Fight Aging!

As I noted a little while ago, the SAGE Crossroads website rose from the dead this year to restart its series of podcasts on aging research and longevity science, with a focus on policy matters and publicly funded research. That slant isn't quite my cup of tea, but each to their own. The most recent four podcasts are themed on economics:

What do the current economic models say about longevity?

KYLE JENSEN: The audience of the SAGE Crossroads website is made up of scientists, policy makers, and curious consumers. If there is one last statement you would like to make to them regarding the economics and longevity science in the future, what would it be?

ROBERT FOGEL: Don’t be afraid of it; it’s actually the leading industry. The demands of healthcare are going to pull all other industries forward. Of course they require new technologies in steel and heavy industry and as well as delivery systems. I think they should be looked at positively. Again I say if this were a privatized system, we would all say “gee it’s wonderful. All these people want more health care, this industry is thriving”. Let me put one other analogy. Suppose we made cars a government entitlement. Instead of cheering when auto production went up, we’d say, “Oh my God, we can’t afford this!”. How you finance it may greatly affect the psychology and actually the freedom of the economy to take advantage of these new opportunities.

Which is interesting, as this fellow spends the rest of his talk telling us that government entitlements are great and can always be fixed if they're not. "Fixed" is a word that springs to mind, yes, but not in the sense of "repaired."

How does longevity science contribute to the economy?

KYLE JENSEN: Mr. Perry, how have developments in aging research, longevity science, and public health affected the ways that Americans live the 65 plus years of their life?

DANIEL PERRY: Well, we are probably too close to the changes to appreciate them and to understand them, but we’ve really succeeded in scrambling the images of life’s mileposts of aging. We’ve added 50% to average life expectancy in the last 100 years, and all of the studies suggest that people are not only living longer, but they are living with less disability and they are healthier than any other time we have known in the past. The short hand for this is to say that 50 is the new 30 or that 65 and 70 are still the prime years of life, and I wouldn’t be a bit surprised if we were going to be saying that 85 is the new 60 before very long. In fact, at age 65, which at one point most Americans considered the beginning of the end if you will, most Americans can count on living another 18 years of life, and half of them will live past 90. All of this has had huge positive economic impact. The vast majority of people at middle age are now saying in surveys that they expect to work well past retirement age, traditional retirement age, half expect to work into their 70s, either because they need to or because they want to stay working and engaged.

Measuring the economic benefits of medical research and longevity science

KYLE JENSEN: Your work also seems to argue that longer, healthier life is very valuable yet historically undervalued and conservative. Why do you believe this is true?

DAVID MELTZER: Well, so the way I like to think of it is in terms of length of life and quality of life. So a lot of work in medical cost effective analysis and in other areas have tried to determine the gains to health in terms of both length of life and quality of life. You then weigh those gains versus the costs of the interventions that produce them. What my work is focused on, or at least an aspect of my work, is understanding how extensions of life create costs in ways that may not be obvious. So, for example, when you live longer, you have more years in which you have to support the cost of being alive, medical expenditures. Conversely, if you're living longer and working, you take earnings away from that. It's traditionally been the case that fields of medical cost effective analysis haven't included costs of living longer. As a result, cost effectiveness has also systematically underestimated the costs of life extending interventions. In contrasts, interventions that improve the quality of life don't have these costs due to length of life. As a result, there has tended to be a bias in traditional methods of cost effective analyses. You spend too much money on things that make you live longer relative to things that improve the quality of life. And that's been one of the major focuses in the work that I've done on cost effectiveness.

This way of looking at things is very much a function of the limited medical technology of today. When you can ensure increased longevity with accompanying extension of health - which is very much not the focus of mainstream aging and late-life disease research today - economic problems go away. Daniel Perry has it right: a healthy, working person at any age is a net producer of wealth. The more healthy people that exist, and the longer they live, the more wealth is produced.

Trying to find any economic benefit or trade-off in loss of function and aging to death is a form of the broken window fallacy. Destruction is always, exactly, and only destruction - there is no gain that comes from it.

Why living longer can only be beneficial to society

KYLE JENSEN: Do you feel that Americans that are living longer would impact social security, Medicare, and various other entitlement fields negatively?

GREGORY STOCK: Well, they certainly should impact those programs. The question is that these kinds of programs which always come up in these kinds of discussions are set up so that people when they are no longer functional and vital are able to be supported in some way by society, so if you have much, much older people chronologically that can be fully active and participate in society, then they should have to do that or should have to provide for themselves. And, you know, the other point of it is that something like social security is already going to be bankrupt, so of course if you have people living longer and you don’t make any adjustments and you try to support a large segment of the population that isn’t going to be a good solution.

KYLE JENSEN: Do you think we are on the right track to revamp those programs?

GREGORY STOCK: I don’t think we’re doing much at all, but those things will clearly occur and the political process will allow them to occur and will force them to occur when there is a real problem that is proximate rather than some real distant thing that can be passed off or left to the next generation or to later politicians.

Radical change is certainly ahead, as the present culture of entitlements and forced wealth transfer is barely sustainable even without the near future technologies of healthy life extension. Something has to give, and the longer the present political system lasts, the worse off we'll all be.

Via ScienceDaily, continued progress in instructing our cells to do the right thing: "In recent years, stem cell researchers have become very adept at manipulating the fate of adult stem cells cultured in the lab. Now, [researchers] achieved the same feat with adult neural stem cells still in place in the brain. They successfully coaxed mouse brain stem cells bound to join the neuronal network to differentiate into support cells instead. ... It was quite surprising that stem cells in the adult brain maintain their fate plasticity and that a single gene was enough to reprogram these cells. We can now potentially tailor the fate of stem cells to treat certain conditions such as multiple sclerosis. ... The discovery [not] only attests to the versatility of neural stem cells but also opens up new directions for the treatment of neurological diseases, such as multiple sclerosis, stroke and epilepsy that not only affect neuronal cells but also disrupt the functioning of glial support cells."

Link: http://www.sciencedaily.com/releases/2008/06/080630093621.htm

EurekAlert! reports on a very promising cancer therapy that's been featured at SENS conferences in the past: "The treatment will involve transfusing specific white blood cells, called granulocytes, from select donors, into patients with advanced forms of cancer. A similar treatment using white blood cells from cancer-resistant mice has previously been highly successful, curing 100 percent of lab mice afflicted with advanced malignancies. ... In mice, we've been able to eradicate even highly aggressive forms of malignancy with extremely large tumors. Hopefully, we will see the same results in humans. Our laboratory studies indicate that this cancer-fighting ability is even stronger in healthy humans ... The team has tested human cancer-fighting cells from healthy donors against human cervical, prostate and breast cancer cells in the laboratory - with surprisingly good results. ... In a small study of human volunteers, the scientists found that cancer-killing activity in the granulocytes was highest in people under age 50. They also found that this activity can be lowered by factors such as winter or emotional stress. They said the key to the success for the new therapy is to transfuse sufficient granulocytes from healthy donors while their cancer-killing activities are at their peak level."

Link: http://www.eurekalert.org/pub_releases/2008-06/wfub-ci062308.php

Cells would do as we desired, changing form and purpose, if we just understood the vocabulary and timing of biochemical signals. ScienceDaily relays another step forward to that end goal: researchers have "genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain ... mice afflicted by stroke showed tangible therapeutic improvement following transplantation of these cells. None of the mice formed tumors, which had been a major setback in prior attempts at stem cell transplantation. ... MEF2C is a transcription factor that turns on specific genes which then drive stem cells to become nerve cells. ... To move forward with stem cell-based therapies, we need to have a reliable source of nerve cells that can be easily grown, differentiate in the way that we want them to and remain viable after transplantation. MEF2C helps this process first by turning on the genes that, when expressed, make stem cells into nerve cells. It then turns on other genes that keep those new nerve cells from dying. As a result, we were able to produce neuronal progenitor cells that differentiate into a virtually pure population of neurons and survive inside the brain."

Link: http://www.sciencedaily.com/releases/2008/06/080624174843.htm

Anders Sandberg provides a transhumanist perspective on the problem that plagues aging research, as well as other fields of medicine - a phobia of vision and directed goals: "Senior scientists and technologists are often asked about their visions and views about the future [but the] economics of research favours talking about means rather than ends, and the allowable ends will be short-term generally agreed on goods. Grants applications dutifully mentions cures for Alzheimers and increased economic competitiveness ... the biotechnology debate has become impoverished: professional competition has shifted the debate away from a 'thick' substantively rational debate about the ends of genetic engineering to a 'thin' formally rational debate about the means to achieve a few predetermined ends like safety, efficiency and health. That has left a lot of people (both for and against) disaffected and unable to participate in the mainstream thin debate since they really want to discuss thick issues. This is why I think the 'shut up, you are scaring the grant bodies' approach the wrong one. They should be scared. Otherwise we will have a science and technology where acceptable research is determined by unaccountable minorities setting 'proper' goals, rather than by a society where numerous wildly different views need to coexist. The big, dramatic and far-fetched transhumanist visions have a place here as values and ends to aim."

Link: http://www.aleph.se/andart/archives/2008/06/dont_scare_the_kids_and_grant_bodies.html

I notice that two good review papers on the topic of stem cells, stem cell niches and aging are presently freely available in the latest Aging Cell. Journal publishers tend to put out these free full text promotions for a limited time, so take a look while the looking is there.

Stem Cell Review Series: Aging of the skeletal muscle stem cell niche

Declining stem cell function during aging contributes to impaired tissue function. Muscle-specific stem cells ('satellite cells') are responsible for generating new muscle in response to injury in the adult. However, aged muscle displays a significant reduction in regenerative abilities and an increased susceptibility to age-related pathologies. This review describes components of the satellite cell niche and addresses how age-related changes in these components impinge on satellite cell function.

You can find more about satellite cells and the aging stem cell niche back in the Fight Aging! archives as well. Just follow those links.

Stem Cell Review Series: Regulating highly potent stem cells in aging: environmental influences on plasticity

Significant advances in the past decade have revealed that a large number of highly plastic stem cells are maintained in humans through adulthood and are present even in older adults. These findings are notable in light of the reduced capacity for repair and regeneration in older tissues. The apparent dichotomy can be reconciled through an appreciation of the age-associated changes in the microenvironmental pathways that govern adult stem cell plasticity and differentiation patterns.

As this second paper illustrates, the weight of evidence is shifting to the view that we are packed full of functional stem cells even as we age. These stem cell populations are shut down by changes in biochemical signals and systems, possibly due to accumulated damage that causes aging and malfunction, possibly as an evolved defense against the increasing likelihood of cancer in old tissue. As cancer medicine becomes increasingly sophisticated, safe and effective, learning the signals to set our stem cells back to work begins to look like a plausible near term strategy for enhancing longevity.

The Aging 2008 event at UCLA is tomorrow evening, leading into the Understanding Aging conference: "Applying the new technologies of regenerative and genetic medicine, the engineering approach to aging promises to dramatically extend healthy human life within the next few decades. How do you and your loved ones stand to benefit from the coming biomedical revolution? Are you prepared? Is society prepared? At Aging 2008 you will engage with top scientists and advocates as they present their findings and advice, and learn what you can do to help accelerate progress towards a cure for the disease and suffering of aging. Doors open at 4:00 pm on June 27th, 2008, at UCLA's Royce Hall. All attendees must register in advance; entry is free and includes a complimentary drinks reception before the presentations begin. For an additional $30, attendees also have the opportunity to attend a special dinner with the speakers."

Link: http://www.mfoundation.org/ADCI/

The Aging Intervention Foundation is another new nonprofit initiative in the same sphere of advocates and scientists as the Gerontology Research Group and Supercentenarian Research Foundation: "The Aging Intervention Foundation (AIF) was created to develop new therapies to control and reverse the underlying causes of aging, as well as treat and prevent the diseases of aging. The goal is to eventually control the processes of aging, reverse their effects, and stay younger longer - and ultimately create indefinite youthful, happy and productive lifespan using innovative scientific methods that are under development today in biotech companies and research labs around the world. ... We'll accomplish these goals by creating strategic partnerships with world class organizations. The AIF will provide the vision, clearly defined project plan and goals, specific technical expertise and money. All teams will be racing together toward the common goal of greatly extending and improving our lifespan, and the quality of our lives." We should encourage these seeds to grow from their humble beginnings, as some do very well indeed, and the more that do, the faster we progress towards working longevity medicine.

Link: http://www.agingintervention.org/

A timely piece in Wired today:

Gandhi once said, describing his critics, "First they ignore you, then they laugh at you, then they fight you, then you win."

After declaring, essentially out of nowhere, that he had a program to end the disease of aging, renegade biogerontologist Aubrey de Grey knows how the first three steps of Gandhi's progression feel. Now he's focused on the fourth.

"I've been at Gandhi stage three for maybe a couple of years," de Grey said. "If you're trying to make waves, certainly in science, there's a lot of people who are going to have insufficient vision to bother to understand what you're trying to say."

This weekend, his organization, The Methuselah Foundation, is sponsoring its first U.S. conference on the emerging interdisciplinary field that de Grey has helped kick start. (Its first day, Friday, will be free and open to the public.) The conference, Aging: The Disease - The Cure - The Implications, held at UCLA, is an indication of how far de Grey has come in mainstreaming his ideas.

The Methuselah Foundation's research is beginning to produce results:

In research that will first be presented on Friday at the conference, Methuselah-funded scientists will demonstrate a proof-of-concept experiment for using bacterial enzymes to fight atherosclerosis, or the hardening of the arteries. That's an idea that de Grey has been pushing for years.

The signs continue to be promising for the Methuselah Foundation to be the boulder that leads the avalanche, gathering legitimacy and researchers to the task of repairing aging at an accelerating rate. Those folk who helped to get this initiative off the ground back in 2004 should be feeling pretty pleased right about now.

The Telegraph reports on a new finding in the biochemistry of human longevity: "White blood cells fend off infection - in effect delaying death - so [researchers] investigated longevity by taking samples of white blood cells from 45 men and women aged between 75 and 90 who all had parents born in Sicily between 1900 and 1908. Twenty-five of the donors had one parent who had reached 100 and one who had died of old age before reaching average life expectancy for Italians - which is 67 for men and 72 for women. The remaining 20 donors served as controls having lost both parents before they reached average life expectancy ... Our main finding was the increase in naive B-cells in individuals who had centenarian parents ... Unlike mature B-cells - which are primed to attack foes the body has seen before - naive B-cells are ready and waiting to attack microbes not previously encountered." You'll recall that depletion of naive T-cells is a strong component of immune system aging. As naive cells diminish, the ability to mount a response to new challenges also diminishes.

Link: http://www.telegraph.co.uk/news/uknews/2194078/Blood-tests-'could-be-used-to-predict-lifespan'.html

From ScienceDaily: researchers have confirmed that "epigenetic marks on DNA - chemical marks other than the DNA sequence - do indeed change over a person's lifetime, and that the degree of change is similar among family members. The team suggests that overall genome health is heritable and that epigenetic changes occurring over one's lifetime may explain why disease susceptibility increases with age." Alternately, and more likely in my opinion, epigenetic changes are cellular responses to an increasing level of biochemical damage and damage-induced changes in the operation of bodily systems. We should expect to see epigenetic changes when anything relating to the body is changed, all the way from diet and exercise to immune system aging or accumulation of amyloid between cells, and everything in between. Still, research is at its earliest stages, and any hint of correlations in epigenetic changes across larger populations is intriguing.

Link: http://www.sciencedaily.com/releases/2008/06/080624174849.htm

Hair loses its color with age due to a decline in activity of melanocyte pigment-producing cells, likely another symptom of the general fading of stem cell populations throughout the body. A recent paper adds evidence for that view:

Hair graying is one of the prototypical signs of human aging, but its mechanism is largely unknown. To elucidate the mechanism of hair graying, we investigated gene expression related to melanogenesis in human hair.

The key molecules in melanogenesis, microphthalmia-associated transcription factor-M (MITF-M), Sox10, Pax3, tyrosine related protein-1 (TRP-1), and tyrosinase, were absent or greatly reduced in the bulbs of white hair compared to black hair.

Melanocyte stem cells (MSCs) or melanocytes express markers for neural crest cells, Sox10, Pax3, and MITF-M. Taken together, our data suggest that hair graying is caused by defective migration of MSCs into the bulb area of hair.

Setting any given group of aging stem cells back to work by introducing appropriate biochemical signals - or cloning many more stem cells to reintroduce into the body - are very plausible projects for the decade ahead. Either could greatly improve the immediate situation, and the second strategy has already been demonstrated in heart therapies. I can envisage cloning and reintroduction of massive numbers of melanocytes as a clinical method to reverse hair graying in the late 2010s.

Risk of cancer is the challenge to all these attempts to put stem cells back to work in the aging body. That risk is why evolution has left us with stem cell populations that decline in old age, as damage to cells and biological systems is accumulating. Introducing cloned stem cells seems pretty safe, based on the evidence to date, but turning stem cells back on through the use of biochemical signals is much more of an unknown. This challenge will be overcome, but it's yet more of an incentive to address the fundamental issue of age-related biochemical damage rather than patching issues one by one.

You'll recall that mice with the PAPP-A gene deleted live 30% longer in good health than their fellows. Following up, researchers are eliminating possibilities in the search for the mechanism of action: "We determined whether 18-month-old PAPP-A knock-out (KO) mice compared to their wild-type [WT] littermates have reduced energy expenditure and/or altered glucose-insulin sensitivity. Food intake, and total energy expenditure and resting energy expenditure as measured by calorimetry, were not different between PAPP-A KO and WT mice ... However, there was an increase in spontaneous physical activity in PAPP-A KO mice. Both WT and PAPP-A KO mice exhibited mild insulin resistance with age, as assessed by fasting glucose/insulin ratios. Oral glucose tolerance and insulin sensitivity were not significantly different between the two groups of mice ... Thus, neither reduced 'rate of living' nor altered glucose-insulin homeostasis can be considered key determinants of the enhanced longevity of PAPP-A KO mice." We'll be hearing more on this topic in the years ahead, I'm sure - more healthy life with no downside through a simple genetic manipulation is an attractive idea.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18566100

Age-damaged mitochondria are age-damaged because they have lost genes necessary to produce proteins they need to function. This damage causes a good degree of age-related degeneration. There are a number of approaches here: fix the mitochondrial DNA, or provide the proteins some other way. New reseach suggests a novel way to accomplish the latter goal: "Scientists have determined that human cells are able to shift important gene products into their own mitochondria ... The gene products, known as tRNAs, assemble amino acids for the production of proteins within mitochondria. If the mitochondrial tRNA genes are defective or missing, and proteins are not manufactured, the mitochondria are unable to generate adequate energy. ... This was totally unexpected, to find an innate, built-in mechanism that we humans have ... If you have a mutation in a tRNA that you suspect is involved in disease, you theoretically should be able to bring a healthy tRNA from the cytoplasm into the mitochondria and correct the malfunction."

Link: http://researchnews.osu.edu/archive/mitorna.htm

We know that calorie restriction slows the accumulation of nuclear DNA damage - possibly by enhancing DNA repair mechanisms - just as it slows more or less every other age-related change of interest that scientists have investigated. The degree to which ongoing random damage to nuclear DNA contributes to degenerative aging is debated, however:

A paper by Aubrey de Grey outlines his view of nuclear DNA damage and aging: "Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage - whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones - has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer. However, its role in contributing to the rates of other aspects of aging is less clear. Here I argue that, in animals prone to cancer, evolutionary pressure to postpone cancer will drive the fidelity of nDNA maintenance and repair to a level greatly exceeding that needed to prevent nDNA damage from reaching levels during a normal lifetime that are pathogenic other than via cancer or, possibly, apoptosis resistance." In other words, beyond sufficient work to prevent cancer, we don't need to repair nuclear DNA over a human lifetime. Maybe. This debate is ongoing; there are many others who argue that DNA damage is an important root cause of aging.

A paper caught my eye today - a comparison in mice of the effects of calorie restriction versus Ames dwarfism on nuclear DNA damage. Both extend life, and both reduce DNA damage:

Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis [i.e. Ames dwarfism] significantly increase life span in the mouse and reduce multiple symptoms of aging, including cancer.

To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from tissues and organs into Escherichia coli to measure mutant frequencies. Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf.

While both CR wild-type and ad lib dwarf mice lived significantly longer than the ad lib wild-type mice, under CR conditions dwarf mice did not live any longer than ad lib wild-type mice. While this may be due to an as yet unknown adverse effect of the C57BL/6J background, it did not prevent an effect on spontaneous mutation frequencies at the lacZ locus, which were assessed in liver, kidney and small intestine of 7- and 15-month-old mice of all four cohorts.

A lower mutant frequency in the ad lib dwarf background was observed in liver and kidney at 7 and 15 months of age and in small intestine at 15 months of age as compared to the ad lib wild-type. CR also significantly reduced spontaneous mutant frequency in kidney and small intestine, but not in liver. In a separate cohort of lacZ-C57BL/6J mice CR was also found to significantly reduce spontaneous mutant frequency in liver and small intestine, across three age levels. These results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR.

Or it may be any of the many other line items of age-related degeneration resisted by both CR and Ames dwarfism. The present trouble with debates on the contribution of nuclear DNA damage to aging is the lack of any good demonstration of extended life (or no extension to life) through prevention of mutational damage only. There are too many confounding factors.

There's dead and then there's dead and definitely not coming back. Cold water drowning victims can be restored to life if treated quickly. Cryosuspended people can plausibly be restored to active health by medicine of the future. Life renewed isn't a possibility for the buried or cremated, however: the pattern of the brain, the definition of who they are, is lost. That last is information-theoretic death, wherein all the information that is you is gone. In a future in which aging is cured, reducing the risk of this form of death becomes the primary concern. From Depressed Metabolism: "Perhaps the most logical proposal to achieve a negligible chance of information-theoretic death is to duplicate a person. If enough duplicates are made, the chance that all of them will die can be made very small. But this raises the issue of whether such duplicates are the same individual. Some people would argue that this strategy does not produce atomistic non-serial immortality. It is also not clear how the question of whether a copy of an individual is the same individual can ever be resolved by empirical observation or logical deduction. Perhaps the most realistic proposal to reduce the probability of information-theoretic death would be to separate the neurological basis of the person from its body in such a fashion that the risk of complete destruction of the person would become negligible."

Link: http://www.depressedmetabolism.com/2008/06/22/radical-life-extension-and-information-theoretic-death/

Forbes notes that Pfizer "is funding the creation of a biotech company in San Diego called EyeCyte, which will develop stem-cell treatments for eye diseases. The company is based on work by Scripps Research Institute ophthalmologist Martin Friedlander, who has pinpointed bone- and blood-marrow stems cells that, in animal experiments, have a remarkable ability to target and repair damaged blood vessels in the eye. Abnormal blood vessels are a key problem in both diabetic eye disease and macular degeneration. In the future, patients with early signs of blood-vessel damage in the eye might go to the doctor in the morning and leave a blood sample. Adult stem cells would be isolated in the lab over the next few hours, and then the patient would come back in the afternoon and get an injection of his own purified stem cells into the eye. That single injection could stave off further blood-vessel damage for years, preserving eyesight that would otherwise be lost."

Link: http://www.forbes.com/business/2008/06/21/pfizer-blindness-research-biz-health-cx_rl_0623stemcell.html

The methuselah gene in fruit flies, which when expressed gives rise to the methuselah cell receptor (or mth), has been known for a decade now. It is one of a small number of single gene manipulations which can meaningfully extend longevity in this species - by 35% in this case.

When it comes to figuring out what's going on under the hood, even single gene manipulations in small creatures are terribly, enormously complex. This is one of the many truths that leads those researchers who focus on genetic and metabolic engineering to say that any significant extension of human life span through these methods is far in the future. It's a huge, huge undertaking, from our present position, to consider engineering any form of significant change to the way in which our metabolism works.

(Which is why I support far less complex and more certain approaches aimed at repairing the metabolism we have. The mountain of metabolic complexity is there, climb it if you must, but to get to the valley of enhanced longevity on the other side in good time, then use the level road of damage repair strategies that winds around the mountain's base).

You should take a look at a recent PLoS ONE paper on the methuselah gene for an impression of the complexity involved, as well as for a longevity gene in action in wild populations, where it varies from group to group and between individuals:

Williams' theory of antagonistic pleiotropy describes how pleiotropic alleles that increase fitness early in life may experience positive selection even though they incur a fitness cost later in life. Identified aging genes have consistently shown costs to lifespan extension, particularly in reproduction. Although there is some evidence that lifespan and reproductive success can be decoupled, multiple analyses have revealed previously undetected tradeoffs under specific conditions.

In addition to demonstrating negative effects on reproduction, longevity mutations are positively correlated with stress resistance. Such correlations may explain aspects of lifespan evolution, and why loss-of-function mutants can result in lifespan extension. However, it remains unclear whether identified aging genes are major contributing factors to the genetic variance for longevity that is routinely observed in populations.

The researchers then provide a good slab of evidence for variations in the methuselah gene to contribute to observed variations in longevity in wild fly populations. It makes sense for any successful species to have central controlling points in their biochemistry for such things as energy devoted to reproduction, stress resistance, longevity and so forth. Varied abilities across generations and individuals means a species more able to populate new habitats and survive environmental changes that favor one set of abilities over another - so we'll see more of that versus any other alterative biochemical arrangement.

The 30-50% range keeps coming up in experiments to extend life span in small mammals and flies; a number of different ways of achieving this degree of success have been demonstrated in the past 20 years. It seems that this is the natural plasticity of longevity for the biochemistry of many complex species. In some cases, it can be achieved by signficant changes in diet alone, while in others a change to one or a couple of genes is needed - a small change from the point of view of evolution. For the reasons given above, I suspect that this plasticity is a feature of most successful species, a buffer against change inherited from the ancestral past.

If you somehow prevent your mitochondria from generating as much power as they were going to, making them less efficient, you lower the rate at which damaging reactive oxygen species are produced as a byproduct. This is important: "Calorie restriction is the most effective non-genetic intervention to enhance life span known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy." Antioxidant because it prevents the oxidants from being created in the first place. A good proof of concept.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18505478

You have to look hard in the scientific literature to find evidence of any age-related changes made worse by the practice of calorie restriction - the only one that springs to mind right now is that progression of ALS is likely to be worsened. The much more common story is that detrimental change is resisted or attenuated: immune system aging, stem cell decline, heart aging, DNA damage, loss of health, loss of vitality, increase in risk of age-related disease ... all slowed by simply eating less while still obtaining optimal levels of nutrients. Almost everything studied by reserchers to date shows strong evidence of being made better through calorie restriction as a lifestyle choice.

Now we can add sarcopenia, age-related muscle loss, to this long list. That is counterintuitive - eating more leading to losing more muscle mass over the years - but then what is straightforward and simple in biology? Here's the abstract at PubMed:

Sarcopenia, the loss of muscle mass with normal aging, devastates quality of life - and related healthcare expenditures are enormous. The prevention or attenuation of sarcopenia would be an important medical advance.

Dietary restriction (DR) is the only dietary intervention that consistently extends median and maximum life span, as well as health span in rodents. Evidence suggests that DR will have a similar effect in primates. Furthermore, DR opposes sarcopenia in rodents.

We tested the hypothesis that DR will reduce age-related sarcopenia in a nonhuman primate. Thirty adult male rhesus monkeys, half fed a normal calorie intake and half reduced by 30% in caloric intake, were examined over 17 years for changes in [muscle mass]. Body weight-adjusted skeletal muscle mass declined somewhat in both groups but was far more rapid in the control group. We have shown that moderate, adult-onset DR can attenuate sarcopenia in a nonhuman primate model.

That would seem to shoot down the sarcopenia as dietary issue theory, in which the lower-protein diets of the elderly are supposed to cause problems. In fact, those diets should be protective, if this calorie restriction connection follows through to humans. You might also look back at evidence suggesting that sarcopenia stems from one obscure but important biochemical process becoming slowly less efficient, and that leucine supplementation from middle age onwards may reverse this growing inefficiency.

For my money, in advance of further research, I suspect that the stem cell connection is the easy answer. If calorie restriction slows the decline in stem cell activity, then the normal ongoing turnover in muscle tissue should be more readily maintained. We shall see what the real answer is in due course, but practicing calorie restriction in the meantime is still the smart thing to do.

Researcher Chris Patil comments on aging research and the media over at Ageing Research, which you can contrast to Aubrey de Grey's position on the same issue: "For academic biogerontologists, there are two related aims of aging research. The explicit, near-term goal is improving our understanding of the aging process at multiple levels - at the cellular and molecular levels ... The (occasionally) implicit, longer-term goal is to use this understanding to create interventions that will improve the health and happiness of human beings - and here the ambitions range from the treatment of single aging-related diseases to therapies that will delay or even reverse the aging process itself. ... I think [media representations are] largely positive. Even when individual articles get their 'zing' from focusing on what I consider to be quite long-term goals, I think they still do a tremendous amount of good by raising consciousness about the biology of aging. We're entering a period of history when people will become more and more willing to appreciate the benefit of long-term thinking, especially as related to technology - we're already seeing that with the environment, and I think aging research and anti-aging medicine will be another example."

Link: http://ageing-research.blogspot.com/2008/06/chris-patil-ageing-research-and-media.html

You have a great deal of control over the course of your future health: how healthy you're likely to be, and how long you're likely to live. The unexpected always happens, but you can greatly influence the odds. Your actions over the years can move your life span across decades, just through simple lifestyle choices and good health practices, and even without the expected advances in medicine that lie ahead. An illustration:

A Finnish study of identical twins has found that physical inactivity and acquired obesity can impair expression of the genes which help the cells produce energy. The findings suggest that lifestyle, more than heredity, contributes to insulin resistance in people who are obese. Insulin resistance increases the chance of developing diabetes and heart disease.

And more:

Here's some very good news: your genes are not your destiny. Earlier this week, my colleagues and I published the first study showing that improved nutrition, stress management techniques, walking, and psychosocial support actually changed the expression of over 500 genes.

Taking up exercise and a sane diet rapidly changes the way your body operates at the cellular level, and for the better. The body is a complex machine of regulated processes, interactions and feedback loops, and like all machinery, it will fail and malfunction more rapidly if run poorly and without maintenance.

Amazing medical technologies will arrive in the next few decades, with the promise of repairing the biochemical damage of aging and rejuvenating the old. The more you run yourself down, however, the lower your chances of living to benefit from the future of longevity medicine. Why risk it?

From Ouroboros: "Do DNA double-strand breaks (DSBs) have anything to do with aging? We have some reason to believe that they do. ... Paul Hasty has written two recent reviews, critically evaluating the role of DNA DSBs in the aging process. In the first (written with colleagues Han Li and James Mitchell), the authors argue from genetic evidence that DSB repair pathways are intimately connected with aging, but that the relationship is distinct from the well-documented connection between aging and repair of UV-type damage. ... In the second review, Hasty [argues] that non-homologous end-joining (NHEJ), a major pathway of DSB repair, evolved primarily as a means to slow aging - rather than to prevent cancer, as is likely the case for other DNA repair pathways." You'll find a two part discussion on the subject back a way in the Fight Aging! archives. The role of DNA damage in aging is more hotly debated and uncertain than, say, the role of mitochondrial damage or stem cell decline in aging.

Link: http://ouroboros.wordpress.com/2008/06/19/dna-double-strand-breaks-and-aging/

The Telegraph brings news of progress in cancer immunotherapy. Interestingly, this was a comparatively "simple" immune therapy - no genetic or other manipulation of immune cells, but rather generating a very large number of them, far more than the body would generate on its own. This is a similar approach to the first autologous stem cell therapies: "A cancer patient has made a full recovery after being injected with billions of his own immune cells ... The 52-year-old, who was suffering from advanced skin cancer, was free from tumours within eight weeks of undergoing the procedure. After two years he is still free from the disease which had spread to his lymph nodes and one of his lungs ... Doctors took cells from the man's own defence system that were found to attack the cancer cells best, cloned them and injected back into his body. ... The patient was one of nine with metastatic melanoma, that is skin cancer that has spread, who were being treated in a recently completed clinical trial to test bigger and bigger doses of their own white blood cells. Larger, more elaborate, trials are now under way."

Link: http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scicanc118.xml

By way of a reminder, the Aging 2008 symposium will be held later this month, on June 27th at UCLA, Los Angeles. It's a free event for the public, organized by the Methuselah Foundation, and attended by many of the movers and shakers in aging science and advocacy for longevity research:

Applying the new technologies of regenerative and genetic medicine, the engineering approach to aging promises to dramatically extend healthy human life within the next few decades.

How do you and your loved ones stand to benefit from the coming biomedical revolution? Are you prepared? Is society prepared?

At Aging 2008 you will engage with top scientists and advocates as they present their findings and advice, and learn what you can do to help accelerate progress towards a cure for the disease and suffering of aging.

The symposium leads into the Understanding Aging scientific conference, an extension of the Strategies for Engineered Negligible Senescence conference series of past years. These events are a necessary part of establishing a research community sufficiently large and well-organized to make significant progress in longevity science. We'll be seeing more of this sort of thing in the years ahead: connections made, minds changed, notes swapped, science moved forward.

In theory, given that every cell contains all our DNA and the necessary mechanisms for replication, it should be possible to generate any type of cell from any other type of cell using little more than the biotechnology of today. We just don't yet know how. Here, the Telegraph looks at small steps forward in manipulating cell state: "a new front has opened up in regenerative medicine: the direct conversion of one cell type, say a skin cell, into another, say a brain cell. ... pioneering work [showed] it is possible, turning white blood cells into red cells, but now a new [study] 'is a timely reminder' that this method is worth more study to find out the best way to create new cells and tissues for repair. ... [researchers] took specialist 'pancreatic exocrine cells' that secrete digestive enzymes, which make up to 95 per cent of the pancreas, and converted them directly into another cell type, called beta cells, which make the hormone insulin to control blood sugar levels. ... it adds to the existing evidence that a cell's destiny is no longer fixed." If you can generate all the cells you need from any cells you have to hand, that will go a long way to speeding advances in tissue engineering and regenerative medicine.

Link: http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scistem118.xml

Scientific American looks a some recent initiatives aimed at regrowing lost or damaged cartilage: "Scientists envision implanting nanotubes through small incisions (in, say, a knee) that a patient's own cartilage cells would colonize. The benefit [is] that the cartilage would grow more quickly and be stronger than if it was not supported by nanotubes - similar to the way that steel rebar is used to reinforce cement or concrete." This sort of technology platform has broader application once developed: "Nanoscale materials are increasing growth in all of these tissue types. The key is getting the nanomaterials to mimic the roughness of the natural tissue, which creates more surface energy and allows for the absorption of proteins important for the tissue to function ... Webster has come a long way since his original experiments with in vitro bone tissue growth. Over the past decade, he added bladder, cartilage, central nervous system, and vascular tissue growth to his repertoire. The principle is the same in each: Growing cells are more likely to adhere to and thrive on a rough nanotube surface than on smooth bone or fraying cartilage."

Link: http://www.sciam.com/article.cfm?id=nanotech-cartilage

Many species of animal age very slowly, and some so slowly that researchers have not yet been able to pin down either a rate of aging or a life span absent predation and accident. Some of those species might not age at all, but we'll have to wait for researchers to establish whether or not this is the case. Take the lobster, for example. Despite all the eating and farming that takes place, there's less funding for basic research into lobster biology than you might expect. As a consequence:

To date, there is no proven method to determine the exact age of a lobster. ... as best scientists can tell, lobsters age so gracefully they show no measurable signs of aging: no loss of appetite, no change in metabolism, no loss of reproductive urge or ability, no decline in strength or health.

Lobsters, when they die, seem to die from external causes. They get fished by humans, eaten by seals, wasted by parasites, but they don't seem to die from within. Of course, no one really knows how the average lobster dies. There are no definitive studies.

Turning to another common sea creature, species of sea urchin appear to be in the same boat as the lobster: if they're aging, they're doing it very slowly.

The red sea urchin Strongylocentrotus franciscanus is a long-lived species and may live in excess of 100 years based on tagging studies in the field and corroboration from radiocarbon analyses as reported in the literature. Size-specific survival estimates reported here show no change in annual survival probability across the 6 largest 0.5cm size classes from 14.6 to 18.1cm. In addition to no change in survival probability there is no reduction in reproductive capacity with size. Red sea urchins show no evidence of senescence and so do not fit well within the context of the disposable soma theory of the evolution of longevity.

You'll recall that a baseline definition for aging is an increase in mortality rate with time, which doesn't happen for these urchins, or at least to any degree that can be detected via study methods at the present level of funding. This presents a challenge for the classic interpretation of the evolution of aging, which suggests that putting more resources towards tissue repair and the upkeep of biological systems that can support extended life spans is a losing proposition. Evolution favors the quick win, a fast and efficient organism that can reproduce quickly - and rapidly fall apart afterwards.

Or so the thinking goes. Clearly, extremely long-lived and possibly ageless species did evolve, so theory must be extended. The latest thinking on the matter theorizes that crowding can lead to a runaway evolutionary competition for longer lives, an arms-race for the biology that lets you wait out the competition for limited space:

adults live in crowded but stable conditions in which new opportunities for maturation arise rarely. In such situations, it behooves an individual organism to outlive its neighbors, so that when they die its seedlings or larvae have a place to dig in and grow up.

Does the humble urchin have any relevance to the future of human aging and longevity medicine? Not directly, I'd imagine, in the sense of applying learned science. But as more people understand the range of what is possible in living organisms, support for engineering a better healthy life span in our species will grow, whether or not that goal is achieved by mining nature for new metabolic biotechnology.

From Anne C.: "why is it that whenever a group characterized at least in some part by its members' vulnerability stands to benefit from some emerging development, it is assumed that the impetus falls on the vulnerable group to 'prove' its worth? More to the point, why is it not assumed instead that individual lives are of primary value, and that the socioeconomic complications which may arise from saving more lives are just things we're going to have to suck up and deal with? ... You don't (unless your name happens to be Ebenezer Scrooge) sit there playing numbers games, trying to determine whether saving this old person will mean that maybe 10 younger people don't get a big tax break that year, or whether a healthier elderly population might 'hurt the job market' for young people. ... Put another way, the acknowledgment of the goodness of saving lives when possible should be non-negotiable. In this framework, no project claiming the goal of 'improving' conditions in the world can hinge upon the necessity of people dying by a particular age."

Link: http://www.existenceiswonderful.com/2008/06/non-negotiable-goodness-of-saving-lives.html

State funding programs for embryonic stem cell research continue to be established: "Massachusetts Gov. Deval Patrick signed a bill on Monday that will direct $1 billion of state funds toward biotechnology over 10 years ... Patrick said the money would support research grants and strengthen facilities used by both public and private scientists. ... Patrick's plan includes $250 million in tax incentives to encourage companies to expand, $250 million in grants for research, fellowships or workforce training, and $500 million for infrastructure, including a stem cell bank at the University of Massachusetts Medical School. ... Polls have shown a majority of the U.S. public back stem cell research, which scientists believe could one day be used to provide individually tailored tissue and organ transplants, or repair spinal cord injuries." This has been in the works for a while, and may be followed by others in still more states; it's a popular cause that involves giving out large sums of money. That always catches the eye of politicians, for all the obvious reasons.

Link: http://news.yahoo.com/s/nm/20080616/tc_nm/usa_stemcells_massachusetts_dc_3

There's nothing wrong with becoming old, but everything wrong with aging. Old means experienced, invested, wealthier, time-tested and just all-round better for having been around the block. Aging, on the other hand, is the direct result of biochemical damage you picked up along the way - ongoing deterioration that is a side-effect of being alive. The passage of years brings a constant flow of opportunities for growth and self-improvement, until aging takes away your ability to compete, your ability to take care of yourself, and eventually your life. Someone should look into that.

If you're not one to think much about medical research, you might be under the impression that aging is fairly mysterious, a primal and inevitably metered process quite separate from the diseases of old age. In fact that's not the case. Aging is exactly and precisely the root cause of those diseases of old age, and scientists have a good understanding of what aging actually is, once you get under the hood and start looking at cells and the cellular environment:

• Loss of important cells without replacement over the years
• Accumulation of damaged, malfunctioning and senescent cells
• Free radical damage resulting from damaged mitochondrial DNA
• Accumulation of waste chemicals that cannot be broken down inside cells
• Accumulation of biochemicals gummed together by sugar outside cells
• Formation of amyloid deposits throughout the body
• Breakdown of cell control processes, leading to the runaway growth of cancer

The short story is that aging is damage and change, rust and wear for our biology that is caused by the normal operation of human biochemistry. You can't run machinery without causing wear, and you can't run factories full of machinery without creating waste by-products. Machinery with a lot of rust and wear breaks down in any number of ways, and biological machinery is no exception - just a few classes of wear, rust and buildup of waste lead to a vast array of different malfunctions.

When you can't do anything about the rust, wear and waste, you put on the best face possible under the circumstances and soldier on. Perhaps you convince yourself that the miseries of an increasingly damaged body and mind are for the best. It's a slowly boiling pot, but it's our slowly boiling pot, and it's all we have. We humans are good at that sort of proactive self-deception for the sake of sanity in the face of the inevitable - we've been doing it for a very long time indeed.

All habits outlive their usefulness, however, and self-deception about aging has lingered past its time. These early years of the 21st century are the opening notes in a symphony of biotechnology, an expanding revolution in medicine, research and computation. The breadth and speed of research in modern biotechnology is breathtaking; already, the laboratories of of this decade are far beyond those of the 1990s:

• Cancer researchers are developing targeted, precise, safe cell destruction therapies that will applicable to any unwanted, damaging cells.

• Scientists are turning the immune system to destroy the amyloid buildup of Alzheimer's disease, and other amyloids of aging will follow.

• Methods to repair and replace damaged mitochondrial DNA are emerging from the laboratory.

• The regenerative medicine community is deciphering the genetic and chemical controls that will make our stem cells do our bidding, to replenish cells lost to age.

• Researchers are plundering the bacterial world for enzymes that can break down damaging biochemicals that build up with age.

If you think aging is inevitable, and that we should make the best of it, then you're probably not helping the world's researchers in their efforts to repair the damage that causes aging. You see, funding for research is very dependant on the zeitgeist of the age. If most people think that aging is inevitable, conservative funding bodies won't fund research aimed at the repair of biochemical damage that causes aging. Thus little progress occurs, no-one in the public is given any reason to doubt that aging is inevitable, and medicines to repair aging are pushed further into the future, perhaps out of reach for you and I.

Given the choice to be old, wise and better without being aged, frail and ill, wouldn't you choose to repair the damage? It's not a hypothetical question anymore, and the number of years it takes to develop medicines of repair for aging depends upon your answer.

The reliability theory of aging is a framework for thinking about how biochemical damage leads to later dysfunction. When we damage ourselves, we pay the price later in an increased risk of disease and a shorter life expectancy. The body is a complex machine, and like all complex machines it runs less reliably as the wear and tear mounts. This research illustrates the point well: "Infections during the first year of life are a marker of increased risk of developing specific types of arthritis later in life ... infants who were hospitalised for infection before their first birthday had an increased likelihood of developing either juvenile idiopathic arthritis (JIA) or adult rheumatoid arthritis (RA) in later life." Some damage we can't help, but the majority is self-inflicted through poor choices in lifestyle: excess fat, lack of exercise, and so forth. Why lower your chances of living to benefit from the longevity medicine of the future?

Link: http://www.eurekalert.org/pub_releases/2008-06/elar-eli061308.php

Researchers are working their way around the signalling mechanisms that damp down stem cell activity with age. From EurekAlert!: "As we age, our stem cells are prevented, through chemical signals, from doing their jobs ... the stem cells in old tissue are still ready and able to perform their regenerative function if they receive the appropriate chemical signals. Studies have shown that when old tissue is placed in an environment of young blood, the stem cells behave as if they are young again ... Aging and the inevitable march towards death are, in part, due to the progressive decline of Notch and the increased levels of TGF-beta, producing a one-two punch to the stem cell's capacity to effectively rebuild the body ... But what would happen if researchers blocked the adult stem cells in old tissues from reacting to those TGF-beta signals? ... muscles in the old mice whose stem cell 'aging pathway' had been dampened showed levels of cellular regeneration that were comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of 'untreated' old mice." The decline in function exists to protect against cancer - but if researchers solve that problem too, it seems we can get much more from our stem cells.

Link: http://www.eurekalert.org/pub_releases/2008-06/uoc--scr061108.php

Dominick Burton of Ageing Research asked this of biogerontologists: "The main purpose of ageing research at present is NOT to make people young and immortal as is often publicised in the media, but instead to prevent/combat disease and disability, allowing everyone to live healthier lives for longer. Is this media representation of ageing research detrimental to the true focus of ageing research? If you disagree with the main purpose of ageing research outlined in the question please state why?" Aubrey de Grey came back with a comprehensive answer; you should take a look: "Yes, I believe it is immensely detrimental. (I don't precisely blame the journalists in question, you understand - they're just doing what they're paid to do - but still.) Ultimately, the reason why calling my goal 'immortality' sells papers is because it trivialises it - it confuses my work with something that we all know is impossible, i.e. the technological elimination of any risk of death. And an awful lot of people need that confusion - they need to be helped to believe that what I'm doing is really not science but just entertainment. Why do they need that? Because they've made their peace with aging."

Link: http://ageing-research.blogspot.com/2008/06/ageing-research-and-media.html

One thing to bear in mind about cryonics is that the logistics of a successful cryopreservation are far from simple, and careful preparation is a must. People focus on the technology, but organization of a cryopreservation is also a challenge - and it's a credit to the cryonics community that matters usually proceed smoothly. Here, Alcor notes new funding to improve logistics for this important step in the process: "On June 7th and 8th, 2008, the Alcor board and management held a 2-day strategic planning meeting at the Alcor facility in Scottsdale, Arizona. Many general issues relating to the organization were discussed. A major topic of discussion was a funding offer brought forward by board member, Saul Kent. The offer is for the Life Extension Foundation and two other donors to each contribute $150,000 a year to Alcor for three years, totaling $1,350,000. These contributions are to fund improvements in cryopreservation case readiness, a new Standby Coordinator staff position, and an Executive Director search and salary support. Fuller details are below. The offer, with its associated conditions, was accepted by a majority vote of the Alcor board."

Link: http://www.alcornews.org/weblog/2008/06/on_june_7th_and_8th.html

The rough estimate of resources required to develop - for mice - the medical capabilities called for by the Strategies for Engineered Negligible Senescence (SENS) is presently $1 billion over ten years, give or take.

Each of these [six lines of research] would require total funding in the range of $2m to $15m per year, spread over at least three and sometimes ~15 research teams. These teams will typically be working in a university or other research setting. [The lines of research] span six of the seven types of "damage" that Dr. de Grey has identified as the key intermediates in aging; the one not listed here is cell loss, whose rectification by stem cell and growth factor therapies is the subject of sufficient existing work worldwide.

That's for the whole spectrum of longevity therapies: engineering the body to make cancer impossible; replacing lost cells; ensuring mitochondrial DNA damage can no longer cause issues; destroying unwanted cells that cause damage; breaking down crosslinks and amyloid that gum up biochemistry; removing hard-to-degrade biochemicals in old cells. Given all that, you should be able to rejuvenate aged mice, and extend their healthy lives considerably. Then it's onto moving the technology to work for humans, where the cost really starts to rack up - but with the technology demonstrated in mice, there should be plenty of enthusiasm to pay that cost.

What does a billion dollars and ten years really look like when you're taking about warm bodies, concrete and conferences? It turns out to represent something like 500 researchers, plus resources for equipment, facilities and support staff, if you keep things lean and distributed, making the best use of existing research facilities and ongoing programs.

If you apply the 1:9:90 rule to a research community, you can expect that a 500-scientist strong group will include perhaps 5 researchers who are very respected and appear in the media in connection with their research, 50 who are well known in the field and very capable, and the remaining 445 ranging from research associates to skilled scientists yet to reach the heights of their careers. This community might take the form of ten dedicated laboratories at large universities, a few for-profit enterprises, and more than fifty significant initiatives within other large research organizations.

For comparison, that is considerably larger than the present calorie restriction research community but considerably smaller than either the cancer or Alzheimer's research community. Calorie restriction research and development is probably well over $1 billion in investment to date, but only if you count funds for trials and commercialization employed by companies like Sirtris; I would imagine that basic and animal research has consumed rather less than that.

At the present time, I would be surprised to find more than 50 scientists worldwide working to develop biotechnologies that would fit into SENS as-is. Outside the regenerative medicine and cell therapy community, that is. Clearly, there is a way to go for fundraising and other efforts to influence the direction of research in the broader scientific community.

I'm given to note that progress in targeted therapies - in particular those that use nanoparticles like dendrimers to string together homing mechanisms with cell destruction payloads - is very important. All sorts of cells need killing as we get older, to prevent the damage they cause: cancer cells, senescent cells, and so forth. Targeted nanoparticle therapies will soon provide a broad and extensible technology platform to get that job done, for any cell whose biochemistry we know how to distinguish, thus lightening the load of age-related damage in our bodies.

When you stop to think about it, we already have a flexible, targeted cell destruction therapy roaming our bodies from day one: it's called the immune system. Immune cells are very much more sophisticated than the dendrimers being built in laboratories today, and are capable of destroying much more than just errant cells. Any biochemical that can be broken down within a cell is fair game, not just those biochemicals that make up our cells.

Looking ahead, we can see three paths:

• The path of nanoparticles, nanoscale targeting devices and payloads to destroy the specific cells

• The path of manipulating our immune system into destroying targeted cells and cleaning up specific biochemicals

• The merged path: artificial cells built to have a limited subset of natural immune cell functions, and set to a specific cleanup task within the body

I expect it'll be a good 20 years or so before we see the first practical applications of artificial cells in this area, though present progress suggests less complex projects will emerge more rapidly than that. For the purposes of this post, I'm more interested in what will result from work on immune therapies over the next decade, alongside the clinical application of targeted nanoparticle therapies.

If you've been following along, you'll know that the more-than-well-funded cancer and Alzheimer's research establishments are driving early development of immune therapies. In essence, researchers are seeking ways to manipulate the immune system into destroying cancer cells more aggressively, or that it would normally leave alone, and cleaning up the buildup of amyloid compounds in the brain.

Once a technology platform is established for directing the immune system to attack and break down specific compounds in the body, I can see it having just as broad a future set of applications as cell destruction. All sorts of damaging biochemicals build up around our cells as we age, and cause great harm over the years by interfering in important metabolic processes. On the one hand we have advanced glycation end-products (AGEs) that link important molecules together and glueing up the works, on the other hand a whole range of compounds known as amyloids, but that are different from the well-known form of amyloid associated with Alzheimer's disease. The damage done by the buildup of these amyloids is in fact the most common cause of death for those supercententarians who have avoided all other common causes of death.

For example, imagine an immune therapy that directs your immune cells to attack and break down glucosepane, currently thought to be the dominant form of AGE in aged tissue, glueing up important molecules and generally making things work less well. That would be a way down the road, however.

More immediate prospects involve attacking amyloid compounds other than that involved in Alzheimer's disease. Many forms of compound build up between cells with advancing age and are collectively termed "amyloid" - and it looks feasible to rework immune therapies intended for Alzheimer's, presently in development or trial, to attack these amyloids. Such an initiative is presently in the queue at the Methuselah Foundation, awaiting funding:

The Methuselah Foundation is presently in discussion with leading researchers in this field with a view to initiating work on a vaccine - similar to that developed by Elan for Alzheimer’s disease - to stimulate the aged body to clear the widespread amyloids (particular of transthyretin) responsible for senile systemic amyloidosis.

It is good to see that many medical technologies of broad potential application are well advanced in their development cycle at this time. We'll need them to further progress in the repair of aging.

More on recent work on low dose resveratrol from Ouroboros: "Most famously, resveratrol has been reported to increase the median lifespan of mice fed a high-fat diet, but that study has been subject to numerous criticisms. The diet in question was so unhealthy it would have made Morgan Spurlock blush, raising questions about its fairness as a model even for the most deranged Western diet. Furthermore, the quantity of resveratrol administered to the mice in the study corresponded to something like 1000 bottles of red wine per day. A skeptical reader could fairly claim that such a study, in which ridiculously high doses of a compound have an effect on an obscenely unhealthy animal, teaches us exactly nothing about what manageable doses of the same compound might accomplish in reasonably healthy people (which is, arguably, the point). So: do manageable doses of resveratrol have health benefits - specifically, with respect to diseases of aging or aging itself? The first evidence in the affirmative has recently been published by Barger et al., who demonstrate that mice eating a normal ad libitum diet supplemented with resveratrol (at a much lower dose than in previous studies) undergo many of the same transcriptional changes as animals undergoing caloric restriction (CR)."

Link: http://ouroboros.wordpress.com/2008/06/12/low-dose-resveratrol-as-a-calorie-restriction-mimetic/

The Biogerontology Research Foundation has launched in the UK: the Foundation "seeks to fill a gap within the research community, whereby the current scientific understanding of the ageing process is not yet being sufficiently exploited to produce effective medical interventions. The BGRF will fund research which, building on the body of knowledge about how ageing happens, will develop biotechnological interventions to remediate the molecular and cellular deficits which accumulate with age and which underlie the ill-health of old age. Addressing ageing damage at this most fundamental level will provide an important opportunity to produce the effective, lasting treatments for the diseases and disabilities of ageing, which are required to improve quality of life in the elderly. The BGRF seeks to use the entire scope of modern biotechnology to attack the changes that take place in the course of aging, and to address not just the symptoms of age-related diseases but also the mechanisms of those diseases." The Foundation is backed by a number of forward-looking, pro-longevity members of the aging research community: the chief scientific officer is researcher Michael Rose, for example.

Link: http://www.bg-rf.org.uk/news/press20080609.html

Does intelligence correlate with longevity? And if so, is that because more intelligent people tend to make better health choices, or because some genes that correlate with intelligence also aid biochemistry in resisting the accumulation of damage and dysfunction? From the Telegraph: "Intelligent people could live up to 15 years longer than their less bright counterparts, according to scientists who have linked a 'smart gene' to longevity. Researchers in Italy found those with the less 'smart' variant of the gene, which has already been linked to IQ levels by scientists, were unlikely to live beyond 85. ... others with a 'good' version of the same gene could expect to live to 100. The gene known as SSADH is already known to 'detoxify' the brain by getting rid of excess acid. That process is believed to protect brain cells from damage which would otherwise accelerate the ageing process. ... Although the sample size is small, with only 115 taking the test compared with the thousands expected in today's studies, the reported associations with cognitive ability are significant and in line with our previous results." More questions than answers here.

Link: http://www.telegraph.co.uk/news/worldnews/europe/italy/2111096/Clever-people-could-live-15-years-longer.html

Terry Grossman is representative of the more ethical end of "anti-aging" medical practices. It's up to you to decide what you feel is useful in that toolbox, but from where I stand, for a healthy person it presently ranks below exercise and calorie restriction, and far below working to ensure that the longevity science programs like SENS advance more rapidly: Grossman "combines what he believes are the best practices from conventional and alternative medicine into a single, comprehensive procedure for detecting and preventing any and all ailments. ... Life is not a randomized, double-blind placebo-controlled trial. You only have one shot at it. So we make the best choices with the information we have. ... Grossman and Kurzweil believe this sort of aggressive anti-aging strategy is the first of three bridges that will lead humanity to eternal life. The second bridge is the biotechnology revolution, a point in the next ten years or so when scientists will learn to control our DNA, turning diseases off with ease, not to mention cloning and regenerating our organs, developments that will dramatically increase life spans. The third bridge is the point at which nanotechnology and artificial intelligence allow humans to control their existence at the atomic level, the dawn of the singularity."

Link: http://www.westword.com/2008-06-12/news/doctor-eternity/full

I was looking at a review of what is known of the role of sirtuins in aging and longevity earlier today:

Calorie restriction lengthens lifespan, in part, due to mitochondrial metabolism reorganization through [sirtuin 1-regulated] mitochondrial biogenesis. This reduces radical oxygen species levels that cause macromolecule damage, a major contributor to aging.

Little is known about these processes in stem cells, whose longevity is implicated in human aging. Recent work indicates that sirtuin 1 influences growth-factor responses and maintenance of stem cells. Sirtuin 1 is required for calorie restriction-induced lifespan extension in mice, and calorie restriction upregulates sirtuin 1 in humans. Sirtuin 1 also appears to influence lineage/cell-fate decisions of stem cells via redox status.

I notice that sirtuins are also theorized to link processes important to cancer suppression and processes important to insulin metabolism (one of the important metabolic determinants of life span), which is why rate of aging and cancer risk seem balanced against one another in most organisms:

Recent evidence suggests that the sirtuin family of proteins act as central mediators of this molecular crosstalk. The coordination of DNA repair with overall energy balance may be essential for reducing the risk of developing cancer as well as for determining the rate at which we age.

On the way past Ouroboros, I notice that Chris Patil has posted on sirtuins as well. So sirtuins it is today:

As theories reach maturity (and middle age), they are naturally subject to challenge, and the sirtuin story is no exception. The role of sirtuins in [calorie restriction] has been challenged, sometimes by the very founders of the field. The mechanism(s) of action of resveratrol are also under close scrutiny. Even some of the most famous studies of sirtuins - specifically, regarding effects on median lifespan and exercise tolerance - used animals eating such horrifyingly fatty diets or ingesting such gigantic doses of resveratrol that their relevance to humans must be questioned.

It’s therefore high time that we turned a skeptical eye to the sirtuin story.

It's all a good illustration that researchers still have a way to go to untangle the workings of calorie restriction - you'll find gaps and contradictions when you look closely at the brace of theories, experiments and knowledge produced to date. I'm still betting on four to five years for a solid picture of this biochemistry of enhanced health and longevity, based on the current rate of progress.

Meanwhile, sensibly eating less works just as well as it always has.

Whole-body Interdiction of Lengthening of Telomeres (WILT) is the Strategies for Engineered Negligible Senescence (SENS) answer to cancer, filed under the OncoSENS project category. Get to the root of it all, and yank that root out:

This is a very ambitious but potentially far more comprehensive and long-term approach to combating cancer than anything currently available or in development. It is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres, the long stretches of gibberish DNA that cap their chromosomes.

Telomeres fulfil a role that is similar to that of the nibs on the tips of your shoelaces, keeping the DNA from becoming frayed and unravelled. Each time a cell reproduces, the telomeres become a little worn down, and when a cell runs out of telomeres it quickly self-destructs.

Because cancer cells reproduce at a furious pace, they quickly reach the ends of their telomeric "ropes," and need to find a way to exploit the cell’s natural machinery for renewing telomeres (telomerase and [alternative lengthening of telomeres, or ALT]) to restore normal telomere length, or their growth will come to an end. The thorough elimination of these genes from all of our dividing cells thus spells the doom of cancer.

So eliminate telomerase, and eliminate whatever turns out to be the gene or genes necessary for ALT. Cancers are little evolution engines, capable of mutating their way around pretty much any chemotherapy given enough leeway - but they are vanishingly unlikely to be able to mutate their way into an entirely new gene to lengthen telomeres. That's too big a handful of disabled fundamental machinery to work around.

As it happens, WILT has never been my favorite strategy in SENS - which is interesting, given that it is just as scientifically sound as the rest. I think that my instinctive objection stems from it being the one portion of SENS we can point to today and say "that would need a touch-up procedure every 10 years ... or else." The need to return to the clinic exists because a WILT recipient has no more telomerase anywhere, including - especially - the stem cell populations vital to health. There are genetic diseases that tell us what happens when your stem cells stop being able to lengthen their telomeres; it's a slow and unpleasant way to go, taking about a decade to show up in earnest, and running downhill from there as regeneration and repair starts to shut down.

So the WILT recipient of 2030 would have to receive new stem cell populations, or more likely some form of gene therapy that restored telomere length in the existing populations, every decade or so. To me, ten years is not a broad enough margin to account for error, falling into bankruptcy, heading out to the backwaters of the solar system and back again, and so forth. It's all too easy for something to go wrong. The ideal hypothetical longevity therapy (or component of longevity therapy) lengthens your life span even if you never see another clinic again - but WILT dramatically reduces your life span under that set of circumstances.

A procedure every ten years compares very favorably with developing cancer, of course. But do we need a final solution like WILT to make it through decades of later life? Will the continuing advance of more conventional "detect, target and pinpoint cell destruction" cancer medicine get the job done for long enough to make it into the next phase of medical science, sometime in the 2040s?

The risk of cancer in any tissue increases with age - and as for most failing machines, quite dramatically so in later life. This stems from underlying changes in biochemistry and the simple rules that determine failure rates in machinery based on gradual wear in component parts - possibly the shortening of your telomeres, possibly damage to stem cells, possibly something else, possibly all of the above. Is it good enough to have a good after-the-fact cure on hand when the risk of occurance is increasing enormously with each passing year? Is there a point past which a good therapy is just overloaded by sheer weight of new cancer bursting from your cells, and where does that point occur?

Ultimately, we would want to change our biochemistry so as to prevent cancer from occuring at all. Like all projects aiming to safely re-engineer a very complex system, this will be challenging indeed - but it will get easier with time. At what point will we need to have absolute cancer prevention in hand to beat the curve of aging, and thus remain alive and in good health to take advantage of the next anti-aging technology in line? At what point does a cure for cancer fail us?

It might also be the case that eliminating telomerase reveals that telomerase has other important roles in the cell. The Methuselah Foundation is in fact funding a study on this very issue. Just a few days ago, I pointed out research suggesting that telomerase actually slows the rate of damage suffered by mitochondrial DNA, and therefore influences life span by dampening the biochemical processes that amplify and spread that mitochondrial damage throughout the body. If verified, this means that eliminating telomerase will speed up aging through these mitochondrial damage mechanisms.

That suggests that WILT can only be safely implemented on top of a successful project to either periodically replace your damaged mitochondrial DNA, or render mitochondrial DNA damage moot by moving the vital portions of it into the cell nucleus. The latter, of course, is a part of SENS.

Chris Patil talks about some of his recent work: "Within groups of species that share a given body plan (e.g., bats, birds, dogs, or primates), there is significant variation in maximum life expectancy, and we believe this variation is genetically determined. In other words, natural selection has performed dozens of parallel 'experiments' in which more or less similarly constructed organisms end up with different lifespans, based on variations in a range of factors (some known or long-suspected, like antioxidant enzymes, and others as yet undetermined). Some of these factors may be unique to specific body plans, whereas others might be universal. The challenge we set ourselves was ambitious: How can we use the 'data set' (i.e., variation in lifespan among related organisms) to identify novel determinants of longevity? Thus was born the Comparative Biogerontology Initiative. ... The CBI was conceived not as a replacement for more direct studies of more relevant models (like humans), but as a complement: by carefully examining aging in understudied organisms, and by systematically identifying the factors that contribute to their differential longevities, our hope is to discover entirely new determinants of aging and lifespan."

Link: http://ouroboros.wordpress.com/2008/06/05/in-which-i-get-funded-the-comparative-biogerontology-initiative/

Alzheimer's appears to be a lifestyle disease for most people, with the same risk factors as type 2 diabetes. Via ScienceDaily: "A 115-year-old woman who remained mentally alert throughout her life had an essentially normal brain, with little or no evidence of Alzheimer's disease ... Our observations suggest that, in contrast to general belief, the limits of human cognitive function may extend far beyond the range that is currently enjoyed by most individuals, and that improvements in preventing brain disorders of aging may yield substantial long-term benefits. ... her body was donated to science when she died at age 115. At the time, she was the world's oldest woman. Examination after death found almost no evidence of atherosclerosis (narrowing of the arteries) anywhere in her body. The brain also showed very few abnormalities - the number of brain cells was similar to that expected in healthy people between 60 and 80 years old." Many people could do just as well, even without future advances in longevity science, by consistently taking care of the health basics, year after year. Why sabotage your potential with fat, gluttony and sloth?

Link: http://www.sciencedaily.com/releases/2008/06/080609093252.htm

In the Pipeline looks at recent results for the calorie restriction mimetic resveratrol in mice: "Because most age-related diseases are likely to be secondary to the aging process itself, the discovery of such compounds could have a profound public health impact by reducing disease incidence and possibly extending the quality and length of the human lifespan. ... That's a fine list of things that everyone would like to avoid: cancer, decline, and death. And the last sentence makes a key point, that the age-related diseases are not inevitable, but can be attacked as a group by attacking aging itself. A few years back, that statement might not have made it into a scientific paper at this level, but it can now. ... So resveratrol appears to be a pretty close mimic of caloric restriction - but it's closest in the non-age-related genes, which is interesting. The thing is, there's no guarantee that all these transcriptional changes are good - presumably a lot of the ones that reverse age-related changes are beneficial (although we don't know that for sure), but the ones that aren't involved in aging could be more of a mixed bag. ... this is a very interesting study, and a very hopeful one, but it also points out just how much we don't know."

Link: http://pipeline.corante.com/archives/2008/06/06/resveratrol_in_mice.php

Those folk who aspire to immortality - in the sense of "living a really long time without aging to death, and working out some of the details later" - would do well to spend a little time thinking about a taxonomy of this much abused word: "In 'Philosophical Models of Immortality in Science Fiction,' (in: Immortal Engines: Life Extension and Immortality in Science Fiction and Fantasy) John Martin Fischer and Ruth Curl construct a taxonomy for immortality. ... only some models of immortality meet the criterion of real personal immortality in which an individual leads an indefinitely long single life ... If we leave the issue of solipsistic and non-solipsistic immortality to the side (see David Deutsch on solipsism), the only mature method listed to achieve immortality which is available right now is cryonics. Strictly speaking, cryonics itself does not achieve immortality, but it can enable a person to reach a time when technologies that can produce immortality may be available. ... Even individuals who hope to benefit from SENS and have made arrangements for cryonics live in a world with a non-trivial probability of information-theoretic death. Minimizing the probability of information-theoretic death should be the objective of radical life extension."

Link: http://www.depressedmetabolism.com/2008/06/08/immortality-and-cryonics/

Regenerative medicine holds great - albeit not unlimited - promise for extending healthy life by replacing age-damaged tissue, and ultimately replacing age-damaged organs. However, as for everything involving our biology, the path forward is not as simple as it might appear. Repairing the damage of aging by simply replacing tissue - even assuming you've repaired any age-related damage in the stem cells taken from the patient to use in therapy - runs into the interconnected nature of the body's systems:

Tissue engineering for a new heart, plus the necessary understanding to repair any damage in your stem cells? One problem you quickly run into in this sort of thought experiment is that everything of importance is influenced by everything else. New cells will be damaged by the old intracellular environment, as well as by the actions of old cells next door. An age-damaged immune system can't protect rejuvenated cells in a new heart.

And so on; I'm sure you could list many more important connections that will trip you up if you replace only one component of the aging body. This is a challenge for the near future of regenerative medicine - also known as cell therapy in its present form - as this paper reminds us:

Cell therapy is a promising option for treating ischemic diseases and heart failure. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia, and clinical trials have confirmed that autologous cell therapy using bone marrow-derived or circulating blood-derived progenitor cells is safe and provides beneficial effects.

However, aging and risk factors for coronary artery disease affect the functional activity of the endogenous stem/progenitor cell pools, thereby at least partially limiting the therapeutic potential of the applied cells. In addition, age and disease affect the tissue environment, in which the cells are infused or injected. The present review article will summarize current evidence for cell impairment during aging and disease but also discuss novel approaches how to reverse the dysfunction of cells or to refresh the target tissue. Pretreatment of cells or the target tissue by small molecules, polymers, growth factors, or a combination thereof may provide useful approaches for enhancement of cell therapy for cardiovascular diseases.

A challenge, but not an impassable barrier. As I've said before, present directions in research and funding culture suggest that the regenerative medicine research community - large and well funded - will soon be branching out into attempts to repair the damage of aging at the cellular level. That is a natural outgrowth of trying to make cell therapies and tissue engineering work more effectively in the aged:

One consequence of the dominance of the aging [stem cell] niche is the direction taken in order to develop the next generation of stem cell therapies. Clearly it's not enough to gain far better control over stem cells if the damaged niche then sabotages your efforts.

I believe that this will likely see the large and well-funded regenerative medicine industry start down the path of trying to rejuvenate and repair stem cell niches. I don't know when that will start in earnest, but it will be a tremendous opportunity for those of us interested in the success of more general strategies for biochemical repair throughout the body - a chance to apply large-scale funding and a large research community to specific challenges in repairing the damage of aging.

You might recall that researchers have put forward evidence to suggest that telomere shortening is caused by accumulated damage to mitochondrial DNA - essentially collapsing two areas of intense interest for gerontologists down to one root cause, if confirmed. Back then, I said:

We know that mitochondrial damage is tied to aging via mechanisms such as the production of damaging free radicals such as ROS - and that some researchers are working on solutions, such as the ability to replace all mitochondrial DNA in the body via protofection. We also know that progressive telomere shortening is tied to aging and age-related disease, and a number of different groups are working on strategies to safely lengthen telomeres.

There is strong evidence to believe that "tied to aging" in this context means "contributes to aging as a cause." Remember that aging is no more than an accumulation of damage in biochemical systems; when we look at these changes that take place with aging, we are looking at damage. This paper offers the possibility that if we repair or prevent the progressive accumulation of mitochondrial degeneration and damage, then the telomeres will take care of themselves - if the results are replicated, of course.

Building on this, I see that researchers are now pulling the action of telomerase into the forming picture:

Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress

Telomerase is a ribonucleoprotein that counteracts telomere shortening and can immortalise human cells. There is also evidence for a telomere-independent survival function of telomerase. However, its mechanism is not understood.

We show here that TERT, the catalytic subunit of human telomerase, protects human fibroblasts against oxidative stress. While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner.

Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, [mitochondrial DNA] is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT.

So, poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase.

Damaged mitochondria are a fundamental root cause of age-related degeneration far above and beyond the matter of telomeres. If telomerase acts to improve the state of mitochondria, this might explain why telomere length correlates so well with general measures of health in the old. It might even be the case that, setting aside cancer for one moment, telomere length really isn't that important in comparison to your mitochondrial health.

This all cries out for more research - the prospect of reducing two thorny problems down to one in the development of medical technologies to repair and prevent aging is very welcome. Regardless of the outcome, efforts to repair mitochondrial damage will remain very important to our future health and longevity, and are presently greatly underfunded in comparison to that importance.

It may be possible to direct stem cells lying dormant in the brain to set forth and repair damage: scientists "have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. ... Chen believes that tapping the brain's dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinson's or Alzheimer's disease or traumatic brain or spinal cord injuries. Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue ... Chen's team learned that stem cells existed everywhere in the brain by testing tissue from different parts of adult mice brains in cultures containing support cells (known as astrocytes) from the hippocampus, where stem cells do regenerate. ... In the [second] study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules ... They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells."

Link: http://www.eurekalert.org/pub_releases/2008-06/seri-b060608.php

Another demonstration of stem cells used to generate new dopamine-generating neurons is announced via EurekAlert: "adult stem cells harvested from the noses of Parkinson's patients gave rise to dopamine-producing brain cells when transplanted into the brain of a rat. The debilitating symptoms of Parkinson's such as loss of muscle control are caused by degeneration of cells that produce the essential chemical dopamine in the brain. ... When stem cells from the nose of Parkinson's patients were cultured and injected into the damaged area the rats re-aquired the ability to run in a straight line. ... All animals transplanted with the human cells had a dramatic reduction in the rate of rotation within just 3 weeks ... This provided evidence the cells had differentiated to give rise to dopamine-producing neurons influenced by being in the environment of the brain. In-vitro tests also revealed the presence of dopamine. ... stem cells from the olfactory nerve in the nose are 'naive' having not yet differentiated into which sort of cells they will give rise to. ... They can still be influenced by the environment they are put into. In this case we transplanted them into the brain, where they were directed to give rise to dopamine producing brain cells."

Link: http://www.eurekalert.org/pub_releases/2008-06/ra-asc060608.php

If you're familiar with the work of aging researcher Michael Rose, you'll know that he uses "immortality" to mean no increase in mortality rate with advancing time. He demonstrated that mortality rates in flies, for example, stop rising after a certain age. This is counterintuitive for most people, given our experience with the world - we expect the chance of death on any given day to continue to increase as age-related degeneration piles up.

The flies all still die, of course, because the odds come up sooner or later, but they don't get any more likely to die per unit time whilst in this "immortal phase." You can find a more detailed explanation in Rose's essay in the online version of The Scientific Conquest of Death - it's the first essay in the book.

Biological "immortals" will often die, just not because of a systematic, endogenous, ineluctable process of self-destruction. Death is not aging. Biological immortality is not freedom from death. Instead, the demonstration of immortality requires the finding that rates of survival and reproduction do not show aging.

...

In caged insects, kept under good conditions, mortality rates stop increasing in late life. The new facts of death reveal three phases of mortality: juvenile, aging, and late life. In the juvenile period, mortality rates do not show sustained increases. In the aging phase, mortality rates increase rapidly. In the third phase of life, mortality rates are roughly constant, though they tend to maintain a very high level. Organisms that reach the third phase can be said to be biological immortal, in that they no longer age.

This all sprang to mind when I noticed a paper on cancer rates in the old:

Increased age is regularly linked with heightened cancer risk, but recent research suggests a flattening around age 80. We report that, independent of cancer site or time period, most incidence rates decrease in the more elderly and drop to or toward zero near the ceiling of human life span. ... Almost all cancers peak at age approximately 80. Generally, it seems that centenarians are asymptomatic or untargeted by cancers. We suggest that the best available justification for this pattern of incidence is a link between increased senescence and decreased proliferative potential among cancers. Then, thus far, as senescence may be a carcinogen, it might also be considered an anticarcinogen in the elderly.

Your guess is as good as mine as to the mechanism by which cancer rates fall after 80, though the centenarian mention is probably a red herring. Centenarians tend to suffer less of everything bad, being more healthy and active than their peers at every age, as a result of (to some degree) genetic luck and (more influentially) lifestyle choices like exercise and light calorie restriction. That every cancer type is affected probably points to something global, such as the immune system, but nothing plausible springs to mind.

In any case, we can speculate that this is one component of Rose's late life immortality, as demonstrated in humans. Less cancer means a decreasing contribution to mortality rate due to death by cancer. Does human mortality rate in fact flatten out in old age? I believe that remains debated but plausible, lacking the irrefutable sort of statistical data one can produce with flies in the laboratory.

Do people care more about their hair than their internal organs when it comes to rejuvenation through medical science? Possibly. Out of sight is out of mind, at least until things start to fail - which is a touch too late to wish you'd supported viable rejuvenation research back in the day. In any case, here's the Economist on one line of hair regeneration: "Some years ago it was discovered that when [dermal papilla] cells are relocated, an entirely new hair will grow. That observation is only useful, though, if you can multiply dermal papilla cells - and do so in a way that allows them to keep their ability to induce hair growth. For, in normal culture, dermal papilla cells quickly lose this sought-after ability. ... The long and short of it is that being able to multiply these cells while preserving their efficacy opens the way for unlimited supplies of head hair. Intercytex is therefore conducting a trial of the technology in Manchester. ... The trial's full results will not be available until March 2009, but the company has already said that at least two-thirds of its patients have generated new hair within six months. Unfortunately for eager baldies, regulations require more trials. As a result it is likely to be five years before any product is on the market."

Link: http://www.economist.com/science/displaystory.cfm?story_id=11487403

Here's a podcast interview with biomedical gerontologist Aubrey de Grey, conducted by two commenters on the UK pension industry. You'll have to dig a little to get to the podcast page, and the podcast MP3 file itself. Those people in the business of making money from life insurance, pensions, tontines and the like find themselves in an interesting position these days: they are largely two or more steps removed from the aging research community, and so understanding the probable course of longevity science, and so the financial risks involved in their businesses, is a challenge. That is especially true given the wide divergence of very reputable predictions within the aging research community itself. Everything is poised for a massive leap forward in the medical technologies of longevity ... that may or may not come soon. Such great uncertainty is a form of pain for those who make money by managing mortality risk, and so it's not surprising to see such a keen interest.

Link: http://www.podcastproduction.eu/archives/36-Pensions-Radio-celebrates-birthday-with-Aubrey-de-Grey.html

Falling costs of biotechnology are making it ever more feasible to explore and experiment with the complexities of metabolism. I expect to see some success in engineering better mammalian biochemistry over the next two decades, with the aim of extending healthy life and slowing the changes and damage that cause aging. An example of the type: "Glucose tolerance progressively declines with age in humans and is often accompanied by insulin resistance and a high prevalence of type 2 diabetes. Little is known about the mechanism underlying the age-related changes in glucose metabolism. Here we reported that acid-sensing ion channel 3 (ASIC3) is functionally expressed in adipose cells. ASIC3(-/-) mice were protected against age-dependent glucose intolerance with enhanced insulin sensitivity. Acute administration of ASIC3-selective blocker APETx2 improved the glucose control and increased the insulin sensitivity in older (25-27 weeks) ASIC3(+/+) mice. ... Taken together, our data suggest that ASIC3 signaling might be involved in the control of age-dependent glucose intolerance and insulin resistance." It has been surprising to see just how many comparatively minor changes improve either the life span of mice, or the quality of their metabolic processes.

Link: http://www.ncbi.nlm.nih.gov/pubmed/18466760

Researchers continue to explore resveratrol as a calorie restriction mimetic. There's a way to go yet before we see a weight of science to match plain old calorie restriction, but it looks more promising as evidence accumulates: "scientists included small amounts of resveratrol in the diets of middle-aged mice and found that the compound has a widespread influence on the genetic causes of aging. ... Caloric restriction is highly effective in extending life in many species. If you provide species with less food, the regulated cellular stress response of this healthy habit actually makes them live longer. In this study, the effects of low doses of resveratrol (on genes) were comparable to caloric restriction, the hallmark for life extension. ... Previous research has shown that high doses of resveratrol extend life in invertebrates and prevent early death in mice given a high-fat diet. The new study extends those findings, showing that resveratrol in low doses, beginning in middle age, can elicit many of the same benefits as a reduced-calorie diet. ... Resveratrol is active in much lower doses than previously thought. ... In the heart [there] are at least 1,029 genes whose functions change with age. In animals on restricted diets, 90 percent of those heart genes experienced alterations in gene expression, while low doses of resveratrol thwarted age-related change in 92 percent."

Link: http://www.eurekalert.org/pub_releases/2008-06/uof-sir060408.php

As you might know, Aubrey de Grey's Strategies for Engineered Negligible Senescence (SENS) places the known forms of biochemical damage that cause aging into seven categories, each with a recommended path towards repair or prevention:

1) Too few cells: Some tissues lose cells with advancing age, like the heart and areas of the brain. Stem cell research and regenerative medicine are already providing very promising answers to degeneration through cell loss.

2) Cancer: We must eliminate the telomere-related mechanisms that lead to cancer. de Grey suggests selectively modifying our telomere elongation genes by tissue type using targeted gene therapies.

3) Mitochondrial damage: Mitochondrial DNA is outside the cellular nucleus and accumulates damage with age that impairs its critical functions. de Grey suggests using gene therapy to copy mitochondrial DNA into the cellular nucleus. Other strategies for manipulating and repairing damaged mitochondrial DNA in situ were demonstrated for the first time in 2005.

4) Molecules gummed together with crosslinks: Some of the proteins outside our cells, such as those vital to artery walls and skin elasticity, are created early in our life and never recycled or recycled very slowly. These long-lived proteins are susceptible to chemical reactions that degrade their effectiveness. Scientists can search for suitable enzymes or compounds to break down problem proteins that the body cannot handle.

5) Too many cells: Certain classes of senescent cell accumulate where they are not wanted, such as in the joints. We could in principle use immune therapies to tailor our immune systems to destroy cells as they become senescent and thus prevent any related problems.

6) Junk between the cells: As we age, junk material known as amyloid accumulates outside cells. Immune therapies (vaccines) are currently under development for Alzheimer's, a condition featuring prominent amyloid plaques, and similar efforts could be applied to other classes of extracellular junk material.

7) Junk inside the cells: Junk material builds up within non-dividing, long-life span cells, impairing functions and causing damage. The biochemistry of this junk is fairly well understood; the problem lies in developing a therapy to break down the unwanted material. de Grey suggests searching for suitable non-toxic microbial enzymes in soil bacteria that could be safely introduced into human cells.

The Methuselah Foundation has modestly funded work on items #2 and #7 above since 2006, whilst research fundraising was in the early stages, as MitoSENS and LysoSENS:

The most promising approach [for LysoSENS], in my view, is to enable cells to break the junk down so that they don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and preliminary work in my old department in Cambridge, as well as work now being carried on at Arizona State University, has already confirmed this optimism.

...

MitoSENS research began at Cambridge University, in the MRC-Dunn Human Nutrition Unit. Ian Holt, Ph.D., head of the Mitochondrial Diseases research at the Dunn - who supervised the first MitoSENS projects - commented, "For over 30 years mutations in mitochondrial DNA have been suspected to be important contributors to aging. If we can incorporate working copies of that mtDNA into our nuclear DNA, the mtDNA will be rendered superfluous and any mutations it suffers will be inconsequential. Researchers have tried to do this for many years, with only limited success. The work that Mark will perform in my lab is the most systematic attempt yet to get this technology to work."

This March 2008, the Methuselah Foundation has transferred its MitoSENS Research program to the lab of Dr. Marisol Corral-Debrinski in the newly opened Institut de la Vision in Paris. Dr. Corral-Debrinski began her career studying mRNA localization to the mitochondria in yeast, a process which she identified as essential for mitochondrial gene therapies. She now heads a lab that is applying the mRNA localization approach to the development of gene therapies for treating inherited mitochondrial diseases. The same approach can, in theory, be used to treat the somatic mutations of mitochondrial DNA that play a definitive role in aging. For this reason, we have chosen to collaborate with her to hasten the development of gene therapies that may obviate mitochondrial DNA mutations.

With growth in philanthropic research funding through to the present day, thanks to many generous donors and the rising profile of the Foundation, these promising research programs are expanding. In addition, looking ahead, we can see the groundwork taking place for Methuselah Foundation-funded programs in the other categories of SENS:

AmyloSENS - cleaning up extracellular junk:

The Methuselah Foundation is presently in discussion with leading researchers in this field with a view to initiating work on a vaccine - similar to that developed by Elan for Alzheimer’s disease - to stimulate the aged body to clear the widespread amyloids (particular of transthyretin) responsible for senile systemic amyloidosis.

ApoptoSENS - removing senescent and other "gone bad" cells:

During 2008, the Methuselah Foundation will launch a project to develop a procedure for clearing aged T cells from the blood of mice, and potentially thereafter in primates. This work will be supervised by one of the top professors in the immunosenescence field.

GlycoSENS - breaking down crosslinks and AGEs:

The Methuselah Foundation is currently planning out a project to engineer enzymes capable of cleaving the ubiquitous glucosepane crosslinks, which may comprise as much as 98% of all the long-lived crosslinks in aged human tissue. This work is still in the early planning stages, but we hope to be able to begin full-time research before the end of 2008.

OncoSENS - alter cells to prevent cancer:

The Methuselah Foundation is planning to launch three projects in the OncoSENS strand during 2008.

The first project aims to characterise the enzyme responsible for [alternative lengthening of telomeres], which is still unknown. Recently, however, observations in two different organs have given good reason to consider a hitherto unsuspected gene. A relatively simple series of experiments could test this hypothesis.

The second project addresses a potential problem with the WILT strategy. It’s possible that telomerase activity per se - independent of telomere length - may have roles in maintaining the health of the stem cells themselves, or of their rarely-dividing neighbours in the so-called "stem cell niche". We are arranging a project to address this question, in the blood of mice, with the world’s leading professor in the area.

Finally, the theory that non-cancer-causing mutations are unlikely to be harmful in a normal lifetime - protagonistic pleiotropy - is not yet widely accepted. We are therefore initiating a rigorous study into the effects of such mutations in mouse brains.

RepleniSENS - replacing lost cells:

We need more work in all these areas, even though they are all progressing very encouragingly. However, the current fashion for stem cell research in the international scientific community means that the Methuselah Foundation does not currently intend to allocate its limited resources to projects in this area.

Stem cell research is a well funded field indeed, moving rapidly. I'd wager that the most important technologies for the repair of age-related tissue loss will be developed before 2020, if not fully commercialized (given the present state of what it takes to push anything past the FDA). What I'd also like to see by that time is the growth of active, well-funded research communities for the other areas of SENS. I think that this is very likely: even modest early success in SENS research will gather more established research groups to the fold, more independent funding for the science, and accelerate the process of change and progress in the broader aging research community.

A long article at COSMOS magazine, which opens as follows: "Developments in a number of scientific disciplines suggest that we may soon be able to increase life expectancies from the 70- to 80-year range already seen in the richest countries to well over 100 and, perhaps, to over 1,000. We shall, in one sense, have made ourselves immortal. We shall not be immortal in the sense that we cannot die; plainly we could still be killed in a car accident or by a cosmic event such as an asteroid striking the Earth. But we could not be killed by disease or age, our bodies would be immune to infection, dysfunction or the ravages of time. We would be medically immortal. Some say this will happen quickly within, perhaps, 30 years with the first clear signs that we are on the right track appearing within the next decade. Others think we are at least a century or two away from attaining medical immortality. Some consider it completely unattainable. But the majority of scientists and thinkers in this area now consider life extension and even medical immortality possible and likely." What's more, folk like you and I can all pitch in to help to make it happen by supporting organizations like the Methuselah Foundation.

Link: http://www.cosmosmagazine.com/node/2029/full

There's one very crucial hurdle to implanting artificial components and replacement parts into the human body: how to integrate implants with living tissue at the smallest scales. One could make a good argument that it is this barrier, over and above anything else, that has prevented advances in prosthetic replacements to match advances in materials science. All barriers fall eventually, however: "scientists describe how they took an elastic scaffold (the material that gives the artificial graft its shape) of compliant poly(carbonate-urea)urethane and incorporated human vascular smooth muscle cells and epithelial cells from umbilical cords. Then they took the artificial grafts and simulated blood flow in the laboratory to test their durability. They found that as the pulsing fluid flow slowly increased, the artificial graft's performance actually improved. ... The notion that any body part could be engineered in a lab, attach to existing tissue 'naturally,' and grow stronger as it is being used is something thought completely impossible just 20 years ago. It is only a matter of time before human tissues can be engineered to be at least as good as the originals, and this study moves us toward that reality." Prosthetics might still give tissue engineering a run for its money when it comes to building replacement organs.

Link: http://www.eurekalert.org/pub_releases/2008-06/foas-sd060308.php

I thought I'd draw your attention to a couple of worthy updates at Ouroboros from the past few days. We'll start by revisiting the biochemistry of clam longevity once more:

So: long-lived molluscs have much higher antioxidant capacities than short-lived molluscs, suggesting a mechanism by which their much slower (possibly "negligible" senescence) might have evolved.

...

No defense based on prevention of damage (in this case, oxidation of protein and DNA) is 100% efficient. Assuming that protein and DNA oxidation contributes to the aging process in bivalves, even a very efficient SOD system will eventually allow oxidative adducts to accumulate to dangerous (i.e., gerontogenic) levels. If A. islandica is truly biologically ageless, then it must also have efficient repair systems in order to reverse, as opposed to merely prevent, oxidative damage. Then again, if this clam is simply aging very, very slowly, then maybe high levels of SOD are enough. Which is it? Only time will tell.

The long-lived actic quahog species of clam, the one with all the antioxidants, manages about nine times the lifespan of a more common or garden species of bivalve. That is interesting, because it calls to mind the difference between naked mole-rat lifespan and that of similarly sized rodents - also about a factor of nine, give or take. In both cases, the research focus appears to be on oxidative damage, mitochondria, and antioxidants in the right place to slow down resulting damage:

Mitochondria churn out damaging free radicals as a side-effect of their job as the cell's power plants. The chain of biochemical events that follows on from this fact is a major component of age-related damage, disease and degeneration. You can look back into the Fight Aging! archives for an introduction to that topic.

It has been demonstrated that soaking up the free radicals produced by mitochondria right at the source extends life span. This has been achieved by means of antioxidants like catalase, targeted to the mitochondria by gene therapy or other bioengineering means. This is quite different from taking antioxidants as a supplement, I should add; those don't go anywhere near your mitochondria, and thus don't do much good.

So it's reasonable to theorize that if you happen to be a member of a species that naturally generates a lot of antioxidants around the mitochondria, you're going to live longer than members of another, similar species with worse luck in the antioxidant stakes.

As Chris Patil at Ouroboros points out, it's a little too early to say that this isn't just a case of looking where the lamp shines, but it all hangs together well.

Moving on, the "human dignity" backlash: you can only claim for so long that our worth as human beings requires us to live in dirt and suffering, renouncing progress, before getting called on it.

the theoconservative movement cites considerations of "dignity" in cautioning against broad classes of biological research, including stem cell therapeutics and - more recently, as the idea becomes more thinkable - biogerontology ... Thus, in the process of enumerating the shortcomings of dignity as a desideratum, Pinker incidentally engages in a brief but cogent defense of life extension technologies.

...

I believe that dignity does have a place in the discussion, in the following sense: There is nothing dignified about pain, senility, incontinence, or frailty; therefore, one of the primary justifications for studying the processes of aging in human beings is that we might hope to someday prevent the scourges of late-life disease and thereby increase dignity for all.

I feel it is necessary - as many times as it takes - to examine and hold up to just ridicule those who call for an enforced relinquishment of medical progress towards increased healthy longevity. They would have us, we billions, all suffer and die before our time because the whim pleases them; ridicule is effective and humane, but too kind.

One component of aging is the damage caused by senescent cells, those that have stopped dividing, have not destroyed themselves in a form of programmed cell death or otherwise been removed from the picture, and have started to do a variety of things that are harmful to surrounding cells over time. Removal of senescent cells, say by adapting one of the many flexible and precise cell killing technologies being developed in the cancer research community, is one of the line items in the Strategies for Engineered Negligible Senescence:

So-called 'senescent' cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer.

Why do senescent cells accumulate with age? And accumulate they do:

the Brown team began to study aging animals - baboons living on a research preserve that ranged in age from 5 to 30. In human years, that age range is roughly 15 to 90. ... For replicative senescence, the most important biomarker is telomere dysfunction-induced foci, or TIFs. Presence of these structures signals that the protective chromosome caps called telomeres have dwindled enough to halt cell division. ... What they found: The number of senescent cells increased exponentially with age. TIF-positive cells made up about 4 percent of the connective tissue cell population in 5-year-olds. In 30-year-olds, that number rose as high as 20 percent.

Over at Ageing Research, some thoughts on the matter:

If the accumulation of senescent cells are so detrimental to the tissues in which they reside, why haven't we evolved mechanisms to remove them? The answer is that we probably have, but the mechanism which removes them from the tissues becomes impaired as with age.

...

One possibility is that senescent cells are removed by the immune system. Senescent cells secrete cytokines to attract immune cells to their location (for their removal), secrete matrix degrading proteins to allow the immune cells easy access and secrete growth factors to stimulate the proliferation of surrounding cells for its replacement once the cell is removed. However, since the immune system itself is governed by ageing mechanisms, its ability to remove senescent cells gradually decreases, therefore the accumulation of senescent cells gradually increases.

Which is plausible, and those unremoved senescent cells sit there releasing biochemicals that damage and misdirect cells in the surrounding tissue. The aging immune system has a lot to answer for already, in terms of the damage done due to its decline, and it wouldn't surprise me to see more items added to the list.

UPDATE 11/2011: You might also take a look at a more recent study that makes for a compelling demonstration of the merits of destroying senescent cells:

Scientists at the Mayo Clinic, in the US, devised a way to kill all senescent cells in [mice genetically engineered to age more rapidly than normal, and therefore accumulate senescent cells more rapidly than normal]. ... when they were given a drug, the senescent cells would die. The researchers looked at three symptoms of old age: formation of cataracts in the eye; the wasting away of muscle tissue; and the loss of fat deposits under the skin, which keep it smooth. Researchers said the onset of these symptoms was "dramatically delayed" when the animals were treated with the drug. When it was given after the mice had been allowed to age, there was an improvement in muscle function.

UPDATE 03/2015: There is now a more recent overview of senescent cells in aging here at Fight Aging! In addition, the state of the science continues to advance. Researchers recently demonstrated improved health in normal aged mice via partial clearance of senescent cells in some tissues using a combination of existing drugs:

The scientists coined the term "senolytics" for the new class of drugs. "We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders. When senolytic agents, like the combination we identified, are used clinically, the results could be transformative. The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging. It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time."

Wired provides insight into the viewpoint of those longevity researchers focused on drug development and manipulating metabolism to slow aging: "'It's not a matter of if, but when,' said gerontologist David Sinclair of a drug that promises a long and healthy life -- not quite a fountain of youth, but perhaps a fountain of fitness. ... Sinclair predicted that the drugs 'could have as big an impact as antibiotics in the 20th century, and it's just around the corner.' ... The biggest myth is that if we extend lifespan, that would involve more unhealthy years at the end. But we'll add years of healthy life. ... Every major pharmaceutical company is conducting research on the handful of genes activated by caloric restriction. ... Sirtris' resveratrol formulation is now in Phase II clinical trials for diabetes. When it hits the market in four or five years, [Sinclair] said, "It'll be on the market as a diabetes drug. It'll have to sell for $3 or $4 a pill, in order to stay competitive. And once it goes off-patent, companies will be able to make it for pennies. It'll be like aspirin.'" Slowing the damage of aging is a far cry from repairing the damage of aging, however, and given that the research and development costs are roughly similar, there's no reason to favor it.

Link: http://blog.wired.com/wiredscience/2008/06/pharmaceutical.html

A layman's introduction to the origins of aging, and ongoing investigation into aging in bacteria once thought to be immortal, can be found at the Boston Globe: "For people, aging appears to be the result of damage that gradually accumulates in cells over a person's lifetime. Gene sequences get garbled, for example, and proteins become damaged and take on defective shapes. Cells have a more difficult time carrying out their functions and grow more and more slowly. Yet cells also have a remarkable capacity to repair themselves. They can proofread DNA and destroy defective proteins, replacing them with new ones. So why hasn't evolution favored perfect repair - in other words, immortality? ... To never get old, organisms would have to invest a huge amount of energy in repair. They'd be left with little energy to reproduce. Natural selection would instead favor other organisms that put less energy into repair and produced more offspring. A common solution to this trade-off is to set aside a special population of cells that will reproduce. Our bodies put a great deal of energy into keeping eggs and sperm from becoming damaged. They put much less care into repairing the rest of our cells."

Link: http://www.boston.com/news/science/articles/2008/06/02/aging_is_older_than_you_think/?page=full