Fight Aging!

In recent years a number of researchers have used blood transfusions and mixing to discover and investigate systematic differences in biochemistry between old and young mammals. Many of the body's distributed systems use the circulatory system as a means of carrying signals and instructions throughout the body. Thus introducing old blood into the young or young blood into the old can bring about measurable biochemical changes that tell us more about the specific changes that occur with aging.

Aging is damage, but all of our biological systems are highly responsive to changing circumstances - so where there is damage, there will also be an evolved response to that damage. In theory that will be a coping response, but what evolution considers "coping" might not match with your opinions on the subject. For example, one form of characteristic response that occurs as we age is a progressive diminishing of growth and repair: stem cell populations stop doing their jobs as enthusiastically, for example, and the quality of our tissues suffers for it. It reduces the risk of cancer, but that's cold comfort for someone who is effectively being worn away, every bodily structure decaying faster than it is being repaired.

But back to the blood: here is a fresh example of what can be learned from mixing the blood of mice.

Stanford University School of Medicine scientists have found substances in the blood of old mice that makes young brains act older. These substances, whose levels rise with increasing age, appear to inhibit the brain's ability to produce new nerve cells critical to memory and learning. ... An early step in the Stanford team's study involved connecting the circulatory systems of pairs of old and young mice via a surgical procedure, so that blood from the two mice comingled. "This way, we could examine the effects of old mice's blood on young mice's brains, and vice versa. ... We saw a threefold increase in the number of new nerve cells being generated in old mice exposed to this 'younger' environment." ... In contrast, the young members of old/young mouse pairs exhibited fewer new nerve cells in the dentate gyrus than did young mice untethered to elders.

...

To identify specific circulating factors associated with aging and tissue degeneration or tissue regeneration, the researchers assayed 66 different immune-signaling proteins found in mice's blood. Six of these factors were elevated in both unpaired old mice and young mice that had been paired with older ones. At the top of the list was eotaxin, a small protein that attracts a certain type of immune cells to areas where it has been secreted by other types of cells. Highlighting this discovery's possible relevance to humans, [tests] conducted on blood and cerebrospinal fluid samples drawn from healthy people between the ages of 20 and 90 showed a parallel age-related increase in eotaxin.

Much of today's research is channeled into what is effectively a process of trying to patch over damage: the fastest way to try to move from laboratory to building something that the FDA might actually allow into the clinic is to (a) identify a single component is a biological system that might be manipulated to some palliative effect, then (b) design a drug to manipulate it with as few side-effects as possible. This two-step process is what much of the pharmaceutical industry and regulatory bodies are geared up for, and all they recognize. Try to do something different and your path will be longer and more challenging - see, for example, the fact that early stage stem cell therapies still cannot be obtained in US clinics, despite having been available overseas for a number of years now.

My point here being that work like that quoted above is interesting as a potential foundation for a way to patch over some of the issues that crop up with aging - but patching is a very different matter from repairing root causes, and will always ultimately fail. If better ways ahead are possible, and they are, then strategies involving patching should take second place in the priority queue.

Via EurekAlert!: "When the body fights oxidative damage, it calls up a reservist enzyme that protects cells - but only if those cells are relatively young, a study has found. [Biologists] discovered major declines in the availability of an enzyme, known as the Lon protease, as human cells grow older. ... Lon protects the mitochondria - tiny organisms in the cell that convert oxygen into energy. The conversion is never perfect: Some oxygen leaks and combines with other elements to create damaging oxidants. Oxidation is the process behind rust and food spoilage. In the body, oxidation can damage or destroy almost any tissue. Lon removes oxidized proteins from the mitochondria and also plays a vital role in helping to make new mitochondria. ... To fight the oxidant, young cells doubled the size of their Lon army within five hours and maintained it for a day. In some experiments, young cells increased their Lon army as much as seven-fold. Middle-aged cells took a full day to double their Lon army, during which time the cells were exposed to harmful levels of oxidized proteins. Older cells started with a standing Lon army only half as large and showed no statistically significant increase in Lon levels over 24 hours." It is worth noting that the age of individual cells and the age of a person don't have much to do with one another except in some long-lived tissues where the same cells operate throughout life. But you might recall that mitochondrially-targeted antioxidants can increase life span in mice, and mitochondrial damage is important in aging - this research is consistent with all of that, and may lead to another way to extend life via protection of mitochondria.

Link: http://www.eurekalert.org/pub_releases/2011-08/uosc-nad083011.php

Researcher João Pedro de Magalhães and colleagues are working on a new online resource: "We have developed a new web portal to integrate molecular, physiological ,and pathological age-related data that may be of interest. ... The Digital Ageing Atlas is a portal of changes covering different biological levels. There are currently portals for both humans and mice. The idea is to integrate molecular, physiological and pathological age-related data and create an interactive portal that serves as the first centralised collection of ageing changes and pathologies. ... It allows users to search and retrieve age-related changes at different levels, allowing a better understanding of the interplay between such changes and obtain new insights. We also think this will be an important new resource for modelling and for the systems biology of ageing and hope you will find it useful. Although so far we focused mostly on human aging, a preliminary mouse version of the portal is on-line already."

Link: http://human.ageing-map.org/

One of the reasons that work on heat shock proteins are attracting interest in the research community is that these proteins are deeply involved in cellular housekeeping processes. They are one of the components of the machinery of hormesis, wherein the body is improved by mild stress and a little cellular damage, because that stress causes repair and housekeeping systems to spring to life and work earnestly to make everything shipshape. Heat shock proteins are so named because they were first identified in the response to molecular damage caused by heat - but they are brought into play by all sorts of stresses that can cause damage to the delicate protein machinery of cells.

As is the case for autophagy, it is worth thinking about where we might be taken by the ability to boost the heat shock response on demand, or selectively alter and improve it. Beyond thoughts on slowing aging, calorie restriction mimetics, and modestly increasing human longevity, a number of mainstream research groups investigate housekeeping mechanisms as a possible way to treat neurodegenerative diseases. I noticed another example of this sort of work recently:

Protecting Cells: Evidence Found for a Neuronal Switch to Prevent Neurodegenerative Diseases

Neurodegenerative diseases, ranging from Huntington's and Parkinson's to amyotrophic lateral sclerosis and Alzheimer's, are believed to stem from early events that lead to an accumulation of damaged proteins in cells. Yet all animals, including humans, have an ancient and very powerful mechanism for detecting and responding to such damage, known as the heat shock response.

"Why are these diseases so widespread if our cells have ways to detect and prevent damaged proteins from accumulating? Can our body fix the problem? That is the conundrum. In our study, much to our surprise, we discovered that the nervous system sends negative signals to other tissues in the animal that inhibit the ability of cells to activate a protective heat shock response. The machinery to repair the damaged proteins is intact, but the nervous system is sending a signal that prevents it from doing its job."

When the signal from the nervous system was reduced, the cells' heat shock response returned, leading to elevated levels of special protective proteins, called molecular chaperones, that kept the damaged proteins in check

This is early stage work in nematode worms: we'll have to wait a few years to see how well it carries through into mice, let alone people.

Given the current state of research, I'd say that optimizing exercise for its effects on longevity is as much a fool's game as optimizing diet - if you want to take it on as a hobby, then by all means, but don't expect to beat the scientific community in terms of finding a better way, or to know how well you're doing. Obtaining significant benefits to life expectancy is easy: just exercise as recommended by physicians, the standard 30 minutes of aerobic exercise a day. The tricky question is whether there is a reliable way of gaining more expected years of life than are provided by that 80/20 position. But the research keeps rolling in, so perhaps one day there will be sufficient weight of evidence to say in confidence that one way of exercising is significantly better than another: "A study conducted among cyclists in Copenhagen, Denmark showed that it is the relative intensity and not the duration of cycling which is of most importance in relation to all-cause mortality and even more pronounced for coronary heart disease mortality. The [study] concluded that men with fast intensity cycling survived 5.3 years longer, and men with average intensity 2.9 years longer than men with slow cycling intensity. For women the figures were 3.9 and 2.2 years longer, respectively ...The groups were adjusted for differences in age and conventional risk factor levels. Current recommendations prescribe that every adult should accumulate 30 minutes or more of moderate physical activity in leisure time, preferably every day of the week. The optimal intensity, duration and frequency still have to be established. ... this study suggests that a greater part of the daily physical activity in leisure time should be vigorous, based on the individuals own perception of intensity."

Link: http://www.eurekalert.org/pub_releases/2011-08/esoc-cfv082811.php

Via EurekAlert!: "It is a well-established fact that as we grow older, our bones become more brittle and prone to fracturing. It is also well established that loss of mass is a major reason for older bones fracturing more readily than younger bones, hence medical treatments have focused on slowing down this loss. However, new research [shows] that at microscopic dimensions, the age-related loss of bone quality can be every bit as important as the loss of quantity in the susceptibility of bone to fracturing. Using a combination of x-ray and electron based analytical techniques as well as macroscopic fracture testing, the researchers showed that the advancement of age ushers in a degradation of the mechanical properties of human cortical bone over a range of different size scales. As a result, the bone's ability to resist fracture becomes increasingly compromised. This age-related loss of bone quality is independent of age-related bone mass loss. ... Mechanical properties of stiffness, strength and toughness arise from both the characteristic structure at the nanoscale, and at multiple length scales through the hierarchical architecture of the bone. These length scales extend from the molecular level to the osteonal structures at near-millimeter levels. An osteon is the basic structural unit of compact bone, comprised of a central canal surrounded by concentric rings of lamellae plates, through which bone remodels. ... Mechanisms that strengthen and toughen bone can be identified at most of these structural length scales and can be usefully classified, as in many materials, in terms of intrinsic toughening mechanisms at small length scales, promoting non-brittle behavior, and extrinsic toughening mechanisms at larger length scales acting to limit the growth of cracks. These features are present in healthy, young human bone and are responsible for its unique mechanical properties. However, with biological aging, the ability of these mechanisms to resist fracture deteriorates leading to a reduction in bone strength and fracture toughness."

Link: http://www.eurekalert.org/pub_releases/2011-08/dbnl-tbo082911.php

The latest book to emerge from the longevity advocacy community is entitled "100 Plus: How the Coming age of Longevity Will Change Everything, From Careers and Relationships to Family and Faith", and is penned by Sonia Arrison, whom you might have heard of. The foreword is by Peter Thiel, whose name you should certainly know by now - you might recall his $3.5 million funding of the SENS Foundation's program of rejuvenation biotechnology, back when it was a branch of the Methuselah Foundation. Thiel makes a point in the opening pages, and it's one to keep in mind when reading the rest of the book:

Unlike the other animals, we have knowledge of death. The origins of language, of culture, and of religion can perhaps all be traced to that point in the distant past when our ancestors first acquird this terrible knowlege and needed to tell themselves stories to make sense of life and death. Every myth on this planet is an untrue story that tells people that the purpose of life is death. Nationalistic myths tell us that it is sweet and fitting to die for one's country, ideological myths tell us that progress requires violence and that one must break some eggs to make an omelet, and religious myths tell us to worship the old, the ancient, and the spirits of the dead.

The crisis of the modern world is the crisis of mythology. We no longer believe in the old stories about life and death, but we also cannot go back to a time when we were not yet human and did not know about death. We cannot go back in time [to the innocent ignorance of youth] and we would prefer not to be turned [into animals]. As the same time we cannot simply deal with death as a "fact of life." What we desperately need is a new story - a true story - to help make sense of the world in which we find ourselves.

It is important to understand that we as a species tend towards building our mythology, recapitulating it in technology just as soon as we are able - though nowadays people are more likely to talk of "vision" and "cultural aspirations" than to tie present research and development to the legacy of stories and desires that emerged from the deep past. Unlike Thiel, I don't think that all of the old tales are bad for being lies. In some, humanity lives in a world in which objects think and speak, aging can be banished, wounds healed with a touch, and spirits and gods watch over all - and with progress in artificial intelligence and biotechnology most of that will come to pass. There are good reasons why certain forms of story survive the millennia: a portion of human nature is hard-wired into our biology, and thus there is a consistency in myths. They attract us and steer us just as much as we steer them, and thus for so long as there are at least a few people who prefer to build a tower rather than talk of building a tower, we will wind up building our mythology. Thiel is, however, right about the prevalence of tales that celebrate death and aging when compared with those that celebrate life and longevity - and that is a scale crying out for a rebalancing.

As a sidebar to that line of thinking, I noticed a review of 100 Plus from researcher Jay Olshansky, who appears to more or less get the point I make above, at least in the modern terms of "vision," but at the same time rejects the presentation as too enthusiastic. To understand why this is so, one has to first grasp the nature of the rift in the research community: between those who see the only path ahead as slowing aging though changes to metabolism, versus those who would leave metabolism unaltered and focus instead on reversing the damage and change that differentiates the old person from the young person. It is hard to argue against the view that the research community should in principle be able to build a better, longer-lived human through metabolic changes, as handful of other species of mammal are far superior to humans in one way or another. Take the cancer resistance and longevity of whales, or the apparent cancer immunity enjoyed by the naked mole rat, for example. But it is a long way indeed from where we stand today to the advent of an engineered human who can live longer, or the means of applying the same changes to a version 1.0 human. That is the span of a lifetime or more - a project far beyond the scope of anything our species has yet attempted, of a complexity that is hard for most people to envisage. Today we can barely tweak a single gene safely, let along reengineer the entirety of the fantastic complexity of thousands of genes and feedback loops that run the day to day operation of our bodies.

Thus the metabolic engineers tell us that the research community is not going to make great progress within our lifetimes on their path, and I believe they are right. It's a long road.

Fortunately, we have an alternative. The path of reversing and repairing damage within the present human metabolism is far more promising than metabolic alteration: look at the work of the SENS Foundation, for example. The SENS planners can realistically suggest that a billion dollars and ten to twenty years would give the research community a good shot at robust rejuvenation in old mice. From there it would be a matter of the standard process of moving victory in the laboratory to the clinic: another decade or two, and a good deal more than a billion dollars. But by that point, there will be a lot of people willing to pay. The repair-based strategy for tackling aging is still is a minority voice in the aging research community, but it does offer the vision of significant progress within our lifetimes - and that makes the old guard of the research community unhappy. Up until this point the only people singing that tune were the frauds and the marketeers of the "anti-aging" marketplace - the potion sellers with deep pockets, loud voices, and little regard for science. A quiet little war has been fought between researchers and "anti-aging" marketing over the past few decades, waged over perceptions of legitimacy and the resulting effects on the bottom line at the cash register and the research funding institution. The old habits of the battle seem hard to let go for some folk: they cannot see vision and enthusiasm in the public eye without also seeing a threat, and that is a pity.

But I digress. The point of books, this blog, and sundry other efforts focused on advocacy and education for engineering greater human longevity is "vision," "cultural aspiration," or whatever you want to call it. It is to raise up from the past the better myths, the celebrations of life and the defeat of death, or to inculcate new myths where the old are unsuitable or gone without trace. If a myth (a "vision") catches and spreads, then it will in due course be built. There are myths to celebrate agelessness, but there are many more that celebrate death - and anyone who has spent time trying to talk to be people about extending healthy life will have seen that we are nothing if not a society that celebrates death:

This is an age of progress and biotechnology. Yet we folk who might be the first ageless humans stand atop a bone mountain. Its slopes are the stories of the dead, created, told, and appreciated by people who knew their own mortality. It is an enormous, pervasive heritage, forged by an army of billions, and no part of our culture or our endeavors is left untouched by it. This is one part of the hurdle we must overcome as we strive to convince people that a near future of rejuvenation biotechnology is plausible, possible, and desirable.

Burying the bone mountain is a big job, but that's why we write.

This post is, allegedly, a book review - or at least what passes for such here at Fight Aging! - so I should probably say something more on the topic of what you'll find inside 100 Plus. To my eyes, the book is essentially a fast overview of the last ten years of science, debate, important subjects, and noteworthy people in the aging research and longevity advocacy communities. A survey of the historical and mythological roots of present day attitudes serves as a springboard into a fast look at some of the important lines of medical research and development - SENS, tissue engineering, longevity genes, and so forth. Then it's off to observe the squawking of Malthusians and their resource-based objections to engineering greater human longevity, followed by a side-trip into philosophical discussions of longevity, and then a soujourn in the realm of economics to talk seriously about how the length of life shapes society. The book is rounded out by a glance at some of the present cast of vocal movers and shakers in the longevity advocacy and research communities: Aubrey de Grey of the SENS Foundation, David Gobel of the Methuselah Foundation, Peter Thiel, Ray Kurzweil, and a range of others in that same broad network - people willing to stand up, set forth, and make efforts to do something about aging.

100 Plus is, I think, a good book to give to the average fellow in the street who would be flattened and slain by the attempt to read Aubrey de Grey and Michael Rae's Ending Aging. That book is where the meat is - but 100 Plus is a Cliff's Notes for the current state and direction of longevity science and the advocacy community supporting it. That is a useful thing: a person reading 100 Plus will wind up in roughly the same place as a casual reader of the high points of Fight Aging!.

As I've pointed out in the past, the ideas that support engineered longevity as a concept - its desirability and plausiblity - are many, complicated, and not widely appreciated. Yet the same was once true of the world wide web and the internet itself, and everyone gets the picture now. Books like 100 Plus are necessary and needed, as they are a part of the process by which society moves from finding engineered longevity a hard sell to it being obvious, accepted, and well supported. Not everyone can sit through Ending Aging, or wade through a decade of Fight Aging! posts to assemble the whole picture. There must be summaries and explanations and high level views, gentle introductions to the current state of play. That is how the community grows and spreads its ideas: books like 100 Plus are seeds, from which great things may later flower.

When you read 100 Plus, bear in mind what I said at the top of this post about myths, and how that relates to both the role of this book and the far broader role of the longevity advocacy community as a whole. We make the stories and we build the future: neither tales nor progress just happen in and of themselves. But one person cannot do much on their own - many hands make light work, and a great part of this grand process of construction lies in persuading other people to join in and see things your way.

Small blood vessels are a great challenge in tissue engineering: both creating them in the first place in order to supply blood to constructed tissue, and then linking them into the body's existing blood supply when tissue is transplanted. The smaller the blood vessels, the harder this all becomes - so better ways of linking blood vessels together are necessary. "Reconnecting severed blood vessels is mostly done the same way today - with sutures - as it was 100 years ago ... Now, a team of researchers [has] developed a sutureless method that appears to be a faster, safer and easier alternative. In animal studies, a team [used] a poloxamer gel and bioadhesive rather than a needle and thread to join together blood vessels ... The big drawback of sutures is that they are difficult to use on blood vessels less than 1 millimeter wide. ... Sutures are troublesome in other ways, too. They can lead to complications, such as intimal hyperplasia, in which cells respond to the trauma of the needle and thread by proliferating on the inside wall of the blood vessel, causing it to narrow at that point. This increases the risk of a blood clot getting stuck and obstructing blood flow. In addition, sutures may trigger an immune response, leading to inflamed tissue that also increases the risk of a blockage. The new method could sidestep these problems. ... [Researchers used a] thermoreversible poloxamer called Poloxamer 407. It is constructed of polymer blocks whose properties can be reversed by heating. [They modified] the poloxamer so that it would become solid and elastic when heated above body temperature but dissolve harmlessly into the bloodstream when cooled. The poloxamer then was used to distend both openings of a severed blood vessel, allowing researchers to glue them together precisely. The researchers used a simple halogen lamp to heat the gel. In tests on animals, the technique was found to be five times faster than the traditional hand-sewn method, according to the study. It also resulted in considerably less inflammation and scarring after two years. The method even worked on extremely slim blood vessels - those only 0.2 mm wide - which would have been too tiny and delicate for sutures."

Link: http://www.eurekalert.org/pub_releases/2011-08/sumc-sr082611.php

From the SENS Foundation: "The fifth biannual Strategies for Engineered Negligible Senescence biomedical conference is just days away. Getting ready for the trip has cast my mind back not only to previous meetings of this exciting interdisciplinary series, and also to the recent 40th meeting of the American Aging Association (AGE). Along with its international sister organization, the International Association for Biomedical Gerontology (IABG), AGE was the first, and remains the premier, professional scientific organization focused specifically on biomedical research in aging. That is, much of biogerontology research is dedicated to pursuing an ever-more-granular understanding the metabolic processes that contribute to, or fail as a result of, the degenerative aging process. But the scientists at AGE (and IABG) focus their work not on understanding age-related decay, but on its biomedical amelioration. ... While the rest of the conference included a wide diversity of biogerontology research, there was still a noticeably higher content of experimental interventions in the aging process and aspects of age-related degeneration than in previous years. ... Organized by Dr. de Grey, the preconference 'Late-onset intervention against aging: Tools, approaches, impact' brought the focus squarely back on AGE's interventive raison d'être -- and shed its most intense light on progress toward interventions that could meaningfully bend the degenerative aging curve when administered to persons who are already in the last decades of a current life expectancy. It is these people - individuals past the age of ~60 - for whom the medial need for intervention is most pressing, and whose generational demographic trajectory under 'aging as usual' poses the most dire social challenges. Therefore, therapies that will slow, arrest, or reverse age-related ill-health and frailty stand to provide the most good - to each aging person, and to societies as a whole."

Link: http://sens.org/node/2375

The latest issue of Life Extension Magazine is fairly focused on the long view, and taken as a whole is a more than usually explicit call for the defeat of aging through research and development of the appropriate biotechnology. It is my sense that the mouthpiece of that organization has been steering more towards that direction in recent years, and I'm pleased to see it - the less the LEF folk conduct themselves as a standard issue supplement shop and the more they conduct themselves as a source of advocacy and funding for serious longevity research such as SENS the better they look to my eyes.

There are a couple of articles worth thinking on, starting with one penned by Aubrey de Grey subject that I've held forth on in the past.

Why Aren't More Wealthy People Funding Aging Research?

Since aging is indisputably humanity's worst medical problem, with the treatment (albeit only minimally effective) of age-related diseases consuming the vast majority of the industrialized world's medical budget, one would imagine that all reasonable approaches to the development of medicine to postpone it would be vigorously pursued and well funded. Unfortunately, none of them are. Neither the retardation of aging nor its repair receives a fraction of the research budget - whether from the public purse or from the for-profit biotech sector - that is enjoyed by disease-specific research. And this is despite the fact that gerontologists have been pointing out for decades that even modest progress in the implementation of "preventative geriatrics" - which is exactly what treatment for aging would be - would be staggeringly cost-effective. I believe that the overwhelming reason why politicians (and, to a lesser extent, companies) have not heard this message is not because they fail to understand it but because they dispute the premise. There is a profoundly deep-seated belief that aging is untreatable.

The Ellison Medical Foundation

The Ellison Medical Foundation is the largest private funder of research on aging and the second largest overall funder - second only to the federal government's National Institute on Aging. Since its inception in 1998, Ellison's Medical Foundation has provided more than $300 million to fund basic biomedical research on aging relevant to understanding life span development processes and age-related diseases and disabilities, including stem cells, telomeres, longevity genes, DNA and mitochondrial damage, Werner Syndrome, Alzheimer's disease, neural development, degeneration and cognitive decline, and cellular response systems to aging and toxins.

An Initiative to Accelerate Anti-Aging Research:

Never before has such a volume of scientific knowledge existed about the underlying mechanisms of aging and how they may be thwarted. A growing number of researchers are predicting major advances in our ability to slow and reverse degenerative aging processes. One obstacle is the bureaucratic regulations that slow the development of new medical technologies. An even more troubling concern, however, is an epidemic of apathy as it relates to providing funding for promising age-reversal research projects.

Those with disposable income and assets donate monies to all kinds of so-called charities, yet overlook research that could help them live in a youthful state of health for a very long time. When one considers that aging is the disease that eventually kills us all, you would think that this is where the bulk of medical research emphasis would be focused. Instead, billions of dollars are squandered developing band-aid approaches to degenerative diseases instead of seeking to intervene directly in the aging process itself.

...

So what Life Extension has done is set up a website for the purpose of ascertaining how many humans today would be willing to assist in funding accelerated anti-aging research. Activist members have pledged to reach out to wealthy individuals to see if they are willing to help support aggressive research projects aimed at finding a cure for aging. If enough pledges of support are received, Life Extension and others will coordinate programs and present them to those who indicate a desire to contribute.

I will be interested to see how well this initiative proceeds; the LEF has a broad base of customers and readers, and it will be informative to see just how many of them can be converted from the mindset of supplement purchaser to the mindset of supporter of meaningful longevity science. There is a large gap between those two points on the cultural map, as demonstrated by the near complete lack of funds, attention, or interest flowing from the vast "anti-aging" marketplace towards serious research projects. The LEF spokespeople and mouthpiece are very atypical examples of that industry, sad to say, and there is no useful connection between the bulk of the industry and real longevity science. If there was, we'd have seen the effects already.

Researchers are turning up a great many human genetic variants associated with natural differences in longevity - a complex, patchwork array of them, each contributing a small amount to the whole: "Aging is a complex phenotype with multiple determinants but a strong genetic component significantly impacts on survival to extreme ages. The dysregulation of immune responses occurring with increasing age is believed to contribute to human morbidity and mortality. Conversely, some genetic determinants of successful aging might reside in those polymorphisms for the immune system genes regulating immune responses. Here we examined the main effects of single loci and multi-locus interactions to test the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-α) genes may influence human life-expectancy. ... SNPs have been determined for 1071 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes ... Single-locus analysis showed that only ADA 22G>A is significantly associated with human life-expectancy in males ... a significant two-loci interaction occurs in females between ADA 22G>A and TNF-α -238G>A ... both two-loci and three-loci interaction are significant associated with increased life-expectancy over 88years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-α genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21865054

From the Technology Review: "I was observing an intimate demonstration of how stem-cell technologies may one day combine with personal genomics and personal medicine. I was the first journalist to undergo experiments designed to see if the four-year-old process that creates induced pluripotent stem (iPS) cells can yield insight into the functioning and fate of a healthy individual's heart cells. Similar tests could be run on lab-grown brain and liver cells, or eventually on any of the more than 200 cell types found in humans. ... This is the next step in personalized medicine: being able to test drugs and other factors on different cell types. ... the cardiomyocytes derived from iPS cells are a huge improvement over the cadaver cells sometimes used to test potential drug compounds. Unlike the cadaver cells, IPS-­generated cells beat realistically and can be supplied in large quantities on demand. What's more, iPS-generated cells can have the same genetic makeup as the patients they came from, which is a huge advantage in tailoring drugs and treatments to individuals. ... Virtually everything about iPS cells is overhyped. But for the purpose of testing drug candidates, I think the possibilities are considerable, and we and lots of other people are pursuing this. There are lots of problems. Are iPS cells really normal? How do you get enough pure differentiated cells? But the potential is definitely there."

Link: http://www.technologyreview.com/biomedicine/38348/

A copy number variation is either a large deletion or repeat of a sequence in your DNA. We all have them, and some people have more than others:

Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. ... We observed that the burden of common but not of rare CNVs influences mortality. ... A higher burden of large (≥500 kb) common deletions associated with 4% higher mortality.

We might speculate on what this means - and it's interesting to do so in light of the present debate over the role of nuclear DNA damage in aging. Is having generally more ragged DNA a bad thing in and of itself, or is it instead a marker for poor quality in other important biological processes, such that the DNA repair and copy checking mechanisms that exist to prevent this sort of issue from coming about in the first place? Only a handful of CNVs have been linked to raised risk of specific diseases, but that there is a general correlation with mortality rate suggests that researchers will find many more specific issues and areas of enhanced risk if they go looking for them.

Fortunately, the long age in which we humans were at the complete mercy of our inherited DNA is coming to a close - it'll be a fading memory only a century from now, something to look back on with mild horror, much as we look back on the comparatively recent ages in which infectious disease was a scourge. One of the great benefits of biotechnology is that every advance will allows the medical community to balance a small part of the genetic heritage we came into this world with. Some people enter the game with a bad hand: that matters less now than it did in the past, and it won't be too many decades more before it hardly matters at all - the sooner the better, I say.

Cryonics provider Alcor dedicates a section of their website to challenges and problems, and it is well worth reading: "When you buy a house, the seller is legally obliged to disclose any known defects. When you review a company's annual report, it tells you every problem that could affect the corporate share value. Since arrangements for cryopreservation may have a much greater impact on your life than home ownership or stock investments, we feel an ethical obligation to disclose problems that affect cryonics in general and Alcor specifically. We also believe that an organization which admits its problems is more likely to address them than an organization which pretends it has none. Thus full disclosure should encourage, rather than discourage, consumer confidence. ... As of 2011, Alcor is nearly 40 years old. Our Patient Care Trust Fund is endowed with more than 7 million dollars and is responsible for the long-term care of over 100 cryopatients. In almost every year since its inception Alcor has enjoyed positive membership growth. We are the largest cryonics organization in the world - yet in many respects we are still a startup company. We have fewer than a dozen employees in Scottsdale, Arizona and approximately 20 part-time independent contractors in various locations around the USA, mostly dedicated to emergency standby and rescue efforts. We serve fewer than 1,000 members and the protocols that aid our pursuit of the goal of reversible suspended animation continue to be developed. At the present time the technology required for the realization of our goal far exceeds current technical capabilities. Cryonics will not be comparable with mainstream medicine until our patients can be revived using contemporary technology, and we expect to wait for decades to see this vision fulfilled. Nevertheless, we have made important progress by introducing brain vitrification to improve patient tissue structure preservation. Alcor shares some of the characteristics of startup companies. The organization is understaffed in some important areas and lacks as much capitalization as would be desired to support maximum growth. Limited resources prevent the organization from hiring as many highly qualified and experienced personnel as desired, and sometimes we have to postpone enhancements to equipment and procedures." I think that this is a great document, and Alcor staff are to be congratulated for publishing it - absolutely the right thing to do.

Link: http://alcor.org/problems.html

Good news from the dental research community: scientists "have developed a revolutionary new way to treat the first signs of tooth decay. Their solution is to arm dentists with a peptide-based fluid that is literally painted onto the tooth's surface. The peptide technology is based on knowledge of how the tooth forms in the first place and stimulates regeneration of the tooth defect. ... This may sound too good to be true, but we are essentially helping acid-damaged teeth to regenerate themselves. It is a totally natural non-surgical repair process and is entirely pain-free too. ... It contains a peptide known as P 11-4 that -- under certain conditions - will assemble together into fibres. In practice, this means that when applied to the tooth, the fluid seeps into the micro-pores caused by acid attack and then spontaneously forms a gel. This gel then provides a 'scaffold' or framework that attracts calcium and regenerates the tooth's mineral from within, providing a natural and pain-free repair. The technique was recently taken out of the laboratory and tested on a small group of adults whose dentist had spotted the initial signs of tooth decay. The results from this small trial have shown that P 11-4 can indeed reverse the damage and regenerate the tooth tissue. ... If these results can be repeated on a larger patient group, then I have no doubt whatsoever that in two to three years time this technique will be available for dentists to use in their daily practice."

Link: http://www.sciencedaily.com/releases/2011/08/110823115402.htm

Researchers are spending a fair amount of time on understanding why regeneration in mammals differs from - and is much worse than - regeneration in lower animals like salamanders. A salamander can grow back a limb any time it needs to, a mouse or a human not so much. But we can do the full regeneration trick to a far lesser degree, as humans and mice can both regrow the tip of a finger or toe when very young or very lucky, for example. You might also recall the MRL mice, an engineered species that can regenerate much more effectively than is normal for most mice.

One of the questions that researchers aim to answer is whether the mechanisms for salamander-like regeneration lie buried in mammalian biology, perhaps turned off for reasons involving cancer suppression. If they are there, perhaps they can be restored via drugs or genetic engineering for long enough to regrow major damage to limbs and organs. That's all speculative at this point, and looking more so after this latest research publication:

Tissue-specific adult stem cells are responsible for the ability of mammals to re-grow the tips of fingers or toes lost to trauma or surgery, say researchers at the Stanford University School of Medicine. The finding discredits a popular theory that holds that previously specialized cells regress, or dedifferentiate, in response to injury to form a pluripotent repair structure called a blastema.

"We've shown conclusively that what was thought to be a blastema is instead simply resident stem cells that are already committed to become specific tissue types," said Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The controversy about limb regeneration in mammals should be over."

If you want to take the glass half full view, this might mean that it will be a shorter path to pushing these stem cells into doing more with less - rather than the alternative and longer path of trying to recreate salamander-like blastema behavior in mammals. But it's anyone's guess as to how much regeneration these cells are capable of if manipulated; no doubt less than we'd all like.

So far research on cellular reprogramming has largely focused on manipulation of cells outside the body. Here a researcher suggests that the future of medicine will involve achieving much the same thing inside the body: "To date, somatic cell reprogramming has been achieved in vitro. It would be of great importance to explore whether the anti-aging agents, e.g. rapamycin, could function to enhance stem cell function, protect stem cell pluripotency and even promote reprogramming in vivo. It is also very interesting to verify whether some or all adult organs/tissues do possess some significant regenerative capacity due to the suspected in vivo reprogramming. Furthermore, it has been reported that agents which effectively function for a common human disease by enhancing self-renewal could lose efficacy in older individuals due to the age-associated decline of replication. Thus understanding and realization of in vivo cell reprogramming is not only a fundamental theoretical question but also a very promising strategy for anti-aging and regenerative medicine. Reprogramming of somatic cells has been enthusiastically hoped to become an arsenal to against aging as it would leads to personalized stem-cell-based rejuvenation therapies. What we learn from research of stem cell and reprogramming could help us to develop two potential anti-aging approaches in adult and older: i) to protect, ameliorate or reverse the age-associated loss function of stem cell in vivo and ii) to replace the lost stem cells by reprogrammed pluripotent cells."

Link: http://impactaging.com/papers/v3/n8/full/100364.html

Researchers here outline one possible mechanism for the known association between chronic stress and biomarkers of health: "While the human mind and body are built to respond to stress - the well-known "fight or flight" response, which lasts only a few minutes and raises heart rate and blood glucose levels - the response itself can cause significant damage if maintained over long periods of time. When stress becomes chronic, this natural response can lead to a number of disease-related symptoms, including peptic ulcers and cardiovascular disorders. To make matters worse, evidence indicates that chronic stress eventually leads to DNA damage, which in turn can result in various neuropsychiatric conditions, miscarriages, cancer, and even aging itself. ... The newly uncovered mechanism involves β-arrestin-1 proteins, β2-adrenoreceptors (β2ARs), and the catecholamines, the classic fight-or-flight hormones released during times of stress - adrenaline, noradrenaline, and dopamine. Arrestin proteins are involved in modifying the cell's response to neurotransmitters, hormones, and sensory signals; adrenoceptors respond to the catecholamines noradrenaline and adrenaline. Under stress, the hormone adrenaline stimulates β2ARs expressed throughout the body, including sex cells and embryos. Through a series of complex chemical reactions, the activated receptors recruit β-arrestin-1, creating a signaling pathway that leads to catecholamine-induced degradation of the tumor suppressor protein p53, sometimes described as "the guardian of the genome." The new findings also suggest that this degradation of p53 leads to chromosome rearrangement and a build-up of DNA damage both in normal and sex cells." p53 is very important in a range of core cellular processes - anything touching on it usually turns out to be influential.

Link: http://www.kurzweilai.net/how-stress-causes-dna-damage

Mitochondria in your cells damage themselves in the course of their vital, life-sustaining operations, and these damaged mitochondria contribute to aging. It's a progressive and complicated process of many steps, by which incidents of atomic-scale damage in the power plants of your cells steadily overwhelm evolved countermeasures and repair systems, corrupting a fraction of your cells and blossoming into a flow of damaged molecules throughout the body. That in turn produces the roots of atherosclerosis and many other age-related forms of degeneration and malfunction.

We would like to be able to do something about this - by hook or by crook restore the damage state of an old person's mitochondria to the way things were when he was young. There are many possible paths forward, most understood in some detail at this time, and which will either be be shown to fail or succeed within the next decade or two. The work proceeds, but very, very slowly. It's not a broad and well populated field of research, sad to say.

The importance of mitochondria is one of the reasons that autophagy is also important when it comes to the progression of aging. Autophagy is the name given to a collection of varied recycling machinery and processes that operate within cells, destroying damaged components - such as mitochondria. It shouldn't be a great leap to think that improving the recycling mechanisms might also improve the situation vis a vis malfunctioning mitochondria. This is probably the case, based on what researchers know of mitophagy, the processes of autophagy concerned with removing damaging mitochondria.

Insofar as the bottom line of health and longevity goes, there is plenty of evidence to suggest that dialing up autophagy extends life, and a further array of evidence to suggest that known life-extending techniques such as calorie restriction depend heavily on autophagy as a principle mechanism of action.

Based on what's coming out of the labs in recent years, I think the research community isn't too far away from conducting studies that will definitively show - or definitively disprove, which would be unexpected - benefits to longevity from improved mitoautophagy alone. Take this, for example:

[Researchers] have defined a specific protein complex that allows cells to rid themselves of damaged mitochondria, which are the energy producing machines of the cell. ... The study highlights the interaction between Hsp90-Cdc37 and Ulk1, a kinase that the authors show is required for the degradation and elimination of damaged mitochondria. Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn phosphorylates its substrate Atg13, which is then released from the complex. Atg13 then eliminates damaged mitochondria via the autophagy pathway. Thus, the study links Hsp90-Cdc37-Ulk1-Atg13 in a direct pathway that is essential for efficient mitochondrial clearance.

"The new study shows that the key regulatory mechanism of this process is the Hsp90-Cdc37 chaperone, which functions as an on-off switch that is critical for the correct functioning of the Ulk1 kinase," Cleveland said. "Thus, if we can control this switch, we can significantly improve the therapeutic window."

Meaning this is a target for designed drug compounds to boost autophagy specifically aimed at clearing out more of the damaged mitochondria than would otherwise be the case. How far would this get us? A good guess would be in the same ballpark as calorie restriction mimetics: it's a similar mechanism. So in other words this may do good things for health in humans, but don't expect spectacular results when it comes to life span.

The problem with attacking mitochondria by boosting autophagy is that we already know that certain forms of mitochondrial damage manage to elude autophagic processes: that's how we end up in the bad place. So boosting autophagy just slows things down, and does't solve the underlying problem. A different type of approach is needed for a real solution, one based on repair rather than slowing existing processes of damage - and as it happens making progress along the paths towards mitochondrial repair shouldn't be any harder than safely and effectively adjusting the processes of autophagy.

Metabolic syndrome is, for the vast majority of us, an avoidable lifestyle condition. If you exercise and avoid gaining excess body fat then in all likelihood you won't suffer from the condition. Here's another reason to make that effort: "Metabolic syndrome comprises a group of medical disorders that increase people's risk of diabetes, heart disease, stroke, and premature death when they occur together. A patient is diagnosed with the syndrome when he or she exhibits three or more of the following characteristics: high blood pressure, high blood sugar, excess body fat in the waist/abdomen, low good cholesterol, and higher levels of fatty acids (the building blocks of fat). People with metabolic abnormalities are at increased risk of developing kidney disease ... [researchers] searched the medical literature and combined data from 11 studies examining the relationship between metabolic syndrome and kidney disease. Altogether, they included 30,416 individuals from various ethnic groups. ... People with metabolic syndrome have a 55% increased risk of developing kidney problems, especially lower kidney function, indicative of kidney disease. Individual components of metabolic syndrome are linked with the development of kidney disease. Kidney disease risk increases as the number of metabolic syndrome components increases. ... Preventing and managing metabolic syndrome - through eating a healthy diet, exercising, losing excess body weight, and lowering cholesterol, blood pressure, and blood sugar levels - may help prevent kidney disease."

Link: http://www.eurekalert.org/pub_releases/2011-08/ason-msm081711.php

Researchers are engaged in a body-wide hunt for stem cells that are easy to work with and easy to obtain - low cost sources will make a big difference to the ultimate cost of therapies: "As we age, our stem cells are less pliant and less able to transform into the stem cells that science needs to find breakthrough treatments for disease. An exception to this can be found in the stem cells of oral mucosa, the membrane that lines the inside of our mouths. ... A wound that might take weeks to heal and leave a life-long scar on the skin will be healed in a matter of days inside the mouth, regardless of the patient's age. ... Prof. Pitaru set out to determine if oral mucosa could be a source for young, fetal-like stem cells with this unique healing ability. Even when obtained from an older patient, he says, these stem cells still have properties of young or primitive stem cells - which have a high capacity to be transformed into different tissues. Prof. Pitaru and his fellow researchers have already succeeded in coaxing oral mucosa stem cells into becoming other significant cells, including bone, cartilage, muscle, and even neurons. ... Prof. Pitaru and his fellow researchers are currently in pre-clinical trials, implanting these stem cells into various tissues within small rodents. Their projects include researching the impact of the innovative cells as a treatment for chronic heart failure; neurodegenerative diseases; inflammatory autoimmune diseases such as Crohn's disease; and diabetes."

Link: http://www.aftau.org/site/News2?page=NewsArticle&id=15122

Diets are like cars; we all deal with them, and up to a certain point the more you know the more you'll get out of them. That certain point is actually a pretty low threshold of knowledge in either case - but you wouldn't know it from the vast literature and ongoing conversations on tinkering with cars or tinkering with diet. A few recent and lengthy posts at Chronosphere serve as an example of the tip of the iceberg:

• Interventive Gerontology 1.0.02: First, Try to Make it to the Mean: Diet as a life extending tool, Part 1
• Interventive Gerontology 1.0.02: First, Try to Make it to the Mean: Diet as a life extending tool, Part 2
• Interventive Gerontology 1.0.02: First, Try to Make it to the Mean: Diet as a life extending tool, Part 3

There's enough reading material beyond those links to keep you occupied for a while, and it's the merest drop in the ocean of basically sensible discussion on optimizing diet, which in turn is the merest drop in the ocean of published nonsense and idiocy when it comes to what we eat. At this point in my years of looking into life extension, and despite a general lack of interest in the finer points of nutrition, I could probably run up a lengthy essay or two of my own - but the final paragraph would be "and ignore all of what came before: just practice calorie restriction as laid out in any of the Calorie Restriction Society-recommended books on the subject, exercise as recommended by your physician, and take a good multivitamin."

Optimizing your diet is like optimizing the engine in your car for long-term use. How much time and money do you want to spend on this as a project? However large your answer, you can easily find ways to spend those resources - it's a deep rabbit hole, with many side-passages, and one that lacks firm measures of success. Unless you make it your hobby and are happy tinkering for the sake of tinkering, I'd suggest that it's largely not worth it. You'd be better off doing something with your time that is more likely to prove constructive in the end.

Look at it this way: the research community has established that no dietary practice is better for health and longevity in a range of species than calorie restriction - coupled with any of the standard, sane, recommended balanced diets of the sort that have been well known and well publicized for decades. The results in humans are eye-opening when it comes to measures of health - if calorie restriction was a drug, pharmaceutical companies would be advertising it on every billboard and it would be a household name. Do you think you can do better than the decades of work put in by the entire scientific community? You can't. If you're investigating odds and ends of interesting publications and theories on diet around the edges of the field, then by all means have fun if that's the way you like to spend your spare time. But don't think that you're getting ahead of the game - that's not the way the world works.

The bottom line is that if you want to optimize your diet, just sensibly practice calorie restriction. End of story.

A proportion of the aging research community think aging to be at least partially a programmed phenomenon, rather than an accumulation of damage, and thus something to be primarily manipulated by changing the operation of our metabolism. Here is an argument for that viewpoint from researcher Michael Rose: "I should be clear that my present view is also not one generally held, at least not yet, even by most evolutionary biologists who work on aging. Like them, I spent more than thirty years thinking that William Hamilton's declining forces of natural selection, which he published in 1966, showed that evolution by natural selection would allow cumulative processes of physiological deterioration to proceed unchecked, provided they killed off their victims at sufficiently late ages. ... By 1994, I was thinking that perhaps evolutionary biologists had misconceived the problem of the evolution of aging. Perhaps it was NOT natural selection just letting go, but something that specifically tracked Hamilton's forces of natural selection. This led me to convince Larry Mueller to do some explicit simulations of evolution, simulations in which we looked at what happened at very late ages, long after Hamilton's forces of natural selection bottom out and stabilize. What the simulations generated were late-life plateaus in mortality ... we then checked how changes in Hamilton's forces would change the age at which mortality plateaus occur, based on explicit simulations. These simulations showed that changing the last age of reproduction in a biological population, the parameter that Hugh Hefner is working on as I write, would tune the age at which mortality rates would plateau."

Link: http://www.alcor.org/magazine/2011/08/16/a-new-choice-for-immortalists/

Via ScienceDaily: researchers "have found a simple way to grow muscle tissue with real muscle structure in the laboratory. They found that the muscle cells automatically align themselves if they are subjected to tension in one direction - this is essential for the ability of the muscle cells to exert a force. The endothelial (blood vessel) cells in the culture also automatically grouped themselves to form new blood vessels. This finding is a step forward towards the engineering of thicker muscle tissue. ... Another important aspect of the finding is that it was not necessary to add any biochemical growth factors to initiate the process. These substances are normally required for processes of this kind, but their action is difficult to control. ... Measurements by the researchers showed that the muscle cells produced the required growth factor themselves, as a result of the tension to which they were subjected. ... The aim of the research is ultimately to allow the treatment of people who have lost muscle tissue, for example through accidents or surgery to remove tumors."

Link: http://www.sciencedaily.com/releases/2011/08/110819080957.htm

So what is Sirtris up to these days? The startup was founded to investigate a line of calorie restriction mimetic compounds based on sirtuin biochemistry, and acquired for a very large sum by GlaxoSmithKline. The hope was that something to modestly slow aging would emerge - though even if so, development would be sidelined into making a therapy for diabetes or something similar, as the FDA outright forbids the commercial development of therapies to treat aging. A sad state of affairs in the land once known and the land of the free, to be sure, but it is what is.

Unfortunately for Sirtris, though not for their early investors, little of practical use has so far emerged from their work. It looks very much like the best case end result will indeed be something like a drug candidate to alleviate some of the consequences of obesity, diabetes or metabolic syndrome, all conditions that the vast majority of sufferers could have avoided through leading a healthier lifestyle, and could still reverse by leading a healthier lifestyle. Given the state of the world today, a medicine like that may yet make a great deal of money for GlaxoSmithKline, but it's not going to do anything of significance for human life spans. So, on the whole, the money poured into Sirtris looks like a failure wearing the clothes of success - and the more so because a bunch of people are going to see that researchers and investors made out like bandits from the deal and follow the same path, rather than trying to do something more ambitious and more useful.

Sirtris has been in the news again of late, with the completion of the latest study on the drug candidate SRT1720. This one doesn't appear to do what was originally thought - manipulate sirtuins in beneficial ways - but it does appear to be protective in obese mice. I see more optimism in the press coverage than is merited by the results, I think; a cynic might write that off to the size of the budget and the sophistication of the public relations crew at GlaxoSmithKline.

Longer Lives for Obese Mice, With Hope for Humans of All Sizes

Sustaining the flickering hope that human aging might somehow be decelerated, researchers have found they can substantially extend the average life span of obese mice with a specially designed drug. The drug, SRT-1720, protects the mice from the usual diseases of obesity by reducing the amount of fat in the liver and increasing sensitivity to insulin.

A Drug to Live Longer? Yes! (But Only If You're a Fat Mouse)

In the new study, SRT-1720 appeared to give obese mice the physiology of much leaner animals, which spared them from some of the negative health effects of excess weight. But the scientists note that while these mice lived longer than untreated obese mice, they didn't live nearly as long as untreated, normal-weight animals. Further, when the researchers looked at the maximum life span of the SRT-1720-treated fat mice, it wasn't much different from that of untreated obese mice. That means that the drug may just help animals enjoy more of whatever life they have, rather than actually extending it by any significant amount.

This is a UK press article on Halcyon Molecular, one of the new companies that has emerged from the pro-engineered-longevity community in recent years. You might also look back in the Fight Aging! archives for more on the views of the founders: "Even by Silicon Valley standards, the grand design drawn up by William and Michael Andregg is hugely ambitious. Halcyon Molecular, the company that the brothers founded in 2008, is developing a way to sequence the human genome - and thus unlock the deepest secrets of DNA - faster and cheaper than ever before. ... William is 29, Michael just a year older, and both are college drop-outs - but given Silicon Valley's impressive track record for nurturing and funding obsessive, unconventional young innovators, their age is hardly unusual. The surprise is the long-term mission of Halcyon Molecular: to solve "the biggest challenge humans can individually face - disease and mortality", as the mission-statement poster in their office reception says. Put another way, they're supercharging the effort to map life's biological code in almost unimaginable digital detail and, by doing so, ultimately, to attempt to conquer death itself." The difference between the here and now and 20 years ago is that you declare your plans to defeat aging and age-related death and both be taken seriously and raise large sums of money for research and development, both inside and outside the scientific community. There has been a sea change in attitudes towards engineered longevity as a goal, and that is one of the reasons that significant progress will be made in the years ahead: things happen when people start earnestly working to make them happen.

Link: http://www.independent.co.uk/life-style/gadgets-and-tech/news/2335404.html

An old Fight Aging! post is dusted off, rewritten, and published at h+ Magazine: "I'm not going to try to convince you that the foreseeable future is a wondrous place: either you accept the implications of the present rate of technological progress towards everything allowed by the laws of physics, in which case you've probably thought this all through at some point, or you don't. Life, space travel, artificial intelligence, the building blocks of matter: we'll have made large inroads into bending these all to our will within another half century. Many of us will live to see it even without the benefits of medical technologies yet to come: growing up without the internet in a 1960s or 1970s urban area will be the new 1900s farmboy youth come 2040. Just like the oldest old today, we will be immigrants from a strange and primitive near-past erased by progress, time travelers in our own lifetimes. A century is an exceptional life for a human, but far greater spans of years will be made possible by the technologies of the 21st century. I'll plant a flag way out there on the field and claim a million years ... Despite being out there, the million year life span is not an unsupported pipe dream. Living for a million years is a goal that can be envisaged in some detail today: the steps from here to there laid out, the necessary research and development plans outlined, and the whole considered within the framework of what is permissible under the laws of physics, and what the research community believes can be achieved within the next 20, 50, or 100 years."

Link: http://hplusmagazine.com/2011/08/19/the-million-year-life-span/

Looking at the near time, it seems that the next five years will see the tissue engineering community move from a few trials and some impressive demonstrations to real, commercialized work available in a scattering of clinics. Few of those clinics will be in the US, of course, as the FDA will add a cost of years and vast sums through the entirely unnecessary process of going from "can do" to "can do and allowed to do" - but the capabilities will exist. Take this, for example:

Stem cell researchers in Hong Kong and the United States are trying to grow spare parts for the human heart that may be ready for tests on people within five years ... When you get a heart attack, there is a small time window for a cure when the damage is still small. You can cure with a patch, a small tissue, so you won't progress to late stage heart failure ... The team will use approved human embryonic stem cell lines to build these human heart muscle strips, as well as [biological pacemaker tissues] for people with arrhythmia, or irregular heart beat.

The team plans first to transplant these muscle strips and pacemakers into pigs, and, if successful, to move to human clinical trials where they will transplant parts of the heart that are grown using the patients' own stem cells in about five years.

You might compare the research effort discussed in the article quoted above to other recent work on patching a damaged heart using stem cells. The two are illustrative of quite different directions in regenerative medicine: one path is to put cells into the body and let them build new tissue and repair damage in situ, whilst the other is to build new tissue structures (or even entire organs) outside the body and then surgically implant them. Personally, I favor the former approach, provided it can be made to achieve the same degree of effectiveness in the future - despite advancing technology, surgery remains surgery, and not something that any sane person would want to undergo unless absolutely necessary.

An open access paper on the biology of one of the longest-lived engineered mouse species: "The age-associated decline in tissue function has been attributed to ROS-mediated oxidative damage due to mitochondrial dysfunction. The long-lived Ames dwarf mouse exhibits resistance to oxidative stress, a physiological characteristic of longevity. It is not known, however, whether there are differences in the electron transport chain (ETC) functions in Ames tissues that are associated with their longevity. In these studies we analyzed enzyme activities of ETC complexes, CI-CV and the coupled CI-CII and CII-CIII activities of mitochondria from several tissues of young, middle aged and old Ames dwarf mice and their corresponding wild type controls to identify potential mitochondrial prolongevity functions. Our studies indicate that post-mitotic heart and skeletal muscle from Ames and wild-type mice show similar changes in ETC complex activities with aging, with the exception of complex IV. Furthermore, the kidney, a slowly proliferating tissue, shows dramatic differences in ETC functions unique to the Ames mice. Our data show that there are tissue specific mitochondrial functions that are characteristic of certain tissues of the long-lived Ames mouse. We propose that this may be a factor in the determination of extended lifespan of dwarf mice."

Link: http://impactaging.com/papers/v3/n8/full/100357.html

The SENS Foundation Academic Initiative is a long-term project aimed at helping to build the research community of tomorrow - one interested in the repair and reversal of aging, rather than a next generation that is only interested in slowing down aging a little via manipulation of metabolism, a simple repeat of today's research community. Here is an update from the Foundation: "The SENS Foundation Academic Initiative's new structure is actively in the process of being implemented, and involves a number of significant changes. Among these are the separation of the Initiative into branches, an updated membership system that allows students to become involved more easily and in more ways, the creation of volunteer committees, and the addition of outreach projects to the Initiative's activities. ... There will be three branches: Research, Outreach, and Education. The Research branch will be focused on the actual accomplishment of scientific research. This research will always be done with an eye to publication, but its most important function will be to provide our students with learning experiences, to help them develop into career scientists. The Outreach branch will be focused on spreading the word about the Academic Initiative and about the SENS Foundation, while the Education branch will be focused on educating students about science and SENS. ... While the Academic Initiative has long helped students to complete research projects, it has not done much in the past to encourage students to be advocates of the Initiative and the SENS Foundation. This will change with the implementation of outreach projects. These will generally be simple, off-the-shelf projects that students can finish in an afternoon, such as printing fliers from a pre-made template and distributing them at their university."

Link: http://sens.org/node/2345

What happens across your lifetime to change you from young to old is known as stochastic damage - the integrity of your bodily systems nibbled away, one damaged or misplaced clump of atoms at a time. At the detail level of molecular machinery, this is basically random. But the process is statistically predictable when you start to look at the bigger picture: our bodies are all, sadly, headed downhill in much the same general direction, and we can even talk about trends, environmental factors, and speeds of decline when we examine large groups of people.

For you, personally, what this means is that you have a ticket to ride and you can steer the bounds of the possible by your actions. But there's no such thing as absolute control - there are only risks to be shifted one way or another. Laze around and grow fat, and watch the risk of diabetes, cancer, and dementia grow much larger. Or smoke and suffer the likely consequences. Or avoid doctors like the plague for two dozen years and you're making your own bad luck, slowly but surely.

Some people sail through all that exactly because they were lucky, or both lucky and possessed of rare protective genes. Equally, you could do everything right, live the healthiest life possible, and get nailed by cancer in your twenties, or by the sudden onset of an unsuspected genetic condition in your thirties, or by an autoimmune disease despite no history of it in your family. Or, hell, by some idiot operating heavy machinery without a license while you're minding your own business on the sidewalk. These things happen. They're rare, but the point is that they're on the ticket: all you can do is swing the odds.

Some people die young and despite living well: it happens. I'm sure we can all think of a few we've known. But that doesn't remove any of the value of living well, doing the right things for your health, and generally trying to keep on the right side of heavy machinery. It's a matter of odds. Too many people look at disease in later life as exclusively bad luck, whereas they in fact had a hand in moving the needle the wrong way:

Lifetime physical inactivity interacts with secondary aging (i.e., aging caused by diseases and environmental factors) in three patterns of response. First, lifetime physical inactivity confers no apparent effects on a given set of physiological functions. Second, lifetime physical inactivity accelerates secondary aging (e.g., speeding the reduction in bone mineral density, maximal oxygen consumption, and skeletal muscle strength and power), but does not alter the primary aging of these systems. Third, a lifetime of physical activity to the age of ~60-70 years old totally prevents decrements in some age-associated risk factors for major chronic diseases, such as endothelial dysfunction and insulin resistance. The present review provides ample and compelling evidence that physical inactivity has a large impact in shortening average life expectancy. In summary, physical inactivity plays a major role in the secondary aging of many essential physiological functions, and this aging can be prevented through a lifetime of physical activity.

In some things we can make our own luck; in others we can't. Not much that can be done today about the bolt from the blue cancer in your teens, or the genetics that dealt you a heart that'll have to be nursed like the engine in a second hand car for the rest of your life. But for the rest of it: the prepared and the foresighted have what looks like great luck in life - at least from the perspective of people who didn't pay attention to all the groundwork that led to that point.

That part of the research community focused on manipulating metabolism to slow down aging has advanced to the point of considering multiple distinct simultaneous changes to achieve the desired end result: "Modern medicine is directed towards the prevention, detection and cure of individual diseases. Yet, current medical models inadequately describe aging-associated diseases. We now know that failure in longevity pathways including oxidative stress, multisystem dysregulation, inflammation, sarcopenia, protein deposition and atherosclerosis are associated with age-related diseases. Such longevity pathways are potential targets for therapeutic intervention. Interventions in specific pathways have been shown to ameliorate and postpone the aging phenotype by activation of multiple genes. The strategy that we propose in this paper is to apply interventions simultaneously on complementary longevity pathways to achieve a synergistic result. For instance, aging is known to attenuate the HSF1 pathway leading to production of very toxic beta-amyloid fibrils. Consequently, the FoxO pathway is activated, resulting in the formation of less toxic high molecular weight aggregates as a defense mechanism. Thus the simultaneous upregulation of the HSF1 and FoxO pathways could potentially decrease protein deposition and proteotoxicity, thereby retarding or possibly preventing the onset of neurodegenerative diseases. Modulating these two pathways may also delay the onset of other age-related pathologies including cognitive decline, cancer, diabetes and cardiovascular disease due to its multi-gene effect. "

Link: http://www.ncbi.nlm.nih.gov/pubmed/21834787

Researchers find what looks to be a proxy measure for the degree to which a person is sedentary - but of course there might be other important correlations here, such as with wealth or intelligence: "Watching TV for an average of six hours a day could shorten the viewer's life expectancy by almost five years ...The impact rivals that of other well known behavioural risk factors, such as smoking and lack of exercise, the study suggests. Sedentary behaviour - as distinct from too little exercise - is associated with a higher risk of death, particularly from heart attack or stroke. Watching TV accounts for a substantial amount of sedentary activity, but its impact on life expectancy has not been assessed, say the authors. They used previously published data on the relationship between TV viewing time and death from analyses of the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), as well as Australian national population and mortality figures for 2008, to construct a lifetime risk framework. AusDiab is a national survey of a representative sample of the population, starting in 1999-2000, and involving more than 11,000 adults aged 25 or older. The authors then constructed a risk framework for the Australian population in 2008, based on the answers the survey participants had given, when quizzed about the total amount of time they had spent in the previous week watching TV or videos. ... These figures compare with the impact of other well known lifestyle factors on the risk of death from cardiovascular disease after the age of 50, including physical activity and obesity. For example, other research has shown that lifelong smoking is associated with the shortening of life expectancy by more than 4 years after the age of 50, with the average loss of life from one cigarette calculated to be 11 minutes - equivalent to half an hour of TV watching, according to the authors' risk framework." I applaud the researchers for finding a way to present their work that will likely get a lot of play in the media.

Link: http://www.eurekalert.org/pub_releases/2011-08/bmj-dtq081511.php

The aged immune system begins to fail at its job for a variety of reasons that seem to have more to do with its evolved structure and control systems than with the outright incapacity of immune cells, or the inability to generate more immune cells. The immune system evolved to work very effectively in younger life, and that comes at the cost of controlling processes that fall down badly in the long term.

A small reserve of memory cells is needed to respond effectively to previously encountered threats - one reserve per threat. The more threats you have encountered, the more cells become devoted to memory; eventually you don't have enough naive T cells left to mount any sort of effective defense.

Given the capabilities that remain in the body, an aged immune system could, in theory, get up to fight and fight well - but it doesn't. That shortcoming may be addressed by selectively manipulating the system and its cells, however. For example, in recent years researchers have demonstrated that we can (a) intervene via modern medicine to expand the population of useful immune cells, or (b) destroy the accumulation of useless immune cells and thereby immediately free up space so that the body creates more useful immune cells, or even (c) wipe out and recreate the entire immune system as a fresh start, which works to cure autoimmune diseases in which immune cells run amok and attack the body.

I noticed a research release today that discusses the identification of another potential source of useful cells in the aged immune system, cells normally left inactive thanks to the evolved control systems that focus on early life at the expense of later life. The researchers show that these cells can be activated for duty:

Professor Arne Akbar of UCL (University College London), who led this research, explains "Our immune systems get progressively weaker as we age because each time we recover from an infection a proportion of our white blood cells become deactivated. This is an important process that has probably evolved to prevent certain cancers, but as the proportion of inactive cells builds up over time our defences become weakened. What this research shows is that some of these cells are being actively switched off in our bodies by a mechanism which hadn't been identified before as important in ageing in the immune system. Whilst we wouldn't want to reactivate these cells permanently, we have an idea now of how to wake them from their slumber temporarily, just to give the immune system a little boost."

...

When the researchers blocked this newly identified pathway in the lab they found that the white blood cells appeared to be reactivated. Medicines which block this pathway are already being developed and tested for use in other treatments so the next step in this research is to explore further whether white blood cells could be reactivated in older people, and what benefits this could bring.

I see it as a good sign that there are a range of different potential lines of research that might lead to varying degrees of immune system rejuvenation, temporary or otherwise. Variety and competition are signs of a healthy field of medicine.

Gaining a large fraction of the estimated maximum possible long-term benefits from exercising can be achieved with only modest levels of regular exercise according to researchers. This recent paper is representative of earlier, similar findings: "The health benefits of leisure-time physical activity are well known, but whether less exercise than the recommended 150 min a week can have life expectancy benefits is unclear. We assessed the health benefits of a range of volumes of physical activity in a Taiwanese population. In this prospective cohort study, 416,175 individuals (199,265 men and 216,910 women) participated in a standard medical screening programme in Taiwan between 1996 and 2008, with an average follow-up of 8.05 years. On the basis of the amount of weekly exercise indicated in a self-administered questionnaire, participants were placed into one of five categories of exercise volumes: inactive, or low, medium, high, or very high activity. We calculated hazard ratios (HR) for mortality risks for every group compared with the inactive group, and calculated life expectancy for every group. Compared with individuals in the inactive group, those in the low-volume activity group, who exercised for an average of 92 min per week or 15 min a day, had a 14% reduced risk of all-cause mortality, and had a 3 year longer life expectancy. Every additional 15 min of daily exercise beyond the minimum amount of 15 min a day further reduced all-cause mortality by 4% and all-cancer mortality by 1%. These benefits were applicable to all age groups and both sexes, and to those with cardiovascular disease risks. Individuals who were inactive had a 17% increased risk of mortality compared with individuals in the low-volume group."

Link: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60749-6/abstract

A short piece on mitochondria and their role in aging: "Despite propaganda to the contrary, aging is rarely a pleasurable experience. A lifetime of damage to cells and tissues results in malfunction, making old age a significant risk factor for ailments such as cancers and neurologic disabilities typified by Alzheimer's disease. As a consequence, the graying of world populations has triggered a scientific frenzy to unravel the basic processes behind aging and find ways to slow down and perhaps even prevent age-related degeneration. ... Two linked ideas are at the core of our current aging theory. The first is that proteins, RNA and DNA are bombarded with and damaged by reactive oxygen species (ROS) generated during normal cellular respiration and this results in eventual decline and disease. The second is that mitochondria are the major culprits behind aging. ... micro-injection of mitochondria from 'young' cells, those which haven't divided very much, can overcome senescence in cells that are reaching the natural end of their lives and will probably, in the usual course of things, undergo programmed cell death, or apoptosis which is also largely controlled by mitochondria. ... Further support for the 'mitochondrial theory' of aging [comes] from studies in a range of organisms including yeast, nematode worms, flies and mice showing that by silencing certain mitochondrial genes - mitochondria have their own circular genomes - life span is extended."

Link: http://www.decodedscience.com/mitochondria-life-death-and-the-agents-of-aging/2428

For those of you who herd servers, sling code, and live the freelance life of many concurrent clients, I see that the SENS Foundation is looking for a part time IT resource:

SENS Foundation, a Californian non-profit, seeks an IT manager to work as part of its expanding team. The position is 2.5 days per week.

About SENS Foundation: SENS Foundation is a non-profit, life sciences organization with a mission to develop, promote and ensure widespread access to rejuvenation biotechnologies which comprehensively address the disabilities and diseases of aging. Our Research Center in Mountain View, California is the hub for a growing team of researchers, and outreach and executive staff. Several members of staff are located outside California, in the USA or Europe. In addition, we award grants to affiliated universities and research organizations.

About the position: The IT Manager will, in the first instance, report to our Director of Research Operations, Tanya Jones. However, the successful candidate will be required to work with all members of staff to consolidate and expand our IT infrastructure, both internal and public-facing. Initial projects will include: migration of email systems from legacy servers; implementation of a collaboration framework for files and documents; a review of our web systems, their integration with finance and customer relations back-ends, and associated social networking sites.

About the candidate: The successful candidate will have proven abilities in the technical aspects of the position, detailed below. He or she will also have experience with project planning, including gathering user requirements, performing software and hardware comparisons, creating functional specifications, implementation plans and costings, managing a budget, etc. The position requires an ability to understand the key business requirements at all levels of the organization, whilst demonstrating independent management skills at the IT project level.

This might actually be a good client relationship for a couple of people at 8-10 hours a week or less each - one web developer with a good understanding of Drupal and social media, and one IT-focused resource who lives and breathes mail servers and networking. It's rare to find one person in the 4-6 years of experience range who can both develop websites and manage the back end of servers and networks - and for some reason Drupal developers seem to be hard to find as well. I've always thought that to be strange, given the framework's popularity. If it's next to impossible to find Drupal developers to hire, who are the people building that huge developer ecosystem, posting to the forums, and erecting thousands of websites? One of life's little mysteries, I suppose.

In any case, I see the steady stream of help wanted ads emerging from the SENS Foundation to be another positive sign of progress. We want to see funds put to good use, and keeping the lamps lit and the servers running at the Foundation is a good use. So if you think you can help, contact the Foundation and make a pitch - I know this community has a fair number of more technical folk lurking in the wings.

A lesser but still important detail in tissue engineering is given some thought: "scientists are seemingly approaching a day when they will be able to make nearly any type of tissue from human embryonic stem cells. You need nerves or pancreas, bone or skin? With the right combination of growth factors, skill and patience, a laboratory tissue culture dish promises to yield therapeutic wonders. But within these batches of newly generated cells lurks a big potential problem: Any remaining embryonic stem cells - those that haven't differentiated into the desired tissue - can go on to become dangerous tumors called teratomas when transplanted into patients. Now researchers [have] developed a way to remove these pluripotent human embryonic stem cells from their progeny before the differentiated cells are used in humans. ... We've used a combination of antibodies to weed out the few undifferentiated cells that could be left in the 10 or 100 million differentiated cells that make up a therapeutic dose. ... The researchers studied two sets of antibodies - one commercially available and one they generated themselves - to identify which among them bound most strongly to pluripotent, but not differentiated, cells. They found one newly generated antibody that was highly specific for a previously unknown marker on undifferentiated cells that they termed stage-specific embryonic antigen-5, or SSEA-5. The cells bound by this antibody, anti-SSEA-5, expressed high levels of pluripotent-specific genes and resembled embryonic stem cells in appearance. Anti-SSEA-5 also bound strongly to the inner cell mass of an early human embryo, the group of cells from which embryonic stem cell lines are derived. ... anti-SSEA-5 recognizes and binds to a cell-surface carbohydrate structure called a glycan. As the pluripotent cell differentiates, this glycan is modified to other glycan structures not recognized by the antibody."

Link: http://www.eurekalert.org/pub_releases/2011-08/sumc-sdm081211.php

A great many interesting demonstrations of tissue engineering have taken place in recent years, and here is another: "Every organ in the human body has a scaffold or a structure, which provides it with its shape, and within this scaffold are many different types of cells with different functions. Tissue engineering aims to create the organ scaffold - either through the use of synthetic materials such as polymers, or through decellularization, which uses the whole organ as a scaffold after removing its cells. Decellularization is ideal for tissue regeneration because it preserves the three-dimensional structure of the organ and the extracellular matrix (ECM) - the framework between the cells - that are complex and difficult to mimic. While current methods use specific ECM proteins to transform stem cells into a particular cell type, scientists have found it difficult to imitate the natural ECM. Using the decellularization approach, a team of [researchers] removed the cells from the heart of a mouse and implanted the empty heart scaffold with [human embryonic stem cells] to observe if these cells could attach to the scaffold and develop into heart cells. After 14 days, the cells developed into two different types of cells found in the heart: cardiac marker expressing cells and endothelial or blood vessel cells. The cell-laden scaffold was then implanted back into the mouse where it was observed to develop visible blood vessels. The formation of blood vessels in the scaffold is critical for the transport of nutrients and oxygen to the heart, and has posed a major challenge in tissue engineering."

Link: http://www.azonano.com/news.aspx?newsID=23217

A thought for the day: nobody out there is seriously arguing for the impossibility of radical life extension, and I don't think anyone has been for quite some time. It is a given in the present diffuse discussion on the future of medicine and human longevity that at some point advances in biotechnology and nanotechnology will lead to greatly extended lives: centuries and longer lived in good health and vigor. Aging will be brought under control by medicine, like any number of other once intractable medical conditions.

It wasn't always this way. People in past centuries might have hoped for the plausibility of radical life extension, but couldn't have said in certainty that it was possible. We, on the other hand, know far more about physics, chemistry, and biology: we know that there is no wall created by the way the universe works standing in our way. The only reason we presently age and suffer is because we haven't yet advanced far enough down the path of biotechnology that is clearly visible and well understood. Aging is, at root, a matter of atoms and molecules in the wrong place and the wrong configuration. Moving atoms and molecules around to order, en masse, and with precision, is a task that we know is possible. We do it all the time, and are learning ever greater finesse with each passing decade.

Yesterday the tools were found molecules that happened to do something useful with other molecules. Today we make use of designed molecules for particular operations, knowing much more about the molecular machinery of our cells. Tomorrow the biotechnologists will build and repair complex molecular machinery that performs far more effectively than our evolved biology.

Thus discussions on the engineering of human longevity focus on how, when, and (sadly) whether it should be done at all. I see great strategic importance in the right groups gaining ground in the "how" discussion - we're all going to age to death just like our ancestors if the scientific community remains focused on metabolic manipulation to slow damage accumulation rather than the repair of damage exemplified by SENS, for example. Similarly if there are not good inroads made in growing the community of researchers interested in SENS and related lines of research.

Discussions on "when" can probably be skipped as lacking rigor: no-one knows. All the meaningful timelines depend greatly on seeds sown now that will only bear fruit in the 2030s - the course of twenty years remains a matter of long term planning and great uncertainty in specific outcomes while we're stuck living lives that top out at a century (and that with great luck). The beginnings of a larger research community, the outcome of the debate over strategy in longevity research, and so forth. It is interesting to ponder and plot the windings of future events, but that time is probably better spent on influencing the "how" discussion or materially contributing to progress.

As to the discussion on whether engineering longevity is desirable, or should be blocked by people in power - I think it never hurts to take a little time to oppose such lines of thought. Unthought opposition to extending human life or even simply intervening in the disease of aging is widespread, and success in building the research communities and funding institutions of the next few decades depends on a certain degree of broad public support.

But all that said, no-one out there is seriously arguing that radical life extension is impossible.

Damage to mitochondrial membranes is an important feature of the complex process by which mitochondrial DNA damage contributes to aging. It is known that differences in membrane composition may be an important factor in species of unusual longevity, such as naked mole rats. Here is another open access study on this topic: "The cellular energy produced by mitochondria is a fundamental currency of life. However, the extent to which mitochondrial (mt) performance (power and endurance) is adapted to habitats and life-strategies of vertebrates is not well-understood. A global analysis of mt genomes revealed that hydrophobicity (HYD) of mt membrane proteins (MMPs) is much lower in terrestrial vertebrates than in fishes and shows a strong negative correlation with serine/threonine composition (STC). Here, we present evidence that this systematic feature of MMPs was crucial for the evolution of large terrestrial vertebrates with high aerobic capacity. An Arrhenius-type equation gave positive correlations between STC and maximum lifespan (MLS) in terrestrial vertebrates ... In particular, marked STC-increases in primates (especially hominoids) among placentals were associated with very high MLS-values. We connected these STC-increases in MMPs with greater stability of respiratory complexes." This sort of study should be viewed as supporting evidence for the importance of work on repairing mitochondrial damage - confirmation of the importance of mitochondria to aging and longevity.

Link: http://gbe.oxfordjournals.org/content/early/2011/08/10/gbe.evr079.abstract

Uncoupling proteins are involved in the processes by which metabolism determines natural longevity through their effects on mitochondrial activity, and are of interest to calorie restriction researchers: "The brown fat specific UnCoupling Protein 1 (UCP1) is involved in thermogenesis, a process by which energy is dissipated as heat in response to cold stress and excess of caloric intake. Thermogenesis has potential implications for body mass control and cellular fat metabolism. In fact, in humans, the variability of the UCP1 gene is associated with obesity, fat gain and metabolism. Since regulation of metabolism is one of the key-pathways in lifespan extension, we tested the possible effects of UCP1 variability on survival. Two polymorphisms (A-3826G and C-3740A), falling in the upstream promoter region of UCP1, were analyzed in a sample of 910 subjects from southern Italy (475 women and 435 men; age range 40-109). By analyzing haplotype specific survival functions we found that the A-C haplotype favors survival in the elderly. Consistently, transfection experiments showed that the luciferase activity of the construct containing the A-C haplotype was significantly higher than that containing the G-A haplotype. Interestingly, the different UCP1 haplotypes responded differently to hormonal stimuli. The results we present suggest a correlation between the activity of UCP1 and human survival, indicating once again the intricacy of mechanisms involved in energy production, storage and consumption as the key to understanding human aging and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21827845

Wealth, in the most general sense, is a blade of many edges. Let us consider food, for example, which has moved over the centuries of growing wealth from being expensive and unreliably supplied to its present state of being cheap and exceedingly reliable in supply in all the stable regions of the world. That has been a passage of stages: from the bootstrapping of early longevity gains and better land use in the 1700s, all the way through to the stunning advances in productivity that resulted from applications of the first wave of modern biotechnology in the 60s and 70s. Unfortunately we humans are not well adapted for an environment of abundant and cheap food: by following our instincts and ingrained preferences we wind up fat and sedentary, a state that causes significant harm to health and longevity.

This is one of those temporary issues, a matter of a handful of decades. Medical biotechnology will catch up to the new demands of the population, and at some point humans will learn to alter themselves such that there are no longer any detrimental consequences to overeating, or being fat, or being sedentary. That isn't so far away: perhaps fifty years at the outside. In the meanwhile there is willpower or there is a shorter, less healthy life. Your choice.

The data on what exactly excess body fat will do to you - on average, statistically speaking - has been growing over the past years. Fat is metabolically active, an eager and pushy partner in the feedback loops and controlling systems of your metabolism. A lot of what it does is bad in the long term: spurring chronic inflammation, for example. Even comparatively early in life, putting on the pounds and keeping them on for years at a time has a sizable impact on your risk of later suffering all of the most common age-related conditions. Failing to exercise appears to be just as bad in a whole different set of ways.

In any case, here is recently published research from a long-term study that adds yet more data on the costs of fat tissue - and thus the costs of the lifestyle choices needed to gain and maintain that fat tissue:

While some past studies have shown that persons carrying a few extra pounds in their 70s live longer than their thinner counterparts, a new study that measured subjects' weight at multiple points over a longer period of time reveals the opposite. Research from Adventist Health Studies recently published in the Journal of the American Geriatrics Society showed that men over 75 with a body mass index (BMI) greater than 22.3 had a 3.7-year shorter life expectancy, and women over 75 with a BMI greater than 27.4 had a 2.1-year shorter life expectancy. Generally, a BMI between 18.5 and 24.9 is considered normal weight, and a BMI of 25 to 29.9 is considered overweight. A BMI of 30 or more is considered obese.

Previous work in this area by others found a protective association for a high body weight among the elderly. Pramil N. Singh, DrPH, lead author of the paper and an associate professor in the School of Public Health at Loma Linda University, says the data from many past studies is problematic because only a single baseline measure of weight was taken, which does not account for weight changes or how weight changes affect life expectancy. Additionally, most past studies had mortality surveillance of fewer than 19 years, which analyses have shown to be an inadequate amount of time to study risks associated with weight.

"We had a unique opportunity to do 29 years of follow-up with a cohort that was also followed for mortality outcomes," Dr. Singh said. "Across this long period of time, we had multiple measures of body weight, which provided a more accurate assessment."

A novel way to manipulate stem cells: "Though the heart is known to contain some stem cells, they have a very limited ability to repair damage caused by a heart attack [and] researchers have had to look elsewhere. One of the first efforts to use stem cells to reduce heart scarring involved harvesting them from the bone marrow and inserting them back into the heart muscle, close to the heart's blood supply, but this had limited success. Prof. Oron, who has long used low level lasers to stimulate stem cells to encourage cell survival and the formation of blood vessels after a heart attack, was inspired to test how laser treatments could also work to heal the heart. He and his fellow researchers tried different methods, including treating the heart directly with low level lasers during surgery, and 'shining' harvested stem cells before injecting them back into the body. But he was determined to find a simpler method. After a low-level laser was 'shined' into a person's bone marrow - an area rich in stem cells - the stem cells took to the blood stream, moving through the body and responding to the heart's signals of distress and harm ... Once in the heart, the stem cells used their healing qualities to reduce scarring and stimulate the growth of new arteries, leading to a healthier blood flow. To determine the success of this method, Prof. Oron performed the therapy on an animal model. Following the flow of bone marrow stem cells through the use of a fluorescent marker, the researchers saw an increase in stem cell population within the heart, specifically in the injured regions of the heart. The test group that received the shining treatment showed a vastly higher concentration of cells in the injured organ than those who had not been treated with the lasers."

Link: http://www.eurekalert.org/pub_releases/2011-08/afot-ta081011.php

The I'm Not Dead Yet (INDY) gene is one of the earlier longevity genes discovered by researchers in course of investigating the effects of calorie restriction. Here is a recent update: "It is known that excess calorie consumption leads to obesity, insulin resistance and increased mortality, whereas calorie restriction reduces accumulation of body fat and improves cellular energy balance and insulin action - reversing obesity and type 2 diabetes, delaying the aging process, and prolonging life in primates and many other species. It has also been shown in the past that reduced expression of the so-called 'INDY' gene in D. Melanogaster flies and C. elegans worms promotes longevity in a manner similar to calorie restriction. But until now, the cellular mechanism by which this happens was unknown. [Researchers] generated a mouse with the so-called 'INDY' gene deleted. Loss of the gene altered chemical levels in the cellular signaling network in a way that improved mitochondrial action in the liver, metabolism of fatty acids, and cellular energy transport. Overall, these traits protected the mice from diet-related accumulation of body fat and insulin resistance that evolve, as we age, into type 2 diabetes. Discovering how deletion of the INDY gene would impact mitochondrial metabolism in the liver was key, because that is the main organ where the INDY gene does its work."

Link: http://opac.yale.edu/news/article.aspx?id=8772

The immune system is a powerful tool for the selective destruction of unwanted cells, and researchers are a fair way down the road of engineering the activity of the immune system to form therapies. You might look at granulocyte transplant therapy as an example of the sort of tools that are under development. Here is an article on another line of research that has just reached the stage of early tests in humans:

In the research published Wednesday, doctors at the University of Pennsylvania say the treatment made the most common type of leukemia completely disappear in two of the patients and reduced it by 70 percent in the third. In each of the patients as much as five pounds of cancerous tissue completely melted away in a few weeks, and a year later it is still gone.

...

the researchers removed certain types of white blood cells that the body uses to fight disease from the patients. Using a modified, harmless version of HIV, the virus that causes AIDS, they inserted a series of genes into the white blood cells. These were designed to make to cells target and kill the cancer cells. After growing a large batch of the genetically engineered white blood cells, the doctors injected them back into the patients. In similar past experimental treatments for several types of cancer the re-injected white cells killed a few cancer cells and then died out. But the Penn researchers inserted a gene that made the white blood cells multiply by a thousand fold inside the body. The result, as researcher June put it, is that the white blood cells became "serial killers" relentlessly tracking down and killing the cancer cells in the blood, bone marrow and lymph tissue.

An editorial and research paper are available if you are interested in delving further into the details. Unfortunately this work suffers from much the same problem as efforts to develop granulocyte transplant therapies, which is that there are next to no sources of funding for research groups at the cutting edge of immunotherapy. The article relates what is a sadly common story in this part of the scientific community:

So why has this remarkable treatment been tried so far on only three patients? Both the National Cancer Institute and several pharmaceutical companies declined to pay for the research. Neither applicants nor funders discuss the reasons an application is turned down. But good guesses are the general shortage of funds and the concept tried in this experiment was too novel and, thus, too risky for consideration. The researchers did manage to get a grant from the Alliance for Cancer Gene Therapy, a charity founded by Barbara and Edward Netter after their daughter-in-law died of cancer. The money was enough to finance the trials on the first three patients.

This is a good example of how philanthropy modeled on venture investment - backing a range of early stage, high risk, high reward projects - can help break up the log-jams that result from institutional reluctance to fund the cutting edge in any field. The larger an institution, the more they will tend towards only backing the safe choices, but by doing that they ensure that the backing of their resources has little chance of producing radical change. Hopefully other projects, such as work on granulocyte based therapies, can find the connections needed to benefit from similar sources of funding and vision.

Why are hearts in humans and other higher animals not able to regenerate like salamander hearts? Answering that question would be a step on the road to recreating that ability when needed: "A new study has shed light on why adult human cardiac cells lose their ability to proliferate, perhaps explaining why our heart have little regenerative capacity. The study, done in cell lines and mice, may lead to methods of reprogramming a patient's own cardiac myocytes, or muscle cells, within the heart itself to create new muscle to repair damage ... Recent research suggests that mammals do have the ability to regenerate the heart for a very brief period, about the first week of life. ... During human development, cardiac myocytes are made by progenitor stem cells and proliferate to form the heart. Once the heart is formed, the myocytes transform from immature cells into mature cells that cannot proliferate. That's not so for newts and salamanders, whose cardiac myocytes can go back and forth between immature, or primitive, states to proliferate and repair damage and then revert back into mature cells once the damage is repaired. [Researchers believe] the reason adult human cardiac myocytes can't do this is quite simple - when the myocytes are in a more primitive state, they are not as good at contracting, which is vital for proper heart function. Because humans are much larger than newts and salamanders, we needed more heart contraction to maintain optimum blood pressure and circulation."

Link: http://timesofindia.indiatimes.com/life-style/health-fitness/health/articleshow/9553629.cms

Another of the many benefits of exercise: a study "shows that a small amount of physical exercise could profoundly protect the elderly from long-term memory loss that can happen suddenly following infection, illnesses or injury in old age. ... aging rats that ran just over half a kilometer each week were protected against infection-induced memory loss. ... Our research shows that a small amount of physical exercise by late middle-aged rats profoundly protects against exaggerated inflammation in the brain and long-lasting memory impairments that follow a serious bacterial infection. Strikingly, this small amount of running was sufficient to confer robust benefits for those that ran over those that did not run. This is an important finding because those of advanced age are more vulnerable to memory impairments following immune challenges such as bacterial infections or surgery. With baby boomers currently at retirement age, the risk of diminished memory function in this population is of great concern. Thus, effective noninvasive therapies are of substantial clinical value. ... Past research has shown that exercise in humans protects against declines in cognitive function associated with aging and protects against dementia. Researchers also have shown that dementia is often preceded by bacterial infections, such as pneumonia, or other immune challenges. ... Previous research has shown that immune cells of the brain, called microglia, become more reactive with age. When the older rats in the study encountered a bacterial infection, these immune cells released inflammatory molecules called cytokines in an exaggerated and prolonged manner. ... In the current study we found that small amounts of voluntary exercise prevented the priming of microglia, the exaggerated inflammation in the brain, and the decrease of growth factors."

Link: http://www.eurekalert.org/pub_releases/2011-08/uoca-sao080911.php

Good news is now arriving frequently from the tissue engineering community, who really seem to be hitting their stride of late, especially when it comes to muscle. Recreating structured muscle is the simple stuff on a relative scale of difficulty - at least in comparison to lungs and other intricate organs - but this is still a very challenging task. Dumb muscle isn't just dumb muscle: it has to be the right shape, have the right nerve structures, the right distribution of tiny blood vessels, the right layering and fiber types, and so forth. Don't underestimate just how much work was involved in coming to the point at which researchers can announce this latest advance:

Researchers have built the first functional anal sphincters in the laboratory, suggesting a potential future treatment for both fecal and urinary incontinence. Made from muscle and nerve cells, the sphincters developed a blood supply and maintained function when implanted in mice.

...

Current options for repair of the internal anal sphincter include grafts of skeletal muscle, injectable silicone material or implantation of mechanical devices, all of which have high complication rates and limited success. To engineer an internal anal sphincter in the laboratory, the researchers used a small biopsy from a human sphincter and isolated smooth muscle cells that were then multiplied in the lab. In a ring-shaped mold, these cells were layered with nerve cells isolated from mice to build the sphincter. The mold was placed in an incubator for nine days, allowing for tissue formation. The entire process took about six weeks.

Numerous laboratory tests of the engineered sphincters, including stimulating the nerve cells, showed normal tissue function, such as the ability to relax and contract. The sphincters were then implanted just under the skin of mice to determine how they would respond in the body. Mice with suppressed immune systems were selected so that there would be no issues with rejection. ... After 25 days of implantation, each sphincter was re-tested and also compared with the animals' native sphincters. The engineered sphincters had developed a blood vessel supply and continued to function like native tissue.

As the news release points out, this is one of the areas where the available prosthetic alternatives are just not that great; engineering a replacement sphincter in machinery is a hard challenge at our present level of technological prowess. So that a research team has constructed a functional biological sphincter is very promising - and this is especially true given that there are dozens of sphincters scattered throughout the body. It is an oft-reused structure, and being able to build any one type of sphincter from a patient's own cells implies that building the others is also a very realistic goal. So all in all, this is an encouraging example of progress in the field.

An interesting open access paper describes one of many approaches to building skin from a scaffold material and a patient's own cells: "The ideal biomaterial should promote attachment, proliferation and growth of cells. Additionally, it should degrade in an appropriate time period without releasing harmful substances, but not exert a pathological immune response. Spider dragline silk from Nephila spp meets these demands to a large extent. ... Native spider dragline silk, harvested directly out of Nephila spp spiders, was woven on steel frames. Constructs were sterilized and seeded with fibroblasts. After two weeks of cultivating single fibroblasts, keratinocytes were added to generate a bilayered skin model, consisting of dermis and epidermis equivalents. ... Both fibroblasts and keratinocytes cell lines adhere to the spider silk fibres and proliferate. Guided by the spider silk fibres, they sprout into the meshes and reach confluence in at most one week. A well-balanced, bilayered cocultivation in two continuously separated strata can be achieved by serum reduction, changing the medium conditions and the cultivation period at the air/liquid interphase. Therefore spider silk appears to be a promising biomaterial for the enhancement of skin regeneration."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144206/

The aging immune system is misconfigured, overpopulated by too many of the wrong sorts of immune cell, while having too few useful cells left to perform the important jobs - such as resisting infections, attacking cancers, and removing senescent cells, for example. One approach to dealing with this problem is to destroy the unwanted cells, and there's evidence for at least some parts of the immune system to show that this is beneficial. Another approach is to use biotechnology to expand the population of useful cells, and this recent release fits into that line of work: "Aging brings about a selective decline in the numbers and function of T cells - a type of white blood cell involved in the immune system's response to infection - and T cells that survive the longest may better protect against infections such as the flu ... The finding may lead to targeting these cells with vaccinations that increase their number and improve protection against disease in older adults. ... The decline in immune function with age is viewed as the most important contributing factor to older adults' increased susceptibility to infections and decreased responses to vaccinations. ... We have discovered that aging brings about selective attrition of those T cells that defend us against new infections that we have not encountered before. Not all T cells age the same and the ones that will survive the longest have special features. ... Finding ways to expand them is our next and final challenge, and our team [should] be able to achieve that in the next few years."

Link: http://www.sciencedaily.com/releases/2011/08/110801160224.htm

You might recall that researchers published earlier this year on a demonstration of the ability to rejuvenate B cell populations in old mice and thereby improve failing immune function. This was achieved by essentially culling the cells - which fits in with the idea that much of what is wrong with the aging immune system involves the configuration of the controlling biological programs, not incapacity of the cells themselves or of the ability of the body to produce new cells.

Collectively, our results suggest that immunosenescence in the B-lineage is not irreversible, and that depletion of the long-lived B cells in old mice rejuvenates the B-lineage and enhances immune competence. .... depletion of B-cells in old mice was followed by expansion of [populations of progenitor cells that create B-cells and] a revival of [lymphopoiesis, or the creation of B-cells] in the bone marrow, and generation of a rejuvenated peripheral compartment that enhanced the animal's immune responsiveness to antigenic stimulation.

The same research team has put out another more recent paper that adds a little more confirming information to the picture:

Aging is accompanied by a decline in B lymphopoiesis in the bone marrow and accumulation of long-lived B cells in the periphery. The mechanisms underlying these changes are unclear. To explore whether aging in the B lineage is subjected to homeostatic regulation, we used mutant mice bearing chronic B cell deficiency from birth. We show that chronic B cell deficiency from birth [prevents] age-related changes in the B lineage. Thus, frequencies of early and late hematopoietic stem cells, B lymphopoiesis, and the rate of B cell production do not substantially change with age in these mice, as opposed to wild-type mice where kinetic experiments indicate that the output from the bone marrow is impaired. Further, we found that long-lived B cells did not accumulate and peripheral repertoire was not altered with age in these mice. Collectively, our results suggest that aging in the B lineage is not autonomously progressing but subjected to homeostatic regulation.

Which is interesting - mice with effectively ageless (or at least only very slowly aging) portions of their immune system. It suggests that there should be better forms of configuration in our immune systems for long-term use, and that these forms of configuration are not in fact very far removed from what we have now. Presumably these better configurations were not selected for because they were not as effective in the earlier part of life when mammals are fecund and thus evolutionary pressure is greatest. From the point of view of evolutionary success, it only matters how well a biological system operates over the time in which descendants can be created and nurtured: it's all downhill after that.

The bottom line is that selective cell destruction technologies of the sort under development by the cancer research community have great potential as tools to enable immune system rejuvenation. If doing no more than selectively removing very distinctive populations of cells can have a strongly positive outcome, it shouldn't be too many more years before biotech companies start in on this line of work.

From the SENS Foundation, a look at what might be done to remove damaging cellular aggregates, such as the amyloid beta (Aβ) implicated in Alzheimer's disease (AD), by manipulating the function of lysosomes, the cellular recycling machinery: "Dr. Ben Bahr and his colleagues with the Neurosciences Program and Division of Pharmaceutical Sciences at the University of Connecticut have for some time now been investigating the effects of elevating lysosomal activity using the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK). ... In a new study, Dr. Bahr's group has extended this work into a transgenic mouse model of AD, testing PADK's ability to retard, and to reverse, AD neuropathology and cognitive dysfunction in two models of transgenic AD mice ... . Systemic PADK injection of PADK in both models caused 3- to 8-fold increases in cathepsin B levels and similar elevations in the enzyme's activity in lysosomal cell fractions ... Accordingly PADK-induced lysosomal modulations cleared a significant amount of the intra- and extraneuronal burden of Aβ from treated mice, reducing intraneuronal Aβ regions of the hippocampus and piriform cortex by 63 - 73% in younger mice and by ~50% in older ones ... As expected, model AD mice also exhibited substantial impairment of performance on cognitive-behavioral tests including the suspended rod, exploratory habituation, and spontaneous alternation behavior in a T-maze tests. PADK-induced Aβ clearance resulted in the complete restoration of normal function in both young and old animals. ... As a tribute to the power of the cellular waste-disposal machinery, these results are impressive. Equally, they are not a solution to human brain aging. These animals, like most transgenic models of AD, exhibit no tau pathology nor significant neuronal loss - problems that will also have to be addressed in order to achieve the full prevention of AD and rejuvenation of aging brains."

Link: http://www.sens.org/research/research-blog/overtime-pay-municipal-waste-team

As noted in the past here at Fight Aging!, the weight of evidence suggests that presently available antioxidant supplements either do nothing or somewhat harm long term health - the fervor for them is nothing more than magical thinking based on the effects antioxidants can have on cells in culture, and on the beneficial effects of mitochondrially targeted antioxidant compounds. That, however, is a long way removed from what you eat and what happens in a complex system like a living animal. Fortunately, sense is slowly starting to emerge in the media: "Few medical remedies have a more sterling reputation than that assortment of foods, pills, and general life maneuvers known collectively as 'antioxidants.' At last, here's something that promises better heart health, improved immunity, a pellucid complexion as well as relief against cancer, arthritis, and the blahs - and it's all-natural! What's not to like? Well, there is a wee small problem in our ongoing anti-oxidize-athon: As it turns out, we have no evidence that antioxidants are beneficial in humans. ... In fact [the] best available data demonstrate that antioxidants are bad for you - so long as you count an increased risk of death as 'bad.' ... But, hey, who ever let a little evidence stand in the way of a good time? Especially in this case, when the charge toward lifestyle legitimacy has been led by willowy celebrities with karmic equipoise."

Link: http://www.slate.com/id/2300578/pagenum/all/

There exists a fair-sized research community whose members think about extending healthy human life by manipulating the long term operation of metabolism. They are looking at small and incremental gains, however, and don't expect success in their work over the next ten to twenty years to go much beyond providing a few additional years of life and generally better health throughout life. This will be achieved through ways of mimicking calorie restriction or other life-extending genetic and epigenetic alterations discovered in mice. This is a far cry from the quality and quantity of life extension we'd expect to emerge from a mature SENS technology base, focused on repair of the low-level biological damage that causes aging, but it is the focus of the mainstream - much as we'd like that to be different.

In this world of incremental advances and manipulation of metabolism, researchers are becoming increasingly aware that they cannot ignore the vast population of symbiotic bacteria we carry with us throughout our lives. You can look back in the Fight Aging! archives to see that evidence has emerged in recent years to support the idea that changes in gut bacteria may be significant for long-term health:

• Intestinal Bacteria and Ageing
• Aging and the Role of Your Bacteria

The intestinal microbiota is important for maintenance of host health, providing energy, nutrients and protection against invading organisms. Although the colonic microbiota is relatively stable throughout adult life, age-related changes in the gastrointestinal (GI) tract, as well as changes in diet and host immune system reactivity, inevitably affect population composition. Recent studies indicate shifts in the composition of the intestinal microbiota, which may lead to detrimental effects for the elderly host.

Here is a more recent paper on the same topic, entitled "Gut microbiota as a candidate for lifespan extension", which looks toward turning understanding into action:

On the basis of recent knowledge in worms, flies, and humans, an important role of the gut microbiota in aging and longevity is emerging. The complex bacterial community that populates the gut and that represents an evolutionary adapted ecosystem correlated with nutrition appears to limit the accumulation of pathobionts and infections in all taxa, being able of affecting the efficiency of the host immune system and exerting systemic metabolic effects.

There is an urgent need to disentangle the underpinning molecular mechanisms, which could shed light on the basic mechanisms of aging in an ecological perspective. Thus, it appears possible to extend healthy aging and lifespan by targeting the host as a metaorganism by manipulating the complex symbiotic ecosystem of gut microbiota, as well as other possible ecosystems of the body.

I think we'll be seeing more of this line of thinking in the years ahead - it hasn't been greatly explored and there's an increasing level of interest in slowing aging through metabolic manipulation. This fits right in to that research community and its interests.

Another step forward for the field of regenerative medicine: researchers have "discovered a novel way to convert human skin cells into brain cells ... Rather than using models made in yeast, flies or mice for disease research, all cell-reprogramming technology allows human brain, heart and other cells to be created from the skin cells of patients with a specific disease. The new cells created from the skin cells contain a complete set of the genes that resulted in that disease - representing the potential of a far-superior human model for studying illnesses, drugs and other treatments. In the future, such reprogrammed skin cells could be used to test both drug safety and efficacy for an individual patient with, for example, Alzheimer's disease.
... This technology should allow us to very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days - rather than the months required previously. ... used two genes and a microRNA to convert a skin sample from a 55-year-old woman directly into brain cells. (MicroRNAs are tiny strands of genetic material that regulate almost every process in every cell of the body.) The cells created [exchanged] the electrical impulses necessary for brain cells to communicate ... Using microRNA to reprogram cells is a safer and more efficient way than using the more common gene-modification approach. In ensuing experiments, [the researchers hope] to rely only on microRNAs and pharmaceutical compounds to convert skin cells to brain cells, which should lead to more efficient generation of cells for testing and regenerative purposes."

Link: http://www.sciencedaily.com/releases/2011/07/110728123107.htm

An interview with one of the Thiel Fellows: "The goal is to extend the healthy human lifespan. In the past couple of decades, we've learned a lot about the basic science of aging. Now it's time to start translating the basic science into marketable therapies. I want to find and fund the projects creating those therapies. ... When I was eight, my mom told me about death and I couldn't stop crying for days. What a tragedy! Life is incredible, but death is inevitable. I already knew biology was fantastic fun. But that moment, for me, made science more than fun. It made it into a power that could save lives. And I couldn't imagine doing something more fascinating or important. ... When I was twelve, I was lucky enough to meet Cynthia Kenyon (biogerontologist and molecular biologist), who is a pioneer in the field of anti-aging research. She is amazing. I ended up working in her lab, at the University of California San Francisco, for a few years. She had a way of describing scientists as detectives, trying to solve mysteries and catch genetic culprits. Growing up at UCSF, getting to tinker with tiny worms in a biology lab and sit in on classes about genetics and biochemistry ... that was an incredible experience. ... Anti-aging is such an important field, but it is underfunded. Building business around an anti-aging therapy is no mean feat, especially when the FDA does not recognize aging as a disease. The goal here is to create a profitable, self-sustaining structure that will fund a portfolio of anti-aging projects, and then commercialize the research. It will be important that scientists get a stable source of funding for long-term lifespan projects, and a cut of the revenue from the projects they create."

Link: http://www.dailybrink.com/?p=1990

A recent long Popular Science article looks at Sierra Sciences and its founder, a group that has been working on telomere biology and its role in aging for some years. Alongside a number of other research groups, the Sierra crowd believe that telomeres are a lynchpin portion of our biochemistry and manipulating them might significantly extend life.

Make poor lifestyle choices, and you're likely to die of heart disease or cancer or something well before your telomeres would otherwise become life-threateningly short. But for the aerobicized Andrews, for anyone who takes reasonable care of himself, a drug that activates telomerase might slow down the baseline rate at which the body falls apart. Andrews likens the underlying causes of aging, free radicals and the rest, to sticks of dynamite, with truncated telomeres being the stick with the shortest fuse. "I believe there's a really good chance that if we defuse that stick," he says, "and the person doesn't smoke and doesn't get obese, it wouldn't be surprising if they lived to be 150 years old. That means they're going to have 50 more years to be around when somebody solves the other aging problems."

Telomeres, you might recall, are the frayed ends of our chromosomes, there in order to prevent problems during cellular replication - though more correctly they might be thought of as one portion of a more complex and regulated system that touches upon many cellular processes. You can't consider telomeres in isolation from the behavior of the telomerase enzyme that acts to rebuild telomere length, for example. Telomeres appear to erode away over a lifetime in many tissues, and their length in immune cells correlates decently with general health and levels of stress, shortened telomeres go hand in hand with increased cancer risk, and there's some interesting interplay between telomere length and levels of mitochondrial damage - both implicated in aging, and we might suspect these two things to be aspects of the same underlying process, though that remains a theory that can be argued either way at this time.

It would be hard to argue that telomeres are anything other than connected to aging - but are they a lynchpin that can be manipulated alone, in absence of other therapies, to significantly extend life? I am a skeptic on that count in the sense that I don't think the evidence presently in hand wholly supports that view. If you look at the most beneficial example of telomere manipulation in mice, a 50% life extension was achieved by combining genetic manipulation of p53 and telomerase levels together - but telomerase has a range of other potential effects on metabolism beyond affecting telomere length. I am not aware at this time of a study that categorically shows benefits accruing because of telomere length versus because of any other effects of telomerase - such as, for example, acting to protect mitochondrial DNA from damage, which in turn protects telomeres from shortening.

The bottom line for me is that this is certainly a line of research worth chasing further - there are a range of experiments that show benefits from telomerase therapies, such as improved immune system function, for example. But is the telomeres, or is it something else that's the important underlying mechanism? Either way, Sierra Sciences ran out of money for research in the end and now seems to be removing itself from the game through a mechanism we've sadly seen before, which is to get into bed with the supplement industry. I cannot think of a small company that has done this and remained a serious contender in advancing the state of medical science - the end result more often looks like the protandim debacle, in which whatever interesting scientific work once existed is abandoned and its echoes used to promote herbal compounds sold with a garnishing of lies. From the Popular Science article:

The stock-market crash of 2008 nearly wiped out two investors who had until then been his primary funders. Without the money to continue refining the nearly 40 telomerase-activating chemicals he and his team had already discovered, Andrews made the decision last September to cut a deal with John W. Anderson, the founder of Isagenix, an Arizona-based "network marketing" supplement company. This month, Isagenix will launch an anti-aging product containing several natural compounds that Sierra Sciences has verified to have "telomere-supporting" properties.

So you're basically looking at the genesis of another set of worthless products and magical thinking that apes the scientific method while rejecting everything that makes it work - just like most of the rest of the "anti-aging" marketplace. And beside that, another set of names who might have gone on to do good work will instead never be taken seriously again. Which is sad, given that they had a better vision of the necessary strategy for longevity science than most of the scientific community.

Via EurekAlert!: "There is a reason exercise becomes more difficult with age. [Research] ties the weakness of aging to leaky calcium channels inside muscle cells. But there is some good news: the researchers say a drug already in Phase II clinical trials for the treatment of heart failure might plug those leaks. Earlier studies [showed] the same leaks underlie the weakness and fatigue that come with heart failure and Duchenne muscular dystrophy. ... It's interesting, normal people essentially acquire a form of muscular dystrophy with age. The basis for muscle weakness is the same. ... Extreme exercise like that done by marathon runners also springs the same sort of leaks, [but] in that case damaged muscles return to normal after a few days of rest. ... The leaks occur in a calcium release channel called ryanodine receptor 1 (RyR1) that is required for muscles to contract. Under conditions of stress, those channels are chemically modified and lose a stabilizing subunit known as calstabin1. ... Calcium inside of muscle cells is usually kept contained. When it is allowed to leak out into the cell that calcium itself is toxic, turning on an enzyme that chews up muscle cells. Once the leak starts, it's a vicious cycle. The calcium leak raises levels of damaging reactive oxygen species, which oxidize RyR1 and worsen the leak. The researchers made their discovery by studying the skeletal muscles of young and old mice. They also showed that 6-month-old mice carrying a mutation that made their RyR1 channels leaky showed the same muscular defects and weakness characteristic of older mice. When older mice were treated with a drug known as S107, the calcium leak in their muscles slowed and the animals voluntarily showed about a 50 percent increase in the amount of time spent wheel running. Now in clinical trials for patients with heart failure, the drug is known to work by restoring the connection between costabilin and RyR1."

Link: http://www.eurekalert.org/pub_releases/2011-08/cp-wia072911.php

Singularity Hub here looks at some of the research work that will lead to the ability to generate blood as needed: "Researchers [have] found a way to hunt down and isolate the stem cells from which your entire blood supply is derived. Until now, these hematopoietic stem cells (HSC) have been remarkably hard to track and isolate ... researchers were able to identify the CD49f protein as a key surface marker for hemotopoietic stem cells. Single CD49f HSCs were placed inside immunosupressed mice, and monitored to see how they developed. The entire spectrum of blood cells were produced, and just as important: they were self-renewing. The CD49f HSC wasn't just creating blood, it was creating an expanding and sustaining blood supply that should theoretically survive long term in the body." This will lead to a number of potential ways to generate sufficient quantities of blood to remove the need for blood donations, and ultimately will allow a patient's own cells to be used to generate blood on demand.

Link: http://singularityhub.com/2011/08/03/scientists-bag-and-tag-the-stem-cell-that-may-create-an-endless-supply-of-blood/

Many of the worlds longest-lived people became the world's longest-lived people despite a history of what are considered to be poor lifestyle choices from the perspective of long term health. Amongst their number are smokers, the overweight, and the sedentary - all items shown to cause great harm to health in the long term. Studies have shown that each of these considered in isolation can shave as much as a decade from your life expectancy, and that's quite aside from what they will do to your quality of life via an increased risk of suffering chronic and debilitating medical conditions.

So how is it that we see a fair proportion of extremely old people with such a poor track record for basic good health choices over the course of their lives? So far it looks like that can be attributed to fortunate genes:

People who live to 95 or older are no more virtuous than the rest of us in terms of their diet, exercise routine or smoking and drinking habits ... Overall, people with exceptional longevity did not have healthier habits than the comparison group in terms of BMI, smoking, physical activity, or diet. For example, 27 percent of the elderly women and an equal percentage of women in the general population attempted to eat a low-calorie diet. Among long-living men, 24 percent consumed alcohol daily, compared with 22 percent of the general population. And only 43 percent of male centenarians reported engaging in regular exercise of moderate intensity, compared with 57 percent of men in the comparison group.

...

In previous studies of our centenarians, we've identified gene variants that exert particular physiology effects, such as causing significantly elevated levels of HDL or 'good' cholesterol. This study suggests that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle. ... Although this study demonstrates that centenarians can be obese, smoke and avoid exercise, those lifestyle habits are not good choices for most of us who do not have a family history of longevity. We should watch our weight, avoid smoking and be sure to exercise, since these activities have been shown to have great health benefits for the general population, including a longer lifespan.

Why rely on having a genetic buffer against subtle forms of self-harm when the odds are good that you have no such thing? The only reliable ways to ensure that you live for a long, long time in good health will come from progress in medical technology aimed at engineering greater human longevity: repair biotechnologies capable of reversing the known forms of cellular and molecular damage that cause aging. That progress in turn depends on the degree to which we choose to support and advocate rejuvenation research today.

Depressed Metabolism here notes the existence of a double standard when it comes to the science and practice of cryonics - actually one you'll find exists for all serious endeavors in life extension, such as SENS research: "One of the most predictable features of public debates about cryonics is that those arguing in favor of cryonics are held to more rigorous standards than those seeking conventional medical treatment. Advocates of cryonics do not just have to prove that cryonics will work, they are also supposed to solve problems like overpopulation and the presumed boredom arising from expended lifespans. To some, people who make cryonics arrangements have an inflated perception of their own importance and should just forgo such selfish attempts to extend their lives. The default position seems to be that people should not exist and that life needs justification. Could you imagine such antinatalist rhetoric being employed when a person seeks conventional medical treatment to extend their life? We can't, and such responses are quite indicative of the fact that people are not interested in serious evaluation of the cryonics argument."

Link: http://www.depressedmetabolism.com/2011/07/29/the-double-standard-about-cryonics/

Changes in stem cell biology and capabilities are considered important in age-related degeneration. For example: "A decline in cellular homeostasis in older individuals underlies age-related pathologies like osteoporosis and osteoarthritis. [Researchers] report key differences in the patterns of expressed mRNAs in bone-marrow mesenchymal stem cells (bmMSCs) of young donors compared with old human donors. The distinct subsets of expressed genes associated with glycobiology are consistent with the underlying age-related decline in bone marrow function. ... It is now well established that in older individuals stem cells can become 'aged' and thus incapable of renewing surrounding tissues and organs as efficiently as young individuals. Experimental and clinical evidence has revealed the importance of stem cell aging in bone marrow transplants, as recipients of bone marrow from older donors do not fare as well as recipients of bone marrow from younger donors. However, the molecular mechanisms governing stem cell aging are not well understood. An important first step towards this goal is to delineate the gene expression differences between stem cells from young and old individuals. Bone marrow stem cells are particularly well suited for such studies, as they are relatively easy to purify to homogeneity. ... bmMSCs showed age-increases in the expression of genes associated with the degradation of N-glycans and glycosaminoglycans and with the biosynthesis of glycosphingolipids. These results reveal major differences in the glycobiology and glycan compostion of young and old bmMSCs, associated with age-related changes in the cellular responses to autocrine and paracrine signals. The difference in glycan pathways may not be limited to bmMSCs or even to stem cells, but could be more widely prevalent among other cell types."

Link: http://impactaging.com/papers/v3/n7/full/100356.html

Up until comparatively recently the scientific consensus was that neurogenesis, the process by which new neurons are created and assimilated into the workings of the brain, simply didn't happen in adults to any significant degree. Fortunately we are supplied with a modest flow of new brain cells as life goes on, and this post is a reminder that, amongst all the other benefits caused by calorie restriction, it also increases neurogenesis. Eat fewer calories whilst still obtaining an optimal amount of nutrients and you gain more functional brain cells as a result:

Adult neural stem cells in the dentate gyrus of the hippocampus are negatively and positively regulated by a broad range of environmental stimuli that include aging, stress, social interaction, physical activity, and dietary modulation. Interestingly, dietary regulation has a distinct outcome, such that reduced dietary intake enhances neurogenesis, whereas excess calorie intake by a high-fat diet has a negative effect.

This has actually been known for at least a decade, as you'll see if you look back into the scientific archives. For example, this from 2000:

We found that maintenance of adult rats on a DR regimen results in a significant increase in the numbers of newly produced neural cells in the dentate gyrus of the hippocampus ... The increase in neurogenesis in rats maintained on DR appears to result from decreased death of newly produced cells, rather than from increased cell proliferation. We further show that the expression of brain-derived neurotrophic factor, a trophic factor recently associated with neurogenesis, is increased in hippocampal cells of rats maintained on DR. Our data are the first evidence that diet can affect the process of neurogenesis, as well as the first evidence that diet can affect neurotrophic factor production. These findings provide insight into the mechanisms whereby diet impacts on brain plasticity, aging and neurodegenerative disorders.

Or this from 2002:

We now report that neurotrophin expression and neurogenesis can be modified by a change in diet. When adult mice are maintained on a dietary restriction (DR) feeding regimen, numbers of newly generated cells in the dentate gyrus of the hippocampus are increased, apparently as the result of increased cell survival. The new cells exhibit phenotypes of neurons and astrocytes.

So what exactly does a modest increase in the creation of new functional brain cells mean for humans? That remains to be determined in detail, and seems to boil down to quantifying the effects of increased plasticity in the brain. There is the expectation in the scientific community that increased plasticity will be shown to be beneficial in a range of ways, but to date few lines of research have managed to definitively link changes in plasticity with cognitive ability, resistance to age-related neurodegenerative diseases, and so forth. That would seem to be just a matter of time, however.

Meanwhile, the benefits of calorie restriction are so broad and large - on a par with exercise in humans, and thus still better for healthy people than any presently available medical technology - that it would seem foolish not to give serious thought to trying it.

IGF-1 can be manipulated to alter species longevity, and here researchers are starting to try tissue-specific alterations rather than global alterations: "Transgenic mice with low levels of global insulin-like growth factor-I (IGF-I) throughout their life span, including pre- and postnatal development, have increased longevity. This study investigated whether specific deficiency of liver-derived, endocrine IGF-I is of importance for life span. ... Liver-specific inactivation of the IGF-I gene was induced in mice at one month of age in most experiments. However, food intake, body composition, oxygen consumption at rest, and activity level were measured in mice that underwent inactivation of liver-derived IGF-I at 12 months of age. ... Serum IGF-I was reduced by approximately 80% in mice with adult, liver-specific IGF-I inactivation (LI-IGF-I-/- mice), and body weight decreased due to reduced body fat. The mean life span of LI-IGF-I-/- mice increased 10% vs. control mice ... Body weight and body fat decreased in LI-IGF-I-/- mice, possibly due to increased energy expenditure during exercise. Genes earlier reported to modulate stress response and collagen aging showed consistent regulation, providing mechanisms that could underlie the increased mean life span in the LI-IGF-I-/- mice."

Link: http://dx.doi.org/10.1371/journal.pone.0022640

From the MIT Technology Review: researchers "developed a liquid that, when injected into patients, forms a matrix of loosely tangled nanofibers. Each of these fibers is covered in microscopic protuberances that mimic vascular endothelial growth factor, or VEGF - a protein that occurs naturally in the body and causes chemical reactions that result in the growth of new blood vessels. By mimicking VEGF, the nanofiber has the same biological effect. ... Tissue engineers have tried using VEGF itself to stimulate the growth of blood vessels, but clinical trials with the protein were unsuccessful ... This is because VEGF tends to diffuse out of the target tissue before it can do its job. Maintaining a therapeutic concentration in the target tissue would require a series of expensive, invasive injections. The new nanomaterial has a similar effect, but it lasts much longer, and is completely biodegradable once its job is finished. ... The researchers tested their material in mice. The blood supply to the animals' hind legs was restricted. Left untreated, these limbs would die. The nanofiber treatment rescued the limbs, and resulted in better motor function and blood circulation than the other treatments, including a treatment with VEGF. ... there could be more uses for nanofibers that mimic proteins from the body. For example, they could be used to stimulate the formation of connective tissues such as bone and cartilage, or to regenerate neurons in the brain."

Link: http://www.technologyreview.com/biomedicine/38206/

If you have to replace a part of the body, it's not necessary to replace it with an exact replica of what was there before: it just has to perform the same job, and perform that job at least as well. With this in mind, the medical research community has in recent years produced a range of ways to sculpt biological materials, such as collagen, as well as produce biodegradable scaffolding material that can be colonized by a patient's own cells to build new tissue. Thanks to these and other closely related technologies, many of the structural components of the body will be amenable to clinical repair and replacement via scaffolds and bioartificial prosthetics by the time the 2020s have rolled around - the list includes joints, bones, muscles, tendons, soft tissues of the face, and so forth.

I noticed two recently publicized advances from the biomaterials research community today, and here they are for your consideration:

New composite material may restore damaged soft tissue:

Biomedical engineers at Johns Hopkins have developed a new liquid material that in early experiments in rats and humans shows promise in restoring damaged soft tissue relatively safely and durably. The material, a composite of biological and synthetic molecules, is injected under the skin, then "set" using light to form a more solid structure, like using cold to set gelatin in a mold. ... The researchers created their composite material from hyaluronic acid (HA), a natural component in skin of young people that confers elasticity, and polyethylene glycol (PEG), a synthetic molecule used successfully as surgical glue in operations and known not to cause severe immune reactions. The PEG can be "cross-linked" - or made to form sturdy chemical bonds between many individual molecules - using energy from light, which traps the HA molecules with it. Such cross-linking makes the implant hold its shape and not ooze away from the injection site.

Cornell researchers create bioengineered spinal disc implants:

We've engineered [spinal] discs that have the same structural components and behave just like real discs," says Bonassar. "The hope is that this promising research will lead to engineered discs that we can implant into patients with damaged discs." ... Bonassar's lab, which focuses on the regeneration and analysis of musculoskeletal tissue, engineered artificial discs out of two polymers - collagen, which wraps around the outside, and a hydrogel called alginate in the middle. They seeded the implants with cells that repopulate the structures with new tissue. Remarkably, as opposed to artificial implants today that degrade over time, the scientists are seeing that the implants get better as they mature in the body, due to the growth of the cells.

An open access paper on the goals and structure of the International Aging Research Portfolio: "Aging and age-related disease represents a substantial quantity of current natural, social and behavioral science research efforts. Presently, no centralized system exists for tracking aging research projects across numerous research disciplines. The multidisciplinary nature of this research complicates the understanding of underlying project categories, the establishment of project relations, and the development of a unified project classification scheme. We have developed a highly visual database, the International Aging Research Portfolio (IARP), available at AgingPortfolio.org to address this issue. The database integrates information on research grants, peer-reviewed publications, and issued patent applications from multiple sources. Additionally, the database uses flexible project classification mechanisms and tools for analyzing project associations and trends. This system enables scientists to search the centralized project database, to classify and categorize aging projects, and to analyze the funding aspects across multiple research disciplines. The IARP is designed to provide improved allocation and prioritization of scarce research funding, to reduce project overlap and improve scientific collaboration thereby accelerating scientific and medical progress in a rapidly growing area of research. Grant applications often precede publications and some grants do not result in publications, thus, this system provides utility to investigate an earlier and broader view on research activity in many research disciplines."

Link: http://dx.doi.org/10.1371/journal.pone.0022597

Sarcopenia is the name given to age-related loss of muscle mass and strength. Here is a review paper on the current state of knowledge regarding exercise as a way to slow the onset of sarcopenia: "Numerous studies have demonstrated that the etiology of sarcopenia is multi-causal and very complex process. The degradation of muscle mass leads to a loss of strength, later on to a decreased functional status, impaired mobility, a higher risk of falls, and eventually an increased risk of mortality. Present guidelines state that physical inactivity or a decreased physical activity level is a part of the underlying mechanisms of sarcopenia and therefore physical activity can be seen as an important factor to reverse or modify the development of sarcopenia. ... Results in the area of physical activity and aging have not always been homogeneous. The inconsistent findings in this research area are related to the different understanding of terms and underlying constructs along with different population, type of intervention, or measurement methods. ... With regard to the formulated future role of physical activity this article will discuss in addition different barriers and challenges in the prevention and treatment of sarcopenia. A multitude of studies shows that structured exercise programs including progressive resistance or power training have positive effects on sarcopenia and sarcopenia-related outcomes but less or inconclusive information is available for the transfer to functional outcomes. ... Both physical activities and exercise have shown to decrease risk of sarcopenia and onset of functional limitations in older persons. Unfortunately the cohort of older persons is the one with the highest percentage of individuals classified as inactive or sedentary. Therefore motivating older persons to increase their physical activity level as well as providing safe access to exercise programs seems to be a mandatory task."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21792532