Chemopreservation Versus Cryopreservation

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 has noted, 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.


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.

Targeting Cancer With Salmonella

Researchers continue to expand the set of tools available to build therapies targeted to very specific types of cell. Via ScienceDaily: "Salmonella bacteria can be turned into tiny terminator robots that venture deep into cancerous tumors where conventional chemotherapy can't reach. Once in place, the bacteria manufacture drugs that destroy cancer cells. ... It sounds like science fiction, doesn't it? But Salmonella are little robots that can swim wherever they want. They have propellers in the form of flagella, they have sensors to tell them where they are going and they are also little chemical factories. What we do as engineers is to control where they go, what chemical we want them to make, and when they make it." The future of artificial or engineered cells and bacteria is a bright one - they will likely form the first generation of nanomedical robots, given how much easier it is to alter existing designs rather than build afresh.


Working to Prevent Dry AMD

Researchers are making progress towards therapy and prevention of the dry form of age-related macular degeneration (AMD): "a deficiency of the CD36 receptor prevents the evacuation of oxidized lipids in the eye. Those oxidized lipids in turn accumulate and attack the layers beneath and over the retina - thereby causing vision loss. ... We found that a deficiency in CD36 receptors leads to significant and progressive age-related macular degeneration. CD36 deficiency leads to central vision loss -- a key feature of dry AMD ... Now that we have also developed the molecules that activate [the] CD 36 receptor, we are working on the validation of the efficacy of these molecules as potential therapeutic agents for dry AMD treatment with prospect at the horizon of 2015." A better approach would be to identify the source of those oxidized lipids and deal with that problem. They are likely a result of changes in the level of free radicals in the body, perhaps relating to the mitochondrial free radical theory of aging. But you won't know if you stop investigating as soon as you have a temporary patch for the symptoms.


Discussing the Longevity Dividend at Future Current

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:

Probing the Roots of Calorie Restriction

A clever experiment: "The ability of dietary restriction to increase animal life span is often thought to arise from differential allocation of resources between somatic investment and reproduction. In this theory, reproduction is repressed upon dietary restriction to make scarce nutrients available to somatic functions that increase survival. Here, we label nitrogen and carbon in the dietary yeast of Drosophila melanogaster with stable isotopes to determine whether resources are invested to somatic tissues at the expense of reproduction. We find that females on a full diet acquire and allocate more dietary carbon, nitrogen and essential amino acids (EAA) to eggs than females on a restricted diet. Full-diet females also invest more carbon, nitrogen and EAA into somatic tissue than those on a restricted diet. Thus, the longer lifespan of flies on a restricted diet relative to those on a full diet cannot be explained by greater absolute somatic investment, and high somatic investment does not ensure longevity." Alternative explanations: calorie restriction leads to changes in the efficiency with which resources are used, or in the efficiency with which cellular damage is repaired, either of which will reduce the rate at which damage accumulates - and thus tend to lengthen life.


Update on Targeting Specific Cell Types

The next generation of cancer therapies will safely destroy cancer cells through targeting mechanisms that home in on specific cell characteristics. These technologies will be also be used to build therapies for any condition that can be treated by eliminating errant cells - and one of those conditions is aging itself. Removing the buildup of senescent cells - eliminate their detrimental effect on the cellular environment - will be a part of any successful attempt to repair the damage of aging. The technology base for targeted therapies being developed by the cancer research community is ideal for that task. Here, Forbes looks at the state of the art: "If you look at where we were five years ago, there was nothing mature enough that the FDA would even consider [it]. Today, there are 20 to 30 small companies in both diagnostics and therapeutics. A handful of those are in clinical trials, and we expect another three or four will file applications this year ... Cancer researchers believe that further engineering the shape or surface properties of nanoparticles can enable the particles to actively target tumors, and thereby maximize their diagnostic or therapeutic function at the cancer site, while minimizing collateral damage to healthy tissue."


Niches, the Future of Regenerative Medicine

It is becoming increasingly clear that many of the very powerful future applications of regenerative medicine - such as replacing age-damaged tissue with newly repaired, youthful tissue - depend upon understanding and control of stem cell niches in addition to control of stem cells: "Niches are local tissue microenvironments that maintain and regulate stem cells. Long-predicted from mammalian studies, these structures have recently been characterized within several invertebrate tissues using methods that reliably identify individual stem cells and their functional requirements. Although similar single-cell resolution has usually not been achieved in mammalian tissues, principles likely to govern the behavior of niches in diverse organisms are emerging. Considerable progress has been made in elucidating how the microenvironment promotes stem cell maintenance. Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood."


Refining the Mitochondrial Free Radical Theory of Aging

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.

The Work of Engineering New Nerves

ScienceDaily looks at progress in the tissue engineering of replacement nerves: researchers "induce tracts of nerve fibers called axons to grow in response to mechanical tension. They placed neurons from rat dorsal root ganglia (clusters of nerves just outside the spinal cord) on nutrient-filled plastic plates. Axons sprouted from the neurons on each plate and connected with neurons on the other plate. The plates were then slowly pulled apart over a series of days, aided by a precise computer-controlled motor system, creating long tracts of living axons. These cultures were then embedded in a collagen matrix, rolled into a form resembling a jelly roll, and then implanted into a rat model of spinal cord injury. ... the axons at the ends of the construct adjacent to the host tissue extended through the collagen barrier to connect with the host tissue as a sort of nervous tissue bridge." The researchers have also demonstrated essentially the same process with human nerve tissue.


What We Know About Calorie Restriction, Health and Longevity

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?

Investigating the Damage Done By AGEs

A buildup of AGEs, advanced glycation endproducts, is responsible for a portion of the damage of aging. As biotechnology advances, researchers can investigate how this happens in more detail: "The Maillard reaction and its end products, AGE-s (Advanced Glycation End products) are rightly considered as one of the important mechanisms of post-translational tissue modifications with aging. We studied the effect of two AGE-products [on] the expression profile of a large number of genes potentially involved in the above mentioned effects of AGE-s. The two AGE-products were added to human skin fibroblasts and gene expression profiles investigated using microarrays. ... Most of the gene-expression modifications are in agreement with biological effects of Maillard products, especially interference with normal tissue structure and increased tissue destruction." This sort of investigation should be able to confirm present thinking on the most important forms of AGE - such as the emphasis on glucosepane - and therefore focus efforts on ways to safely remove those forms first of all.


Pondering IGF-1 Signaling

Ouroboros looks at the unknowns of IGF-1 signaling. It is clearly important to aging and longevity, but we are still left with many unanswered questions: "it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce. ... The underscored passage brings up an issue that we've discussed here previously: Why is it that IGF-I pathway mutations can confer long healthy lives on organisms, even though supplementation with IGF-I is often quite beneficial, and depletion of IGF-I is often bad for individual organ systems? Indeed, according to another recent study, low doses of IGF-I appear to protect the mitochondria in aging rodents - why then do completely IGF-I-deficient animals enjoy extended and healthy lives?"


Aging: the Disease, the Cure, the Implications

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.

Pointing the Finger at Mitochondria Again

You may be familiar with the mitochondrial free radical theory of aging - that accumulated damage to mitochondrial DNA provides a strong contribution to age-related degeneration. A little more contributory evidence here: "we have used a systems biology approach to study the molecular basis of aging of the mouse heart. We have identified eight protein spots whose expression is up-regulated due to aging and 36 protein spots whose expression is down-regulated due to aging ... Among the up-regulated proteins, we have characterized five protein spots and two of them, containing three different enzymes, are mitochondrial proteins. Among the down-regulated proteins, we have characterized 27 protein spots and 16 of them are mitochondrial proteins. Mitochondrial damage is believed to be a key factor in the aging process. Our current study provides molecular evidence at the level of the proteome for the alteration of structural and functional parameters of the mitochondria that contribute to impaired activity of the mouse heart due to aging." Aging is the chain of events resulting from important changes in biochemistry - the more we know about those changes, the better placed we are to reverse them.


The Spreading Search For Longevity Genes

Via the Hindu Business Line, news of a longevity study in India: "The Avestagenome project, that seeks to plot the genetic and medical database of the Parsi community, expects to start its Mumbai-leg of the study this April. The project would open a base in Mumbai, the centre with the largest Parsi population, for voluntary collection of blood samples from the community ... With Parsis showing high levels of longevity, the project seeks to undertake genetic studies to examine the basis of the longevity, besides identifying genes that may be linked to age-related neurological conditions such as Alzheimer's and Parkinson's. The study will also focus on two cancers, including breast cancer." The article compares the work to that of deCODE in Iceland, though it seems closer in nature to longevity studies of the Ashkenazi Jewish population - a small, distinct population in which it is easier to uncover meaningful genetic differences.


Why No Healthy Life Extension Grand Challenge?

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?


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.

Towards Regenerative Therapies For the Liver

Folk at Advanced Cell Technology are touting their latest technology demonstration: "a robust and highly efficient process for the generation of high-purity hepatocytes (liver cells). ... Highly enriched populations of definitive endoderm (DE) were generated from [human embryonic stem cells (hESCs)] and then induced to differentiate along the hepatic lineage by the sequential addition of inducing factors implicated in physiological hepatogenesis. The differentiation process was largely uniform with cell cultures progressively expressing increasing numbers of hepatic lineage markers. The hepatocytes exhibited functional hepatic characteristics such as glycogen storage, indocyanine green uptake and release, and albumin secretion. In an animal model of acute liver injury, the hESC-DE cells differentiated into hepatocytes and successfully repopulated the damaged liver. ... the research represents another one of Advanced Cell Technology's efforts aimed at the large-scale differentiation of human embryonic stem cells [into] critical replacement cell types."


On Porcine Xenotransplants

From the perspective of 2008, it seems plausible that xenotransplantion could become economically competitive with stem-cell based tissue engineering of replacement organs for long enough to become widespread. Competition is good - it drives people to achieve more, faster. "Alternatives to the use of human organs for transplantation must be developed and these alternatives include stem cell therapy, artificial organs and organs from other species, i.e. xenografts. For practical reasons but most importantly because of its physiological similarity with humans, the pig is generally accepted as the species of choice for xenotransplantation. Nevertheless, before porcine organs can be used in human xenotransplantation, it is necessary to make a series of precise genetic modifications to the porcine genome, including the addition of genes for factors which suppress the rejection of transplanted porcine tissues and the inactivation or removal of undesirable genes which can only be accomplished at this time by targeted recombination and somatic nuclear transfer."


Why You Can't Just Flip Switches

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.

The Source of Age-Related Diabetes

How is it that eating too much eventually leads to insulin resistance, diabetes and a shorter life? Just as scientists are making progress in uncovering the biomechanisms of calorie restriction, they are also showing how excess food causes its predictable effects: "For quite some time now, scientists suspected the so-called hexosamine pathway - a small side business of the main sugar processing enterprise inside a cell - to be involved in the development of insulin resistance. ... For the first time we have a real understanding of how the insulin signaling system is turned on and off ... researchers believe that the hexosamine pathway acts as fuel gauge, protecting the body's cells against the toxic effects of too much glucose and other high-energy molecules. Excessive quantities of nutrients - the result of a lifestyle where food is plentiful and exercise is optional - [dampen] the insulin response, paving the way for a relentless progression of insulin resistance. ... the enzyme OGT [is] the last in a line of enzymes that shuttle sugars through the hexosamine pathway. ... when [researchers] put OGT into overdrive in the livers of mice, the animals developed insulin resistance and abnormal blood lipid levels, emphasizing the importance of the hexosamine pathway for the development of insulin resistance, the first step towards full-blown type 2 diabetes." A step on a path you can choose not to follow, needless to say.


Quantifying Progress in Treating Cancer

Cancer is the great bugbear of aging, the mechanisms of your biology slipped into destructive ways. But even before the development of the cancer cures of future decades, cancer will become a merely unpleasant chronic condition - a tax on your wallet rather than your life. EurekAlert! notes the progress made to date, even as the population ages, and even prior to the introduction of impressive next generation therapies presently in trials and the laboratory: "death rates from cancer in the United States have decreased by 18.4 percent among men and by 10.5 percent among women since mortality rates began to decline in the early 1990s ... for the number of cancer deaths to decrease, the decline in the overall cancer mortality rate must be large enough to offset the increasing numbers due to growth and aging of the population." Take the policy mumbo jumbo in the article with a grain of salt: it is progress in medical technology - and resulting lowered cost and increased effectiveness of existing techniques - that underlies the drop in death rates for many age-related conditions.


A Little Calorie Restriction Research For the Day

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.


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.

More Cancer Immunotherapy

The broad heading of "immunotherapy" covers a very wide range of efforts to convince the immune system to attack specific cells. Here's another example of using viral vectors to induce immune cells into specific actions: "The researchers used a virus stripped of its disease-causing genes as a vehicle to deliver two therapeutic proteins directly into the [glioblastoma multiforme (GBM)] tumor cells. One protein, FMS like tyrosine kinase 3 ligand (Flt3L), drew dendritic cells into the brain. Another protein, herpes simplex virus type 1 thimidine kinase (HSV1-TK), combined with the antiviral gancyclovir (GCV), killed tumor cells. Dendritic cells clean up debris from dying cells and in the process alert immune system cells of the existence of foreign entities, or antigens - in this case, GBM cells. Newly 'educated' immune system cells then swarm to the tumor cells to destroy them. In an earlier study, [researchers] used HSV1-TK and GCV alone to treat GBM and found that about 20 percent of the animals survived, compared to controls. By adding the dendritic-cell inducing Flt3L, the survival rate jumped to about 70 percent. Systemic immune activity was sustained, even fending off a 're-challenge' with additional tumor cells."


Embryonic Stem Cells Versus Stroke Damage

Via EurekAlert!, work on repairing neural damage following stroke: "Neural cells derived from human embryonic stem cells helped repair stroke-related damage in the brains of rats and led to improvements in their physical abilities ... [researchers hope] the cells from this study can be used in human stroke trials within five years. ... At the end of two months, the cells had migrated to the damaged brain region and incorporated into the surrounding tissue. None of those transplanted cells formed tumors. Once in place, the replacement cells helped repair damage from the induced stroke. The researchers mimicked a stroke in a region of the brain that left one forelimb weak. This model parallels the kinds of difficulties people experience after a stroke. Testing at four weeks and again at eight weeks after the stem cell transplants showed the animals were able to use their forelimbs more normally than rats with similarly damaged brain regions that had not received the transplants."


What is Wealth?

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.

Getting to the Future of Engineered Biology

A rather interesting article from Edge, which looks at how we might get from where we are today in biotechnology to the future we'd all like to see. It's very much along the lines of earlier discussions at Fight Aging! on open source biotech and the cost of infrastructure as they relate to progress and research communities: "How can I make biology easy to engineer? ... Going back hundreds of years, people had imagined that you could always design and build or make life, but nobody could really do that much about it. ... Now, 30 years after the initial successes of biotechnology, it has only realized really one of the early promises. ... Nevertheless, biotechnology exists, it's a huge positive contributor to our health and economy and the human condition generally, and now it's 2008. And so the question is, can we realize the initial promise of biotechnology? Or, forget that question, how do we make biology easy to engineer, so that anything we might want to manufacture out of the living world is something that we can pull off? ... Are we going to ever get to the point where it's not an exclusive technology, it's not a technology that requires experts? Are we ever going to get to the point where we can make many component integrated systems?"


The Latest Rejuvenation Research

The latest issue of the journal Rejuvenation Research is available online. Most of you skip the cover blurb, I'm sure, but it's worth noting: "Rejuvenation Research publishes cutting-edge work on rejuvenation therapies in the laboratory and clinic, as well as the latest research relevant to what these novel therapeutic approaches must do at the molecular and cellular level in order to be truly effective. Aubrey de Grey, at the helm of this multidisciplinary peer-reviewed journal, seeks to understand and ultimately defy the mechanisms of aging. He was featured in a recent 60 Minutes segment titled 'The Quest for Immortality'; in a cover story on de Grey, MIT's Technology Review said, 'His tireless efforts...have put him among the most prominent proponents of antiaging science in the world. ... De Grey has become more than a man; he is a movement.' Dr. de Grey and his outstanding international editorial board have the opportunity to further explore and advance the science, and perhaps achieve the ultimate goal of slowing or reversing the process of aging."


Mechanisms Linking Mitochondria, Calorie Restriction and Longevity

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:

An Overview of Calorie Restriction

Via the St. Louis Post-Dispatch, a decent overview of the practice of calorie restriction and some present scientific efforts to quantify effects on health and aging: "Early tests showed the practitioners, who call themselves 'CRONies,' (Calorie Restriction, Optimal Nutrition), had virtually no risks of cardiovascular disease or cancer ... It's becoming clear from studies with the CRONies - and from this brief, prospective study - that calorie restriction does change some of the markers we associate with aging ... Proponents of calorie restriction, which they call 'CR,' boast of disappearing triglycerides, healthy cholesterol levels, the elimination of low-level inflammation through the body caused by oxidation damage, lowered and more stable blood sugar, nonexistent cardiovascular disease and even instances of being cured of early stage diabetes. ... The attraction to CR by researchers was sparked by more than 60 years of uncommonly consistent tests on laboratory mice and rats. [When] laboratory animals were placed on calorie restricted diets, 'their life spans increased 20 to 40 percent.'" The quality of media examination of calorie restriction has greatly increased in past years thanks to the efforts of advocates and educators in the community.


Kurzweil's Vision of Accelerating Longevity

This Living on Earth transcript gives a concise look at the view of future longevity outlined by Ray Kurzweil in Fantastic Voyage: "there are three bridges, to dramatically extending our life - to radical life extension. ... only 10-15 years from now [we'll] have bridge two which [is] the full-flowering of the biotechnology revolution where we'll have the means of re-programming our own biology. ... health and biology and medicine are becoming information technologies, they are subject to what I call the 'Law of accelerating returns' which is this doubling of the power of these technologies every year. ... Bridge Three is nanotechnology. ... within about 20 years we will have fully reverse-engineered biology. We will have the means through biotechnolgy and nanotechnology to fix anything that goes wrong - ultimately at the cellular level and at the molecular level - with nanobots going inside our body and fixing each cell as something goes wrong. And that would really enable us to live indefinitely - it's a little bit different than a guarantee, I mean you could end up in an explosion somewhere or something. But it will really extend our human longevity indefinitely." I'm amongst those who think Kurzweil's projections are aggressive - but only by a decade or two.


Longevity SNPs

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:

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.

The Power of Targeting, Modularity

Via EurekAlert!, one example of work to combine targeting mechanisms with anti-cancer mechanisms to safely attack cancer cells. Here, researchers "slowed the growth of two particularly stubborn solid tumor cancers - neuroblastoma and peripheral nerve sheath tumors - without harming healthy tissues by inserting instructions to inhibit tissue growth into an engineered virus ... this [therapy] enhanced anti-tumor activity by stimulating multiple biological processes, including directly killing the cancer cells and reducing the formation of blood vessels that fed the tumors ... oncolytic herpes simplex virus (oHSV) and similar viruses can infect and kill human cancer cells without harming normal, healthy cells or causing disease. [Researchers armed] oHSV with a gene that carries instructions for a cancer-fighting protein, human tissue inhibitor of metalloproteinase 3 (TIMP3). TIMP3 blocks enzymes that aid the development and progression of cancer, called matrix of metalloproteinases (MMP)." While this is not as effective as other examples, the present breadth of exploratory work in targeted cancer therapies is impressive. Most importantly, even partial successes yield improved component parts for other targeted therapies - the modularity of this work greatly speeds overall progress.


The Guardian on Cryonics

The Guardian looks at modern day cryonics and its goals: "First, cryopreservation techniques need to improve so patients' bodies - and especially their brains, the repositories of memory and personality - suffer minimal damage. Second, the medical techniques for [revival] must be developed. ... If we succeed in our mission, cryonics will become a process carried out in hospitals by medical staff for much shorter times. ... That in itself is a change from the early days. [The] demographics are changing. Formerly, most cryonicists were young, male and geeky. Now, Alcor gets whole families. The important unknown is: Can a cryosuspended brain, warmed and revived, retain the memories and personality of its owner? ... I think within 30 years we'll see a successful revival, but the people revived then would be cryopreserved 30 years from now. ... Last in, first out: the earliest patients to be cryopreserved suffered the worst damage. James Bedford, who in 1967 became the first person ever to be cryonically suspended and who is now at Alcor, was barely perfused at all. ... For the people being cryopreserved now, under the best conditions, my guess is 50 to 100 years. ... Given the current rate of medical progress and research into nanotechnology [if] we haven't done it in 100 years, it's not going to work." How far we've come in the past decade, to see respectful, balanced articles on the serious work of the cryonics community as the new media norm.


Our Folding@Home Team Passes Rank 200, $1000 For Longevity Science

At the end of last year, during the very successful Methuselah Foundation donation drive, I said:

The Longevity Meme Folding@Home team has been steadily rising through the ranks since its inception, thanks to the volunteer efforts of the many team members. The team is closing in on rank 200, a point that has been marked as a milestone for while. The lower ranks are a tough slog, but the team has been doing well - growing and producing results.

I have decided that the best thing to do to mark the passage of rank 200, rather than send out another round of Longevity Meme tchotchkes, is to donate a chunk of change to the Methuselah Foundation, where it can be put to good use in advancing longevity science. Here is my incentive for the team: pass rank 200, and stay beneath that level for a week, and I'll donate $1000 in support of Strategies for Engineered Negligible Senescence (SENS) research carried out by the Foundation.

The team recently steamed past rank 200 and, judging by the stats for surrounding teams, sub-200 ranks are here to stay. Please do drop by the Immortality Institute discussion thread for the Longevity Meme Folding@Home team to congratulate the volunteers. Congratulations all round, in fact!

I'll shortly be writing that check to fund a little more of the Methuselah Foundation's longevity science - and I hope that some of you folk decide to do the same this year. Don't forget that donations to SENS research are presently tripled by matching funds from Ryan Scott and Peter Thiel; my $1000 check will send $3000 to the researchers working on the LysoSENS and MitoSENS projects.

You might want to take a look at last month's update from the Foundation on the money rolling in and the new longevity research rolling out - things are moving along very nicely, and we hope to see even more progress in 2008.

Bone Regeneration Trials

News-Medical.Net passes along results of a trial for another first generation stem cell therapy. It's a clear improvement over presently widespread procedures for repairing bone injuries. The trial "involved 10 patients with leg fractures which refused to heal ... All the patients have apparently new bone formation and seven patients have achieved union of their long bone defects within an average of 4.9 months; three others continue to show progressive new bone formation. Before the stem cell implantation none of the 10 had shown any evidence of new bone formation for 5 to 41 months; the seven with the successful long bone union have been able to fully weight bear and resume daily activities. ... The study found there was a direct relationship between increasing the dose of stem cells implanted and shortening the time to heal the bony defect, which the researchers say indicates that the stem cells work in a similar way to a pharmaceutical drug."


Thoughts on Epigenetics, Damage and Aging

You might recall the reliability theory of aging and longevity, with its implication that we are born with a surprisingly high level of existing damage, reducing our life span. There is also the relationship between solar radiation during pregnancy and resulting life expectancy. Here's a paper speculating on the mechanics that might link early environmental circumstances with the odds on life span: "Recently a cluster of new hypotheses of aging has been suggested, which explicitly predict the importance of early-life events in health and life span modulations. It has been widely assumed that these long-lasting consequences of early-life exposures may depend on the same mechanisms as those underlying 'cellular memory,' that is, epigenetic inheritance systems. There is a growing body of evidence that environmentally induced perturbations in the epigenetic processes (which involve alterations of gene expression without a change in DNA sequence) can determine different aspects of aging, as well as [cause and course] of age-related diseases."


An Interesting View of Telomeres

This unorthodox overview of telomere biology is well worth your time: "Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age."


A Return to the Ethical Imperative

A bioethical examination of the documentary "Do You Want To Live Forever?" can be found at BioethicsBytes: "ultimately it's a matter of choice. Do we want to continue our youthful lives of the people who are already alive, or do we want to have turn-over of people dying ... and being replaced by people who are born? ... [Aubrey de Grey] acknowledges that people may have different opinions about which of these options is the most desirable, but argues that if we are able to extend healthy lifespan and thereby avoid people having to die horribly our ethical obligations lie with those who are already alive. Thus, de Grey's arguments suggest that research and development into life-extension technology is, not only desirable, but an ethical imperative. He positions this choice as both the individual and societal level." That modern societies operate as though there is a "social level," at which the few can force their decisions upon the many, is the real problem. Healthy life extension technology is, fundamentally, the greatest possible expression of individual choice - the choice to keep on living in good health, one day at a time, and the choice to work towards creating a future in which that will always be possible.


Steps Towards Rebuilding the Aged Immune System

There are many reasons why you, in some future year, may want to destroy your immune system and replace it with a new one. It's not an unreasonable goal, given that medical researchers are already doing just that in clinical trials aimed at curing automimmune conditions. The reason I have in mind - exhaustion of immunological space and effectiveness due to a lifetime of cytomegalovirus exposure - occurs to all of us, is a contributor to the degenerations of aging, and is outlined in detail back in the Fight Aging! archives.

One main reason your immune system fails with age appears to be that chronic infections by the likes of cytomegalovirus (CMV) cause too many of your immune cells to be - uselessly - specialized. ... researchers are looking into a possible way of clearing these infections from the body.

The flip side of clearing out CMV is to reboot your immune system. Clean it out and start afresh, absent the clutter of memory cells devoted uselessly to CMV that were crowding out the naive T cells needed to respond to new threats. There's more to the aging of the immune system than just this process of crowding, but it's a good start.

Here's an example of some of the foundational work that could lead to safe reconstruction of an age-damaged immune system:

A new study demonstrates for the first time that embryonic stem cells [ESCs] can be used to create functional immune system blood cells


In this study, a team of scientists from Iowa, Taiwan, and Germany used HOXB4-containing ESCs to engraft the bone marrow and rescue mice that genetically lacked any immune system and had been irradiated to destroy their bone marrow. Only cells containing HOXB4 were able to engraft, rescue the mice, and produce blood cells long term. These engrafted cells were shown to be derived from the transplanted ESC-derived cells.

To determine if these transplants were able to rebuild the defunct immune system, the scientists injected the mice with LCMV, a common rodent virus, and watched for T-cell activity, a sign that the body was defending itself against the infection. Although the number of T cells generated by the new hematopoietic cells was low, they were able to respond effectively to the virus. In addition, the transplanted hematopoietic cells were also able to produce B cells and other defensive cells called antigen-presenting cells, which have a role in signaling T cells to action. They also tested the ability of the mice to respond to vaccination and demonstrated the induction of specific immune cells. Although the level of immune response was not what is seen in normal adult mice after exposure to the virus or vaccine, it was measurable and effective.

A way to go yet, but that's progress.

What We Know About Stem Cells and Aging

A good overview of the present consensus on stem cells and aging can be found at Science News Online: "over the past few years, researchers have found stem cells in many, perhaps most, of the body's organs and tissues. Even the brain, which scientists once thought never replaced its nerve cells during adulthood, is now known to have stem cells that make new nerve cells throughout life ... Imagine that, as a person ages, these fountains of cellular youth might start to run dry. As the supply of fresh cells dwindles, tissues would gradually decline and show signs of age. 'That was the initial mode' of how stem cells could be involved in aging ... Yet evidence is mounting that the connection between adult stem cells and aging is more complex. Some kinds of stem cell actually grow more abundant with age. And just as stem cells affect aging, the aging body affects stem cells. ... Whether the bodily declines that come with aging are due to the depletion of stem cells depends on which organ is in question - and on which scientist you ask. ... There's still a tremendous amount of debate about even the [blood stem cell] system, which is one of the best-studied systems."


Aubrey de Grey on the Colbert Report

Biomedical gerontologist Aubrey de Grey, the quintessentially English driving force behind the Methuselah Foundation and SENS research, appeared on the Colbert Report last night - all very last minute for advance warning and confirmation as so many of these television shows are. A healthy discussion is underway over at the Immortality Institute: "Just saw him on the re-air, awesome to see him on the Colbert Report. I remember people suggesting on here that Aubrey should go on the show, but others figured that would never happen ... never say never. Great way to expose the Methuselah Foundation. ... [That] was great! Aubrey handled the interview really well. ... I'm fairly convinced that scientists will collectively come to the same conclusion that majority of non-genetic disorders are all related to the aging process, a process that can be modified to obviate it's deleterious effects. Some of us have simply realized this sooner than the rest of the world and have a head-start. It'll sink in. We just need more Aubrey's shouting this from rooftops."


Inserting Repair of Aging Into Tissue Engineering

A comment on yesterday's post on advances in stem cell infrastructure technologies:

Great news, but I have this question: what possible reason or mechanism exists for assuming that an "induced" stem cell created from an already aged cell wouldn't get some of the induced damage carried along with the machinery? I can't see how this would be a 100% "reset".

Still, I imagine even a slightly pre-aged replacement organ from your own cells would be a helluva a lot better than a foreign transplant with rejection problems.

Here's another one - if you're replacing an organ or tissue because of genetic disease, how long before the newly constructed replacement would start to fail in the same way?

Which is true; a new organ grown from your own tissue is not an automatic benefit under all circumstances. However, I see the building of new organs from small numbers of stem cells as just one component of what can potentially be achieved when you can create new pluripotent stem cells to order. There is a point early in the process at which you are working with just a handful of cells, freshly extracted. There, the opportunity exists to economically apply any form of new technology aimed at manipulating, repairing or changing those cells prior to growing new tissue.

For example, lengthening telomeres, or correcting simple genetic errors. These are things that can be done today in a limited fashion - we don't fully understand the consequences, and our knowledge is small in the grand scheme of things. That won't always be the case, however, and this point of opportunity in the growth of new tissue tailored for the individual will remain as we find new and better ways to take advantage of it.

The damage of aging in our cells is "just" a wrong arrangement of molecules, when it comes down to it. It seems plausible that selecting the least damaged cells, or repairing specific forms of damage - such as replacing age-damaged mitochondria with freshly repaired versions - is a near-future approach to minimizing the damage of aging in induced pluripotent stem cells.

One caveat: it looks likely that the behavior of stem cells, or any new tissue, in the body has a great deal to do with the holistic functioning of signaling networks and the cellular environment. You can't just take the cells in isolation when thinking through potential technologies and applications - you have to consider the aged environment of the surrounding tissue.

In general, there is a great deal of good that could be achieved with the technology to create pluripotent cells from any cell - and many other lines of research that can be applied atop this foundation with the goal of building better, less damaged tissue from aged cells. Beyond that, who knows? At some point we'll be skipping the extraction of cells and just building them outright from raw materials - and around about there aging becomes somewhat moot, given the biotechnoloy that implies.

Common Sense and Those "Modifiable Factors"

No new information here, but frequent reminders never hurt: researchers "studied a group of 2,357 men who were participants in the Physician's Health Study. At the beginning of the study, in 1981 to 1984, the men (average age 72) provided information about demographic and health variables, including height, weight, blood pressure and cholesterol levels and how often they exercised. ... A total of 970 men (41 percent) lived to age 90 or older. Several modifiable biological and behavioral factors were associated with survival to this exceptional age. ... Smoking, diabetes, obesity and hypertension significantly reduced the likelihood of a 90-year life span, while regular vigorous exercise substantially improved it. ... Adverse factors associated with reduced longevity - smoking, obesity and sedentary lifestyle - also were significantly associated with poorer functional status in elderly years." Take care of the health basics today to improve your chances of living into the era of working rejuvenation technology.


A Popular Science View of Longevity Research

From Popular Mechanics: "We've long regarded aging as something almost mystical or supernatural, and it's easy to see why. ... But research demonstrates that aging isn't a supernatural proc­ess; it's a physical one that gradually occurs as systems wear out beyond the body's ability to repair them. Cells fill up with metabolic debris called lipofuscin that they can't digest, accompanied by decreasing functionality. They also undergo glycation, gumming up and caramelizing with sugars that have bonded to proteins. Mitochondrial DNA can suffer mutations, and the body slowly loses stem cells, which weakens healing and repair. Aging is breakdown, but broken things can be fixed. After all, cars and airplanes tend to wear out as they get older, but with sufficient maintenance they can last far beyond their design life. ... Americans now live longer, healthier lives by several decades than the majority did a century ago. Most of us think it's a good thing. Would extending this phenomenon by several more decades be good, too? Seems like it to me."


An Update on Induced Pluripotent Stem Cells

The research community is steaming ahead with a promising methodology for producing the building blocks of all tissue types directly from your own cells:

researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells.


Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient’s skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types - beta islet cells to treat diabetes, hematopoetic cells to create a new blood supply for a leukemia patient, motor neuron cells to treat Parkinson’s disease.


Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells. Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications.

Infrastructure is important: any advance that lowers the cost of a common tool or resource will speed progress. The new news in this latest press is that the procedure has been reproduced fairly rapidly by different research groups. It is therefore probably viable as a technology base for regenerative medicine, organ regrowth, drug testing, research into the biomechanisms of disease, and everything else you'd want a cheap supply of pluripotent stem cells to achieve.

1% For Longevity Research

A generous donation by one of the founders of startup company Mediox: "The co-founder and president of Mediox, Inc., Alex Zhavoronkov, today announced a donation of portion of his company stock representing 1% of company total issued shares to the Methuselah Foundation. ... From the inception of Mediox, our team decided to model the company after Google and benchmark their best practices. This 1% donation to the Methuselah Foundation is our way of giving back to society. Helping extend human lifespan indefinitely has been my goal for many years. The Methuselah foundation has a strategy and the tools required to combat aging and we are proud to have them as shareholders of Mediox Inc. ... Over the past several years many prominent businessmen including Peter Thiel, founder of PayPal, Jay Walker, founder of Priceline, William Haseltine, founder of HGS, donated to the Methuselah Foundation to help accelerate anti-aging research."


Still Underestimating

Judging by this Gobal Pensions article, the big players in the insurance and risk markets are still betting against even the present rate of increase in healthy longevity: "Nearly half of the FTSE 100 companies amended the mortality assumption of their pension scheme ... They had become increasingly conscious of longevity and investment risk in current markets. ... Research into annual reports showed companies now estimated current pensioners would live an average extra 16 months but those retiring in 15 years time would live an extra 21 months. ... The longevity changes are, by contrast, concrete and in the here and now, and reflect an expectation of increased real cost of benefits due to members living longer, rather than a change in the approach to measurement." At present, medical science is adding one year every five years - and we are in the early years of nothing less than a revolution in the capabilities of biotechnology. That 21 month figure seems a fair way below the mark, and I predict a great deal of money will be lost in these industries in the decades ahead.


The Promise of Cancer Stem Cells

The promise - the hoped for possibility - of cancer stem cells is that they represent a small, manageable, less complex range of biochemical targets to prevent and destroy cancer. The biotechnology of this year and next can flip genetic switches and safely destroy cells with specific markers - if we just know where to look, what to destroy, what to change.

The promise of cancer stem cells is that cancer has a simple, easily severed root. This may or may not be the case, but you can be sure that this path will be well explored over the next decade. Here is an example of the sort of result that makes cancer researchers excited:

Discovery of good -- and bad -- liver stem cells raises possibility of new treatment

Many scientists believe up to 40 percent of liver cancer is caused by stem cells gone wild - master cells in the organ that have lost all growth control. But, despite years spent looking, no one has ever found these liver "cancer stem cells" - or even normal stem cells in the organ. Until now.


"After locating the cancer stem cells that help control development of these tumors, we were able to find a potential vulnerability that might form the basis of a new treatment for this disease - which is greatly needed," said the study’s lead author


"We found that all of these [cancer] stem cells had lost TGF-beta,” she said. “Without the brakes that TGF-beta puts on cancer, the stem cells had turned into bad guys.”

The scientists turned to mouse models of liver cancer to see what would happen if they took out the "stemness" in the cancer stem cells and found that only 1 in 40 mice bred without a stat3 gene developed liver cancer. "But with the stat3 gene intact, 70 percent of mice developed the cancer."

Off switches for various different types of cancer - that prospect keeps researchers working hard to uncover, detail and understand more of our biochemistry.

Methionine Restriction and Longevity

A fair weight of research suggests that lower intake of methionine plays a large role in the effects of calorie restriction: "Available information indicates that long-lived mammals have low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, many studies have consistently shown that dietary restriction (DR) in rodents also decreases mitochondrial ROS (mtROS) production and oxidative damage to mitochondrial DNA and proteins. It has been observed that protein restriction also decreases mtROS generation and oxidative stress in rat liver, whereas neither carbohydrate nor lipid restriction change these parameters. This is interesting because protein restriction also increases maximum longevity in rodents (although to a lower extent than DR) and is a much more practicable intervention for humans than DR, whereas neither carbohydrate nor lipid restriction seem to change rodent longevity. Moreover, it has been found that isocaloric methionine restriction also decreases mtROS generation and oxidative stress in rodent tissues, and this manipulation also increases maximum longevity in rats and mice. In addition, excessive dietary methionine also increases mtROS generation in rat liver. These studies suggest that the reduced intake of dietary methionine can be responsible for the decrease in mitochondrial ROS generation and the ensuing oxidative damage that occurs during DR, as well as for part of the increase in maximum longevity induced by this dietary manipulation."


Grow Your Own Replacement Parts

CBS News looks at the state of tissue engineering: "From blood vessels to muscle tissue, Atala and his team at Wake Forest University believe that in theory anything inside the body can be grown outside the body ... And it's real: They've made 18 different types of tissue so far. ... In a clinical trial at Thomas Jefferson Hospital in Philadelphia, a patient got a bladder transplant - with a new bladder grown from her own cells. ... the company also plans to mass-produce blood vessels and kidneys ... When people ask me 'what do you do,' we grow tissues and organs. We are making body parts that we can implant right back into patients ... Scientists believe every part of the body has cells capable of regeneration - all researchers need to do is isolate those cells and coax them to grow. ... What's coming from this technology is a future of highly personal, mail-order medicine, where in order to cure your disease, your doctor will order you a replacement organ or body part and it will be custom made for you, using your own cells. ... In regenerative medicine, I think it is similar to the semiconductor industry of the 1980s. You don't know where its going to go, but you know its big."


The Nuts and Bolts of Cryonics

The blog Depressed Metabolism examines the technical side of cryonics, the indefinite low-temperature storage of the recently deceased. Cryonic suspension aims to preserve the fine structure of the brain, so as to allow plausible future medical technologies to repair and revive the suspendees. As Depressed Metabolism puts it:

Cryonics involves placing critically ill patients that cannot be treated with contemporary medical technologies in a state of long-term low temperature care to preserve the person until a time when treatments might be available.

Like all things medical these days, cryopreservation is more easily described than accomplished. A great deal of specialist knowledge, research, investment and experience goes into the present standard for the process, and into the organizations that provide cryosuspension services. For example:

One argument that is often raised in favor of “field vitrification” (or vehicle based vitrification) is that it will reduce the time of (cold) ischemia and eliminate the harmful effects of remote blood washout and transport of a patient on water ice to a cryonics facility. A related argument is that field vitrification will eliminate stabilization.

In fact, field vitrification will not eliminate the need for stabilization because patients need to be protected from warm ischemic injury after cardiac arrest until a location to carry out cryoprotectant perfusion has been secured and surgical access to the patient’s vessels has been established (a procedure that, in cryonics, takes at least fifteen minutes under the best of circumstances). During that period the patient will still require prompt cardiopulmonary support, induction of hypothermia, and administration of anticoagulants and neuroprotective agents. As a consequence, stabilization times should not differ between field vitrification or remote blood washout. In light of the possibility that field vitrification will likely require more demanding and time-consuming surgery, field vitrification might even necessitate longer stabilization times.

The critical period in cryonics is the time taken to safely lower temperature in the brain to a point at which injury is prevented. The faster the better, but as the material above indicates, it's not a straightforward process - just as for any major medical intervention. You can find out more about the technical aspects of cryonics at the Alcor website:

Kirkwood on Longevity and Aging

Colin Farrelly notes a Tom Kirkwood piece on longevity and aging: "The increase in human life expectancy over the past ten years has taken both scientists and the population generally by surprise. Until recently, demographers were confidently predicting that once the gains made by reducing mortality in early and middle life had reached completion, growth in longevity would stop and we would see the fixed reality of the ageing process. This has not happened. ... The continuing increase in life expectancy, which in many countries advances by several hours per day, is one of humanity's most astonishing successes. ... Age is by far the biggest risk factor for a wide range of clinical conditions that are prevalent today. One might therefore presume that a major effort is being made to understand the ways in which ageing renders the elderly more vulnerable to pathology. Nothing could be further from the truth. There is a large number of medical research institutes around the world, many with a focus on one or more of the major age-related diseases - cancer, heart disease, arthritis or dementia. Yet only a tiny fraction of these carries out any research on the intrinsic contribution from the ageing process itself."


Bioinformatics and the Ticking Clock

A companion post to yesterday's link to GrailSearch expands on the challenge facing biogerontologists - and medical science in general for that matter: "In cellular immunology, for instance, there are about 100 billion peptide sequences to which the immune system can respond, each targeted by a small set of white blood cells, or T lymphocytes - as many types of T cells in one human being as there are stars in our Galaxy. Just a 100 billion eh? These insane types of numbers constantly whack us up-and-coming bioinformaticians in the head like the proverbial cartoon rake-to-forehead smackaroo. You get to the point that you simply shrug your shoulders, tell yourself there will be an indexed database for that dataset someday, and move on. But will there be a comprehensive set of biological databases in our lifetime? ... To really do this requires this being a primary research goal whereas most research efforts are simply focused on one very small task at hand with a limited research budget. The result is thousands of nonstandard databases and datasets being published all over the net with nobody really synthesizing the data. Our thinking needs to change in our approach to informatics and biology otherwise we'll keep doing the same work over and over. From an aging perspective, we just don't have time to let comprehensive aging models evolve from basic research as the data emerges."


Tenfold Healthy Life Extension in Nematodes

I first noted the gene engineering work on nematode worms that led to a tenfold extension of healthy lifespan late last year:

This and similar work forms an impressive set of technology demonstrations - there is no necessarily direct relevance to extending healthy human life span, but it certainly gets people fired up and excited.

Similar work that immediately springs to mind is the recent news of tenfold healthy life extension in yeast and 50% healthy life extension in mice, both also achieved through gene engineering.

More details on the nematode work (in the species C. elegans) are now available for those of us without a journal subscription at the UAMS website:

C. elegans are barely visible to the eye but are helping scientists unravel the causes of aging and understand what determines life span, Reis said. During the past 15 years, more than 80 mutations have been found that extend life in C. elegans, including components of a worm signaling pathway (a set of genes that responds to signals from the environment or within the worm) that is equally related to insulin signaling and insulin-like growth factor (IGF-1) signaling in mammals.

Insulin alerts cells that there are nutrients in the blood ready to be used, whereas IGF-1 stimulates growth. Interfering with insulin signaling results in insulin resistance, a condition that can develop into diabetes. Interfering with IGF-1 signaling produces effects in mammals more akin to those seen in long-lived worms. Mice mildly deficient in IGF-1 receptor are long-lived and appear healthy, Reis said, adding that the longest-lived humans tend to have diminished IGF-1 signaling as well.

“These observations hint that processes discovered in the worm also are relevant to aging in humans," Reis said, "but we shouldn’t expect exact parallels."

Reis' team discovered that a mutant in the insulin/ IGF-1 pathway of C. elegans slows development but ultimately produces adults he described as "super survivors," able to resist levels of toxic chemicals that would kill an ordinary worm. Although the adult lifespan of C. elegans is normally only two to three weeks, half of the mutant worms were still alive after six months, with some surviving to nine months.

"We knew we had found something amazing," said Srinivas Ayyadevara, Ph.D., research assistant professor in the UAMS Donald W. Reynolds Institute on Aging. "These worms continue to look and act like normal worms of one-tenth their age."

For those of you who like to dig deeper, a PDF of the scientific paper is freely available as well.

The Golden Age of Biology

From GrailSearch, an enthusiastic look at the role of bioinformatics in the mainstream approach to tackling aging by manipulating genes and metabolism: "The golden age of biology is upon us. We have broken through what previously seemed like an impenetrable wall of complexity, size and scale by decoding the human genome and are now building the next generation of tools to tackle the subsequent set of challenges. The most significant of these hurdles is that of aging. It also happens to be humanity's most important problem to tackle as most human suffering stems from this unfortunate and unnecessary process. The best tool we have for understanding the complex biological networks of aging is computational theory, particularly machine learning and its application to Systems Biology. Computational horsepower via high-performance computing, machine learning algorithms and biological data are all reaching a point where the intersection of these will soon allow us to use computational systems approaches for developing predictive models that precisely illustrate how we can tweak biological networks to best affect the dreaded aging process."


Common Sense

Making the most of your natural, inbuilt capacity for longevity is nothing more than applied common sense. For many people, that common sense will make enough of a difference to healthy life span to live into the era of rejuvenation medicine and the repair of aging. Via CNN Money: "Challenge yourself to learn new things. Learn a language. Take up the violin. Crossword puzzles and computer games aren't going to do the trick. You're retrieving information you've got in memory. Learning, though, seems to change the brain - it seems to improve resiliency. ... Obesity and inactivity will kill you. Aim for 30 minutes of exercise a day, but even just 10 minutes will help. Our bodies will benefit from any exercise at any age. Even frail, bedridden 80-year-olds benefit from regular programs of light weight lifting. After exercising they had fewer complaints of pain or discomfort. ... We've got to rethink retirement. Unless you have health issues, there aren't a lot of good reasons to quit working at 65. Work gives structure and meaning to life, though you may not want to work the same long hours as when you were young." Make use of the capacities you have, or be prepared to see them wither away much faster than you'd like.


Inflammation and the Damage of Aging

As I might have mentioned once or twice, chronic inflammation stretched over the years causes damage, suffering and death. It's a significant component of the processes of degeneration that accompany aging.

Inflammatory mechanisms: the molecular basis of inflammation and disease

Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues.

Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The complications of established atheroma, including plaque disruption and thrombosis, also intimately involve inflammation.

Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity

Inflammation is recognized as a major etiologic determinant of multiple disease states including myocardial infarction, stroke, diabetes, and metabolic syndrome, and individuals with elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) are at increased risk of mortality and morbidity from these conditions.

So inflammation is not something you want too much of. But it does serve a purpose, as noted in this position paper.

Inflammation and the aging process: devil or angel

Inflammation is often viewed as a pathologic mechanism leading to tissue damage and interference with function, such as the process of chronic tissue scarring or fibrosis. However, it is important to note that inflammation is a crucial component of normal tissue repair as well as being fundamental to the body's defense against infection. Considering inflammation as a "causative agent in aging" belies the underlying mechanisms whereby the acute inflammatory response is necessary for survival, and efforts to reduce and control the inflammatory response leave the host susceptible to infectious agents and improper healing.

Chronic inflammation inevitably has initiating mechanisms that include immune, autoimmune, and metabolic pathways, leading to the activation and presence of the host-protective response. It is more appropriate to target the underlying initiating conditions than the inflammatory process that ensues and treat the basic mechanisms of disease rather than interfere in a very important protective mechanism of the host.

Which is a good point, and very SENS-like thinking. Follow the biochemical chain of age-related changes until you find the largest lever you can move with the biotechnology of today or tomorrow, and thus shut down all the undesirable changes downstream from that lever. What are these underlying conditions that lead to runaway inflammation?

Inflammaging as a major characteristic of old people: can it be prevented or cured?

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging". Centenarians are unique in that, despite high levels of pro-inflammatory markers, they also exhibit anti-inflammatory markers that may delay disease onset. The key to successful aging and longevity is to decrease chronic inflammation without compromising an acute response when exposed to pathogens.

So one might view an increase of chronic inflammation with age as a slow failure of the immune system under accumulated load, operating far past its point of evolutionary optimization. It is promising that cytomegalovirus - and very similar viruses - contribute so greatly to this failure, given that inroads are already being made into dealing with this root cause of immune system aging:

It's All About the Autophagy

The better known life extension mechanisms in lesser animals are all driven by changes in autophagy - or so say the autophagy specialists. It's true that the various hyperspecialized communities of modern biology are overly cloistered and ignorant of one another's research, but the autophagy researchers are assembling compelling evidence for this position: "Here we show that mutational inactivation of autophagy genes, which are involved in the degradation of aberrant, damaged cytoplasmic constituents accumulating in all aging cells, accelerates the rate at which the tissues age in the nematode Caenorhabditis elegans. According to our results Drosophila flies deficient in autophagy are also short-lived. We further demonstrate that reduced activity of autophagy genes suppresses life span extension in mutant nematodes with inherent dietary restriction, aberrant insulin/IGF-1 or TOR signaling, and lowered mitochondrial respiration. These findings suggest that the autophagy gene cascade functions downstream of and is inhibited by different longevity pathways in C. elegans, therefore, their effects converge on autophagy genes to slow down aging and lengthen life span. Thus, autophagy may act as a central regulatory mechanism of animal aging."


FirstScience Interview With Aubrey de Grey

FirstScience interviews biomedical gerontologist and radical life extension advocate Aubrey de Grey: "I always try to be quite forthright and say that the technologies we develop within the next 30 years will probably only give us another thirty or so years of extra life. It's just that that extra thirty years is a hell of a long time for the technology to grow further. It's a little bit counter intuitive to people, because I often make an analogy with simple man-made machines and that we need to perform repair and maintenance on them. As in the case of cars, it's the rare car that gets a level of maintenance which can keep it going for a hundred years. The difference in the case of the human body is that we don't have a plan for this sort of maintenance. And so we don't know what to do quite so well, and we have to boot-strap to that point even though the machine (the human body) already exists. Once people understand this concept, it does help them to be much more sanguine about the possibility that we might be able to go from the point we are at in this moment – being able to do virtually nothing about aging – to effectively indefinite life spans within a few decades, which otherwise, would just make no sense at all." The path to extreme longevity is a bootstrap process of incrementally better repair technologies for the damage of aging. You don't have to fix everything - you have to fix enough to stay in good health for the next, better technology to be developed.


The State of Knowledge of Longevity Genes

A little while back I linked to a paper outlining the present state of knowledge of longevity genes:

Ample evidence from model organisms has indicated that subtle variation in genes can dramatically influence lifespan. The key genes and molecular pathways that have been identified so far encode for metabolism, maintenance- and repair mechanisms that minimize age related accumulation of permanent damage. Here, we describe the evolutionary conserved genes that are involved in lifespan regulation of model organisms and humans, and explore the reasons of discrepancies that exist between the results found in the various species. In general, the accumulated data has revealed that when moving up the evolutionary ladder, together with an increase of genome complexity, the impact of candidate genes on lifespan becomes smaller. ... currently used methodologies may have only little power and validity to reveal genetic variation in the population. In conclusion, although the study of model organisms has revealed potential candidate genetic mechanisms determining aging and lifespan, to what extent they explain variation in human populations is still uncertain.

Here's more in the same vein - there's no shortage of groups working to pull together a synthesis of research into aging and the genome from the past decade. The sheer amount of data that present day biotechnologies can demonstrate is daunting, however. Bioinformatics is as much a science of data management as anything else.

The genetics of ageing: insight from genome-wide approaches in invertebrate model organisms

Intense effort has been directed at understanding pathways modulating ageing in invertebrate model organisms. Prior to this decade, several longevity genes had been identified in flies, worms and yeast. More recently [it] has become routine to perform genome-wide screens for phenotypes of interest. A number of worm screens have now been performed to identify genes whose reduced expression leads to longer lifespan


Interestingly, these screens have linked previously unidentified cellular pathways to invertebrate ageing. More surprising, however, is the sheer number of longevity genes in worms and yeast.

Contining the "daunting mass of data" theme, it's worth noting that correlations between genes and longevity form but a small part of the puzzle. The bigger portion is how the expression of genes - the process of creating proteins that go on to play their part in biological machinery - change with aging, with other changes in gene expression, with environmental circumstances, with metabolic changes ... it's a big, dynamic, complex system in any organism.

Genomic studies in ageing research: the need to integrate genetic and gene expression approaches

Genome-wide and hypothesis-based approaches to the study of ageing and longevity have been dominated by genetic investigations. To identify essential mechanisms of a complex trait such as ageing in higher species, a holistic understanding of interacting pathways is required. More information on such interactions is expected to be obtained from global gene expression analysis if combined with genetic studies.

Genetic sequence variation often provides a functional gene marker for the trait, whereas a gene expression profile may provide a quantitative biomarker representing complex cellular pathway interactions contributing to the trait. Thus far, gene expression studies have associated multiple pathways to ageing including mitochondrial electron transport and the oxidative stress response. However, most of the studies are underpowered to detect small age-changes. A systematic survey of gene expression changes as a function of age in human individuals and animal models is lacking.

Maps of gene expression changes in different tissues with aging are slowly being constructed - you might recall recent news of the mouse AGEMAP project, for example. A lot more work remains on this path, however.

Bone Engineering Continues to Progress

Via scientists have "replaced a 65-year-old patient's upper jaw with a bone transplant cultivated from stem cells isolated from his own fatty tissue and grown inside his abdomen. ... [The researchers] isolated stem cells from the patient's fat and grew them for two weeks in a specially formulated nutritious soup that included the patient's own blood serum. In this case they identified and pulled out cells called mesenchymal stem cells -- immature cells than can give rise to bone, muscle or blood vessels. When they had enough cells to work with, they attached them to a scaffold made out of a calcium phosphate biomaterial and then put it inside the patient's abdomen to grow for nine months. The cells turned into a variety of tissues and even produced blood vessels, the researchers said. The block was later transplanted into the patient's head and connected to the skull bone using screws and microsurgery to connect arteries and veins to the vessels of the neck. The patient's upper jaw had previously been removed due to a benign tumor and he was unable to eat or speak without the use of a removable prosthesis."


The Thrust of Mainstream Alzheimer's Research

U.S. News gives a fair high-level summary of the main branches of Alzheimer's research at the present time: early diagnosis, immunotherapy and removing aggregates. From the article: "the closer science comes to a treatment for Alzheimer's, the more important early detection becomes. ... Promising techniques include MRIs used to show abnormal shrinking of the brain; pet scans to detect amyloid plaques in the brain or to spot patterns of glucose use associated with Alzheimer's; or spinal taps to look for abnormal concentrations of certain proteins in the cerebrospinal fluid during the early stages of Alzheimer's. ... Immunotherapy for Alzheimer's patients is just one of several new directions promising to transform the treatment of Alzheimer's ... We're at a juncture now where we're trying to make the transition from treating symptoms to disease-modifying treatments [that] hit at the cause of Alzheimer's. [A] whole new window is opening in terms of the approach to the disease. ... Other researchers, for example, are looking at drugs that target enzymes involved in the clumping of beta-amyloid proteins."


Regenerative Therapies: the Slow Move From Horses to Humans

Back in 2005, I noted that horses have enjoyed the benefits of early stem cell therapies since 2002:

In the new treatment, a damaged tendon is rapidly "repopulated" by flexible new tendon tissue, rather than leathery scar tissue that naturally forms over a period of up to 18 months. About 70 per cent of treated horses have returned to racing form - more than double the percentage that would be expected had they received conventional treatment.

As to why the same is not true of injured humans, you'd have to look towards the oppressive medical regulation that has developed over the past decades in most developed countries. Veterinary science continues to provide the shining example of where we could be with even just a little less waste, less socialism and less pointless, self-serving bureaucracy:

In the race to perfect 'regenerative medicine,' stem cell therapy for animals is ahead of treatment for humans because it is not so strictly regulated. It's not experimental - it's here. ... There are no side effects and no problems with rejection, because the patient is also the cell donor. ... I don't see any reason why humans aren't doing it."

Five years later, a few companies are starting to offer autologous stem cell therapies in the US - and they're only able to do it so soon by working their way around the low points in the regulatory landscape. It'll be another five years or longer before therapies that the FDA is overseeing emerge into the light of day - if they do at all. One of these adventurous companies is Regenerative Sciences, focusing on joint disease:

Millions of Americans suffer every year from painful and debilitating orthopedic conditions, such as osteoarthritis of the knee, fractures that won’t heal, and bone degeneration of the hip and other joints, known as osteonecrosis or avascular necrosis. Until now, treatment has focused on pain management and ultimately total joint replacement. Unfortunately, for those under the age of 65, these options are far from optimal.


Our trained staff isolates the mesenchymal stem cells. These cells are then grown using natural growth factors found in your blood. The goal is to achieve much greater numbers of stem cells than you could muster to the injured area.

We live in an age of promise in biotechnology, with the prospect of ever-increasing health and life span ahead of us. The greatest challenges to the promise of modern medicine are posed by the institutional ball and chain we allow to hold back progress.