulate in damaged and old tissues, a defensive reaction that probably evolved to reduce cancer incidence by disabling replication in cells more likely to become cancerous. Unfortunately senescent cells emit all sorts of harmful molecular signals, and in large numbers they cause significant inflammation, tissue remodeling, and degradation of function. The presence of senescent cells is one of the contributing causes of degenerative aging.

It isn't clear from this research whether the use of stem cells produces any reversal of cellular senescence versus prevention of senescence only. By its definition senescence is an irreversible state of growth arrest, but there is a modest amount of evidence to suggest that at least some tissue types can cross the that line in both directions given the right stimulus.

Study Showing How Stem Cells Slow Aging May Lead to New Heart Failure Treatments

Aging is a complex and multifaceted process, resulting in damage to molecules, cells and tissue that in turn leads to declining organs. Mesenchymal stem cells, found in bone marrow, can generate bone, cartilage and fat cells that support the formation of blood and fibrous connective tissue. These stem cells also can be coaxed in the laboratory into becoming a variety of cell types, from cardiomyocytes (heart muscle cells) and neurons, to osteoblasts, smooth muscle cells, and more.

Several studies have already shown that MSCs can reverse age-related degeneration of multiple organs, restore physical and cognitive functions of aged mice, and improve age-associated osteoporosis, Parkinson's disease and atherosclerosis. "We previously showed that MSCs offer an anti-senescence action on cardiomyocytes as they grow older. However, what we didn't know was whether these findings from a cellular model could be applied to more physiological conditions in whole animals. That's what we wanted to learn with this study." They decided to explore their question using rats. After injecting MSCs into rat cardiomyoctyes being cultured in lab dishes and receiving encouraging results, they repeated the procedure on a group of young (4 months old) rats and old (20 months) rats, too. The results in both instances demonstrated that MSCs have a significant anti-aging effect.

Bone Marrow Mesenchymal Stem Cell Transplantation Retards the Natural Senescence of Rat Hearts

Bone marrow mesenchymal stem cells (BMSCs) have been shown to offer a wide variety of cellular functions including the protective effects on damaged hearts. Here we investigated the antiaging properties of BMSCs and the underlying mechanism in a cellular model of cardiomyocyte senescence and a rat model of aging hearts. Neonatal rat ventricular cells (NRVCs) and BMSCs were cocultured in the same dish with a semipermeable membrane to separate the two populations. Monocultured NRVCs displayed the senescence-associated phenotypes, characterized by an increase in the number of β-galactosidase-positive cells and decreases in the degradation and disappearance of cellular organelles in a time-dependent manner. The levels of reactive oxygen species and malondialdehyde were elevated, whereas the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase were decreased, along with upregulation of p53, p21Cip1/Waf1, and p16INK4a in the aging cardiomyocytes.

These deleterious alterations were abrogated in aging NRVCs cocultured with BMSCs. Qualitatively, the same senescent phenotypes were consistently observed in aging rat hearts. Notably, BMSC transplantation significantly prevented these detrimental alterations and improved the impaired cardiac function in the aging rats. In summary, BMSCs possess strong antisenescence action on the aging NRVCs and hearts and can improve cardiac function after transplantation in aging rats. The present study, therefore, provides an alternative approach for the treatment of heart failure in the elderly population.

Stem cell activity declines with age, an evolutionary trade-off that reduces the risk of death by cancer at the cost of increasing frailty and a slower death due to failure of tissue maintenance. This is just one of the many contributing factors that together determine the present human life span and the course of failing health for most people. Researchers would like to be able to restore youthful stem cell activity in old people without significantly increasing the risk of cancer, as continued tissue maintenance would greatly reduce the impact of aging and incidence of age-related disease.

At present this line of work is still in the comparatively early stages: much of the research community involved is searching for the signals and mechanisms responsible for stem cell decline, changes in the tissue environment that are most likely reactions to rising levels of cellular and molecular damage produced over the course of aging. Some points of potential intervention have been found in recent years, such as altering levels of GDF-11 to improve stem cell function in aged mice. Here is news of another potential basis for therapies, discovered by chance during cancer research:

Think of tissue as a building that is constantly under renovation. The contractors would be metalloproteinases, which are constantly working to demolish and reconstruct the tissue. The architects in this case, who are trying to reign in and direct the contractors, are known as tissue inhibitors of metalloproteinases - or TIMPs. When the architect and the contractors don't communicate well, a building can fall down. In the case of tissue, the result can be cancer. To understand how metalloproteinases and TIMPs interact, medical researchers bred mice that have one or more of the four different types of TIMPs removed. The team examined the different combinations and found that when TIMP1 and TIMP3 were removed, breast tissue remained youthful in aged mice.

In the normal course of aging, your tissue losses its ability to develop and repair as fast as it did when you were young. That's because stem cells, which are abundant in your youth, decline with the passing of time. The team found that with the TIMP1 and TIMP3 architects missing, the pool of stem cells expanded and remained functional throughout the lifetime of these mice. "Normally you would see these pools of stem cells, which reach their peak at six months in the mice, start to decline. As a result, the mammary glands start to degenerate, which increases the risk of breast cancer occurring. However, we found that in these particular mice, the stem cells remained consistently high when we measured them at every stage of life." The team also found that despite large number of stem cells, there was no increased risk of cancer. "It's generally assumed that the presence of a large number of stem cells can lead to an increased cancer risk. However, we found these mice had no greater predisposition to cancer." The next step in this research is to understand why this is happening.

Link: http://medicine.utoronto.ca/news/breast-cancer-research-uncovers-fountain-youth

Advanced glycation end-products, AGEs, are a class of sugary metabolic waste produced in the normal operation of cellular biochemistry. Some types of AGE are short-lived and easily disposed of, while others are persistent and accumulate in tissues over time. These longer lived AGEs form cross-links in the extracellular matrix, the scaffolding of proteins that supports cells and determines the structural properties of tissue such as the strength of bone and cartilage or the elasticity of skin and blood vessels. Cross-linking has been shown to degrade tissue elasticity and strength, and is of particular interest as a contributing cause of blood vessel stiffening, one of the first steps leading to age-related cardiovascular disease.

In this paper researchers dig deeper into exactly how one particular type of AGE affects the mechanical properties of elastic tissue. They find, unexpectedly, that they cannot explain increasing tissue stiffness by examining the lowest level of extracellular matrix structure, where AGE cross-links form between collagen strands intended to slide alongside one another:

Collagen cross-linking by AGEs has been increasingly implicated as a central factor in the onset and progression of connective tissue disease. For the first time we report the physical effects of AGEs on collagen molecular and supramolecular deformations under load. We identify and describe altered damage mechanisms that could play a central role in connective tissue disease processes. Our data provide evidence that accumulation of AGEs dramatically affects collagen fibril failure behavior and stress relaxation. These functional parameters strongly reflect how collagen structures accommodate mechanical load and overload. Because the temporal and spatial dynamics of connective tissue damage and repair involve an intricate balance of mechanically driven catabolic and anabolic processes, even slight changes in collagen mechanics or patterns of damage accumulation may detrimentally affect tissue homeostasis. Such changes in extracellular matrix mechanics are likely to be exacerbated by resistance of AGE modified substrates to proteolytic enzymes that drive and regulate balanced matrix remodeling, or by chronic activation of inflammatory mediators that drive fibrosis.

We employed synchrotron small-angle X-ray scattering (SAXS) and carefully controlled mechanical testing after introducing AGEs in explants of rat-tail tendon using the metabolite methylglyoxal (MGO). Mass spectrometry and collagen fluorescence verified substantial formation of AGEs by the treatment. Associated mechanical changes of the tissue (increased stiffness and failure strength, decreased stress relaxation) were consistent with reports from the literature. SAXS analysis revealed clear changes in molecular deformation within MGO treated fibrils. Underlying the associated increase in tissue strength, we infer from the data that MGO modified collagen fibrils supported higher loads to failure by maintaining an intact quarter-staggered conformation to nearly twice the level of fibril strain in controls. This apparent increase in fibril failure resistance was characterized by reduced side-by-side sliding of collagen molecules within fibrils, reflecting lateral molecular interconnectivity by AGEs.

Surprisingly, no change in maximum fibril modulus accompanied the changes in fibril failure behavior, strongly contradicting the widespread assumption that tissue stiffening in ageing and diabetes is directly related to AGE increased fibril stiffness. We conclude that AGEs can alter physiologically relevant failure behavior of collagen fibrils, but that tissue level changes in stiffness likely occur at higher levels of tissue architecture.

Link: http://dx.doi.org/10.1371/journal.pone.0110948

There is no such thing as a scientific breakthrough. Advances in science and its application don't emerge from out of the blue, especially in very complex fields such as medical research, where any meaningful progress requires a team, and in very close-knit fields such as aging research, where everyone knows everyone else and at least a little about what they are working on. If the latest news looks like a breakthrough to you, that just means that you didn't know much about the people who spent years working on the foundations, the incremental advances, and the early prototypes. And why should you? You have your life to live, your own work to get on with. There is far too much going on in the world for any one individual to notice.

That is just as true of me as anyone else. I certainly don't have a view of every interesting corner of the research community, and even now there are no doubt numerous scientists working on projects relevant to the SENS model for human rejuvenation through repair of cellular and molecular damage whom I have never heard of. Even the highly networked folk at the SENS Research Foundation are surprised by what turns up some days, and they have far more insight than I. One of the consequences of rapid progress in biotechnology is that people outside the core aging research community have the ability to make useful and important contributions. Most of the technologies proposed as means of damage repair to treat aging did not originate in the aging research community, and I'd expect that state of affairs to continue as new options arise. So if you have a few fellows in a well-equipped lab in India or on the other side of a language barrier in China, tinkering on a possible approach and actually getting somewhere interesting when it comes to a proof of concept, it is quite plausible that we'd never hear anything of it until after the fact.

Frankly, it's hard enough just to keep abreast of what is going on in the US. Take senescent cell clearance for example; the demonstration in 2011 of improved health in accelerated aging mice via removal of senescent cells was clearly a wake up call for a number of researchers. In what is a comparatively short time for the research community, we have seen the recent publication on the use of existing drugs to clear senescent cells in ordinary mice, showing improved healthspan as a result, and a startup company was funded by the Methuselah Foundation earlier this year to have a go at commercializing a different approach to the removal of senescent cells. That is just the stuff that makes it to the point of press release and news in this community, however. It is not all that is going on, and the 2011 technology demonstration wasn't a sudden breakthrough from nowhere: work on cellular senescence with an eye to selectively destroying these unwanted cells was underway for years before that point.

For example, Cenexys has existed since 2009 and claims to "develops therapies to clear senescent cells from the body to treat age-related diseases." Perhaps it is a dead venture, judging by the lack of news, but perhaps not; the principal director certainly has an interesting and successful history. Then there is SIWA Regenerative Medicine, a company that has apparently also been working on senescent cell clearance for a while. Being first alas often means being bypassed at some speed by later ventures, but SIWA seems to be alive and kicking:

SIWA Regenerative Medicine

We have developed inventions that we believe can retard or reverse the aging process, reduce inflammation and enhance stem cell transplant success by promoting tissue and organ regeneration. We believe these inventions also can be applied as therapies in lessening the impact of diseases associated with aging. Specifically, we have developed processes for identifying and removing senescent cells that inhibit cellular regeneration to obtain the recognized benefits in health and function associated with the results of such cellular regeneration. We have filed multiple families of patent applications covering our inventions.

We were the first to publish a practical description of selectively removing senescent cells in order to retard or reverse aging. In a November 2011, paper that appeared in the journal Nature, other researchers reported creation of an artificial system that independently confirmed the soundness of the scientific principles behind the approach and other intellectual property that we published years before.

SIWA's Approach To Clearing Senescent Cells To Increase Healthspan

SIWA Regenerative Medicine Corporation announced today that Lewis Gruber, founder, CEO and inventor of SIWA's injectable drug-based approach to clearing senescent cells for increasing healthspan, will join scientists from Charles River Laboratories at 2:45 p.m. on March 23, 2015 in San Diego at the Society of Toxicology Annual Meeting to discuss and present SIWA's demonstration of successful use in naturally aged mice of a monoclonal version of SIWA's drug candidate. The results of the work performed by Charles River for SIWA include an increase in gastrocnemius muscle mass and reduction of a senescent cell mRNA marker to the level of young mouse controls.

The company has made some interesting patent filings over the past decade, such as Selective Removal of Cells Having Accumulated Agents:

The present invention makes use of the discovery that the differential resonant frequency of a cell caused by the accumulation of at least one agent that causes, or is associated with, a pathological or undesired condition, such as proteins, lipids, bacteria, viruses, parasites or particles, may be used to distinguish and eliminate cells in which the accumulated agent leads to a difference in the resonant frequency of the cell, by applying ultrasound treatment. The cells associated with the accumulated agent have a resonant frequency which is distinct from cells of the same type. By selecting the frequency of the ultrasound applied to the tissue to feed energy into the resonant frequency, the cells with the accumulated agent will be destroyed or induced to undergo apoptosis.

Cytomegalovirus (CMV) is a herpesvirus that causes few if any noticeable issues in most people when they are first exposed to it. By the time old age rolls around, near everyone tests positive for CMV. It is thought that the presence of this virus goes some way towards explaining the age-related decline of the adaptive immune system. The immune system has in effect a limited number of cells at any given time since the replacement rate is low in adults. Since CMV cannot be cleared from the body, and continually reemerges to challenge the immune system, ever more immune cells become devoted to battling CMV rather than defending the body from new threats.

It is worth keeping an eye on progress towards therapies capable of clearing CMV, but in old people even an excellent clearance treatment will likely be of little use. The damage has already been done at that point, the immune system already misconfigured and out of balance. What is needed is a way to selectively destroy the CMV-specialized cells to free up space and trigger their replacement with fresh immune cells.

Human cytomegalovirus (HCMV) is an extremely common virus, which as other members of the herpes virus family causes life-long infections in humans. Most individuals are exposed to HCMV during childhood, yet symptoms can be easily fought off by a healthy immune system. HCMV infects 60% of the population in industrialized countries, and almost everybody in less affluent places. This virus persists for life by hiding in blood-making ("hematopoietic") stem cells, where it lies dormant and goes completely unrecognized. It occasionally reactivates in the descendants of these hematopoietic stem cells, but these bouts are rapidly tamed by the immune system. However, in people whose immune system has been compromised, e.g. by AIDS, and organ transplant recipients who have to take immunosuppressive drugs, HCMV reactivation can cause devastating symptoms.

Researchers have discovered a protein that switches HCMV between dormancy and reactivation. They found this protein to be bound to the HCMV genome in latently infected hematopoietic stem cells and, upon a variety of external stimuli, to undergo a modification that allows for viral activation. Furthermore, the researchers were able to control this switch with a drug called chloroquine, usually used against malaria. When they treated hematopoietic stem cells containing dormant HCMV with chloroquine, the virus reactivated and became exposed, opening the door to maneuvers aimed at eliminating virus-infected cells.

The simplicity of the study's design underlies its enormous significance. On one hand, it sheds light on the molecular mechanism by which HCMV becomes dormant in hematopoietic stem cells, possibly offering insights into similar infections by other herpes viruses. On the other hand, the study provides a straightforward method for forcing HCMV out of dormancy in infected tissue. Coupled with a simultaneous dose of an antiviral, this could become a standard regimen for eradicating HCMV from high-risk patients and purging it from tissue before transplantation. Researchers are now testing the method's efficiency in purging HCMV from cells to be used for bone marrow transplantation. Following that step, the group will be developing the first trials in humans.

Link: http://www.eurekalert.org/pub_releases/2015-04/epfd-pav040215.php

Of the many proteins and signaling pathways shown to influence the pace of aging, insulin-like growth factor 1 (IGF-1) is perhaps the most studied:

The really fun thing about discussing signaling networks (the inputs that let cells make decisions based on their environment) in aging is the wide range of ways that these pathways exert their influence. They take inputs (nutrition, hormones, toxic molecules) and use their existing programming (epigenetic state) to make decisions. Components that control one process, such as regulating body size, can play roles in completely different processes. Today, I'll discuss an example involving insulin-like growth factor 1 or IGF1, a close relative of insulin (a hormone that regulates blood glucose levels). While IGF1 was initially discovered due to its effect on blood glucose, it has since turned out to exert profound effects on a wide variety of processes that also include body size, longevity and cancer.

People who have too little IGF1 signaling may develop dwarfism (such as Laron syndrome), while too much IGF1 can lead to various forms of gigantism and increased risk of age-related diseases. IGF1 is an important molecule in development, as demonstrated by its key role in size determination; however IGF1 does much more than just determine how large an animal or human will be. IGF1 signaling has cropped up as a central player in fundamental studies on the genetic basis of aging. Using the small roundworm, Caenorhabditis elegans, scientists discovered that IGF1 signaling has a profound effect on aging. When IGF signaling is lost (in this case by losing the receptor, called DAF2 in the worm), juvenile worms enter into a developmental state characterized by small size and a greatly extended lifespan (the dauer). When IGF1 signaling is lost later in development, these worms develop into adults, but still display a long lifespan (twice as long as worms that have normal IGF signaling). This discovery was one of the first to identify a gene linked to extending lifespan, and represents an important milestone the modern field of aging.

Does reducing IGF1 signaling during aging extend lifespan in humans? Unfortunately, the jury is still out on this. Studies lowering IGF1 in adult mice have shown mixed results, however, two other lines of research discussed further support the role of IGF1 as major factor in aging in mammals. The first arises from the differences in IGF1 levels in small dogs. As it turns out, this mutation affects both body size and longevity, that is, small dogs (that make less IGF1) tend to live longer than large dogs that make more IGF1. Second, people with Laron syndrome or Laron-type dwarfism have naturally reduced IGF1 levels. Laron syndrome results from a dysfunction of the growth hormone receptor, resulting in reduced levels of insulin and IGF1 levels. These individuals are typically short in stature (less than four feet) and have a reduced risk of cancer and diabetes; however there have not been comprehensive studies on whether these individuals have an extended life span.

Link: http://sage.buckinstitute.org/dogs-dwarfism-and-aging-lessons-from-igf1/

Neuregulin-1 (NRG-1) is one of those proteins that shows up in a number of places in research relevant to aging and regeneration, and in a variety of quite different contexts. That suggests it is probably not central to the processes of interest, but rather sufficiently related that manipulating it can alter the operation of multiple systems influential in maintenance of tissues and healing. Biology is very complex indeed, and the fact that any given process of interest can be altered by changing circulating levels of any of a score of proteins makes it a real challenge to determine what is actually going on under the hood.

So we have NRG-1 as a possible suspect in naked mole-rat longevity, based on measured levels in the brains of old individuals versus those of old mice and humans. Levels of NRG-1 in the brain seem to correlate with species longevity, in rodents at least. All of that is quite different from the role of NRG-1 in heart regeneration, however: it was noted some years ago that is possible to spur greater than usual tissue maintenance in heart tissues by artificially raising levels of NRG-1. The heart is lacking in regenerative capacity in comparison to other tissue types, so there is some interest in the medical community in finding ways to safely and temporarily work around that limitation.

That heart tissue research took place back in 2009, which rather underscores the point that medical science is not something that moves at the pace of politics or sports. When we talk about the incredible pace of research today, we mean that sometimes you'll see follow-on papers and new advances two to three years after an initial breakthrough. More commonly, expect five to ten years to elapse between an initially promising result and some more practical implementation, and it may take numerous cycles of a few years of work each to make meaningful progress. This is fast in comparison to the past, but it doesn't fit well with the modern news cycle, or with the short-term memory of the public. Supporting science isn't an easy sell to a world that wants all the answers and all of the shiny things right now, or tomorrow at the very latest. Still, here you have the latest in the story of neuregulin-1 and heart regeneration, another incremental advance towards the goal of building a regenerative therapy based on the mechanisms explored in this paper. That end goal still seems about as far away as it was in 2009, frankly:

Research finds turbo-charging hormone can regrow the heart

Researchers have discovered a way to stimulate muscle regrowth in the heart of a mouse. The animal study found it was possible to regenerate muscle cell numbers in the heart by up to 45%, by 'turbo-charging' a hormone that helped coordinate cell growth. "Unlike blood, hair or skin cells, which can renew themselves throughout life, cell division in the heart virtually comes to a standstill shortly after birth, which means the heart can't fully regenerate if it is damaged later in life. Previous studies have demonstrated that it is possible to coax heart muscle cells to proliferate again, but only at very trivial levels. What the research team has been able to do is boost heart muscle cell numbers by as much as 45% after a heart attack."

The scientists focused on a signalling system in the heart driven by a hormone called 'neuregulin'. By switching the neuregulin pathway to 'turbo charge', the researchers found that heart muscle cells continued to divide in a spectacular way in both the adolescent and adult periods. Stimulating the neuregulin pathway during a heart attack led to replacement of lost muscle. "This big achievement will focus the attention of the field on heart muscle cell replacement as a therapeutic option for ischemic heart disease. The dream is that one day we will be able to regenerate damaged heart tissue, much like a salamander can regrow a new limb if it is bitten off by a predator. Just imagine if the heart could learn to regrow and heal itself. That would be the ultimate prize."

​ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

The murine neonatal heart can regenerate after injury through cardiomyocyte proliferation, although this capacity markedly diminishes after the first week of life. ​Neuregulin-1 (​NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the ​NRG1 co-receptor ​ERBB2 in cardiac regeneration.

NRG1-induced cardiomyocyte proliferation diminished one week after birth owing to a reduction in ​ERBB2 expression. Cardiomyocyte-specific ​Erbb2 knockout revealed that ​ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ​ERBB2 (ca​ERBB2) in neonatal, juvenile and adult cardiomyocytes resulted in cardiomegaly, characterized by extensive cardiomyocyte hypertrophy, dedifferentiation and proliferation. Transient induction of ca​ERBB2 following myocardial infarction triggered cardiomyocyte dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ​ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal cardiomyocyte proliferative and regenerative potentials.

This open access review paper comes from scientists long involved in calorie restriction research, in search of mechanisms to explain why a lower calorie intake results in improved health and life span, and attempting to quantify the benefits in humans:

The discovery that aging can be ameliorated by dietary, genetic, and pharmacological interventions has opened up the prospect of a broad-spectrum, preventive medicine for aging-related diseases. Single-gene mutations that extend animal lifespan can ameliorate natural, age-dependent loss of function and the pathology of aging-related diseases, including neurodegeneration. Furthermore, laboratory animal models of slowed aging, naturally long-lived species such as the naked mole rat, and some humans that achieve the age of 100 have all demonstrated that a long life is not inevitably associated with late-life disability and disease. Recent work has shown that specific dietary interventions can also promote long life and healthy old age.

Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Dietary restriction (DR), implemented as chronic and coordinate reduced intake of all dietary constituents except vitamins and minerals, was first shown 80 years ago to extend lifespan in rats. DR in both rats and mice improves most aspects of health during aging. Exceptions include resistance to infection and wound healing. However, these conditions rapidly improve with re-feeding, and DR animals can then outperform controls. DR can produce substantial benefits with, for instance, ∼30% of DR animals dying at old ages without gross pathological lesions, compared with only 6% of ad-libitum-fed controls. DR started in young, adult Rhesus monkeys greatly improves metabolic health; prevents obesity; delays the onset of sarcopenia, presbycusis, and brain atrophy; and reduces the risk of developing and dying of type 2 diabetes, cancer, and cardiovascular disease.

Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily.

Link: http://www.cell.com/cell/fulltext/S0092-8674(15)00186-5

While the evidence for the benefits of regular moderate exercise is voluminous and unassailable, there is comparatively little to back any one approach to exercise over another, and little to show that undertaking any more than moderate exercise will produce meaningfully greater benefits to long-term health. Thus is it always interesting to see studies that show a fairly robust correlation between differences in exercise and mortality rates, but as ever bear in mind that correlation does not imply causation. It is plausible that data reflects the tendency for healthier people to exercise more vigorously rather than it being a case of more vigorous exercise producing healthier people:

The researchers followed 204,542 people for more than six years, and compared those who engaged in only moderate activity (such as gentle swimming, social tennis, or household chores) with those who included at least some vigorous activity (such as jogging, aerobics or competitive tennis). They found that the risk of mortality for those who included some vigorous activity was 9 to 13 per cent lower, compared with those who only undertook moderate activity. "The benefits of vigorous activity applied to men and women of all ages, and were independent of the total amount of time spent being active. The results indicate that whether or not you are obese, and whether or not you have heart disease or diabetes, if you can manage some vigorous activity it could offer significant benefits for longevity."

The current advice is for adults to accumulate at least 150 minutes of moderate activity or 75 minutes of vigorous activity per week. "The guidelines leave individuals to choose their level of exercise intensity, or a combination of levels, with two minutes of moderate exercise considered the equivalent of one minute of vigorous activity. It might not be the simple two-for-one swap that is the basis of the current guidelines. Our research indicates that encouraging vigorous activities may help to avoid preventable deaths at an earlier age. Previous studies indicate that interval training, with short bursts of vigorous effort, is often manageable for older people, including those who are overweight or obese."

Link: http://www.eurekalert.org/pub_releases/2015-04/jcu-wua040215.php

The SENS Research Foundation's April newsletter turned up in my inbox today, along with the news that registration is open for the Rejuvenation Biotechnology 2015 conference to be held later this year in San Francisco, California. This conference series aims to lay the groundwork for closer collaboration between academia and industry in the forthcoming development and commercialization of the first generation of effective treatments for aging. The first conference in the series was held last year and well-received by all accounts; there are a number of very interesting presentation videos to be found online.

Registration NOW OPEN for the 2015 Rejuvenation Biotechnology Conference

SENS Research Foundation is pleased to announce that registration is now open for the 2015 Rejuvenation Biotechnology Conference. For the second year in a row, the Rejuvenation Biotechnology Conference will convene the foremost leaders from academia, industry, investment, policy, and disease advocacy to share knowledge, strategize, and explore the potential for a truly effective approach to managing all age-related disease.

The Rejuvenation Biotechnology Conference Poster Session is now open for abstract submissions. Participants will present their work during two evening poster sessions at the conference. Abstracts are due June 1st. Primary authors of accepted abstracts will be notified on July 1, 2015.

SRF Education: 2015 Summer Scholars Class Selected

SENS Research Foundation is pleased to announce the completion of our evaluation process of an outstanding group of applicants for the 2015 SRF Summer Scholars Program. Sixteen students have been selected to conduct research at eight institutions. Prior host institutions (the Buck Institute for Research on Aging, the Harvard Stem Cell Institute, the University of Oxford, the Wake Forest Institute for Regenerative Medicine and the SRF Research Center) will be joined this year by new host partners Sanford-Burnham Medical Research Institute, the Scripps Research Institute, and Stanford University.

Thank You to our Amazon Smile Users

Everyone at SENS Research Foundation would like to thank our supporters who have made us the recipient of their AmazonSmile donations. We just received a check for $972.82 from the AmazonSmile Foundation based on your purchases from October 1 - December 31st. If you'd like to take this opportunity to help fund our fight against age-related disease, it's not too late to join in! Just sign up, and remember to go to AmazonSmile whenever you are shopping on Amazon.

The latest question of the month is a fairly general query on progress in diagnostic technologies, and the response is a long one. You should definitely head on over and read the whole thing at the SENS Research Foundation website rather than just the preamble quoted below:

Question of the Month #9: What is the role of novel diagnostics in rejuvenation biotechnologies?

Q: I'm a biotech graduate currently reading up to produce a PhD proposal. My main areas of interest are in diagnostics, and after reading about rejuvenation biotechnology I've become very interested in contributing to regenerative medicine against ageing. Is there a crossover between diagnostics and the work under SENS Research Foundation? If so I'd love to hear about it.

A: There is definitely a need for novel diagnostics, particularly in the course of the critical three decades ahead, as the first rejuvenation biotechnologies enter into human clinical use.

As you probably know, rejuvenation biotechnologies are therapies that prevent, arrest, and potentially reverse age-related disease and dysfunction using a "damage-repair" approach. Such therapies work by directly removing, repairing, replacing, or rendering harmless the cellular and molecular damage wrought in our tissues by the biological aging process. This contrasts rejuvenation biotechnology with today's medical approach, in which the target is the metabolic pathways that contribute to such damage instead of the damage itself. Current medicines are thus typically first tested for their effects on the metabolic "risk factors" that ultimately contribute to diseases of aging.

Rejuvenation biotechnologies, by contrast, will not directly perturb these metabolic processes (although in some cases they may maintain or restore metabolic processes in youthful condition, when aging normally leads to their dysfunction). Effects on these "risk factors" will therefore either be nonexistent, or manifest themselves many years later, when recipients continue to exhibit youthful metabolic function, in contrast to the age-related aberrations that emerge in untreated aging persons.

All this means that new ways of evaluating these novel medicines will be needed - first for their initial preclinical and clinical development, and later for their clinical use. Instead of reflecting dynamic, regulated physiological and metabolic processes, diagnostics that will facilitate the development and use of rejuvenation biotechnology will be noninvasive markers of the presence, removal, or repair of the cellular and molecular damage that accumulates in aging tissues.

The article linked below is largely characteristic of the recent media attention given to the SENS research programs, Google Venture's Calico Labs initiative, the Palo Alto Longevity Prize, and so forth. One noteworthy difference is space given to researcher Richard Miller's continued opposition to SENS and its principal proponent Aubrey de Grey, presently chief science officer of the SENS Research Foundation. Miller and de Grey have sparred in public in the past, but I wasn't aware that he continued to hold such views. Other opponents of SENS from past years have either fallen silent or turned around to show their support for the initiative in one way or another. The scientific advisory board of the SENS Research Foundation is an impressive lineup of luminaries of medical and life science research.

At this point Miller begins to look out of touch; de Grey heads a research foundation that has for years funded diverse scientific programs, leading to papers published in collaboration with renowned organizations in the field. Areas of research that de Grey has been advocating and funding for more than a decade are of late beginning to show their worth, such as clearance of senescent cells. It seems out of sorts to be claiming that de Grey "does not do any research" or that you "have never seen him present any data or research findings". Wise up, I say. Get with the times.

Aubrey de Grey of the pioneering SENS Research Foundation, a non-profit partially funded by Peter Thiel is optimistic about longevity. "I've taken plenty of heat for suggesting that someone is alive on earth now who will live to 1,000 and it's extraordinary to me that it's such an incendiary claim. People have a bizarre attitude towards aging. They think that it's some kind of separate thing that isn't a medical problem and isn't open to medical intervention."

However, many scientists do not agree with de Grey and are quite vocal about it. Dr. Richard Miller, who has a PhD in Human Genetics from Yale, has been critical of de Grey's work for quite sometime. Miller, along with many colleagues, published a scathing review of de Grey. In it writing that "the idea that a research programme organized around the SENS agenda will not only retard ageing, but also reverse it - creating young people from old ones - and do so within our lifetime, is so far from plausible that it commands no respect at all within the informed scientific community."

When asked if there have been any breakthroughs from SENS in the last 10 years that might sway him or his colleagues, Miller had this to say: "De Grey does not do any research, so far as I know. He comes to meetings a lot, but I have never seen him present any data or research findings. He does not have a lab; he theorizes. What de Grey does is not science - it's advertising. Asking if the SENS theories have been 'proven' in the last 10 years is like asking if there's new proof for the Nike Theory of Athletic Excellence, 'Just Do It.'"

However, de Grey says he is already doing lab work that targets lifelong accumulating damage. This damage is initially harmless when you're young but grows until your body succumbs to it. For example, de Grey says that people will get heart disease unless work is done to fix it but there are better ways to beat heart disease than surgery. He believes the idea of surgery altogether is primitive. "The technology that needs to be implemented to defeat heart disease is an enzyme or enzymes that can be introduced into human cells and allow them to clean up the garbage of the arteries themselves." De Grey says he has already created a proof of concept of this technology at his lab, albeit only in cell culture so far.

Apart from the lab work that needs to go into fulfilling these goals, there is the problem of societal acceptance. "The major obstacle is public popular misunderstanding of the nature of the crusade and the importance of it," says de Grey. In this respect, de Grey faces an enormous uphill battle from the scientific community. "If you were to poll the authors of the most recent 100 papers on aging in Aging Cell, or Journals of Gerontology, or Science, and ask them whether it will, in the next 100 years, be possible to turn old people young again...I think you'd get nearly 100 percent consensus that de Grey's claims are not based on evidence," says Miller.

The other major problem is the same one that arises in any great endeavor - cash. "We could be going three times faster if we had the funding that we needed, and that means that an awful lot of lives are being lost," says de Grey. "The amount of money that is needed to solve these problems is absolutely trivial. The budget that SENS currently has is around $5 million per year and I reckon that we would very realistically be in a position where the money wasn't limiting if we had only one more zero on that."

Link: http://www.thedailybeast.com/articles/2015/04/04/how-to-hack-your-body-to-live-past-120.html

Much of the most important research into aging, work that might produce the foundations of rejuvenation therapies, is still funded only by philanthropic donations at this stage. As the state of the science advances this support is receiving more attention from the press and public, part of a process that will see more funding institutions join in, arriving after initial technology demonstrations such as clearance of senescent cells. Institutional funding is very conservative and almost never provides support for the early stage, high risk research that advances the state of the art. Philanthropy is needed because little progress would happen without it.

Seated at the head of a table for 12 with a view of the city's soaring skyline, Peter Thiel was deep in conversation with his guests, eclectic scientists whose research was considered radical, even heretical. It was 2004 and Thiel had recently made a tidy fortune selling PayPal, which he co-founded, to eBay. He had spent what he wanted on himself and was now soliciting ideas to do good with his money.

Among the guests was Cynthia Kenyon, a molecular biologist and biogerontologist who had garnered attention for doubling the life span of a roundworm by disabling a single gene. Aubrey de Grey, a British computer scientist turned theoretician who prophesied that medical advances would stop aging. And Larry Page, co-founder of an Internet search darling called Google that had big ideas to improve health through the terabytes of data it was collecting. The chatter at the dinner party meandered from the value of chocolate in one's diet to the toll of disease on the U.S. economy to the merits of uploading people's memories to a computer versus cryofreezing their bodies. Yet the focus kept returning to one subject: Was death an inevitability - or a solvable problem?

A number of guests were skeptical about achieving immortality. But could science and technology help us live longer, to, say, 150 years? Now that, they agreed, was a worthy goal. Within a few months, Thiel had written checks to Kenyon and de Grey to accelerate their work. Since then he has doled out millions to other researchers with what he calls "breakout" ideas that defy conventional wisdom. "If you think you can only do very little and be very incremental, then you'll work only on very incremental things. It's self-fulfilling. It's those who have an optimism about what can be done that will shape the future."

He and the tech titans who founded Google, Facebook, eBay, Napster and Netscape are using their billions to rewrite the nation's science agenda and transform biomedical research. Their objective is to use the tools of technology to understand and upgrade what they consider to be the most complicated piece of machinery in existence: the human body. The entrepreneurs are driven by a certitude that rebuilding, regenerating and reprogramming patients' organs, limbs, cells and DNA will enable people to live longer and better. The work they are funding includes hunting for the secrets of living organisms with insanely long lives, engineering microscopic nanobots that can fix your body from the inside out, figuring out how to reprogram the DNA you were born with, and exploring ways to digitize your brain based on the theory that your mind could live long after your body expires.

Link: http://www.washingtonpost.com/sf/national/2015/04/04/tech-titans-latest-project-defy-death/

It has always been the case that the cause of serious rejuvenation research needs more well-regarded individuals to stand up and talk in public about the road ahead, the prospects for success, and the righteousness of the goal. Just lay out the situation as it is, no need for salesmanship: it is simply the need for this to be a topic not left on the edge of polite society. Aging is by far the greatest cause of suffering and death in the world, and we should all be doing more than we are to help bring an end to all of that pain, disease, and loss. For that to happen, the vast majority of people who never think about aging and rarely think about medical research need to give the topic at least as much thought and approval as presently goes towards the cancer research community.

We find ourselves in a peculiar time. Technological barriers to the successful treatment of aging are next to non-existent; progress is falling out of the woodwork even at low levels of funding and interest; this is an age of revolutionary gains in the tools of biotechnology, and that drives the pace of medicine while the cost of meaningful research plummets. This isn't a space race situation in which the brute force of vast expenditure was used to wrest a chunk of the 21st century into the 20th and land men on the moon. If following the SENS program aimed at repair of the causes of aging, the cost of implementing the first prototype, working rejuvenation treatments in old mice would by current estimates be only 1-2% of the Apollo Program budget. There was vast popular approval for the space race to match the vast expense. The path to human rejuvenation is in exactly the opposite situation: there is very little support for the goal of treating aging as medical condition, but the costs of doing so successfully are so small that given even a minority of the public in favor those funds would be raised.

This is why advocacy is so very important. This is why people with large soapboxes can help greatly simply by talking on the topic. Investor and philanthropist Peter Thiel has been supporting scientific programs such as SENS and related areas in biotechnology for a decade now, but I notice that he is more vocal and direct in public about this cause now that other organizations such as Google Ventures are making large investments. This is all good; we need a sea change in the level of public support for rejuvenation research, and their understanding of the prospects for the future. Aging is far from set in stone, and a range of the biotechnologies needed to treat aging and bring it under medical control are on the verge of breaking out into commercial development, or just a few years away from that point. All it takes to turn the stream into a rapids is a little more rain.

Peter Thiel's quest to find the key to eternal life

WP: Why aging?

Thiel: I've always had this really strong sense that death was a terrible, terrible thing. I think that's somewhat unusual. Most people end up compartmentalizing, and they are in some weird mode of denial and acceptance about death, but they both have the result of making you very passive. I prefer to fight it. Almost every major disease is linked to aging. One in a thousand get cancer after age 30. Nixon declared war on cancer in 1971, and there has been frustratingly slow progress. One-third of people age 85 and older have Alzheimer's or dementia, and we're not even motivated to start a war on Alzheimer's. At the end of the day, we need to do more.

WP: All your philanthropic projects are founded on the idea that there's something wrong with the way the current system works. What are the challenges you see in biomedical research?

Thiel: I worry the FDA is too restrictive. Pharmaceutical companies are way too bureaucratic. A tiny fraction of a fraction of a fraction of NIH [National Institutes of Health] spending goes to genuine anti-aging research. The whole thing gets treated like a lottery ticket. Part of the problem is that aging research doesn't always lend itself to being a great for-profit business, but it's a very important area for a philanthropic investment. NIH grant-making decisions end up being consensus-oriented, focused on doing things that a peer review committee thinks makes sense. So you end up with a very conservative bias in terms of what gets done. [On the other hand,] the original DARPA [Defense Advanced Research Projects Agency] was phenomenally successful. You had a guy running it, and he just gave out the money. It was more focused on substance and less on the grant-writing process. That's the direction we should go. I worry that right now, we have people who are very nimble in the art of writing grants who have squeezed out the more creative.

WP: You're currently funding Cynthia Kenyon, Aubrey de Grey and a number of other researchers on anti-aging. What was it about these individuals and their work that got your attention?

Thiel: They think far outside the conventional wisdom and are far more optimistic about what can be done. I think that's important to motivate the research.

WP: How long is long enough? Is there an optimal human life span?

Thiel: I believe if we could enable people to live forever, we should do that. I think this is absolute. There are many people who stop trying because they think they don't have enough time. Because they are 85. But that 85-year-old could have gotten four PhDs from 65 to 85, but he didn't do it because he didn't think he had enough time. If it's natural for your teeth to start falling out, then you shouldn't get cavities replaced? In the 19th century, people made the argument that it was natural for childbirth to be painful for women and therefore you shouldn't have pain medication. I think the nature argument tends to go very wrong. . . . I think it is against human nature not to fight death.

WP: Assuming the breakthrough in eternal life doesn't come in our lifetime, what do you hope to have achieved through your philanthropy before you die? What would you like to be remembered for?

Thiel: I think if we made some real progress on the aging thing, I think that would be an incredible legacy to have. I have been fortunate with my business successes, so I would like to encourage, coordinate and help finance the many great scientists and entrepreneurs that will help bring about the technological future. It's sort of not important for me to get credit for the specific discoveries, but if I can act as a supporter, mentor and financier, I think that feels like the right thing.

Mortality rates continue to fall for common age-related diseases, especially cardiovascular conditions. Yet the overall death toll increases because the population is larger and on average older. Gaining medical control over degenerative aging only grows more important with the passing of time: there are so very many lives to be saved.

As the global population pushes past 7 billion and more people reach old age, the number of deaths from cardiovascular diseases is on the rise. Cardiovascular diseases, the leading cause of premature death in the world, include heart attacks, strokes, and other circulatory diseases. At the same time, efforts to prevent and treat cardiovascular diseases appear to be working as the rise in deaths is slower than the overall growth of the population. Globally, the number of deaths due to cardiovascular diseases increased by 41% between 1990 and 2013, climbing from 12.3 million deaths to 17.3 million deaths. Over the same period, death rates within specific age groups dropped by 39%, according to an analysis of data from 188 countries. Death rates from cardiovascular diseases were steady or fell in every region of the world except western sub-Saharan Africa.

South Asia, which includes India, experienced the largest jump in total deaths due to cardiovascular diseases, with 1.8 million more deaths in 2013 than in 1990 - an increase of 97%. In line with global trends, the increase in deaths from cardiovascular disease in India is driven by population growth and aging without the decrease in age-specific death rates found in many other countries. This pattern is reversed to some extent in the Middle East and North Africa, which includes countries such as Saudi Arabia, Lebanon, and Jordan. In these regions, population growth and aging have been offset by a significant decline in age-specific death rates from cardiovascular disease, which has kept the increase in deaths to just under 50%. East Asia experienced a similar rise of almost 50%, 1.2 million additional deaths, because declines in the risk of cardiovascular diseases offset the effect of a rapidly aging population. Taken together as a region, the United States and Canada were among a small number of places with no detectable change in the number of deaths from cardiovascular diseases, because aging and population growth balanced out declines in age-specific death rates. The same was true in southern Latin America, including Argentina and Chile, as well as Australia and New Zealand.

Researchers found that population aging contributed to an estimated 55% increase in cardiovascular disease deaths globally, and population growth contributed to a 25% increase. These demographic factors are not the only drivers behind the trend of increasing deaths and falling death rates. Changes in the epidemiology of cardiovascular diseases is another factor. Ischemic heart disease is both the leading cause of death worldwide and accounts for almost half of the increase in the number of cardiovascular deaths, despite a 34% decrease in age-specific death rates. Researchers also examined whether wealthier countries fared better than lower-income countries when it comes to cardiovascular deaths and found there was not a strong correlation between income per capita and lower age-specific death rates. The dramatic improvement in the death rates seen in some regions was attributed to prevention and treatment of cardiovascular diseases, in part by reducing risk factors including smoking.

Link: http://www.eurekalert.org/pub_releases/2015-04/ifhm-dfc040115.php

Mitochondrial damage is considered to be an important contribution to degenerative aging. Here researchers find stem cells performing a preferential assignment of cellular components during cell division, giving one of the daughter cells more of the components likely to be damaged - such as older mitochondria. This differential assignment of damage during replication has been seen in bacteria as well; it is clearly a very ancient aspect of cellular biology.

While interesting, there may or may not be any near term practical application for the treatment of aging resulting from a better understanding of how cells are determining which mitochondria to assign to which daughter cell. A more direct path such as mitochondrial repair or replacement may be a more efficient towards medical intervention in the aging process given the present state of technology and knowledge:

During division, stem cells distinguish between old and young mitochondria and allocate them disproportionately between daughter cells. As a result, the daughter cell destined to remain a stem cell receives predominantly young mitochondria, while the cell meant to differentiate into another cell type carries with it a higher compliment of the aged organelles. This asymmetric apportioning of cellular contents may represent a mechanism through which stem cells prevent the accumulation of damage in their lineage over time.

Among the hallmarks of stem cells is so-called asymmetric cell division. Unlike their ordinary cellular counterparts, which divide symmetrically to create two cells with identical fates, stem cell division can produce one daughter cell that will remain a stem cell and another bound for further differentiation into another cell type. Scientists have observed that non-mammalian organisms are able to apportion damaged components asymmetrically during cell division, but it was unclear whether mammalian stem cells could behave similarly.

To track the destinations of subcellular components during cell division, the researchers tagged the components - including lysosomes, mitochondria, Golgi apparatus, ribosomes, and chromatin - with a fluorescent protein that glows when hit by a pulse of ultraviolet light. By tracing the movements of the glowing organelles, the researchers were able to demonstrate that while normal epithelial cells distributed all of the tagged components symmetrically to daughter cells, stem cells localized their older mitochondria distinctly and passed on the lion's share of them to the daughter cells headed for differentiation. The researchers ultimately found that the number of older mitochondria in those cells was roughly six times that in daughter cells whose fate was to remain as stem cells.

Further, they discovered that chemically disrupting the cells' inherent mitochondrial quality-control mechanisms prevented asymmetric apportioning of young and old mitochondria and caused the loss of stem-like characteristics. Taken together, these results indicate that this disproportionate allocation of aged mitochondria during stem cell division is essential for maintaining stemness in the next generation. "While we do not know how stem cells recognize the age of their mitochondria, forced symmetric apportioning of aged mitochondria resulted in loss of stemness in all of the daughter cells. This suggests that the age-selective apportioning of old and potentially damaged organelles may be a way to fight stem cell exhaustion and aging."

Link: http://www.eurekalert.org/pub_releases/2015-04/wifb-adc033115.php

The goal of aging research should, in a perfect world, be to repair the causes of age-related degeneration, frailty, and disease. Forms of damage to cells and tissue accumulate as a side-effect of the normal operation of metabolism, and that leads to a chain of consequences that is eventually fatal. Think of rust or wear on toothed gears and the consequences of that; aging is much the same thing, only far more complex because we are very complex, self-repairing machines. The best therapies for aging will be those that revert damage and rescue us from the consequences of that damage.

Researchers often work with animals whose biochemistry has been deliberately altered to malfunction. Accelerated aging through DNA repair deficiency, for example. This is done because animal studies are enormously expensive, but if there is a way to compress the time needed to evaluate specific aspects of biology, then that will be done. In the future this will be replaced with simulation and engineered tissue rather than whole animals, but for now there are many lineages of mice and other species engineered to age more rapidly. Except that they are not in fact aging more rapidly: their biology is broken in a fundamental way that happens to produce more of certain types of cellular and tissue damage. That in the end produces consequences that somewhat resemble aging, but it isn't the same. Think of the difference between progeria and normal aging in humans: at the high level there are apparent similarities, but at the level of cells and tissues it is very different.

Researchers interested in aging have engineered lineages of mice in which metabolism is broken in some fundamental way, and then gone on to restore some of the harm done via a prospective treatment. At the high level you might think that this looks very similar to the description of the best path towards the treatment of aging: there is damage, and that damage is restored or worked around. Yet it is a very different situation. It is very rarely the case that researchers can make any useful claim related to normal aging based on rescue of a pathologically dysfunctional metabolism through treatment. Such studies are a starting point only, a comparatively low cost way to carry out a preliminary proof of concept for the mechanisms involved, or to investigate specific biochemical processes by creating a situation in which they function in a different way. It is a way to make sure that the actual mechanics of the potential therapy are in fact doing what they are supposed to be doing. Then research can move on to tests in normal animals.

This is exactly what happened for senescent cell clearance as a treatment for aging over the past few years: the initial proof of concept was carried out in an accelerated aging mouse lineage, and while this was one of the rare cases where being excited about the outcome (a slowing of dysfunction) was actually merited, it was still the case that only a demonstration in normal mice would seal the deal. That happened this year, and the fact that it was a mere four years between the two research reports is noteworthy: that is rapid indeed in the world of life science research.

Given all of this, when reading about the research quoted below bear in mind that this is really only a demonstration to show that the relevant mechanism probably work as expected in mammals. It says little about whether or not the treatment will prove to be in any way useful in normal animals rather than those with an artificial accelerated aging condition produced by genetic damage of DNA repair mechanisms. It is interesting to speculate given the details regarding increased resilience in the face of certain types of DNA damage, but until it is tried in healthy, normal animals that will remain speculation.

Team succeeds in doubling life span of mice suffering from premature aging (PDF)

Mice with low levels of the ATR protein, essential for the repair of damaged DNA, age faster than normal. Researchers have established a method to rescue the premature aging in these mice, doubling their life span. The strategy: to introduce a mutation capable of increasing the body's capacity to produce nucleotides - the building blocks of DNA - available in the cells. Together with the original mutation in ATR that caused the premature aging, the animals contained multiple copies of Rrm2, the key gene for the synthesis of nucleotides. The results showed how the accelerated aging was significantly alleviated in these mice, namely increasing their survival from an average of 24 weeks to 50 weeks.

The genome of every living being contains certain fragile areas. These are defined due to their tendency to break spontaneously, and they have been shown to be involved in human diseases, including cancer. The studies described in this research paper showed that those mice with additional copies of Rrm2 suffered less DNA breaks in these fragile areas, this being the first mammal described to present a genome which is less fragile than that of a normal mouse.

Whether these results are relevant with respect to normal - rather than premature - aging remains to be discovered. Whatever the case, the authors point out that standard medical practice includes prescribing folic acid (or vitamin B12) supplements to the elderly to delay or lessen the degenerative symptoms associated with advanced age. Bearing in mind that folic acid is, among other things, a precursor molecule in the synthesis of nucleotides, these results might indicate that a scarcity of nucleotides could contribute towards the aging process in humans. "The question we are asking ourselves now is whether an increase in the capacity to produce nucleotides could also lengthen life expectancy in normal animals without premature aging."

Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2TG) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.

Here is a popular science article on the topic of bioprinting complex tissues, which at this stage is largely used to provide small living tissue structures for research and development. These represent a great improvement in cost and efficiency when compared with the other options of cell culture and animal studies. Nonetheless, this is but a stepping stone on the path to the greater goal of tissue engineered organs assembled to order via 3-D printing technologies:

Just like you would hope, something very cool was revealed at the 2015 Experimental Biology conference in Boston: the biomedical company Organovo showed off its technique for 3D printing human kidney tissue. Organovo has been working on printing functional human tissue since being incorporated in 2007, and first printed a cellular blood vessel in 2010. Since January 2014, it has offered bioprinted liver tissue for companies to use in drug trials and disease modeling, and it looks as though its bioprinted human kidney tissue will be used for the same tasks, starting sometime in the latter half of 2016. "The product that we intend to build from these initial results can be an excellent expansion for our core customers in toxicology, who regularly express to us an interest in having better solutions for the assessment of human kidney toxicity."

So far Organovo's 3D-printed liver tissue is used for preclinical drug trials because the tissue responds like a real life human liver would for 42 days. That's much longer than the single layers of cells previously used in tests, which wilt in a few days. There are mixed views on how far off printing functional organs for transplant is. Growing tissue is one thing, but growing an organ and integrating it into a living body is another. "Everybody's dream is the 3D-printed organ. Are we ever going to get there?" asked Gabor Forgacs, whose research forms the basis of Organovo's method. Forgacs argued that there was no reason functional organs couldn't be made eventually, but that printing replacement organs on demand was still decades away.

Link: http://motherboard.vice.com/read/3d-printed-kidney-tissue-is-here

Cancer as a threatening medical condition occurs in a third of all people. Given that tiny, non-threatening cancers exist in all people by old age, why not the other two thirds? The glib answer is that they are killed by something else before a threatening cancer arises. Cancer risk is seen as a continual game of odds, the chance of cancer rising throughout most of life as DNA damage accumulates. The third are the unlucky ones. There is probably more to it than that at the detailed level of cellular biochemistry, however:

Approximately one in three people is struck by neoplastic disease in his or her lifetime. But, the other side of that coin is that two out of three people remain unaffected. Even the majority of heavy smokers, who bombard their lungs with carcinogens and tumor promoters over many years, remain cancer free. Naturally, the suffering of cancer patients and their families has inspired researchers to study the cellular changes unique to cancer and the genetics of cancer susceptibility. The genetics of cancer resistance, as a topic in its own right, has remained largely unexplored.

Pathologists have shown that virtually all men age 60 or older have microscopic prostate cancer when examined at autopsy. Most of these microtumors never develop into cancer, however. It is also known that disseminated cancer cells are present throughout the body in most cancer patients, but only a small minority of these cells develop into secondary tumors. The rest are kept under control by the body. Indeed, metazoan evolution has led to many adaptations that protect species across the animal kingdom from outlaw cells. Immune surveillance plays a major role in the defense against virus-associated tumors, where the virally encoded transforming proteins provide readily recognizable foreign targets. But nonviral tumors, which are composed of aberrant host cells, do not provide such targets, and the immune response is suppressed by defenses against autoimmune reactions. Rather, we now know that the main safeguards against cancer are not immunological at all.

Several cancer-resistance mechanisms appear to have evolved to maintain cellular or genomic integrity. For example, normal stroma, the connective material that supports the cells of a tissue, appears to inhibit cancer growth. Other resistance mechanisms include DNA repair, suppression of oncogene activation, tumor-suppressor genes, epigenetic stabilization of chromatin structure, and apoptosis. These mechanisms are well-studied, and each provides a potential road map for prevention and treatment.

Link: http://www.the-scientist.com/?articles.view/articleNo/42469/title/Resisting-Cancer/

It is always pleasant to see scientific media outlets treat the work of the SENS Research Foundation with the respect it deserves. The Foundation staff are engaged in a modest range of research projects, usually in collaboration with major laboratories in the US and Europe, all of which relate to the defeat of degenerative aging. How to achieve that goal? By repairing the cellular and molecular damage that causes aging, and by cutting off major avenues of dysfunction at the simplest possible point of commonality in the underlying biochemistry. In most cases that point of commonality is the damage: for example you might think of the accumulation of metabolic waste products such as amyloid between cells and lipofusin inside cells. Those waste products can in principle be cleared, removing their effects. For cancer, however, there is a different story.

Cancer is the result of nuclear DNA damage. This damage accumulates in a stochastic fashion across a lifetime, and the more of it you have the greater your odds on any given day of a cell running amok and successfully evading the immune system to generate a tumor. Of course it doesn't help that the immune system is itself also increasingly damaged and subject to dysfunction with advancing age, but cancer is fundamentally an age-related condition because of growth in DNA damage over time. Repairing this damage isn't a near term feasible project. Researchers can fairly clearly envisage and model the sort of molecular nanorobotics that would be needed, but their creation is somewhere several cycles ahead in the march of progress.

So what to do in the meanwhile? The challenge of cancer lies in the fact that it is a broad category covering many, many forms of dysfunctional cellular mechanisms. A treatment built using even the best of today's drug discovery approaches may only work on one of the thousands of classified forms of cancer, and an individual tumor of that type may very well rapidly evolve its way out of being vulnerable in any given treated patient. There is, however, one point of commonality shared by all cancerous cells. They must all continually lengthen their telomeres; if deprived of all means to do so, they will cease to replicate in short order upon reaching the Hayflick limit. Each cell division shortens telomeres and cells with very short telomeres will self-destruct or become senescent. All cancers abuse telomerase or the comparatively poorly understood alternative lengthening of telomeres (ALT) mechanisms in order to continue to exist. Here, then, is the root to strike at, the field from which the ultimate cure for cancer may emerge.

While a number of research groups are hard at work on safely disrupting telomerase activity as a cancer treatment, the SENS Research Foundation is largely focused on the building the tools needed to do the same for ALT:

Control ALT, Delete Cancer

Cellular immortality is a hallmark of cancers that distinguishes them from normal tissue. Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called the telomeres, gets shorter. When the telomeres shorten too much, an alarm signal is generated, and the cell permanently stops dividing and enters senescence or undergoes apoptosis. Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Cancer cells, on the other hand, can become immortalized by activating a telomere maintenance mechanism (TMM) that counteracts telomere shortening by synthesizing new telomeric DNA from either an RNA template using the enzyme telomerase or a DNA template using a mechanism called alternative lengthening of telomeres (ALT).

Because the presence of a TMM is an almost universal characteristic of cancer cells, and experimentally repressing these mechanisms results in cancer cell senescence or death, TMMs may be useful targets in treating cancer. Indeed, several therapies targeting the well-described telomerase-based pathway are in the advanced stages of clinical development. There are currently no ALT-targeted therapeutics, however, largely because this process is less well understood.

In contrast to telomerase-driven telomere lengthening, which does occur in the stem cells of healthy tissues and organs, ALT activity is not found in normal human postnatal tissues - a fact that would allow for more-effective dosing with minimal side effects. And based on the conservative estimate that 10 percent of cancers employ an ALT strategy to achieve cellular immortality, there are about 1.4 million new cases and 820,000 deaths globally due to ALT cancers every year. These include some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers. Clearly, targeting ALT is a very attractive strategy in the development of novel cancer therapies.

The development of ALT-targeted therapies is quite challenging, however. Unlike the telomerase pathway, the ALT mechanism has no known specific enzyme activity, and all the enzymes identified to date that play a role in ALT are also essential to normal cellular pathways. The presence of ALT activity has often been inferred from detecting telomere-related phenotypes, such as long and heterogeneous telomere length distributions or ALT-associated promyelocytic leukemia nuclear bodies (APB), which indicate the abnormal presence of telomeres inside a complex formed from otherwise ubiquitous nuclear proteins. These markers are not entirely satisfactory, as they can sometimes yield inaccurate results and are not practical for high-throughput applications or clinical laboratories.

A key step towards the development of ALT-targeted cancer therapeutics and diagnostics was the discovery of the first ALT-specific molecule, the telomeric C-circle. C-circles are an unusual type of circular DNAs that are created from telomeres. The level of C-circles in cancer cells accurately reflects the level of ALT activity, and this biomarker can be found in the blood of patients who have bone cancers positive for ALT activity. The development of the C-circle assay as well as improvements to the APB assay could, in the near future, make it feasible to perform robust high-throughput screenings to search for modulators of the ALT pathway, which will greatly speed the pace of discovery in this field. Further research will no doubt lead to a more complete mechanistic understanding of this phenomenon and to the first ALT-specific therapies against cancer. Controlling ALT could very well help delete the burden of cancer from society.

A reliable means to safely accelerate natural healing would be a generally useful technology for all stages of life, but it is the elderly who suffer the most due to slower and more dysfunctional healing of even minor injuries:

An experimental therapy cut in half the time it takes to heal wounds compared to no treatment at all. Researchers discovered that an enzyme called fidgetin-like 2 (FL2) puts the brakes on skin cells as they migrate towards wounds to heal them. They reasoned that the healing cells could reach their destination faster if their levels of FL2 could be reduced. So they developed a drug that inactivates the gene that makes FL2 and then put the drug in tiny gel capsules called nanoparticles and applied the nanoparticles to wounds on mice. The treated wounds healed much faster than untreated wounds. "We envision that our nanoparticle therapy could be used to speed the healing of all sorts of wounds, including everyday cuts and burns, surgical incisions, and chronic skin ulcers, which are a particular problem in the elderly and people with diabetes."

The wound-healing therapy uses molecules of silencing RNA (siRNAs) specific for FL2. The siRNAs act to silence genes. They do so by binding to a gene's messenger RNA (mRNA), preventing the mRNA from being translated into proteins (in this case, the enzyme FL2). However, siRNAs on their own won't be effectively taken up by cells, particularly inside a living organism. They will be quickly degraded unless they are put into some kind of delivery vehicle, and so the researchers collaborated with another group who had developed nanoparticles that protect molecules such as siRNA from being degraded as they ferry the molecules to their intended targets. The nanoparticles with their siRNA cargoes were then tested by topically applying them to mice with either skin excisions or burns. In both cases, the wounds closed more than twice as fast as in untreated controls. "Not only did the cells move into the wounds faster, but they knew what to do when they got there. We saw normal, well-orchestrated regeneration of tissue, including hair follicles and the skin's supportive collagen network."

Link: http://www.eurekalert.org/pub_releases/2015-03/aeco-nnt032615.php

The forkhead box (FOX) family of proteins includes members such as FOXO3 that seem to be important in longevity and regeneration in a variety of very different species. Here researchers show that FOXO3 is required for the additional longevity created by the practice of calorie restriction:

Forkhead box O (Foxo) transcription factors may be involved in the salutary effect of dietary restriction (DR). This study examined the role of Foxo3 in lifespan extension and cancer suppression in DR mice. Wild-type (WT) and Foxo3-knockout heterozygous (+/-) and homozygous (-/-) mice were subjected to a 30% DR regimen initiated at 12 weeks of age. Control mice were fed ad libitum (AL) throughout the study. The food intake by Foxo3+/- and Foxo3-/- mice was similar to those by WT mice under the AL condition, and thus, the daily allotments for each DR group were almost the same during the lifespan study. The average body weights of WT, Foxo3+/-, and Foxo3-/- mice were also similar under AL and DR conditions.

In contrast to WT mice, DR did not significantly extend the lifespan of Foxo3+/- or Foxo3-/- mice. However, DR reduced the prevalence of tumors at death in WT, Foxo3+/-, and Foxo3-/- mice. These results indicate the necessity of Foxo3 for lifespan extension but not cancer suppression by DR. The findings in Foxo3+/- mice contrast with those in Foxo1+/- mice reported previously by our laboratory and suggest differential regulation of cancer and lifespan by DR via Foxo1 and Foxo3.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12340/