A mind is information. The fine structure of the brain is a mind, information stored in physical structures we are slowly beginning to understand. Preserve the structure of the brain after death, and there is the possibility of restoration to life at a later date, through the use of plausible future technologies. The important thing is that the information is retained - with that in hand, all the details of future restoration from death are well within the realm of what physics tells us is possible.

All we can do today is the preservation part of the equation - but that's all we have to do for now. The dead have all the time in the world to wait, provided we can maintain the fine structure of their brains. Cryonics providers vitrify the brain and body for low-temperature storage in vats of liquid nitrogen, indefinite storage after death paid for by life insurance in most cases.

But why cryonics? Over at Depressed Metabolism, Greg Jordan makes the case for the development of low temperature storage infrastructures to be something of an accident of history. Other options exist:

Twenty years ago, Charles B. Olson published an article called "A Possible Cure for Death" in the journal Medical Hypotheses. In it, he favorably compares methods of chemical preservation to cryogenic preservation. Unfortunately, this article provoked no wide discussion or attempts at implementation. As the author notes on his website, other than requests for reprints, "nothing more came of it." And yet the arguments in it are still sound and just as persuasive today as they were then.

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Part of the confusion around chemopreservation concerns the quality of preservation that is possible with this method. Chemical methods of preservation such as fixation are not only adequate, they have long been the gold standard for biologists studying the structure of cells and the brain.

...

If personal identity is preserved in the brain in physical structures such as synaptic circuits, then we know that chemopreservation can preserve these structures just as well as cryopreservation.

It makes for interesting reading material, though I'm not sure that the economic argument in favor of chemopreservation can be made without a better analysis of the infrastructure you'd need for continuing safe storage of the preserved. See what you think.

Posted by Reason at 9:13 PM
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Future Current provides a valuable service by transcribing and making available the proceedings of meetings on transhumanist topics, such as healthy life extension and the ultimate defeat of degenerative aging. Two recent posts cover talks by Ronald Bailey and Anders Sandberg, given at the 2007 IEET event entitled Securing the Longevity Dividend. They are well worth your time as a reminder of the way in which the policy-focused world thinks.

Policy Scenarios for the Longevity Dividend

Here we have a very important driving factor, that is the belief that it is possible to extend life, which is not that widespread. People are in general very interested in life extension, but they don’t quite believe in it. I think this is very much the same situation as cloning before Dolly. I remember myself two weeks before the cloning of the sheep Dolly actually saying in a public forum, “Oh, cloning of mammals is years away.” It’s good to know that I’m a conservative guy that is sometimes wrong about the future. Life extension might come unexpectedly, and that’s not necessarily just a good thing, because some people might panic. On the other hand, if people don’t believe it’s possible, they won’t fund it.

It's only unexpected if we advocates haven't done our jobs - and the same goes for any alleged panic ("oh no, we don't have to suffer and die quite so soon..."). It seems to me that healthy life extension is a good deal more challenging than mammalian cloning, to the point at which it will take a very large and well supported research community to make real progress. It's more in line with cancer or regenerative medicine in that respect. No-one is going to be surprised by the advent of working rejuvenation therapies, for all the same reasons that no-one will be surprised by the development of cures for a broad range of cancers, or tissue engineered replacement organs.

The Political Economy of the Longevity Dividend

I would like to conclude that I think it is easily the case that these kinds of treatments are very likely to be affordable. The pro-mortalists fail to understand the effort to extend healthy human lifespan is a perfect flourishing of our uniquely human nature. The future generations will look back at the beginning of the 21st century with astonishment that some very well meaning and intelligent people actually wanted to stop biomedical research just to protect their cramped and limited vision of human nature. Those future generations will look back, I predict, and thank us for making their world of longer, healthier lives possible. To end, let me quote Sirtris Pharmaceuticals co-founder David Sinclair who said, "I would be disappointed if we were all born one generation too early." Me too.

For more information on the ongoing Longevity Dividend initiative that was the focus of this IEET event, you might look back in the Fight Aging! archives:

• Pitching Healthy Life Extension as the "Longevity Dividend"
• Criticizing the Longevity Dividend
• The Longevity Dividend: A Call for Endorsements

Posted by Reason at 9:27 PM
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Random damage to your mitochondrial DNA is a bad, bad thing in the long term - or so present theory has it. It happens all the time in your cells, however, as a natural consequence of the mitochondria doing their intended job of turning food into ATP, the universal fuel source used by your cells. The standard issue process by which food becomes ATP is called oxidative phosphorylation (OXPHOS); it generates damaging free radicals as a side-effect of its operation. Those free radicals won't get far before running into some other molecule and reacting with it, changing or damaging it in the process.

OXPHOS requires several key portions of your mitochondrial DNA to be intact and undamaged - or rather it requires the proteins that are created from those DNA blueprints. Now, if the needed portion of mitochondrial DNA is altered or destroyed by free radicals churned out by the OXPHOS process - well, no more OXPHOS for that mitochondrion. No more free radicals, either, and that's a more serious problem:

• Sufficient free radical damage to mitochondrial DNA shuts down OXPHOS within that mitochondrion, as the necessary proteins can no longer be produced. The mitochondrion switches over to using a less efficient method of producing power, one that doesn't produce free radicals, but has to run at a much higher rate to produce the same level of ATP.

• Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers - this is called clonal expansion.

• The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it's old, leaky, inefficient and needs to be replaced with a shiny new power plant.

• BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

• One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.

These cells entirely populated with damaged mitochondria start churning out large quantities of free radicals - through another, more forceful mechanism - into the body at large. That's a path to age-related degeneration and fatal conditions like atherosclerosis. The free radical theory of aging is based upon the harm done to tissues, structures and processes by these damaging biochemicals.

So how does this all get started again? Free radical damage to mitochondrial DNA? Possibly. There has been some debate of late as to how plausible this is as a mechanism, based on mutation rates, examinations of mitochondrial function in mice with many damage-induced point mutations in mitochondrial DNA, and so forth. With that in mind, I noted with interest a recent Nature Genetics paper:

What causes mitochondrial DNA deletions in human cells?

Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues. Understanding the mechanism of the formation and subsequent clonal expansion of these mtDNA deletions is an essential first step in trying to prevent their occurrence. We review the previous literature and recent results from our own laboratories, and conclude that mtDNA deletions are most likely to occur during repair of damaged mtDNA rather than during replication. This conclusion has important implications for prevention of mtDNA disease and, potentially, for our understanding of the aging process.

Deletion mutations are much more damaging than point mutations, and can result in a sequence of many genes being snipped out and lost. Thus a greater likelihood of losing one of the genes vital to OXPHOS. This paper presents an interesting nuance to the source of deletions - serious damage created as a result of errors in the processes that repair minor damage due to OXPHOS free radicals. Irony abounds throughout the mitochondrial free radical theory of aging.

To switch gears a little, I should note that the beauty of the Strategies for Engineered Negligible Senescence (SENS) approach to the mitochondrial free radical theory of aging is that it doesn't require medical engineers to understand why the damage happens. If we can successfully move genes that express the proteins vital to OXPHOS into the cellular nucleus, it then doesn't matter what happens to the mitochondrial DNA, OXPHOS will keep on working.

Similarly for wholesale replacement strategies - we don't need to know how the damage occurred to know that protofecting fresh, undamaged mitochondrial DNA into every cell will fix things for a while. "A while" being at least 30 years, given how long it takes the problem to become damaging to health.

Research is good - there is no such thing as useless knowledge, and every additional level of detail helps those building new therapies. But never feel as though there isn't enough to go on with already when it comes to engineering the repair of aging. Researchers know more than enough to be underway, and it's a tragedy that the field of aging repair - real rejuvenation medicine - is far less funded than present understanding merits.

Posted by Reason at 5:54 PM
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A good scientist is one who takes the time to write introductory papers for researchers outside his speciality, in related research communities that would would benefit from the latest findings, but are unlikely to make their own way to the water. As knowledge grows and science becomes increasingly specialized, each researcher's field of vision a smaller and smaller fraction of the whole, the process of spreading, assimilating and managing information becomes just as important as generating new knowledge.

We lay people also benefit from clear papers that outline the present state of knowledge. Here, for example, is a concise outline of we know about the practice of calorie restriction and its relevance to health and longevity:

An epidemic of overweight/obesity and type 2 diabetes, caused by overeating nutrient-poor energy-dense foods and a sedentary lifestyle, is spreading rapidly throughout the world. Abdominal obesity represents a serious threat to health because it increases the risk of developing many chronic diseases, including cardiovascular disease and cancer.

Calorie restriction (CR) with adequate nutrition improves cardiometabolic health, prevents tumorigenesis and increases life span in experimental animals. The purpose of this review is to evaluate the metabolic and clinical implications of CR with adequate nutrition in humans, within the context of data obtained in animal models.

It is unlikely that information regarding the effect of CR on maximal life span in humans will become available in the foreseeable future. In young and middle-aged healthy individuals, however, CR causes many of the same cardiometabolic adaptations that occur in long-lived CR rodents, including decreased metabolic, hormonal and inflammatory risk factors for diabetes, hypertension, cardiovascular disease and cancer.

Unraveling the mechanisms that link calorie intake and body composition with metabolism and aging will be a major step in understanding the age-dependency of a wide range of human diseases and will also contribute to improve the general quality of life at old ages.

The evidence to date suggests that, barring medical conditions that prevent it, we should all be giving calorie restriction a good long try. The future is pretty scary place if you believe it to involve the full range of obesity-linked degenerative conditions: Alzheimer's, diabetes, heart disease, cancer. Why gamble on the advance of medical technology to rescue you in time from the consequence of bad diet and little exercise? As I've noted in the past, there is already a great deal you can do today, and in the years ahead, to raise your chances of living healthily into the age of working rejuvenation medicine.

Think about it; if you can stash money away in your retirement fund for a time decades distant, why don't you apply the same level of thought and resources to investing in your future health?

Posted by Reason at 6:44 PM
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Aging is a medical condition - a disease, if you will. Like many medical conditions it is the result of damage and changes in your biochemistry that accumulate over the years. As for all medical conditions, we can look for therapies that postpone or reverse its effects. We can - and should - search for a cure.

In that vein, the Methuselah Foundation is playing host to a conference on the scientific path to rejuvenation medicine in Los Angeles this coming June.

The preliminary program already has over two dozen confirmed speakers, all of them world leaders in their field. As for previous conferences I have [co-]organised, the emphasis of this meeting is on "applied biogerontology" - the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to a youthful degree of physiological robustness.

Those of you who follow the latest aging research will recognize many of the names already in the program, and note that the Methuselah Foundation continues to draw together work from different fields in the Strategies for Engineered Negligible Senescence (SENS) approach to the repair of aging.

The conference is preceded by a more press-friendly symposium at which noted folk from the healthy life extension advocates and members of the aging research communities will speak:

The free public preconference "Aging: the disease, the cure, the implications" [will] be held in the 1800-seater Royce Hall, UCLA, on the evening of Friday June 27th, and to the dinner and reception following. This preconference will put the postponement of aging more firmly on the political and social map than ever before.

It will consist of presentations by at least six illustrious speakers, including:

• William Haseltine, Haseltine Global Health, founder of Human Genome Sciences
• Bruce Ames, Children's Hospital Oakland Research Institute, National Medal of Science awardee
• Michael West, Biotime Inc., founder of Geron and Advanced Cell Technology
• Daniel Perry, Director of the Alliance for Aging Research
• Gregory Stock, UCLA Program on Medicine, technology and Society and Signum Biosciences

Mark your calendars - this is something of a "SENS California," and promises to be much like the SENS conference series organized by biomedical gerontologist Aubrey de Grey in recent years.

Posted by Reason at 7:39 PM
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Given the members of the advisory committee for the Grand Challenges for Engineering, there appears to be a large and obvious hole in the list of challenges offered for consideration. Researcher Attila Chordash asks the obvious question:

Why was life extension ruled out of the 14 Grand Engineering Challenges?

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It is a big challenge to learn how could healthy lifespan extension as a big and realistic challenge have been left out? Why did Kurzweil (author of the book Fantastic Voyage: Live Long Enough to Live Forever) not stand up for it? Why nobody out of the luminaries thought that regenerative medicine and stem cells worth discussing more than a tiny side note? And what about Venter, whom I still like to be interview as there are many points in his activity suggesting a life extension connection. Somebody in the committee was clearly against it?

I was also surprised, given the tenor of press articles on the Grand Challenges, most of which focused on Ray Kurzweil and his views on the future of radical life extension and other transhumanist technologies. Given a committee, it seems, you can water down any set of ambitions to thin gruel indeed.

American inventor and futurologist Ray Kurzweil said mankind is on the brink of radical advances in computer science and medicine that will see tiny robots or "nanobots" embedded in people's bodies, fending off disease and boosting our intelligence. Breakthroughs in technologies such as RNA interference, involving inhibiting the functioning of genes, and gene therapy will allow us to flick genetic switches on and off and add new ones - putting an end to many illnesses and expanding lifespans, he added.

Precious little of that in the Grand Challenges themselves. Chordash offers some opinions collected from his network; it boils down to the conservatism of the any old guard, scientific community or otherwise. But there is no debate on the feasibility of healthy life extension in the gerontological community these days; the arguments are all over how the goal will be accomplished, how much can be done, and how long it will take. When you put together a Grand Challenge for Engineering on medicine and manage to completely leave out extending the healthy human life span, you make yourself irrelevant to what is actually taking place in the laboratories and research communities today.

Posted by Reason at 7:39 PM
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Biology is complicated. We are built out of a million evolutionary optimizations, and evolution loves the reuse of component parts. Every newly evolved mechanism will quickly find its place in other evolved systems, while still being used in its original capacities. The human cell is a big cat's cradle of macromolecules, each with twenty-something different purposes, operating in interacting feedback loops and dynamically regulated processes.

When your research indicates that molecule A is the problem in medical condition B, you can be fairly sure that bluntly manipulating molecule A in order to treat B will completely mess up vital systems X, Y and Z.

A good example of this principle came to my attention today, in the form of PGC-1alpha, a protein that's right in the middle of all sorts of important processes. I put out a post a few days back, in fact, on research demonstrating the role of PGC-1alpha in calorie restriction and mitochondrial function.

So, you might think, another target to better recreate the beneficial effects of calorie restriction on health and longevity - without the dieting. Not so fast, now:

Researchers at Dana-Farber Cancer Institute have found a previously unknown molecular pathway in mice that spurs the growth of new blood vessels when body parts are jeopardized by poor circulation.

...

Bruce Spiegelman, PhD, and his colleagues at Dana-Farber discovered that PGC-1alpha - a key metabolic regulatory molecule - senses a dangerously low level of oxygen and nutrients when circulation is cut off and then triggers the formation of new blood vessels to re-supply the oxygen-starved area - a process known as angiogenesis.

Blood vessel formation is not something to be tinkered with lightly - and that's just one of the many processes that PGC-1alpha is involved in.

This hyperconnectivity and reuse of processes, proteins and genes, this rampant complexity, is why aging researchers who focus on metabolic and genetic engineering - which is to say the bulk of the field - see healthy life extension as hard, and any meaningful progress in terms of additional decades as remote in the future. They believe the only viable way forward is to re-engineer our biology into something tougher and better, to slow the processes that cause damage and aging. I agree that this goal is a great challenge, and will likely still be a great and ongoing challenge when the era of hypercomputing and molecular manufacturing is upon us some decades from now.

Fortunately, a much better approach to complex systems exists: work with the examples you have. We have working examples of our biology in good health and operation. Similarly, we have examples that are age-damaged and failing. Rather than try to build some completely new complex biology to resist the ways in which age damages us, we should focus on identifying and reversing the specific differences between youthful metabolisms and age-damaged metabolisms.

Given the level of knowledge today, significant progress in reversing aging - repairing damage, reversing changes in metabolism - is much more plausible for the decades ahead than producing a new slow-aging human metabolism. In addition, any successful therapy that repairs some facet of the damage of aging in our metabolisms can be used over and over again by the same individual. Keep the damage beneath the level at which it causes the degeneration of aging, and you can continue to be healthy and youthful for so long as you please. This is obviously far more beneficial and valuable than a therapy that merely slows aging - slowing aging is of no use to the aged.

The greatest challenge in the scientific infrastructure and community of aging researchers today is to change the focus from slowing aging (slow, inefficient, producing less useful medical therapies) to repairing aging (more efficient, more rapid, producing more useful medical therapies). It is this challenge that spurs groups like the Methuselah Foundation and affiliated researchers. This may seem like an esoteric battle to some, but the future of life and health for everyone alive today depends upon it - which means that we should all pitch in and help.

Posted by Reason at 8:07 PM
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A couple of recent papers on calorie restriction caught my eye today - the standard fare for recent investigations, containing a little clarification, a little muddying of the waters. The behavior of metabolism is complex indeed, not to mention the large differences between species. All sorts of genes, mechanisms and pathways are involved in calorie restriction, and scientists are still in that portion of the discovery process that produces apparently contradictory information.

First off, a little more support for the interesting biomechanisms of calorie restriction - going beyond the benefits of less visceral fat - to be triggered by less methionine in the diet:

Dietary restriction (DR) lowers mitochondrial reactive oxygen species (ROS) generation and oxidative damage and increases maximum longevity in rodents. Protein restriction (PR) or methionine restriction (MetR), but not lipid or carbohydrate restriction, also cause those kinds of changes. However, previous experiments of MetR were performed only at 80% MetR, and substituting dietary methionine with glutamate in the diet.

In order to clarify if MetR can be responsible for the lowered ROS production and oxidative stress induced by standard (40%) DR, Wistar rats were subjected to 40% or 80% MetR without changing other dietary components. It was found that both 40% and 80% MetR decrease mitochondrial ROS generation and percent free radical leak in rat liver mitochondria, similarly to what has been previously observed in 40% PR and 40% DR.

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The results show that 40% isocaloric MetR is enough to decrease ROS production and oxidative stress in rat liver. This suggests that the lowered intake of methionine is responsible for the decrease in oxidative stress observed in DR.

Can human studies be too many years away? I imagine that producing a safe diet with much lower levels of methionine is not impossible, and that people out there in the calorie restriction community will hack away at that problem with more enthusiasm as the evidence mounts.

The second paper adds some additional facts and confusion to discussion of the role of autophagy in calorie restriction, and draws in other work on the TOR gene and calorie restriction.

A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans:

In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles.

In this study, we asked whether autophagy might contribute to the lifespan extension induced by dietary restriction in C. elegans. We find that dietary restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents dietary restriction and TOR inhibition from extending lifespan. The longevity response to dietary restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to dietary restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally regulated response to food limitation.

In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins.

It seems to me that a pressing next step in understanding the biomechanisms of calorie restriction is a definitive account of how autophagic and mitochondrial changes brought on by CR are linked.

Posted by Reason at 5:54 PM
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What is wealth? Let me try a slightly non-standard answer to that question. Wealth is a measure of your ability to do what you would like to do, when you would like to do it - a measure of your breadth of immediately available choice. Therefore your wealth is determined by the resources you presently own, as everything requires resources.

For the sake of argument, let us say that your resources presently amount to a leather bag containing a hundred unmarked silver coins. Interestingly enough, by the "what would you like to do" measure, you are fantastically more wealthy than any given ancestor put in the same position of ownership. You have immensely greater choice. Clearly there is more to wealth-as-choice than present property. We must also consider the historical investment made into increasing choice, and into lowering the cost of specific - usually popular - choices. The engines of technology and open, free markets are turned by people to create new, better, cheaper choices. The choice to fly, the choice to remain alive with heart disease, the choice to avoid that heart disease.

Where do silver coins - or indeed, any other resources you might own - come from? Where does investment come from? After all, we don't come into this world with the proverbial silver implement between the teeth. No, we worked for those coins. We spent time and negotiated payment for that time. Why? Because time is valuable.

But time spent alive, measured in the ticking of heartbeats, is more than valuable - it is wealth itself, the source of all other measures of wealth. All property was created by someone, somewhere, taking their time. The creation and exchange of property is a way to make time fungible, transferrable, a more valuable resource. Time spent alive is the root of all property, all human action, and thus all wealth - both the silver in your pocket that provides for present choice, and the wealth of possible choices created by past investment.

Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

We all go through engineering our cycles of property and time; how can we best optimize time to generate property that can be used to make our time more effective? We do this in small ways and large, but everyone does it. Some people do it so effectively they launch themselves into property escape velocity, exponentially increasing the effectiveness of their time and exploring the outer limits of what it means to maintain ownership of a great deal of property.

Interestingly, despite the grand importance of time as the absolute foundation of wealth, very little progress has been made in the most obvious optimization of all: creating property that can create more time. More heartbeats, more health, more time spent alive and active. Rejuvenation medicine, capable of repairing the damage of aging. Tissue engineering to generate replacements for worn organs. The cure for cancer. If you could do all that, then the much more productive form of escape velocity becomes possible - longevity escape velocity. Why strive to maintain an empire of property that will crumble to dust when the degenerations of age catch up with you when you could be that fit-looking guy having a blast swimming in the breakers every other Sunday for as long as you like?

Wealth is exactly time, and here we are, bordering the era of biotechnology for the repair of aging. Planning ahead for the best possible personal future starts with investment now. Think about it.

Posted by Reason at 8:25 PM
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The present availability of funding for research into the mechanisms of longevity through calorie restriction (CR) continues to lead to important swaths of our biochemistry drawn forth from the darkness. A freely available paper in the latest Aging Cell makes the case for a specific lynchpin linking aging, changes in mitochondrial function and longevity increases due to calorie restriction. It's also a good introduction to present thought on how important mitochondria are to aging:

Mitochondria are the key organelle in substrate utilization and energy production. Transcriptional profiling studies demonstrate that genes involved in mitochondrial energy metabolism are coordinately up-regulated in multiple tissues with calorie restriction (CR), suggesting a change in dynamic of the electron transport system and a role for this alteration in mitochondrial metabolism in the mechanisms of CR. Biochemical analysis suggests that mitochondria from restricted tissues are functionally different from their control counterparts in terms of metabolism and composition

...

Our understanding of the complexity of signalling pathways to and from the mitochondria is increasing, describing a network through which mitochondria may communicate functional status to the nucleus to impact cellular function. Metabolic reprogramming by CR may be central to the mechanism of lifespan extension, where changes in mitochondrial function confer an energetic shift that is conducive to increased cellular fitness, resulting in the promotion of longevity.

A number of research groups have put forward candidates for most important component of calorie restriction biochemistry - or at least most useful, for the purposes of near future therapeutic manipulation. Sirtris is still working on sirtuins, while other groups are digging deeper to find other vital genes, proteins and processes further down the chain. The authors of this paper are looking at PGC-1alpha, a biochemical that - like so many others - appears to be simultaneously involved in the regulation of all sorts of important cellular activities. Evolved systems favor component reuse and intertwined feedback loops, and cellular biochemistry is the prime example of the type. Very few forms of molecule inside a cell have just one purpose.

Mitochondrial function declines with age in humans, and a decline in the expression of components of the electron transport chain is a hallmark of aging across species

...

There is evidence to suggest that CR induces specific pathways that promote longevity. For example, in yeast, CR and numerous low-intensity stressors associated with longevity activate a common pathway to influence lifespan. Here, we show that PGC-1alpha transcriptional activity is induced in the oxidative stress response and CR through a shared mechanism, suggesting that in mammals, regulation of mitochondrial function is a key element in both cellular survival and longevity. We propose that mitochondrial plasticity may be critical for maintaining cell viability and in orchestrating the program of aging retardation by CR, raising the possibility that loss of mitochondrial plasticity is an underlying cause of aging.

You might contrast this conclusion with another derived from discovering necessary biochemistry for longevity through calorie restriction:

Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2(ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span.

While one can speculate on the relationship between the degree of autophagic consumption of failing mitochondria and overall mitochondrial function, it seems clear that a complete picture of the biochemistry of calorie restriction is still a few years away. From where I stand, the greatest benefit of this research will likely be the increase in our detailed knowledge of mitochondrial biochemistry. The more we know, the more feasible mitochondrial repair strategies become for the reversal of aging. The weight of evidence for the role of mitochondrial damage and change in degenerating aging is plenty heavy enough to demand action; the question is how best to proceed. Some of the options are described below:

• Moving Mitochondria
• Can Damaged Mitochondria Repair Their DNA?
• Mitochondrial Protofection
• Xenotransplanting New Mitochondria
• MitoSENS Research at the Methuselah Foundation

Posted by Reason at 3:58 PM
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So what is a SNP - a single nucleotide polymorphism - and why should you care? A quick definition:

A single nucleotide polymorphism (SNP, pronounced snip), is a DNA sequence variation occurring when a single nucleotide - A, T, C, or G - in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual). For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles : C and T. Almost all common SNPs have only two alleles.

Remember that a single gene is thousands of nucleotides long; SNPs are tiny differences considered in that scheme. However, in the same way that researchers - against initial skepticism - have been turning up single gene mutations that cause longevity for some time now, the community is starting to build the case for single SNPs that confer longevity benefits.

The common germline Arg72Pro polymorphism of p53 and increased longevity in humans:

A well known functional SNP in the tumor suppressor TP53 gene leads to increased longevity: in the Danish general population (n = 9219) homozygotes for the minor allele versus homozygotes for the major allele had an increase in median survival of 3 years. This is partly explained by increased survival after development of cancer or other diseases, in accordance with the observation that this Arg72Pro substitution in the p53 protein has important influence on cell death via increased apoptosis. Thus, the increased longevity may be due to a generally increased robustness after a diagnosis of any life-threatening disease.

In contrast to widespread skepticism on the importance of SNPs in humans, this gain-of-function p53 SNP of importance for cell repair mechanisms has a profound influence on longevity.

"Profound" here is in comparison to most examined SNPs, which appear to cause no meaningful differences. I imagine there will be other longevity SNPs uncovered in the future - there are tens of millions identified so far, and only a small fraction well studied. This particular SNP is another confirmation of the potential of p53 engineering for longevity:

• A New Look At p53, Cancer and Aging
• 50% Maximum Life Extension in Mice Via p53 and Telomerase

p53-related engineering looks to have at least as much potential as therapies based on the biochemistry of calorie restriction - which is to say not so much potential if you're already old. This is all about slowing rates of aging, not repairing the damaging of aging. This is why I favor quite different approaches to the engineering of human longevity.

Posted by Reason at 7:14 PM
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