Fight Aging!

Humans are not laboratory mice, whose lives can be styled to best eliminate confounding factors from studies that aim to demonstrate a nice, neat correlation between cause A and result B. So when you study humans for decades, living their complicated and individualistic lives, you get all the confounding factors you can handle and then some. Take studies of fat, for example, and the strong correlation between extra body fat carried over the years, age-related illness, and a shorter life:

American researchers observed more than 17,000 female nurses with an average age of 50 in the U.S. All of the women were healthy when the study began in 1976. Researchers then monitored the women's weight, along with other health changes, every two years until 2000.

For every one-point increase in their Body Mass Index, women had a 12 percent lower chance of surviving to age 70 in good health when compared to thin women. Researchers defined "healthy survival" as not only being free of chronic disease, but having enough mental and physical ability to perform daily tasks like grocery shopping, vacuuming or walking up a flight of stairs.

...

For every 1 kilogram (2.2 pounds) gained since age 18, women's odds of surviving past 70 dropped 5 percent, researchers found. Women who were already overweight at age 18 and then gained more than 10 kilograms (22 kilograms) later in life only had about a 20 percent chance of surviving to age 70 in good health. The most commonly reported diseases were cancer, heart disease, and diabetes.

Fairly straightforward, you might think. But wait: excess body far is also inversely correlated with wealth:

The point here is that sickness, poverty, and obesity are spun together in a dense web of reciprocal causality. Anyone who's fat is more likely to be poor and sick. Anyone who's poor is more likely to be fat and sick. And anyone who's sick is more likely to be poor and fat.

Interestingly, wealth isn't all that correlated with longevity in comparison to body fat:

The billionaires lived 3.5 years longer than average American males. The results would be even more dramatic if we took into account average life expectancies from around the world, since the billionaires on our list are of all different nationalities. According to a 1999 study in the British Medical Journal, higher income is, in fact, "casually associated with greater longevity." But when it comes to living longer, billionaires may not be that much better off than mere millionaires. "While an extra dollar of income is protective," the study reads, "the amount of protective effect tails off as total income rises."

But we can't forget that measures of intelligence correlate with wealth, health, and keeping slim:

Some studies contend that rich live longer because of intellectual Darwinism. "Social status," Seligman writes, "correlates strongly and positively with IQ and other measures of intelligence, and intelligence correlates strongly with health literacy - the ability to understand and follow a prescription for disease prevention and treatment." This theory is not without evidence: Seligman cites a 2003 study by psychologist Ian Deary of the University of Edinburgh that found mortality rates to be 17% higher for each 15-point falloff in IQ.

At this point the layman shrugs his shoulders and points out that people who are better off tend to have become better off by taking an interest in becoming better off - an attitude which doesn't stop at making money. For the vast majority, those people lucky enough to have avoided snake eyes in the genetic lottery, being healthy is both a choice and a vocation. Some people work at it, and some people don't. Those who take an interest in their health and do the work required tend to reap the rewards.

From my point of view, I think that the evidence is very strong for extra body fat - visceral fat, to be specific - as a major contributory cause of accelerated age-related degeneration. By this I mean a direct and biochemical cause, not merely a correlation; people aren't degenerating more rapidly as a direct result of a lack of dollars or IQ points, but changes to the operation of human biochemistry brought about by the presence of larger visceral fat deposits are very damaging over the long term. Aging is absolutely a matter of how much damage your biochemistry has sustained, and the present consensus is that fat-induced inflammation has a lot to do with accumulated damage:

Chronic inflammation spurred by an immune system run amok appears to play a role in medical evils from arthritis to Alzheimer's, diabetes to heart disease. There's no grand proof of this "theory of everything." But doctors say it's compelling enough that we should act as if it were true - which means eating an "anti-inflammatory diet," getting lots of physical activity, and losing the dangerous, internal belly fat that pumps out the chemicals that drive inflammation.

We have previously demonstrated that surgical removal of visceral fat (VF) in rats improves insulin action, thus, we set out to determine if VF removal affects longevity.

We prospectively studied lifespan in 3 groups of rats: ad libitum fed (AL), 40% caloric restriction (CR) and a group of ad libitum fed rats with selective removal of VF at 5 months of age (VF-). We demonstrate that compared to AL, VF- rats had a significant increase in mean and maximum lifespan and significant reduction in the incidence of severe renal disease.

It's all something to think about, especially given that being overweight is a choice. An easy, seductive choice perhaps, but a choice nonetheless. You could do something about it, and hence improve your chances of living to see an era in which longevity medicine restores the elderly to health and vitality.

Here's a long post on the utility of contributing to engineered longevity versus the other forseeable technology most likely to dramatically reshape the world - self-improving artificial intelligence (AI). The author puts that goal in advance of contributing now to advancing longevity science, but I think that a point is missed along the way. Even if your contributions made now don't lead to technologies arriving in time to extend your life, they will bring forward the dates at which the medicine of engineered longevity does emerge in each region of the world. Every day gained in this fashion saves approximately 100,000 lives at present population levels. From the post: "The crux of my conflict is whether there is greater utility in putting money toward longevity or strong AI. ... . And for now, let's pretend that longevity escape velocity (LEV) occurs 25 years from now without any of my investment. Now lets say I buy 5 years of 'progress' in longevity, so it happens only 20 years from now. I think it's likely that within the first few decades of LEV, most of the change in life expectancy will come from wealthy old people in prosperous nations. I just saved and improved many lives, but not a whole bunch ... probably under half a billion. Infectious and lifestyle diseases, accidents and wars still exist, and those who can't afford treatment still die when they get old, even when AI shows up."

Link: http://raelifin.com/thoughts/on-the-utility-of-game-changing-technologies/

Via Calculated Risk, an animated chart that aptly illustrates the gains in life expectancy over the past 60 years and a set of very conservative projections out to 2050. "The population data and estimates are from the Census Bureau. Watch for the original baby bust preceding the baby boom. Those are the people currently in retirement. With the original baby bust now at the age of peak health care expenses, these are the best of times (from a demographics perspective) for health care. Animation updates every 2 seconds." You might compare this with Anders Sandberg's recent models - at some point over the next decade or so we should expect to see the "official" projections adjusted upward or shown to be overly conservative. The uncertainty introducted by advancing biotechnology is a very important topic in actuarial circles these days; a great deal of money rests on being right about the future of longevity, and being right is now harder than ever.

Link: http://www.calculatedriskblog.com/2009/08/us-population-distribution-by-age-1950.html

Here is a good example of the way in which modern genetic studies tend to proceed: genes of interest are disabled one by one to confirm exactly what it is they do. This is how researchers are exploring the complex feedback loops and interlinked mechanisms surrounding calorie restriction induced longevity, for example: "Dietary restriction is the most widely used intervention to promote longevity; however, the mechanisms underlying the effect of dietary restriction remain elusive. In a previous study, we identified two novel genes, nlp-7 and cup-4, required for normal longevity in Caenorhabditis elegans. nlp-7 is one of a set of neuropeptide-like protein genes; cup-4 encodes an ion-channel involved in endocytosis by coelomocytes. Here, we assess whether nlp-7 and cup-4 mediate longevity increases by dietary restriction. [RNA interference] of nlp-7 or cup-4 significantly reduces the life span of the eat-2 mutant, a genetic model of dietary restriction, but has no effect on the life span of long-lived mutants resulting from reduced insulin/IGF-1 signaling or dysfunction of the mitochondrial electron transport chain. The life-span extension observed in wild-type N2 worms by dietary restriction [is] prevented significantly in nlp-7 and cup-4 mutants. ... We conclude that two novel pathways, NLP-7 signaling and endocytosis by coelomocytes, are required for life extension under dietary restriction in C. elegans."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19783783

In Search of Enlightenment ponders obesity and aging: "When it comes to a disease like progeria, which is an extreme form of accelerated aging, I assume we would all agree that we should seek ways of preventing the disadvantage that comes with the disease. No child deserves to be robbed of the opportunity to have a healthy childhood and develop into a healthy adult. Progeria is very rare, affecting about 1 in 8 million births. When it comes to obesity, which also accelerates aging (though is less severe than progeria, but much, much more prevalent) we also think we should strive to prevent this. No one deserves diabetes or heart disease in their 50's or 60's. But what about the 'regular' rate of aging, which is less severe but much, much more prevalent than obesity, what should our attitude be? The inborn aging process limits average life expectancy of humans to around 85. Shouldn't we aspire to retard that rate of molecular and cellular damage if it would help prevent disease and death? Does anyone actually believe people (our to make the point more vivid, their parents, children or spouse) deserve heart disease, stroke, AD, cancer, etc. in late life? [Yet] aging research is grossly underfunded and that young scientists who want to make the world a better place gravitate towards goals like trying to control the global climate or finding a cure for just one disease of aging (e.g. cancer) rather than investigating the aging process itself."

Link: http://colinfarrelly.blogspot.com/2009/09/obesity-and-aging-linked.html

h+ magazine, the Wired of the transhumanist community, is presently running an interview with biomedical gerontologist and longevity science advocate Aubrey de Grey on the subject of the technological singularity and its relationship with a future that includes the engineering of enhanced human longevity:

h+: In the past five years or so, talk about the "Singularity" has become much more mainstream and acceptable, much like talk about radical life extension. Do you think that looking at futurism through the frame of the multi-faceted "Singularity" idea is helpful, or just makes matters more complicated?

AdG: I think it's helpful. People have quite extraordinary difficulty thinking about non-linear change, and the general concept of the Singularity, especially the Kurzweil version... but really all versions, is a nicely canonical example that is as good as any to use to educate people in such thinking, even if that education consists mainly in simple repetition.

In the case of life extension, the concept of "longevity escape velocity" (the rate at which rejuvenation technologies need to be improved in order to stave off age-related ill-health indefinitely) is similar to the Singularity (though subtly different) -- indeed, someone recently gave it the rather neat name "Methuselarity", and I have been mystified at the difficulty I have in explaining it to people -- they find it much more "ridiculous" than the near-term goal of adding 30 years of healthy life, even though in reality it's far LESS speculative.

...

h+: The idea of extreme life extension is closely connected to the Singularity meme. To what extent do you think that technological progress in computers and bioinformatics is pushing along life extension research?

AdG: Well, first of all I would like to qualify your initial statement. I think there is actually not all that much in common between life extension and accelerating change: the defeat of aging will really be just one event in the progress of technology, albeit a particularly momentous one. I therefore think that the only strong connection between the two is in the similarity of mindset and of attitudes to the future that attracts people to the two themes.

As for your question: Bioinformatics is playing a modest but not central role in hastening progress in the biotechnological approach to postponing aging that I pursue. More general progress in developing full-blown artificial intelligence, however, may well result in a much more dramatic hastening of the defeat of aging, if computers can be created that are much smarter than we are and thus able to solve the trickier problems inherent in postponing aging much faster than we can. I therefore strongly support such research.

As I've noted in the past, there's a lot of overlap between the artificial intelligence and longevity engineering crowds, and much of that occurs via the transhumanist community.

Aiming to extend the healthy human life span has come to be a respectable goal in the scientific community over the past ten years. That wasn't always the case, and it's easy to forget just how much of a sea change has taken place since the beginning of the decade. See this representative quote from not too many years past, for example:

'The cure for aging' is the instant-death third rail of grantsmanship and we stay away from it.

Thankfully minds change as evidence accrues. It's very hard to ignore the sound science that shows the potential to repair the damage of aging, and even harder to ignore the many demonstrations of extended longevity in mammals, achieved through genetic and metabolic engineering. That is not to mention the siren song of possible personal gain, amplified by the acquisition of Sirtris Pharmaceuticals last year - a huge market awaits anyone who can develop working longevity medicine.

For all that, respectability is slow to percolate beyond the scientific and medical development communities. It takes years for the public at large to catch up with what's going on in the labs and then rally in support for further progress. So it's always an encouraging sign to see popular press articles of this sort:

Who would have thought it? The quest for eternal life, or at least prolonged youthfulness, has now migrated from the outer fringes of alternative medicine to the halls of Harvard Medical School.

We are fortunate to live in a culture in which, despite its many faults and present downward slide, people still view the halls of science with reverence and uphold scientists as the arbiters of truth. Given time, there will be widespread and enthusiastic support for longevity science - but sooner is much better than later.

It has been known for some years that manipulation or transplant of ovaries can influence longevity in mammals, a fact that might be compared with the mechanisms linking germ cells to nematode longevity. Here is a recent demonstration: "Previously we reported that prepubertally ovariectomized mice that received young transplanted ovaries at a postreproductive age showed a 40% increase in life expectancy. To study this phenomenon in greater detail, 11-month-old ovariectomized and ovary-intact CBA/J mice underwent ovarian transplantation with 60-day-old ovaries or a sham surgery. Results from observations on transplant recipients in the current study extended our previous results. Whereas intact control mice lived an average of 726 days, transplant recipients lived an average of 770 days (i.e., 780 days for intact recipients and 757 days for ovariectomized recipients). If intact recipients had ceased reproductive cycling by the time of transplant, we observed a further increase in mean life span to 811 days. These results demonstrate that young ovaries enhanced longevity when transplanted to old mice and that ovarian status, examined by means of ovariectomy and ovarian transplantation, clearly influenced the potential of young transplanted ovaries to positively impact longevity." We still await an understanding of the biochemical mechanisms involved in this method of life extension.

Link: http://www.ncbi.nlm.nih.gov/pubmed/19776215

The Thiel Foundation is the public face of investor Peter Thiel, noteworthy for his funding of SENS Foundation research. "Freedom is always under siege. Around the world, authoritarian regimes deprive millions of people of basic economic and social rights. Even elected governments can burden their citizens with labyrinthine bureaucracies and complex, unnecessary laws. And while some regimes are obviously worse than others, they all have apologists who obscure these conditions by twisting the relationship between freedom and human fulfillment. The Thiel Foundation defends and promotes freedom in all its dimensions: political, personal, and economic. How do we do this?
(a) By supporting innovative scientific research and new technologies that empower people to improve their lives. (b) By championing organizations and individuals who expose human rights abuses and authoritarianism in all its guises. (c) By encouraging the exploration of new ideas and new spaces where people can be less reliant on government and where freedom can flourish." The goal of freedom taken to its logical ends means not just freedom from human-engineered oppression, but also freedom from the limitations, suffering, and cruelties inherent in the human condition and human biology - such as degenerative aging.

Link: http://www.thielfoundation.org

If you head on over to MSNBC you'll find video of a recent interview with Aubrey de Grey, biomedical gerontologist and advocate for engineered longevity, held whilst punting at Cambridge. If you find it interesting, you should also take a look at some of the other interviews and presentations by de Grey that are available online. For example:

• TED Presentation in 2007
• Interviewed at the SENS4 Conference
• Why Fight Aging?
• UCLA Presentation in 2008

While we're on the subject of media types I don't normally link to, I should also point out a Fast Forward Radio edition from July of this year in which Aubrey de Grey and Terry Grossman give their respective views on extending the healthy human lifespan.

By way of a reminder, de Grey's SENS Foundation is presently very close to gaining $5,000 for longevity science in the Share to Win contest cannily set up by startup company 3banana. The contest closes at the end of September, just a few days away:

The SENS Foundation (which organizes the Strategies for Engineered Negligible Senescence conferences) is in the running for the $5000 grand prize in 3banana's Share to Win event. The contest seeks to raise money 'for causes serving unmet needs in health, education and environment.' And you can help. It’s pretty simple: All you have to do is leave a comment on this page. (The award goes to the cause with the most comments.) You can sign on using a Google account if you already have one of those, or register for a free one-off account. It's painless and takes about thirty seconds. Your comment/vote makes a difference! Right now, SENS is neck-and-neck with the competition - as of this post, they're 17 votes behind first place. (Well, sixteen, since I just commented.) So don't just sit there - this is your opportunity to help send real money to a very important cause, at no cost to yourself. Post your comment now. There are only four days left in the contest, so time is of the essence.

So if you haven't yet done your part, go ahead and help out - every extra dollar we can steer in the right direction is valuable.

You'll find an Aubrey de Grey reprint in the latest issue of Discover: "Many people, when thinking about the idea of adding years to life, commit the 'Tithonus error' - the presumption that, when we talk about combating aging, we're only talking about stretching out the grim years of debilitation and disease with which most people's lives currently end. In fact, the opposite is true. The defeat of aging will entail the elimination of that period, by postponing it to indefinitely greater ages so that people never reach it. There will, quite simply, cease to be a portion of the population that is frail and infirm as a result of age. It’s not just extending lives that I'm advocating; it's the elimination of the almost incalculable amount of suffering - experienced not only by the elderly themselves, of course, but by their loved ones and caregivers - that aging currently visits upon us. Oh, and there's the minor detail of the financial savings that the elimination of aging would deliver to society: It's well established that the average person in the industrialized world consumes more health care resources in his or her last year of life than in an entire life up to that point, irrespective of age at death, so we're talking about trillions of dollars per year."

Link: http://discovermagazine.com/2009/new-science-of-health/23-modest-proposal-how-to-stop-aging-entirely

Researchers still have much to learn about telomere biochemistry and how it interacts with degenerative aging: "The decline in the neuromuscular function affects the physical performance and is a threat for independent living in later life. The age-related decrease in muscle satellite cells observed by the age of 70 can be specific to type II fibers in some muscles. Several studies have shown that different forms of exercise induce the expansion of satellite cell pool in human skeletal muscle of young and elderly. Exercise is a powerful non-pharmacological tool inducing the renewal of the satellite cell pool in skeletal muscles. Skeletal muscle is not a stable tissue as satellite cells are constantly recruited during normal daily activities. Satellite cells and the length of telomeres are important in the context of muscle regeneration. It is likely that the regulation of telomeres in vitro cannot fully mimic the behavior of telomeres in human tissues. New insights suggest that telomeres in skeletal muscle are dynamic structures under the influence of their environment. When satellite cells are heavily recruited for regenerative events as in the skeletal muscle of athletes, telomere length has been found to be either dramatically shortened or maintained and even longer than in non-trained individuals. This suggests the existence of mechanisms allowing the control of telomere length in vivo."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19765243

Heat shock proteins (HSPs) are increasingly seen as important players in the response of our biochemistry to stresses and damage. HSPs are fundamentally chaperones and monitors: they look for damaged proteins that can compromise cellular functions and help to ensure that those proteins are rapidly recycled. When events - such as exposure to heat, hence the name - cause damage in our cells, HSP activity increases for a while to compensate. This is one basis for the phenomenon of hormesis, wherein a little damage applied regularly results in a better, longer lasting biological system: the HSPs are overcompensating.

Since aging is an accumulation of biochemical damage - or, looked at another way, all forms of unrepaired damage lead to loss of function and degeneration - we would expect that greater HSP activity translates into longer lives and a more more robust, resiliant biochemistry. This seems to be the case in laboratory animals:

Heat-shock proteins (Hsps) are increasingly being implicated in aging phenotypes and control of life span across species. They are targets of the conserved heat-shock factor and insulin/IGF1-like signaling pathways that affect life span and aging phenotypes. Hsps are expressed in tissue-specific and disease-specific patterns during aging, and their level of expression and induction by stress correlates with and, in some instances, predicts life span. In model organisms, Hsps have been shown to increase life span and ameliorate aging-associated proteotoxicity. Finally, Hsps have emerged as key components in regulating aging-related cellular phenotypes, including cell senescence, apoptosis and cancer. The Hsps, therefore, provide a metric of individual stress and aging and are potential targets for interventions in aging and aging-related diseases.

Both exercise and calorie restriction (CR) are forms of mild stress that temporarily enhance HSP activity, and it is plausible that boosted HSP activity contributes to the health and longevity benefits produced by regular exercise or cutting down calories whilst still obtaining optimal levels of nutrients in the diet. People who exercise or eat less have more effective self-repair systems, in other words. Along those lines, here is a recent paper looking at the biochemistry of exercise:

The study of the exercise-induced production of HSPs in skeletal muscle is important for the exercise scientist as it may provide a valuable insight into the molecular mechanisms by which regular exercise can provide increased protection against related and non-related stressors ... Data indicate that acute endurance- and resistance-type exercise protocols increase the muscle content of [various HSPs]. Although increased HSP transcription occurs during exercise, immediately post-exercise or several hours following exercise, time-course studies using western blotting techniques have typically demonstrated a significant increase in protein content is only detectable within 1-2 days following the exercise stress.

...

Following 'non-damaging' endurance-type activities (exercise that induces no overt structural and functional damage to the muscle), the stress response is thought to be mediated by redox signalling (transient and reversible oxidation of muscle proteins) as opposed to increases in contracting muscle temperature per se. Following 'damaging' forms of exercise (exercise that induces overt structural and functional damage to the muscle), the stress response is likely initiated by mechanical damage to protein structure and further augmented by the secondary damage associated with inflammatory processes occurring several days following the initial insult.

Exercise training induces an increase in baseline HSP levels, which is dependent on a sustained and currently unknown dose of training and also on the individual's initial training status. Furthermore, trained subjects display an attenuated or abolished stress response to customary exercise challenges, likely due to adaptations of baseline HSP levels and the antioxidant system.

...

As a non-pharmacological intervention, exercise and the associated up-regulation of HSPs and the possible correction of maladapted pathways may therefore prove effective in providing protection against protein misfolding diseases and in preserving muscle function during aging.

It is interesting that ongoing exercise in the form of a training program actually raises baseline HSP activity. You might compare that with present thinking on SIRT1 - that this sirtuin produces benefits in health and longevity by extending the period in which HSPs are more active following a triggering stress.

Morton JP, Kayani AC, McArdle A, & Drust B (2009). The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports medicine (Auckland, N.Z.), 39 (8), 643-62 PMID: 19769414

From In Search of Enlightenment, more to go along with a recent Fight Aging! post on misplaced priorities: "Of all the incredible things that humans have accomplished, our ability to think rationally and consistently about an uncertain and unpredictable long-term future is not one of our strongest attributes. For the vast majority of human history we had a short life expectancy (under 30 years) and thus the cognitive capacities we have inherited from our Darwinian past reflect the reality that, historically, it was much more important to think clearly about short-term goals (like finding food and a mate) than the complex long-term goals facing societies in the 21st century. ... When I reflect upon the issues of what constitutes a harm for humans (as both individuals and collectively as a society), and what it may be possible to do this century if we invest in certain areas of knowledge and innovation, one particular issue stands out far above the rest - global aging. ... these harms are a 100% certainty if we do not modify the aging process. We don't need computer models to accurately predict that middle aged people today will age and become frail." Yet comparatively little attention is given to the rapidly evolving science of aging and enhanced longevity - so there is comparatively little done.

Link: http://colinfarrelly.blogspot.com/2009/09/folly-of-our-times-part-two.html

Anders Sandberg has built simple models to aid in a discussion of possible futures of enhanced human longevity: "Dirk Bruere on the Extrobritannia mailing list asked a provocative question: 'Any serious H+ predictions of longevity trends between now and (say) 2050 for various age groups? I would expect our predictions to start to deviate from the 'official' ones at some point soon.' This led me to develop a simple model of life extension demographics. I'm not a professional demographer and it depends on various assumptions, so take this with a suitable amount of salt. Summary of my results: I do not see any unexpected demographic changes before life extension breakthroughs, and age at death will not rise until a while after - despite potentially extreme rises of cohort life expectancy. (Flickr photostream [of charts]). I also think we 30+ transhumanists should be seriously concerned about speeding basic and transitional research, and look at alternative possibilities (cryonics, possibly [whole brain emulation]). ... What about our chances? It all depends on when we think the basic solutions are going to be discovered. ... My personal intuition is that we are not far from early research breakthroughs (they might have occurred already) ... I end up with the general life extension social breakthrough somewhere 2040-2060. Great news for current kids, a bit more worrying for us at 30+."

Link: http://www.aleph.se/andart/archives/2009/09/life_extension_model.html

The study of forms of accelerated aging often provides insight into the biochemical processes of normal (and equally undesirable) degenerative aging. Here, we'll look at the aging of the immune system, a comparatively structured form of degeneration that might be viewed as the natural consequence of evolutionary selection:

Evolution is a harsh but efficient mistress; you can consider yourself surprisingly well optimised as a piece of machinery, but your warranty only goes so far as the number of years in which your recent ancestors contributed to the success of their offspring. After that, you're on your own - biochemical processes unwind and break down free from any past selective pressure to do better.

Take the immune system, for example, one of many absolutely vital components in the very complex system that supports your life. It is remarkably well optimized for reliable and effective use of resources in early and mid-life, but the rules that govern that optimization lead to a system that breaks down badly after extended usage.

For a low cost in biological resources you get a good immune system at the very start of your life - but that system's prowess is all front-loaded. It is not set up for the long term. There are two principle issues at work here:

1) The supply of new immune cells diminishes as the thymus involutes:

The immune system undergoes dramatic changes with age - the thymus involutes, particularly from puberty, with the gradual loss of newly produced naive T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells.

2) The immune system is limited in the number of cells it can support:

Throughout our lives, we have a very diverse population of T cells in our bodies. However, late in life this T cell population becomes less diverse ... [one type of cell] can grow to become more than 80 percent of the total [T-cell] population. The accumulation of this one type of cell takes away valuable space from other cells, resulting in an immune system that is less diverse and thus less capable in effectively locating and eliminating pathogens.

...

One main reason your immune system fails with age appears to be that chronic infections by the likes of cytomegalovirus (CMV) cause too many of your immune cells to be - uselessly - specialized.

Your immune system is set up to fail - it's only a matter of time. At one end of the candle burns the lack of new immune cells, while at the other end CMV and its ilk ensure that limited resources are increasingly (and uselessly) devoted to combatting them. With that in mind, let me point you to a recent open access paper that illustrates both of these root causes by looking at people who lost their thymus in younger life:

While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells.

A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus.

Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

The next step in immune research should be to do something about these problems. On the one hand, we would want to understand how to safely keep the thymus active, and on the other hand establish methodologies to regularly eliminate CMV-specific immune cells and thus free up capacity. Fortunately, both of these goals look to be very plausible for the next decade of development. Researchers in the cancer science community have been demonstrating methods of safely killing specific cell populations identified by their surface markers for some years now, using either nanoparticles or engineered viruses. Killing specific immune cells should be well within the capabilities of this emerging field. As to the thymus, we can look to regenerative medicine and tissue engineering, a vast and well funded field devoted to restoring and recreating fully functional organs using a patient's own cells. If you can build a heart from scratch, a thymus can't be many years behind.

From a technology perspective, the future is bright and restoring an aged immune system looks very viable in the near term. Unfortunately this is yet another of those longevity science line items that few groups are working on. Like all aspects of "normal" aging, the FDA does not consider immune degeneration in late life a disease, and therefore will not approve treatments for it. Since there is no prospect of bringing such a treatment to market in the US, there is little funding for development, and little interest amongst researchers in undertaking work that will relegate them to an economic backwater.

In this, as in so many areas of medicine, we must look to other strategies and other regions of the world if we wish to see the potential of present scientific understanding and capacities of biotechnology fully realized.

Sauce, D., Larsen, M., Fastenackels, S., Duperrier, A., Keller, M., Grubeck-Loebenstein, B., Ferrand, C., Debré, P., Sidi, D., & Appay, V. (2009). Evidence of premature immune aging in patients thymectomized during early childhood Journal of Clinical Investigation DOI: 10.1172/JCI39269

Depressed Metabolism here critiques cryonics provider Alcor: "Alcor's recent news item about its 2009 Annual Board Meeting and Strategic Meeting contains a number of encouraging statements. On the front of institutional reform, however, there is not much news to report. The passage about the need to balance recruiting new Board members and preserving institutional memory reads as a rather uninspired defense of the Board's recent decisions. In light of the growing recognition that most of Alcor's problems over the years can be tracked back to the composition and functioning of the Board of Directors, one would have expected more innovation on this front. ... One of the most positive items in Alcor's report is the recognition that Alcor would benefit from substantial cost savings in its operations. Throughout most of Alcor's history the organization has been dependent on (unpredictable) donations from wealthy members to sustain normal operations. Obviously, this way of funding the operations of a cryonics organization (as opposed to long term patient care) constitutes an irresponsible gamble. Donors should be commended for being reluctant to contribute to Alcor (any further) until Alcor has shown evidence of getting its financial house in order. A number of sensible proposals were discussed to generate more structural income for the organization such as increasing membership dues, raising cryopreservation minimums, introducing a recommended funding level (as opposed to just a minimum funding level), and creating income-generating endowments."

Link: http://www.depressedmetabolism.com/2009/09/22/the-future-of-alcor/

Via Ouroboros, a chance to help raise funds for longevity science: "The SENS Foundation (which organizes the Strategies for Engineered Negligible Senescence conferences) is in the running for the $5000 grand prize in 3banana's Share to Win event. The contest seeks to raise money 'for causes serving unmet needs in health, education and environment.' And you can help. It’s pretty simple: All you have to do is leave a comment on this page. (The award goes to the cause with the most comments.) You can sign on using a Google account if you already have one of those, or register for a free one-off account. It's painless and takes about thirty seconds. Your comment/vote makes a difference! Right now, SENS is neck-and-neck with the competition - as of this post, they're 17 votes behind first place. (Well, sixteen, since I just commented.) So don't just sit there - this is your opportunity to help send real money to a very important cause, at no cost to yourself. Post your comment now. There are only four days left in the contest, so time is of the essence."

Link: http://ouroboros.wordpress.com/2009/09/22/help-raise-5000-for-sens-by-leaving-an-online-comment/

This ScienceDaily release provides insight into present mainstream research into the mechanisms of osteoporosis and rheumatoid arthritis: a matter of scientists investigating and debating mechanisms to find the next and better target for viable drug development. "Bone is continually recycled to maintain its strength through the competing action of osteoclasts, cells that break down aging bone, and osteoblasts, which build new bone. Osteoclasts also play a central role in common diseases that erode bone, where two signaling molecules, TNF-alpha and RANKL, cause too much bone breakdown. ... the current study argues that TNF-alpha and RANKL have different effects on levels of a key inhibitory protein [called] NF-kappaB p100 ... We believe NF-kappaB p100 limits not only osteoclast maturation, but also the number of inflammatory cells attracted to the joints in response to TNFalpha. If confirmed, it would mean that p100 has more than one role in more than one major bone disease, and thus would create new opportunities to reverse disease by manipulating p100 levels."

Link: http://www.sciencedaily.com/releases/2009/09/090921173134.htm

Greater understanding of the mechanisms of healing brings more opportunities to enhance the body's natural powers of regeneration. Here, researchers "provide conclusive proof that, when a muscle is injured, white blood cells called macrophages play a crucial role in its regeneration. The scientists also uncovered the genetic switch that controls this process, a finding that opens the door for new therapeutic approaches not only to sports injuries but also to diseases such as Duchenne muscular dystrophy. ... After clearing [an injured region], macrophages stop [releasing] pro-inflammatory factors, and start making anti-inflammatory factors that promote repair in the damaged area. This shift from clearing debris to promoting building is known as macrophage polarization ... Normally, inflammatory factors trigger an increase in C/EBP-beta production, which in turn activates genes that cause the macrophage to polarize. ... From a medical point of view, it would seem that the trick to improve muscle repair is finding a way to increase C/EBP-beta production and keep it high. If we can now figure out exactly which key genes C/EBP-beta controls, that will give us even more potential targets [to enhance healing].

Link: http://www.embl.de/aboutus/communication_outreach/media_relations/2009/090921_Monterotondo/index.html

Much of what passes for debate over organization and policy these days completely ignores progress. It is, in effect, debate over what to do if nothing ever changed - if all availabilities remained constant, if prices never changed, if new resources were not developed, if existing technologies were not improved. This is completely irrational - everyone knows that this is an age of change and progress - but yet it is commonplace, yet another aspect of the phobia of change that seems hardwired into human nature.

Take this op-ed, for example:

Imagine that someone invented a pill even better than the one I take. Let’s call it the Dorian Gray pill, after the Oscar Wilde character. Every day that you take the Dorian Gray, you will not die, get sick, or even age. Absolutely guaranteed. The catch? A year’s supply costs $150,000. ... Because the price of these new pills well exceeds average income, it would be impossible to provide them for everyone, even if all the economy’s resources were devoted to producing Dorian Gray tablets.

So here is the hard question: How should we, as a society, decide who gets the benefits of this medical breakthrough? Are we going to be health care egalitarians and try to prohibit Bill Gates from using his wealth to outlive Joe Sixpack? Or are we going to learn to live (and die) with vast differences in health outcomes? Is there a middle way?

This is a nonsensical formulation. It's like thinking about how to survive the endless night that will arrive when the sun goes down, ignoring the obvious and long-established fact that the sun will later rise in the morning - it leaves out the most important and time-proven consideration of time and change. When medicines of engineered longevity arrive in reality, the driving question will not be not how to divide the pie there and then, but rather how rapidly competitive research and development will reduce the price and expand the market of people who can afford this new technology.

Every new medical technology was unaffordable and unreliable at first, and then became reliable and affordable. The incentive for any marketplace is to work to make goods simultaneously more reliable and cheap enough to be affordable to new populations of people eager to buy - selling affordable goods to the masses is how to make serious money, not keeping the price high and the market small. This seems to be one of those forms of change that people like to sweep under the rug and ignore, despite the fact that it takes place right now, all around, and in hundreds of different markets.

This dismissal of progress and unwillingness to look beyond what exists right this instant is, I think, a part of human psychology that greatly enables popular support for government regulation - regulation that has the effect of removing incentives for improvement. So instead of a vigorous marketplace in which improvement and falling prices are the order of the day, we wind up with a stultified and overregulated space in which high prices and poor quality dominate because the rewards of innovation have been squashed.

The Maximum Life Foundation is the brainchild and online presence of engineered longevity advocate and marketing entrepreneur David Kekich - also one of the first Methuselah Foundation donors, as it happens. The Maximum Life Foundation was founded in 1999, and thus predates most of the latest generation of serious ventures in advocacy and fundraising for longevity science, such as the Methuselah Foundation, SENS Foundation, or Immortality Institute. This is reflected in the messaging of the Maximum Life Foundation and its founder, which comes across as a hybrid of two eras: on the one hand the past era of supplements and hopes epitomized by the Life Extension Foundation; on the other hand, the present era of biotechnology and a real chance at medicine that can slow or reverse aging. All, of course, heavily filtered through Kekich's view on markets, health, self-actualization, and progress.

See, for example, Kekich's message as the Maximum Life Foundation founder:

And you’re probably aware that the power of technology per dollar doubles every 12 months. As I said, this means our tools could be 1000 times more powerful in just 10 years… and a billion times more powerful before mid century.

...

Now stop and let this sink in for a moment. Look back on the entire 20th century and mentally calculate what 1000 times more progress would equate to. Try to imagine what effect having tools, a billion times more powerful, could have on you and your well-being. This is an incredible, world-changing concept that will impact YOU more than anything else you have ever experienced. Almost all the old rules and restrictions are tossed out.

I should point you to David Kekich's recently released book, "Life Extension Express," which can be downloaded for free from the Foundation website. This takes the concepts and lessons of longevity advocacy developed over the past decade, and presents them in a jazzy, self-help book stream of consciousness format:

• Aging is the greatest threat to individuals in this world of ours, and age-related disability is the greatest cost we will each bear in suffering and money - but most people don't think about doing something about that.
• We life in an age of advancing biotechnology that will soon make it possible to address the aging process as though it were a disease.
• Medical advances have the potential to produce accelerating gains in longevity in decades ahead - eventually adding years of healthy life faster than we age. But this will only be the case if we step up and help to make it happen.
• Take care of your health, or you might miss the boat. Big and impressive biotechnology is on the way, but that won't help you if you're dead.

There will one day in the not so distant future be published a "Human Longevity for Dummies" book - and I imagine it will look and sound a lot like "Life Extension Express." One of the challenges in the present longevity advocacy movement is reaching out to educate the public at large, putting the implications of the visions and ideas of de Grey, Kurzweil, Vinge, and others in front of people who haven't paid much attention up until now. The flashy self-help space hasn't been widely explored (to the best of my knowledge) by the present generation of advocates for engineered longevity, but here Kekich is placing his best foot forward. We'll see how it goes.

Yet another single gene manipulation to extend life in mice is reported here, with some implications for potential longevity drugs in humans: "Angiotensin II (Ang II) [has] a role in the etiology of hypertension and in pathophysiology of cardiac and renal diseases in humans. Other functions of Ang II include effects on immune response, inflammation, cell growth and proliferation, which are largely mediated by Ang II type 1 receptor (AT(1)). Several experimental studies have demonstrated that Ang II acts through AT(1) as a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Recently, our group has demonstrated that the inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT(1A)) in mice translates into marked prolongation of life span. The absence of AT(1A) protected multiple organs from oxidative damage and the alleviation of aging-like phenotype was associated with increased number of mitochondria and upregulation of the prosurvival gene sirtuin 3. AT(1) receptor antagonists have been proven safe and well-tolerated for chronic use and are used as a key component of the modern therapy for hypertension and cardiac failure, therefore Ang II/AT(1) pathway represents a feasible therapeutic strategy to prolong life span in humans."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19763608

From The National: "The 20th century saw a string of world-changing technological breakthroughs - mass-produced automobiles, television, space travel, computers and the internet - that would have been met with incredulity just a few decades before. But the astonishing speed at which 21st-century medicine is advancing looks set to outstrip even those giant leaps for mankind. It is possible that over the course of our lifetime, vaccines will help prevent or cure many of our most lethal cancers; we will be able to grow an unlimited supply of hearts, kidneys and other organs in the lab for transplantation (rendering irrelevant the current drastic shortage of donors); stem-cell technology will cure some forms of blindness and help paralysed, spine-damaged patients regain mobility; and nanotechnology will allow us to develop drug-dispensing devices no bigger than a molecule. It may sound like science fiction, but these technologies - and many others, too numerous to list here - are either available now, or at least will be in the next decade or two."

Link: http://www.thenational.ae/apps/pbcs.dll/article?AID=/20090921/LIFE/709209980/1196

We humans are irrational beings, for all we like to think ourselves otherwise. This irrationality is well known and often discussed within the pro-engineered longevity community: we all see that death by aging is by far the greatest cause of destruction, death, pain, and sorrow known to man. We also see that few people place a high priority on doing something about that:

The rational actor looks at risks to life and health ahead and acts to minimize those risks. Since we all have limited time and resources, we have to prioritize: we make lists, in our heads if nowhere else, putting the most likely and terrible outcomes up at the top. Highly unlikely but terrible outcomes don't receive much attention: meteors, lightning strikes, that sort of thing. Likely but merely unpleasant events might just be suffered as a cost of getting on with life: catching the flu is an obnoxious happenstance, but not particularly threatening for most of us. There are more important things to worry about while buying insurance and otherwise taking care of essentials.

So you end up with a list involving fires, car accidents, sudden implosion of the company you work for, that sort of thing. In that, most of us are not being terribly rational, as aging isn't on the list. It is absolutely going to happen, and it leads to the most terrible personal consequence possible - death - via numerous other very nasty personal consequences. Alzheimer's, heart disease, cancer, and all the rest. We all have a 100% chance of aging as things stand, and it's the worst thing that will happen to most of us. So why isn't it up near the top of that priority list?

I notice some more thoughts on that topic at In Search of Enlightenment:

Most people alive today will most likely develop, and die from, one of the chronic diseases of aging like cancer, heart disease or stroke. ... Retarding aging would help us delay all age-related disorders simultaneously, thus yielding healthy dividends that far exceed what a cure for cancer or AD or stroke could yield. So one of our top priorities should be to increase the health prospects of humans in late life. Thus aging research ought to be at the top of our priorities.

But it isn't, and so there is much toil, wailing, and gnashing of teeth amongst advocates for longevity science. It is said that you'll know you're onto something big when it becomes extraordinarily hard to convince other people that your ideas are good ... using the tools of biotechnology to extend healthy life and repair the biochemical damage of aging is certainly something big by that measure.

I see further discussion along these lines at Depressed Metabolism. Is the present generation of older folk going to quietly ride their degenerating bodies all the way down to the grave, or will they at some point take note of rapidly advancing capacities in biotechnology and decide enough is enough, perhaps giving rise to an energetic range of advocacy and investment groups?

One question that is going to be of great interest is how aging baby boomers will confront aging and death. Where previous generations have found peace in religion and silent resignation, there are reasons to believe that this generation will not be so complacent. The baby boom generation, or at least those who have shaped contemporary culture and politics, have been more secular and less inclined to accept the constraints of nature (as evidenced by the obligatory contempt for views that allow some degree of biological determinism).

..

There is a lot at stake here.

Yes, indeed there is. More hands make lighter work, and efforts to build the first generation of longevity medicine are very much lacking in the more hands department at the present time.

An interesting paper: "The aging process is one of the best examples of the effects of a deterioration of homeostasis, since aging is accompanied by an impairment of the physiological systems including the homeostatic systems such as the immune system. We propose an integrative theory of aging providing answers to the how (oxidation), where first (mitochondria of differentiated cells) and why (pleiotropic genes) this process occurs. In agreement with this oxidation-mitochondrial theory of aging, we have observed that the age-related changes of immune functions have as their basis an oxidative and inflammatory stress situation ... Moreover, we have also observed that several functions of immune cells are good markers of biological age and predictors of longevity. Based on the above we have proposed the theory of oxidation-inflammation as the main cause of aging. Accordingly, the chronic oxidative stress that appears with age affects all cells and especially those of the regulatory systems, such as the nervous, endocrine and immune systems and the communication between them. This fact prevents an adequate homeostasis and, therefore, the preservation of health. We have also proposed a key involvement of the immune system in the aging process of the organism, concretely in the rate of aging, since there is a relation between the redox state and functional capacity of the immune cells and the longevity of individuals."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19754376

Via Ouroboros, a look at researchers who declare the mitochondrial free radical theory of aging (MFRTA) over and done with: "MFRTA recently turned 50, and consequently has received a lot of attention lately; q.v. this review and this retrospective by Denham Harman, the originator of the theory. The thesis of most pieces seems to be that the theory hasn't been demonstrated to explain the bulk of age-related decline, but that there's still life in the idea. In contrast, the authors of this review argue that the relevant experiments have been performed and that the theory has been falsified - in other words, we've done our scientific duty and it's now time to move on. I doubt very much that this article will put a permanent end to the controversy. Data reported fairly recently have breathed new life into oxidative theories in general and the MFRTA in particular. While these authors contend that the CLK-1 mouse mutant contradicts the underlying mechanisms of the MFRTA, other recently reported work on this pathway supports the claim that inhibiting mitochondrial respiration delays aging, a key prediction of MFRTA. Furthermore, if mitochondrially generated oxidative radicals are truly not playing a causative role in aging, it becomes much harder to explain how mitochondrially targeted antioxidants can extend lifespan in mammals."

Link: http://ouroboros.wordpress.com/2009/09/17/rip-for-mfrta/

Sarcopenia is the name (fairly recently) given to age-related muscle loss, a situation that most people find themselves in with advancing age. In past years, researchers have investigated whether this might related to tendencies for diet to change with age, such as reduced protein intake for example. Interestingly, however, there is also solid evidence for the practice of calorie restriction to slow the process of sarcopenia.

Back in 2005, one group of scientists painted a fairly convincing argument for dysfunctional processing of the essential amino acid leucine as the cause of sarcopenia, a dysfunction that can be overcome by simply consuming more leucine. Those researchers went on to point the finger at increasing chronic inflammation that occurs with aging as a root cause of this amino acid processing problem:

In old rats, the ability of leucine to stimulate muscle protein synthesis was significantly decreased compared with adults. This defect was reversed when old rats were supplemented with antioxidants [but it] was not related to increased oxidative damage ... These effects could be mediated through a reduction in the inflammatory state, which decreased with antioxidant supplementation.

You can look back in the Fight Aging! archives for more of a background on inflammation and aging:

Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs.

Let me direct your attention to another more recent demonstration of the link between age-related chronic inflammation and sarcopenia in rats:

Recently, low grade inflammation has been suspected to be one of the factors responsible for the decreased sensitivity of muscle protein metabolism to food intake.

This study was undertaken to examine the effect of long term prevention of low grade inflammation on muscle protein metabolism during aging. Older rats (20 month of age) were separated into two groups: a control group and a group (IBU) in which low grade inflammation had been reduced with a non steroidal anti inflammatory drug (ibuprofen). After 5 months of treatment, inflammatory markers and cytokines levels were significantly improved in treated old rats when compared to the controls

...

controlling the development of low grade inflammation in old rats significantly decreased muscle mass loss between 20 and 25 months of age. In conclusion, the observations made in this study have identified low grade inflammation as an important target for pharmacological, nutrition and lifestyle interventions that aim to limit sarcopenia and muscle weakness in the rapidly growing elderly population in Europe and North America.

Turning back to calorie restriction once again, you might recall that reduced calorie intake does in fact reduce the level of inflammation suffered with advancing age, an effect possibly achieved though loss of visceral fat tissue. Taken together, all of this is one more reason to take better care of your health, and keep up with those practices known to reduce inflammation - such as not letting yourself get fat.

Rieu I, Magne H, Savary-Auzeloux I, Averous J, Bos C, Peyron MA, Combaret L, & Dardevet D (2009). Reduction of low grade inflammation restores blunting of postprandial muscle anabolism and limits sarcopenia in old rats. The Journal of physiology PMID: 19752122

h+ Magazine interviews calorie restriction (CR) practitioners Meredith Averill and Paul McGlothin, noted for their work to spur the scientific community into greater human studies of CR: "McGlothin says he 'had the good fortune' to come into contact with one of the country's leading internist, who is a calorie restrictor. It was through this physician that McGlothin and Averill both became smitten with CR practice and science and surrounded themselves with a team of doctors in an attempt to sort out fact from fiction in the practice. They also initiated the first CR study of humans, accomplished with MetaMetrix Clinical Laboratory in 2001. Subsequently, they formed a partnership with Drs. Luigi Fontana and John Holloszy at the Washington University in Saint Louis School of Medicine. ... His work in testing CR results led to his being named Research VP of the CR Society, where he works with scientists to plan studies. ... We want everything we do to be backed by solid scientific research and testing. That is why we helped set up the first longitudinal study of calorie-restricted humans. Now, for the past seven years, we and a cohort of other calorie-restricted humans have been thoroughly tested by teams of scientists headed by Drs. Luigi Fontana and John Holloszy at the School of Medicine at Washington University in St. Louis."

Link: http://hplusmagazine.com/articles/forever-young/you-are-what-you-dont-eat

This piece from In Search of Enlightenment is just as applicable to the level of attention given to longevity science by ordinary folk: "Aristotle would scoff at the insularity and specialization of contemporary political theory. While concerns for the good of humans do populate debates in the field (some more than others), that concern is peripheral rather than central. The neglect of science and technology, for example, easily illustrates how wide the gap is between debates in political theory and the real world. If you were born 200 years ago you probably wouldn't live to see your 30th birthday. If you are born today you will most likely live long enough to suffer from one of the chronic diseases of aging in late life (after age 60). We have more than doubled the life-expectancy of humans in just 200 years. And yet the significance of the advances that made this possible - like the sanitation revolution, vaccinations, material prosperity, changes in behaviour, etc. - go largely unnoticed by the political theorist. Such 'macro-level' considerations typically aren't on the radar of theorists because we tend to form our theories and principles on the basis of micro-level considerations (e.g.: 'Look, the Jones's have more money than the Smith's do. Is this inequality in one small dimension of their life prospects fair if it is the result of 'brute luck'?'). So, how does one go about linking political theory to aging research? This is my project."

Link: http://colinfarrelly.blogspot.com/2009/09/political-theory-and-aging-research.html

If you head on over to the Immortality Institute forums, you'll find a thread in which Kevin Perrott of the LifeStar Institute is taking questions and elaborating on that Institute's work:

As you likely know, LifeStar's goal is to be the international organizing entity for the development of "restorative medicine" and that includes everything from discovery to delivery.

It is our assertion that the science necessary to restore and maintain function against the degeneration of the aging process will get done. It is the "when" that we are most concerned with and removing barriers so that the urgent need for therapies can maximally accelerate their development. Such barriers of course include funding and human resources but moreover they are inherent in the way technology is developed after discovery in the issues surrounding intellectual property and commercialization just to name a couple of critical areas. Indeed, the hardest part may not be the science, but making sure that the HUMAN components of the development equation are not the "rocks in the road".

Each community of experts associated with a vital part of the technological development process needs to be approached and engaged to invite their thoughts on building their part of the program for maximal chance of success. In order to have a compelling reason for such communities to become engaged, we need to first ensure that the scientific community is able to assert that such an engagement would be worth their effort and thus the very first part of LifeStar's efforts involve gaining that support.

You might compare that with the stated mission of FasterCures, an organization founded a few years back in response to the obvious issues with medical (over)regulation and resulting slow speed of development. Comparing the two organizations is a somewhat interesting exercise, though I don't know that it is in any way helpful at this stage. FasterCures appears very meshed with the existing political establishment, and an organization that does not or will not acknowledge that the existence of the FDA is the root of the problem isn't going to get very far - in my opinion.

Short of a revolution - which is a whole different exercise in planning - I think that the greatest short term gains in medical technology are going to come from enabling research communities in restricted and overregulated regions to develop and monetize their work in less regulated regions. In the long term, the gains will come from building new research communities beyond the reach of those politicians and bureaucrats who would regulate us all into early graves.

But to return to what the LifeStar folk are up to:

The first thing any non-scientific community is going to ask before they get involved will be "Is it really possible that we have the science to make aging an approachable challenge?" and "Why should we be concerned when there are so many other important global issues to address?". In order to be prepared to answer those questions we approached the world's recognized experts in the biology and social policy of aging and asked them to meet with us to discuss those questions and how an international collaboration might be built that could be the beginning of the LifeStar World Health Inititative's Science Program,

You can see a record of that meeting at the LifeStar Institute website. It took place at the Buck Institute in August:

The theme of the meeting was late-onset interventions in the aging process and building the global collaboration to accelerate their development. ... It was a truly singular experience and one that will be hard to repeat, but LifeStar will be looking to do exactly that with each group of leaders whose input will be necessary to develop the strategic areas critical to realizing its mission. If this meeting is any indication, we are well begun.

There is a great deal more to look over in the Immortality Institute thread, so by all means read the whole thing.

Aging researcher (and competitor in the Mprize for longevity science) Leonard Guarente is profiled at the MIT News: "After winning tenure at MIT in 1986, biology professor Leonard Guarente did some soul-searching. He had made his mark by studying gene regulation in yeast, but that field was getting overrun with researchers, and he wanted to pursue a riskier project, where success would have a dramatic scientific impact. ... With the help of some bright graduate students who arrived in his lab in 1991, he hit on the idea of looking for genes that control aging in yeast. At the time, it was a plan with little prospect for success: Few scientists believed that aging might be controlled by a single gene (or small group of genes). Guarente turned that view around - and pioneered a new field of study - with his discovery of so-called longevity genes, which dramatically boost the lifespan of yeast, worms, mice and potentially humans. The human version of the gene, known as SIRT1, is now the target of several drugs in development to treat the diseases of aging, including diabetes, Alzheimer's and cardiovascular disease."

Link: http://web.mit.edu/newsoffice/2009/profile-guarente-091509.html

Over at Depressed Metabolism, Aschwin de Wolf has assembled a list of literature on how we expect cryosuspended people to be restored in the future. The general class of technologies required are fairly well understood, and a lot of thought has gone into the processes and machineries that must be developed: "There is a growing literature that discusses the technical aspects of revival of cryonics patients. [This list] of the published literature was compiled by Ralph Merkle and Robert Freitas and published as an appendix of their article on molecular nanotechnology in Cryonics Magazine 2008-4." Much of the list is available online for interested readers, such as Merkle's technical feasibility outline: "This paper considers the limits of what medical technology should eventually be able to achieve (based on the currently understood laws of chemistry and physics) and the kinds of damage caused by current methods of freezing. It then considers whether methods of repairing the kinds of damage caused by current suspension techniques are likely to be achieved in the future."

Link: http://www.depressedmetabolism.com/2009/09/10/revival-of-cryonics-patients-literature/

Researchers are making progress in understanding exactly how germline cells are linked to longevity in flies and nematodes: "In Caenorhabditis elegans and Drosophila melanogaster, the aging of the soma is influenced by the germline. When germline-stem cells are removed, aging slows and lifespan is increased. The mechanism by which somatic tissues respond to loss of the germline is not well-understood. Surprisingly, we have found that a predicted transcription elongation factor, TCER-1, plays a key role in this process. TCER-1 is required for loss of the germ cells to increase C. elegans' lifespan, and it acts as a regulatory switch in the pathway. When the germ cells are removed, the levels of TCER-1 rise in somatic tissues. This increase is sufficient to trigger key downstream events, as overexpression of tcer-1 extends the lifespan of normal animals that have an intact reproductive system. Our findings suggest that TCER-1 extends lifespan by promoting the expression of a set of genes regulated by the conserved, life-extending transcription factor DAF-16/FOXO."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19749979

Researchers make flies live longer by interfering with components of the mitochondrial energy-generating machinery: "Mitochondria have long been proposed to play an important role in the aging process. In the nematode Caenorhabditis elegans, genes important for mitochondrial electron transport chain (ETC) function stand out as a principal group of genes affecting life span. However, it has been suggested that this may be a peculiarity of nematode biology. In the present study, we have used an in vivo RNA interference (RNAi) strategy to inactivate ETC genes in Drosophila melanogaster and examine the impact on longevity. ... RNAi of five genes encoding components of mitochondrial respiratory complexes I, III, IV, and V leads to increased life span in flies. ... Our data suggest that the role of mitochondrial ETC function in modulating animal aging is evolutionarily conserved and might also operate in humans. Furthermore, our findings suggest that the longer life span of flies with reduced ETC gene expression cannot simply be attributed to reduced energy production leading to decreased 'rate of living.'"

Link: http://www.ncbi.nlm.nih.gov/pubmed/19747824

Over at Depressed Metabolism, cryonics luminary and "inveterate scribbler" Ben Best reports on the recent SENS4 longevity science conference. He appears pleasantly surprised by the level of interest in cryonics amongst the younger generation of advocates for engineered longevity and researchers:

SENS conferences attract scientists who are eager for science to achieve rejuvenation, and who have a strong belief that science has the capacity to do so. Not surprisingly, such people are often receptive to the idea that future science may be capable of reanimating humans who have been well cryopreserved.

Recently I have heard regret expressed about the aging of the cryonics community and the absence of a next generation of cryonics activists to replace the current ones. My experiences at the 2009 SENS conference dispelled much of my concern about this.

...

I was astounded when a British student approached me and said that he would be devoting all of his graduate school work to the problem of cryoprotectant toxicity.

...

A number of people from KrioRus were at the conference, notably Igor Artyuhov, who is their technical guru. The group also does life extension research. Igor showed me their poster showing extended lifespan of mice administered heat-shock protein through nose-drops.

...

To my surprise, one of the presenters, Dr. Gunther Kletetschka, had a poster and an oral presentation dealing with eliminating the cracking problem in cryonics.

Cryonics is important yet sadly much underdeveloped as an industry. It is the only presently available method of providing even a chance of cheating death, in this case through the low-temperature preservation of the fine structure of the brain. The many hundreds of millions who will die prior to the advent of true rejuvenation biotechnologies might be given a shot at a longer healthy life in the future through cryonics, were the industry a thousand times its present size and influence.

The Telegraph notes the recent SENS4 conference: "Cranks and crooks have been peddling immortality potions since before the dawn of history. All manner of bizarre antidotes to ageing have been tried, including the drinking of mercury salts and the eating of diced monkey testicles. Immortality, it would seem, has long been inextricably entwined with lunacy. But that may be about to change. Earlier this month, 200 scientists descended on Queens' College Cambridge to discuss ways of radically extending human lifespan - and even achieving immortality. The Strategies for Engineered Negligible Senescence (SENS) conference, drew together researchers from disciplines as diverse as tissue engineering, artificial intelligence, law, demographics and politics. 'Most people fail to understand how fast medical science is advancing in this area,' says the conference organiser Dr Aubrey de Grey, editor-in-chief of the journal Rejuvenation Research and co-founder of the SENS Foundation. 'Conventional medical progress has ensured that a child born today can expect to live 120 to 150 years. I think it's possible for them to live far longer. If we make the right breakthroughs in the next 25 years, then there is a 50:50 chance that people alive today could live to be 1,000 years old."

Link: http://www.telegraph.co.uk/health/elderhealth/6175693/Could-there-be-a-cure-for-ageing.html

From Anders Sandberg: " I comment on a Times article that claims life extension will make us worse off because 1) it would be bad for society, and 2) because the finiteness of life give it value. These are bad arguments that seem to crop up again and again. Arguing that we shouldn't do X because of bad social consequences hinges on the assumptions that we can accurately predict these social consequences to be bad, that we cannot fix them in a reasonable way and that their badness will always outweigh the good X could do. The assumptions in the case of life extension are very debatable, since we actually do have data about how societies handle longer lifespans and it suggests that they do adapt nicely and become happier. Maybe an extremely rapid shift would be wrenching, but again that would also correspond to a large number of people who would otherwise have died now not dying often horribly. Trying to find some social effects that can outweigh the badness of 100,000 deaths a day is hard, and I have not seen any convincing argument along these lines. ... the 'death gives life meaning' argument [sounds] deep, but nobody would consider 'divorce gives love meaning' or 'bookworms give libraries meaning' profound or even accurate. The meaning of love is to be found in the deep positive emotions and relations, not in their breakdown or ebb. Similarly life has a meaning based on that it is lived, not any boundary condition."

Link: http://www.aleph.se/andart/archives/2009/09/stupid_arguments_against_life_extension.html

A recent issue of Studies in Health Technology and Informatics includes a number of interesting papers on longevity science, or that relate to developing the tools and research community to enable engineered longevity. You might start with an essay by Aubrey de Grey, in which he coins a new term for an aspect of what has in the past been called actuarial escape velocity - the point at which steadily increasing life expectancy rises by more than one year with each passing year:

Aging, being a composite of innumerable types of molecular and cellular decay, will be defeated incrementally. I have for some time predicted that this succession of advances will feature a threshold, which I here christen the 'Methuselarity,' following which there will actually be a progressive decline in the rate of improvement in our anti-aging technology that is required to prevent a rise in our risk of death from age-related causes as we become chronologically older. Various commentators have observed the similarity of this prediction to that made by Good, Vinge, Kurzweil and others concerning technology in general (and, in particular, computer technology), which they have termed the 'singularity.' In this essay I compare and contrast these two concepts.

At present, life expectancy is increasing at about one year for every five years that pass - only 20% of what is needed to keep our expected remaining years of life increasing at the same speed with which we age. That said, it is worth remembering that life expectancy is a statistical construct based on past data - it is a helpful measure of progress, but not necessarily an indication of where we are now. I suspect it lags present medical advances, for example, because their effects on mortality rate might not show up for a decade or more.

In any case, you'll want to take a look at some of the other papers that pertain to the future development path of medical nanorobotics, as laid out by Robert Freitas:

Welcome to the Future of Medicine

This chapter describes the negative consequences of medical technology development and commercialization that is too slow, and makes the case for an immediate large scale investment in medical nanorobots to save 52 million lives a year. It also explains the essence of nanotechnology, its life-saving applications, the engineering challenges, and the possibility of 1000-fold improvement over our current human biological abilities. Every decade that we delay development and commercialization of medical nanorobotics, half a billion people perish who could have been saved.

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids

Molecular electronics and nanoscale chemical sensors could enable the construction of microscopic sensors capable of detecting patterns of chemicals as they flow passively in a fluid. Information from a large number of such devices allow the estimation of properties of tiny chemical sources in a macroscopic tissue volume. Although such devices cannot yet be fabricated, estimates of plausible device capabilities in small blood vessels allow the evaluation of their performance for typical chemicals released by tissues in response to localized injury or infection. The devices can readily discriminate a single cell-sized chemical source from the background chemical concentration, providing high resolution sensing in both time and space. ... These microscopic, programmable devices could also aid treatments, such as precisely targeting drug delivery and improving speed and accuracy of microsurgery.

Fight for Chromallocyte

This paper reports on the most important recent technological event and its significance to the human race: chromallocyte designed by Robert Freitas - a nanorobot that would be capable of replacing chromosomes on a cell by cell basis throughout the body in vivo.

The significance of chromallocyte comes from its ability to painlessly reverse the effects of genetic disease and other accumulated damage to our genes thus preventing aging. It could reduce suffering, save lives and enhance human potential. By analogy to the successful effort to put man on the moon, we should aim at chromallocyte landing on the liver by 2039 which would commemorate 70th anniversary of man landing on the Moon. The same strategic planning principle could be applied. We should have a dream with a deadline of 2039.

Note that there is still some debate over the role of nuclear DNA damage in aging - is it important on the time scale of present human life span or not? The consensus appears to be that it is important, but there are those who argue the opposite viewpoint.

Aubrey D.N.J. de Grey (2009). The Singularity and the Methuselarity: Similarities and Differences Studies in Health Technology and Informatics, 149 : 10.3233/978-1-60750-050-6-195

The Calorie Restriction Society is trying something a little different for this year's society conference in November, the sixth in the series:

The Sixth CR Society Conference (CR-VI) will be held in Atlanta from November 18-22, 2009 as a part of The Gerontological Society of America's 62nd Annual Scientific Meeting at the Hilton Atlanta and Atlanta Marriott Marquis.

The first five CR Society conferences were small "CRS only" events attracting between 25 and 85 attendees. This time we are partnering with the Gerontological Society of America (GSA) to have our conference as a part of the much larger GSA Meeting. The GSA has over 5000 members with over 3300 attending their last conference. The theme of this year's conference is "Creative Approaches to Healthy Aging," fitting our goals perfectly!

...

CR Society members (paying membership levels) will be able to register for the Conference at the GSA member rate ($275 Early Bird). The CR Society member registration includes both the CR Society conference and the GSA Conference. Instructions for registering are in the Members Only Area of [the CR Society website]. To view the instructions, you must be a paid CR Society member and login with your CR Society account information. Non-members must first join the CR Society in order to register for the conference.

For an example of the sort of conference the Society hosts, you might look back into the Fight Aging! archives. It's a lot of calorie restriction research and biochemistry mixed in with the nuts and bolts of practicing calorie restriction as a lifestyle:

• Coverage of the 2006 CR Society conference
• Blogging a CR conference
• Video of CR research presentations given at the 2006 conference

While we're on the subject, I should also point out noted calorie restriction practitioner Michael Rae (and co-author of Ending Aging) waxing enthusiastic in the Immortality Institute forums:

Even if you're not on CR, there are plenty of reasons to attend: wanting to learn more about the science of CR and possible CR mimetics; to attend, at a discounted rate, the scientific session of the GSA, which is solid, often-unpublished biogerontological (including but not limted to CR) research; to hang out with fellow prolongevists, CR or not; and to mix it up a bit with the gerontological establishment and hopefully push some paradigms. As I also say in my review, "considering the total coup that Robert and David have pulled off in getting us into GSA, I'd especially like to encourage anyone with a serious interest in the science of aging and CR to attend, both because you'll have the opportunity to track down most of the big players in the field to ask about scientific developments and research issues [and] because we will make a more favorable impression on THEM - and thereby humanize their interest in CR [and serious life extension research] and maybe help spur more thought about human translation and more CR human research."

One of the big long term goals now in longevity research circles is building a research community that is set up to grow and generate results over the next twenty to thirty years. This is something akin to what the cancer researchers of the 1960s were up to: groundwork to create sustainable growth in the field and the progress it produces.

Some thoughts on the SENS4 conference at Transhuman Goodness: "The conference included around 90 talks, most of them by academic biomedical researchers, many of whom from 'serious' universities such as UCL, Cambridge University, etc. A typical topic would be 'we have this hypothesis about how this part of the ageing process works, and we tested it in this trial/we built this device'. ... Now, as far as conquering death for those people who are currently within a few decades of dying goes, we are going to have to do an awful lot more, and pull out a lot more stops than I saw evidence of at SENS; if there's one overriding impression I really want to avoid, it is the impression that now that SENS exists, the ageing problem is handled, for that would be a fatal mistake to make. The problem of ageing is a very hard one, primarily because the human body is very, very complicated and very, very messy. The average biomedical talk given at SENS, which represented the work of a few researchers for a total time of perhaps a few months to a year, would typically make some small increment of progress on some small subsystem of the human body, and in some cases that progress was the refutation of some previous promising piece of work. ... Coming back to the subject of the conference itself, I was pleased overall: it was well-organized, professional and contained a lot of good science. ... My thanks go out to and all those who worked hard to make the conference a success; we should all be grateful to those who work towards the betterment of humankind by trying to defeat ageing, for they are the true heroes of our time."

Link: http://transhumangoodness.blogspot.com/2009/09/sens4-overview-and-review-how-evolution.html

From the Vancouver Sun: "People who stay even moderately fit as they age may live longer than those who are out-of-shape, a new study suggests. The study, of nearly 4,400 healthy U.S. adults, found that the roughly 20 percent with the lowest physical fitness levels were twice as likely to die over the next nine years as the 20 percent with the next-lowest fitness levels. That was with factors like obesity, high blood pressure and diabetes taken into account - underscoring the importance of physical fitness itself ... Our findings suggest that sedentary lifestyle, rather than differences in cardiovascular risk factors or age, may explain (the) two-fold higher mortality rates in the least-fit versus slightly more fit healthy individuals. ... These results emphasize the importance of improving and maintaining high fitness levels by engaging in regular physical activity, particularly in poorly fit individuals ... Since it is recent physical activity that offers protection, it is important to maintain regular physical activity throughout life. ... And since fitness is linked to longevity regardless of weight and health conditions like high blood pressure and high cholesterol."

Link: http://www.vancouversun.com/health/Even+modest+fitness+extend+lifespan/1917357/story.html

This is why cryonics is important - it is the only viable chance at great longevity for the billions who will not live to see the technologies of radical life extension: "there's bad timing, and then there's this: Instead of a day late and a dollar short, most of us are a day early and ... well, money doesn't even play into it, because we're gonna die. ... But a lot of us alive today are likely to really have our noses rubbed in that vexing mortality thing, because it's looking more and more as if nanotech-boosted medicinal biology is going to make 'life extension' an everyday term. Nanobots will be able to repair the slightest defect arising from defective genes, a detrimental environment, and even, yes, aging. In short, people are going to live forever. ... Which is all well and good - hell, great - for anyone around when our progressive, humane national health care system of the future starts accepting appointments for regular 3,000-mile/3-year nanobot tune-ups. (It's fun to imagine Jiffy-Lube-like life-extension outlets - without the pneumatic lug-nut tighteners, one hopes - but it'll probably be geekier and more complicated than that.) Many of the rest of us, though, will live to be just close enough to the breakthrough to know that it's coming, and to eat our deteriorating hearts out: Those lucky blankety-blanks are going to live forever, and all I get is this lousy shroud."

Link: http://www.sdnn.com/sandiego/2009-09-08/blog-forum/arthur-salm-immortality-its-the-new-health-care

Via EurekAlert!: scientists "are reporting development of the first nanoparticles that seek out and destroy brain cancer cells without damaging nearby healthy cells. ... glioblastoma multiforme (GBM) [often] causes death within months of diagnosis. Recent studies show that titanium dioxide nanoparticles, a type of light-sensitive material widely used in sunscreens, cosmetics, and even wastewater treatment, can destroy some cancer cells when the chemical is exposed to ultraviolet light. However, scientists have had difficulty getting nanoparticles, each about 1/50,000th the width of a human hair, to target and enter cancer cells while avoiding healthy cells. ... The scientists' solution involves chemically linked titanium dioxide nanoparticles to an antibody that recognizes and attaches to GMB cells. When they exposed cultured human GMB cells to these so-called 'nanobio hybrids,' the nanoparticles killed up to 80 percent of the brain cancer cells after 5 minutes of exposure to focused white light." This research is representative of many other similar projects; this sort of approach typifies the impending next generation of cancer therapies.

Link: http://www.eurekalert.org/pub_releases/2009-09/acs-tan090909.php

You'll find a few more posts on SENS4 conference sessions at the group science of aging blog Ouroboros, to go along with the other coverage from previous days:

• SENS4 Conference Converage From Ouroboros
• More SENS4 Conference Coverage

Links to the latest Ouroboros posts follow, starting with a clever use of modern abilities in nanotechnology: if you can somehow tag cells (such as age-damaged immune cells) with a magnetic nanoparticle, then you can use a magnetic field to selectively remove them from a fluid environment:

SENS4, Session 15: Rejuvenating the immune system

Justin Rebo spoke about some initial experiments that show it’s feasible to selectively remove anergic T cells from old mice. The basic idea: remove some blood from a mouse; mix it with some selective superparamagnetic antibodies; clean the blood by applying a magnet to separate out tagged cells; put it back into the animal.

SENS4, Session 16: Delivering genes, proteins and larger structures in vivo

Carlos Barbas talked about altering the activity of individual genes using zinc finger recombinases. They have developed an automated approach for producing enzymes that can accurately target any region of DNA, and made it publicly available.

SENS4, Session 18: Recent advances in cell therapies

Daniel Kraft spoke about stem cell transplantation in bone marrow. They developed an alternative method of 'making room' in bone marrow for new stem cells that uses antibodies (which is much less toxic than chemotherapy, the usual approach). Also, they developed MarrowMiner, a faster and less painful way to extract bone marrow from a donor using only a single entry site - previous methods require making hundreds of individual needle jabs.

SENS4, Session 21: Tissue engineering

Sally Dickinson spoke about the first transplant of a tissue-engineered airway, which took place in June 2008. She played a cool video explaining the whole procedure, which is up on youtube. Using a donor trachea, they first treated it to remove all the donor's cells; they then took some stem cells from the patient’s bone marrow, turned them into chondrocytes, grew them up and seeded them onto the scaffold; finally, they transplanted the engineered trachea into the patient.

One of the things that stands out from the conference presentations is that the infrastructural technologies and techniques - upon which the next generation of therapies will be built - are improving in leaps and bounds. What's coming out of the labs is moving very rapidly indeed, far more rapidly than clinical development, as clinical development operates under the crushing weight of regulation. This means that there is a tremendous and growing opportunity for the development of advanced therapies and centers of medical tourism in less regulated parts of the world - and if we want to benefit from the biotechnology revolution, that is exactly what must happen.

An update on induced pluripotency work from ScienceDaily: "human fat removed during liposuction conceal versatile cells that are more quickly and easily coaxed to become induced pluripotent stem cells, or iPS cells, than are the skin cells most often used by researchers ... Fibroblasts, or skin cells, must be grown in the lab for three weeks or more before they can be reprogrammed. But these stem cells from fat are ready to go right away ... Unlike highly specialized skin-cell fibroblasts, these cells in the fat have a relatively wide portfolio of differentiation options - becoming fat, bone or muscle as needed. It's this pre-existing flexibility, the researchers believe, that gives these cell an edge over the skin cells. ... These cells are not as far along on the differentiation pathway, so they're easier to back up to an earlier state. They are more embryonic-like than fibroblasts, which take more effort to reprogram." Every discovery that makes it easier and cheaper to work with stem cells will help speed up progress in developing working regenerative therapies.

Link: http://www.sciencedaily.com/releases/2009/09/090907162316.htm

Vision has an interview with Gerontology Research Group co-founder Robert Nathan: "For me, extending our healthy years is an immediate short-term step on the longer path to reverse the aging process and thereby attain physiological immortality with high quality of life, though it isn't clear how well we can avert catastrophic accidental death. Also, the big killer diseases appear to be age related: heart, cancer, stroke, Alzheimer's. If we reverse aging, do we avoid these killers? ... Over the past 50 years that I've been following this field not much real progress occurred until this last decade, starting with the mapping of the human genome. More attention has recently been focused on the mitochondria. And the most recent focus is on the control of stem cells already in our bodies. But please note, we all carry immortal cells within us. These are our germ cells, those involved with reproduction: sperm and eggs. There are also a limited number of nearly immortal stem cells. The rest of our body is composed of somatic cells that no longer divide and tend to die under some kind of programmed control. When I was young, the medical dogma declared that muscle, neural and kidney cells no longer increase in number once we mature. Today all that has been reversed. We have always had in our bodies different kinds of nearly immortal stem cells, which can replenish all three of these tissues on demand."

Link: http://www.vision.org/visionmedia/article.aspx?id=18196

The details of organizing the final few days or hours of your transition from alive-but-fading to the low temperature preservation of your body and mind (stored in the fine structure of your brain) are not much dwelled upon, but they are very important. The step, taken years earlier, where you arranged with a cryonics provider to be cryopreserved on clinical death is not the crucial part of the process: you were active and healthy enough to see it through, it could always be redone if there were issues, and you had plenty of time.

No, the critical point is the process of dying and being preserved. The laws surrounding end of life matters - as in most areas of law these days - put you at a great disadvantage. You cannot choose the time of your death in most jurisdictions and you will have to go to some lengths to prevent interference by employees of the state (who might try to claim the body to conduct an autopsy, which needless to say will ruin your chances of a good cryosuspension). If you suffer from a condition that will likely greatly damage your brain - and thus destroy your mind - before death, you will be prevented from bypassing this horror via assisted suicide followed by cryopreservation. The end of your life is an excellent example of a reach where law has run wild to trample on freedom, innovation, and common sense.

The biggest practical issue that results from this legal state of affairs is the uncertain timing. The transition from being alive to being stored in liquid nitrogen should happen as rapidly and smoothly as possible, but that requires trained personnel and equipment. In turn that requires funds, and the greater the uncertainty the more has to be spent to keep those resources on standby. Thus a great deal of the expense and opportunity for delay or slippage in the crucial final days or hours leading up to cryopreservation is in fact the result of laws that prevent assisted suicide and other forms of self-determination in one's own life and body.

Sadly we live in an era in which men are compelled to serve laws, rather than vice versa.

I notice that Alcor recently posted a couple of case summaries; if you are contemplating signing up for cryopreservation then you should take a look. They are good examples of how things tend to go when there are no serious hitches - and I'm sure you can imagine how any additional uncertainties or medical complications could greatly increase the time required on standby and thus the cost.

Case Summary A-2061:

One of our members, A-2061 suffered cardiac arrest at his home in Colorado Springs, CO. The gentleman had suffered from Parkinson's disease for many years and had 24-hour home health care. At the request of the member and the cooperation of the home health care program, Alcor had pre-positioned a mini-medical support kit with instructions for medical professionals, to administer after pronouncement. In the event of a sudden and unexpected clinical death, these important initial medications could be administered, while simultaneously cooling the body with ice. This would accomplish a key first step in the stabilization process that would provide Alcor additional time to respond to the scene while maintaining the hope for a quality cryopreservation. Since this was the exact scenario that played out, our early efforts paid off.

Case Summary A-2420:

Alcor received notice from an extended care facility that one of our members was experiencing a significant decline in health and therefore the family was in the process of changing the patient to hospice care. Alcor's deployment committee was actively involved in monitoring the situation when it was decided to have an Alcor representative at the patient's bedside to better determine when to initiate a full team response. Aaron Drake traveled to St. Louis to interact with the patient, family and medical staff. Throughout the course of the seven days on location, we continually ramped up the level of readiness as the patient's condition worsened

As you can see, one of the services provided by a cryonics group like Alcor is experience in ways to mitigate risk and uncertainty in time of death. People look at Alcor and tend to focus on the vats of liquid nitrogen, stored preservees, and physical premises, but the standby teams, talent, and experience needed to manage the cryopreservation process and its lead-in are no less important.

The Times uses a forthcoming film adaptation as an excuse to pack a little of almost every previously discussed aspect of longevity science into a general interest article. Consider it a sign of the times: "While in the developed world every succeeding generation has enjoyed a longer life expectancy than the one before it - thanks primarily to modern sanitation, nutrition, disease control and a virtual end to infant mortality, which has stretched life expectancy from under 50 years to more than 75 in the past century - it is only this generation that has really dared to think of ageing as a 'disease' that requires curing. So, while the middle-aged of today can look forward to notching up about 80 or 90 years, some biologists have speculated that our children will routinely surpass the 120-year mark with their faculties intact. ... Some researchers believe that if senescence (the ageing of an organism) can be reduced or even reversed, its end point - death - is no longer inevitable. The controversial British researcher Aubrey de Grey sees no reason why the human body cannot last for 1,000 years (barring accidents). He believes that such a modern-day Methuselah already walks among us. De Grey's vision is close to that of 'transhumanists', people who believe in using science to transcend the limitations of being human, the most obvious limitation being death."

Link: http://women.timesonline.co.uk/tol/life_and_style/women/the_way_we_live/article6825180.ece

From the New Scientist: "It is becoming clear that people who break through the 90-plus barrier represent a physical elite, markedly different from the elderly who typically die younger than them. Far from gaining a longer burden of disability, their extra years are often healthy ones. They have a remarkable ability to live through, delay or entirely escape a host of diseases that kill off most of their peers. Supercentenarians - people aged 110 or over - are even better examples of ageing gracefully. ... As a demographic group, they basically didn't exist in the 1970s or 80s. They have some sort of genetic booster rocket and they seem to be functioning better for longer periods of time than centenarians. ... The average supercentenarian had freely gone about their daily life until the age of 105 or so, some five to 10 years longer even than centenarians, who are themselves the physical equivalent of people eight to 10 years their junior. ... Alzheimer's disease, the most common form of dementia, is relatively rare among centenarians yet, intriguingly, autopsies reveal that the brains of the oldest old, who had shown no outward sign of dementia, are sometimes riddled with the lesions associated with Alzheimer's disease. The basis of this resilience to Alzheimer's is largely unknown. The simple fact is that many people who become centenarians seem able to tolerate damage that would significantly harm less robust individuals, and although many suffer from dementia as death draws near, most remain mentally agile well into their nineties."

Link: http://www.newscientist.com/article/mg20327241.300-secrets-of-the-centenarians-life-begins-at-100.html?full=true

Over at h+ Magazine you'll find an interview with Jason Silva, director of The Immortalists short film, and an article by Silva that outlines his view of what he calls Immortalism. I see his positioning in the same vein as the name of the Immortality Institute - the aim is to move the bounds of the discussion over longevity science by planting a flag far out in the field.

But take a look and see what you think.

When Death is an Outlaw

Really, for me the human condition is summed up better by Ernest Becker's work, The Denial of Death, than any other thinker I've come across. He talks about the mantle of this acutely aware, self-aware creature called man that knows he is mortal. And because he knows he is mortal, he has consciously or unconsciously biased all of his actions. This mortality causes a tremendous amount of anxiety. So, we have to do something with that anxiety, right? I think all of our greatest endeavors - as well as our greatest flaws - stem from this acute awareness of mortality.

The desire to transcend this anxiety with technology, rather than art or religion or a romantic relationship or something like that has led me to biotech, nanotech, and the accelerating exponential fashion in which technology was developing.

Immortalism: Ernest Becker and Alan Harrington on Overcoming Biological Limitations

The Immortalist Solution is simply this: the time has come for man to get over his cosmic inferiority complex. To rise above his condition - and to use technology to extend himself beyond his biological limitations. "We must never forget we are cosmic revolutionaries, not stooges conscripted to advance a natural order that kills everybody," says Harrington.

While Ernest Becker identified our need for heroism and our extensive attempts to satisfy it symbolically, Alan Harrington proposes that we move definitively to engineer salvation in the real world. He proposes that we move directly to physically overcome death itself, "Spend the money, [hire] the scientists and hunt down death like an outlaw."

Cosmic revolutionaries indeed. The human race is change and creation made manifest; we no longer live in caves and filth because our ancestors worked hard to alter that reality. Nowadays we live in the midst of a revolution in biotechnology, and far grander aspects of the human condition are ripe for change: disease, aging, pain, frailty, and involuntary death. We and our descendants will engineer away all these things in exactly the same way as our predecessors engineered away past woes.

As a follow-on from Friday's post, allow me to point you to more coverage of the 4th Strategies for Engineered Negligible Senescence conference held over this past weekend. We'll start with an additional post from Ouroboros:

SENS4, Session 12: Novel anti-cancer approaches

Cassian Yee spoke about treating cancer with adoptive T cell therapy. Briefly, it’s a personalized approach to cancer research that attacks tumours using the patient’s own T cells. T cells are extracted, modified in a number of different ways to improve their function, grown into a much larger population, and then finally re-infused back into the patient.

You should also take a look at the SENS4 conference thread at the Immortality Institute. Institute organizer Mind was in attendance and streaming video as the conference progressed; you'll find a number of those videos archived at the Immortality Institute Ustream Channel - including that presentation on adoptive T cell therapy:

• Cassian Yee on using CD4 T cells to treat cancer
• Mind interviews conference organizer Aubrey de Grey
• Mike Berridge on mitochondrial gene deletion and cancer
• Justin Rebo on magnetic removal of senescent white blood cells

Amonst the other material is a three part video of the presentation (part one, part two, part three) given by Natalia Gavrilova on factors influencing survival to the age of 100. Many thanks go to Mind for taking the time and effort to attend the conference and put this all together.

I expect that more material will surface later, as is customary. Past SENS conferences have been well recorded on video, but that material usually required a couple of weeks to make it online in its final form - see the quality videos of presentations given at SENS3 for example.

An interesting paper: "Women experience more years of vigorous life after ovulation has ceased than do females of other primate species. Is this an epiphenomenon of the greater life expectancy humans have enjoyed in the past century or so, or is long post-menopausal survival the result of an evolutionary selection process? Recent research implies the latter: Long post-menopausal survival came about through natural selection. One prominent line of thought explaining this selection process is the grandmother hypothesis. ... The hypothesis contends that, in past epochs, women who remained vigorous beyond their fertile years may have enhanced their reproductive success by providing care for their grandchildren. This care would have enabled their daughters to resume reproduction sooner, endowing them with greater lifetime fertility. Genes of grandmothers possessing such old-age vigor would be more likely to persist in subsequent generations. Is midlife menopause a uniquely human phenomenon, or does the chimpanzee, our closest primate relative, also display this trait? If so, we might expect a grandmother effect in this species as well. However, female chimpanzees continue to cycle until near the end of their maximum life span of about 60 years. ... Long survival beyond fertility and a long life expectancy are distinctive human adaptations."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19729883

Some types of human mitochondrial DNA are objectively better than others, as demonstrated by comparative absence or prevalence in specific population groups. As we move towards technologies capable of replacing age-damaged mitochondrial DNA, consider that we could also be receiving an upgrade - there is no known biological obstacle to completely replacing a mammal's mitochondrial DNA. The new DNA should simply pick up where the old DNA left off and mitochondria will continue to function as intended: "Elite athletic endurance ability involves multiple genetic and environmental factors, with little known about the specific genotypes involved. As a first step to finding genetic markers of endurance performance, we recruited 66 male endurance runners and 110 control athletes. We investigated the distribution of m.5178CA polymorphisms [in mitochondrial DNA] in male endurance runners. Although the m.5178A genotype has been reportedly associated with longevity, endurance runners in this study showed a significantly higher frequency (71.2%) of the m.5178C genotype than control subjects (52.7%). The-m.5178C genotype may be favorable for performance in elite endurance runners."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19717174

What can be achieved through manipulation of skin stem cells? Quite a lot, it seems, and by virtue of its accessibility we might expect to see important techniques first pioneered in skin regeneration: "Recent advances in skin-resident [progenitor cell] research have revealed that these immature and regenerative cells with a high longevity provide critical functions in maintaining skin homeostasis and repair after severe injuries along the lifespan of individuals. ... enhanced ultraviolet radiation exposure, inflammation and oxidative stress and telomere attrition during chronological aging may induce severe DNA damages and genomic instability in the skin-resident [progenitor cells] and their progenies. ... The progressive decline in the regenerative functions and/or number of skin-resident [progenitor cells] may cause diverse skin diseases with advancing age. Moreover, the photoaging, telomerase re-activation and occurrence of different oncogenic events in skin-resident [progenitor cells] may also culminate in their malignant transformation into [cancer stem cells] and skin cancer initiation and progression. Therefore, the anti-inflammatory and anti-oxidant treatments and stem cell-replacement and gene therapies as well as the molecular targeting of their malignant counterpart, skin cancer-initiating cells offer great promise to treat diverse skin disorders and cancers."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19725922

Here is another review paper examining the (strong) evidence for the central role of autophagy in the way in which metabolism determines natural longevity: "The accumulation of cellular damage is a feature common to all aging cells and leads to decreased ability of the organism to survive. The overall rate at which damage accumulates is influenced by conserved metabolic factors (longevity pathways and regulatory proteins) that control lifespan through adjusting mechanisms for maintenance and repair. Autophagy, the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles, is implicated in aging and in the incidence of diverse age-related pathologies. Recent evidence has revealed that autophagic activity is required for lifespan extension in various long-lived mutant organisms, and that numerous autophagy-related genes or proteins are directly regulated by longevity pathways. These findings support the emerging view that autophagy is a central regulatory mechanism for aging in diverse eukaryotic species."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19726187

Ouroboros contributer Kristen Fortney is covering the 4th Strategies for Engineered Negligible Senescence conference, presently underway in Cambridge. A wide range of researchers are gathered for one of the few scientifically respectable conferences to focus on the elimination of aging and repair of age-related damage in the old - though a lot of the work presented yesterday only pertains to slowing the progress of aging.

Some selected excerpts from the first two days of the conference are linked below, and you might want to wander over to the SENS Foundation website and look at the conference presentation abstracts or the program to see what's coming up next.

SENS4, Session 1: Combating oxidation

Cathy Clarke tested an original and interesting approach to avoiding free radical damage to poly-unsaturated fatty acids, or PUFAs: isotope reinforcement. ... The basic idea here, explained in an earlier paper, is very simple: heavier isotopes make stronger bonds, so isotope-reinforced PUFAs will be more resistant to free radical attack. Will these results transfer to higher organisms? Is there any chance that the deuterium could get incorporated into other molecules, stabilizing proteins that we want to degrade? The authors plan to follow up this study in worms and mice.

SENS4, Session 3: Optimising metabolism against aging

Stephen Spindler described his (ongoing) project to screen a large number of potential lifespan-affecting compounds in mice - so far, several candidates look promising. Interestingly, he also argued that the majority of previous studies measuring the effects of various compounds on rodent life expectancy suffer from serious flaws. In particular, he argued that many of them were confounded by a possible calorie restriction effect: mice are picky eaters, and if you change their diet by adding some compound to it, they will often eat less of it.

SENS4, Session 4: Adult regenerative capacity

Brandon Reines presented a counterintuitive result on regeneration: sometimes old animals have a higher regenerative capacity than young animals. In particular, if you punch a hole in the ear of a young mouse, then it won’t heal; but in a middle-aged mouse it will heal completely. He argued that this happens because mouse ear connective tissues never fully differentiate, and suggested that other neural-crest-derived connective tissues might show similar properties.

SENS4, Session 5: Eliminating recalcitrant intracellular molecules: the lysosome

John Schloendorn discussed ongoing work at the SENS Foundation Research Center to develop new enzymes that can degrade harmful intracellular junk that accumulates with age. So far, they have discovered enzymes that can degrade A2E and 7-ketocholesterol, which are implicated in macular degeneration and osteoporosis, respectively. Their next step will be to construct a drug delivery system to get these enzymes to lysozomes ... On the lighter side, Schloendorn also described some of the Center’s methods for building functional lab equipment on the cheap, all good examples for aspiring DIY biologists.

SENS4, Session 6: Eliminating recalcitrant intracellular molecules: other

Claude Wischik spoke about preventing aggregation of tau protein, which is implicated in Alzheimer’s disease. Clinical trials of their aggregation-inhibiting drug Rember are promising: it seems to slow the down the rate of cognitive decline in patients with mild to moderate Alzheimer’s disease.

SENS4, Sessions 9 and 10: Rejuvenating extracellular material

Kendall Houk gave a very interesting talk on computationally designing enzymes from scratch. They plan to apply their recently published protocol to develop enzymes that can reverse the formation of Advanced Glycation End-products (AGEs) - sugar-modified proteins that accumulate with age and are implicated in several age-related diseases.

One of the many lines of longevity research I've watched over the past couple of years is the work of Vladimir Skulachev on chemicals that target mitochondria when ingested and work as antioxidants to soak up the free radicals that mitochondria produce in the course of their role as the cell's power plants. Preventing the damage that those mitochondrial free radicals would have caused has the effect of extending life - aging is nothing more than the accumulation of damage, after all.

Skulachev's laboratory has demonstrated a 30% healthy life extension in mice through this methodology, while US research groups have used the naturally produced antioxidant catalase and gene engineering to achieve much the same sort of end result: antioxidants localized to mitochondria, and extension of healthy life in mice.

Skulachev, I should note, is involved in the Russian initiative Science Against Aging, and will be presenting at the forthcoming 4th Strategies for Engineered Negligible Senescence conference. I should direct your attention to the abstract of his study, which gives more details on the chemicals used:

There are numerous indications that senescence program declines physiological functions by means of toxic reactive oxygen species (ROS) produced in mitochondria. Hence, one may hope that mitochondrial-targeted antioxidants might be inhibitors of the senescence program. To study such a possibility, a project has been established with participation of several research groups from Russia, Sweden and USA.

A new type of compounds (SkQs) composed of plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized. Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyl decyltriphenylphosphonium (SkQ1), plastoquinonyl decylrhodamine 19 (SkQR1), and methylplastoquinonyl decyltriphenylphosphonium (SkQ3).

...

In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, anemia, disappearance of estrous cycles in females and libido in males, peroxidation of lipids and proteins, etc.

Give the biotech revolution another decade, and synthesizing this sort of stuff in your garage - and then running lifespan studies on flies or nematodes - will be an affordable and plausible project for participants in the open biotech movement.

Another good reason to keep up with exercise: "Age is the major risk factor for cardiovascular diseases (CVD) and this is attributable in part to stiffening of large elastic arteries and development of vascular endothelial dysfunction (e.g., impaired endothelium-dependent dilation, EDD). In contrast, regular aerobic exercise is associated with reduced risk of CVD. Endurance exercise-trained middle-aged/older adults demonstrate lower large elastic artery stiffness and greater EDD than their sedentary peers. With daily brisk walking, previously sedentary middle-aged/older adults show reduced stiffness and improved EDD. The mechanisms underlying the effects of regular aerobic exercise on large elastic artery stiffness with aging are largely unknown, but likely include changes to the composition of the arterial wall. Enhanced EDD in older adults who exercise is mediated by increased nitric oxide (NO) bioavailability associated with reduced oxidative stress. Arteries from old rodents that undergo aerobic exercise training demonstrate increased expression and activity of endothelial NO synthase, reduced oxidative damage associated with reduced expression and activity of the oxidant enzyme NADPH oxidase, and increased activity of the antioxidant enzyme superoxide dismutase. Aerobic exercise also may protect arteries with aging by increasing resistance to the effects of other CVD risk factors like LDL-cholesterol. Habitual aerobic exercise is an effective strategy to combat arterial aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19723776

Thoughts from Anne C.: "however you do it, the important thing is to get your brain geared up to more accurately assess reality, and the claims people make about it. See, there are plenty of hucksters out there who would probably be more than willing to sell you their Super-Longevity Bio-Kit or some other quackish nostrum. And despite not being a biologist myself, I think I'm at least informed enough on the subject of biogerontology to be able to tell you that anyone who claims to have the 'path to immortality' is either deluded or lying. Hence, taking people who make such claims seriously is likely to be a waste of time for everyone involved, and obviously over time this kind of thing is likely to lead to less actual useful real-world work [on engineered longevity] being done. ... Here in the real world, the best any of us can do if we want longer, healthier lives for our loved ones and ourselves is contribute toward actual real-world things that promote health, life, and solid research. And in order to figure out what projects are valid and worth supporting, or worth proposing and starting ourselves, critical thinking is utterly essential."

Link: http://www.existenceiswonderful.com/2009/09/on-longevity-reality-and-critical.html

By now, I would hope, the life science horror stories that turn up here on a regular basis will have convinced you that excess body fat is not good for your long term health and longevity. Some of that is the result of the biochemistry of fat tissue en mass, and some of that is the reaction of your metabolism to the sedentary, high-calorie lifestyle required to gain that fat tissue, but the end result isn't pretty. More fat means a lowered life expectancy and a greater risk of all the common age-related diseases - and the decades of suffering in health and wallet that come with them.

Being overweight is a choice for 99.9% of people. A seductive, easy choice to slip into in a wealthy society whilst surrounded by an adundance of food, but a choice nonetheless. You might think of doing something about that.

In any case, today I thought I'd showcase another motivativational piece of research on the consequences of excess body fat, this time as it relates to the degeneration of your immune system. One of the reasons your immune system fades and fails with age is the involution - or shrinkage and atrophy - of the thymus, the organ responsible for sheltering the growing population of T cells:

The immune system undergoes dramatic changes with age - the thymus involutes, particularly from puberty, with the gradual loss of newly produced naive T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells. Coupled with a similar, though less dramatic age-linked decline in bone marrow function, this translates to a reduction in immune responsiveness

As it turns out, excess body fat speeds this process, to the detriment of health. The immune system performs many vital tasks, such as destruction of senescent or cancerous cells, in addition to dealing with outside threats, and all worsen as the thymus progressively declines:

As the expanding obese population will grow older, their successful immunological aging will be critical to enhancing the health-span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune-surveillance. Here we report that obesity compromises the mechanisms regulating T cell generation via inducing premature thymic involution.

Diet-induced obesity (DIO) reduced thymocyte counts and significantly increased apoptosis of developing T cell populations. Obesity accelerated the age-related reduction [in] recently generated T cells from thymus. Consistent with reduced [T cell creation], dietary obesity led to reduction in peripheral naive T cells

...

In middle-aged humans, progressive adiposity with or without Type-2-Diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T cell diversity by accelerating age-related thymic involution.

You can't say that you weren't warned.

Yang H, Youm YH, Vandanmagsar B, Rood J, Kumar KG, Butler AA, & Dixit VD (2009). Obesity accelerates thymic aging. Blood PMID: 19721009

From Vision: "That our allotted time on this earth is somewhat fleeting has surely not escaped us, especially as we move farther down our life path. ... In recent years, however, a building revolution in the science of gerontology has heralded the possibility of life extension. This is leading some to speculate about just what the limits to human life might be; adding another decade or two or even centuries might be possible. ... As our knowledge of the biochemistry of aging increases exponentially, it is no surprise that around the globe scientists are discovering hopeful paths that will provide ways to increase human longevity. Meanwhile, biotechnology companies are seeking to bring new products to market - drugs, cells, tissues, and procedures - which they, too, hope will go some way toward extending life as well as bring a profit. ... Is death therefore in terminal decline? While the commercial and media hype concerning such a possibility has dismayed some mainstream scientists, others such as Aubrey de Grey have spearheaded efforts to, as he puts it, 'cure the disease of aging.' The [SENS Foundation] chairman and biogerontology researcher is not only chasing the dream of immortality; he expects to catch it."

Link: http://www.vision.org/visionmedia/article.aspx?id=18195

Cryonics provider Alcor has an email newsletter that you might consider signing up for if you'd like to learn more about how cryonics works and the concerns and day to day operations of a provider. For example: "Several outreach initiatives are underway. It has been established that a primary source of membership growth is referral by existing Alcor members, so several board directors have begun proactively contacting prospective members. These communications have the side benefit of offering constructive feedback that will help improve the organization. For instance, one of the individuals informed us that the subscription process for Alcor News was not functioning properly. The malfunction has now been resolved. Another outreach initiative is the formation of a Communications Committee, also composed largely of board directors. Among other endeavors, committee members will participate in screening or soliciting media opportunities and live speaking engagements, identifying appropriate speakers, developing talking points and encouraging media training."

Link: http://four.pairlist.net/mailman/listinfo/AlcorNews

While sirtuins extend life in lower animals, manipulation of sirtuins in mammals hasn't produced the sort of enhanced longevity seen in other genetic engineering techniques, or even just plain old calorie restriction. Here, a reason is suggested: "Sir2 mediates lifespan extension in lower eukaryotes but whether its mammalian homolog, SIRT1, is a longevity protein is controversial. We stably introduced the SIRT1 gene into human vascular smooth muscle cells (SMCs) and observed minimal extension of replicative lifespan. However, SIRT1 activity was found to be exquisitely dependent on nicotinamide phosphoribosyltransferase (Nampt) activity. Moreover, overexpression of Nampt converted SIRT1-overexpressing SMCs to senescence-resistant cells [with] strikingly lengthened replicative lifespan. Thus, SIRT1 can markedly postpone SMC senescence, but this requires overcoming otherwise vulnerable NAD(+) salvage in aging SMCs." With the caution that results in cells are not results in whole animals, you might want to take a look at the role of NAD+ in cells. It is part of a cycling mechanism of metabolism that can cause all sorts of issues if disrupted.

Link: http://www.ncbi.nlm.nih.gov/pubmed/19716821

One of the reasons that the immune system degenerates with age is, and I greatly simplify the reality on the ground in saying this, that only a limited number of immune cells can be supported at once. As the years roll on more and more of the immune cells known as T cells become memory T cells, dedicated to remembering specific threats. That leaves less and less room for naive T cells that can go out and stomp on new threats. Thus as your immune system becomes ever more knowledgable, it also becomes less and less effective at its primary missions - including destroying pathogens, destroying senescent cells, and destroying early stage cancers.

Now in theory, an old immune system that is top-heavy in memory T cells could be at least partially restored (remember that there are other issues and degenerations beyond the one I discuss here) by destroying all the unwanted memory cells. In recent years researchers have destroyed and then used stem cells to recreate the entire immune system in human trial patients, and have done this to essentially remove misconfigured immune cells that were the source of an autoimmune disorder. If that can be done, then it should certainly to be possible to take one of the new generation of targeted cell destruction technologies developed in the cancer researcher community and use to it destroy only a specific population of T cells.

Recall that T cells, like all cells, are richly decorated with specific receptor molecules on the surface, molecules going by such descriptive names as CD28, CD8, or CD4. A cell with a CD8 receptor is called CD8+ for example, though cells can have many combinations of receptors (e.g. CD4+/CD8+/CD28-). Researchers will generally refer to a cell type by the receptors they are interested in at that moment rather than list them all. The surface receptors of T cells are well understood, and would make good targets for engineered viruses or nanoparticles designed to seek out specific cell receptors and kill the cell bearing them.

Is the excess population of memory T cells in an old immune system needed for anything else, however? Would destroying them remove needed portions of the immune system's programming and thus lead to issues more critical than those suffered before the procedure? Recent research suggests that this is not the case:

Highly differentiated CD28 effector T cells which accumulate in a variety of diseases and also with increasing age contribute to inflammatory processes, limit immunological space and diversity, and are associated with immunological dysfunction and reduced responses to vaccination. Elimination of CD28 T cells has been suggested as a measure for immunological rejuvenation but may lead to the loss of important T cell specificities.

...

we show that the same clonotypes are present in CD8(+)CD28(+) naive/early memory and CD8(+)CD28 effector T cells. Therefore, CD28 cells do not seem to contain clones which are not present in the residual population. The elimination of effector T cells would not lead to the loss of important specificities, as relevant clonotypes could be recruited and propagated from naive or early memory T cell subsets in the case of exposure to pathogen.

Which sounds promising from the point of view of moving right on ahead with the destruction of the dead wood. I expect it will not be too many more years before researchers are performing selective culls on old immune systems in order to see if this strategy can indeed produce significant rejuvenation to a more youthful level of performance.

Weinberger B, Welzl K, Herndler-Brandstetter D, Parson W, & Grubeck-Loebenstein B (2009). CD28(-) CD8(+) T cells do not contain unique clonotypes and are therefore dispensable. Immunology letters PMID: 19715728

At least some cases of Parkinson's disease are spurred on by mitochondrial failure: "Parkinson's disease is caused by the degeneration of neurons in the midbrain. The mechanisms leading to the loss of these neurons, however, are largely unknown. Recent research revealed that about ten per cent of cases are caused by defects in so-called Parkinson-associated genes. Furthermore, mitochondria, the cellular powerhouses, seem to play a major role. New results [connect] both phenomena, showing that two Parkinson genes maintain the function of mitochondria. ... Functionally impaired mitochondria have been recognized to trigger Parkinson's disease already in the early eighties ... The relevance of mitochondria to the loss of neurons seems plausible - after all, mitochondria supply the cells with energy in form of adenosine triphosphate and play a substantial role in the regulation of cell death. ... Parkinson-associated genes PINK1 and Parkin functionally interact to maintain mitochondrial function. Loss of Parkin or PINK1 function impairs the morphology and activity of mitochondria, which then produce less adenosine triphosphate."

Link: http://www.sciencedaily.com/releases/2009/08/090824115756.htm