Apoptosis and the Aging Immune System

Beyond the exhaustion of immunological space due to cytomegalovirus, there are other contributing factors leading to the degeneration of the immune system: "Immunosenescence is characterized by a peculiar remodeling of the immune system, mainly induced by lifelong antigenic burden and oxidative stress. Apoptosis or programmed cell death plays a central role in the ageing process. ... The apoptosis remodeling, in addition to inflamm-ageing, i.e. the upregulation of anti-stress responses and inflammatory cytokines, represents one of the major determinants of ageing rate and longevity, as well as of the most common age-related diseases. ... A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative, inflammatory and neoplastic diseases whose incidence increases with age. This review [highlights] emerging anti-ageing therapeutical strategies offered by apoptosis re-modulation. The challenge for the future is to identify factors and signals that regulate apoptotic processes and determine if selective apoptosis manipulation [could] preserve immune function in the elderly." Through increased understanding comes the possibility of action for increased healthy longevity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17584051

Telomere Shortening and Aging

Whatever the mechanisms linking shortening telomeres to aging, the decline appears to accelerate at age 50: "Telomeres play a role in cellular aging and they may also contribute to the genetic basis of human aging and longevity. A gradual loss of the telomeric repeat sequences has been reported in adult tissue specimens. ... There was a tendency that the age-adjusted telomere length was longer in females than that observed in males, while males lose the telomeric sequence faster than females. These data indicated that the percentage of longer telomeres fragments decreased, while the shortest fragments increased quickly with age. In addition, the longest telomere fragments decreased and the short fragments increased with a relatively stable frequency with age. There was also a significant difference in the longest telomere fragment percentage between males and female in their 40s and 50s ... the changing rate of the longest and the shortest range group [seemed] quite different before and after [age 50.] This contrast implies a drastic change around the age of 50 of unknown factors that affect telomere attrition."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17594061

The Complexity of Metabolism and Its Genetic Controls

Metabolism is very complex, and our present grasp of that complexity - for all the rapidity of present progress in biotechnology - is inadequate in the grand scheme of things. A few examples from recent papers illustrate the distance yet to go; so much remains unknown, and the closer you look the more there is to discover:

Long-lived dwarf mice: are bile acids a longevity signal?

Pathways that control aging act via regulated biochemical processes, among which metabolism of xenobiotics (potentially harmful chemical agents encountered as environmental toxicants, for example, drugs, or produced internally) is one possible candidate. A new study of long-lived Ghrhr mutant mice reports that increased bile acid levels activate xenobiotic metabolism via the nuclear receptor, farnesoid X receptor. This increases resistance to xenobiotic stress, possibly contributing to longevity.

Role of VEGF gene variability in longevity: A lesson from the Italian population

Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with an increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases suggesting functions not confined to its vascular effects originally described. Based on the VEGF protective roles undisclosed in pathological conditions, we evaluate whether VEGF variability might be a determinant also for longevity. ... These results suggest that VEGF gene variability can be inserted among the genetic factors influencing the lifespan.

The right path forward is research - a great deal of research - but not to direct that research in service to efforts to rebuild our biochemistry for greater longevity. That is the hard path, and the longer path. Consider the different between the level of knowledge required to maintain an engine and the level of knowledge required to build a better engine. At the present time, the mainstream of medical science appears to be heading along the path of building a better engine: of attempting to slow the accumulation of age-related damage by manipulating metabolism.

This is a hard, expensive road, but there is a better way. Instead of reengineering the system - our biochemistry - to work in a new and different way, we could be identifying and working to reverse those changes that occur with aging. Instead of building a better engine that wears out more slowly, instead learn to repair the engine you have. This is most likely easier, and certainly more cost effective: a better engine still wears out in the end, but repairs can be made over and over again.

We are faced with a massive, complex problem - our bodies beset by aging in many different ways at the cellular and molecular level. We can try to change our biochemistry in ways that will require more work to understand the new system, or we can leave our biochemistry as it stands and learn how to repair it. Every effort counts, when we have all too few years to come to a solution. It matters whether or not the path taken is the most efficient.

Where would you rather the research community directed their efforts?

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Manipulating Regeneration in Dentistry

As Medical News Today notes, dentists push the boundaries of regenerative medicine just as hard as other researchers. One approach is to manipulate cells already in the body to greater efforts by delivering or altering control signals: "The carrier [GAM, a polymer matrix] serves as a scaffold that holds exogenous genes in situ until endogenous wound-healing cells arrive. Up to 50% of available healing repair cells will get gene transfer. Then the cells in the matrix carrier act as local in vivo bioreactors, producing new gene-coding proteins that augment tissue repair and regeneration. GAM implantation at sites of bone injury is associated with retention and expression of the gene of interest for at least 6 weeks. ... At day 7, we observed that the GAM porous architecture provided scaffolding to promote cell ingrowth. The local granulation tissue fibroblasts, along with capillaries, migrated into the GAM. The osteogenic progenitor cells within the tissue uptook the local plasmid DNA and transiently expressed the gene. This leads to a significant augment in periodontal bony tissue regeneration."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=75409

The Role of DNA Damage in Aging

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

Link: http://www.ncbi.nlm.nih.gov/pubmed/17588643

From Around the Blogosphere

A couple of items of interest caught my eye today, starting with a review of "Time" - another example of just how far mainstream attitudes towards radical life extension have come.

A Science Channel program was aired this week, with little fanfare or publicity, but which nonetheless brought the idea of radical life-extension into the mainstream of public consciousness. It was profoundly moving to me for many reasons which I will explain in a bit. The program was titled very simply, "Time."

When I first saw the listing and decided to record it to my DVR, I anticipated a physics-based analysis of the "fourth dimension," which might have been interesting. What I saw, however, was something I did not expect: an analysis of human aging that culminated with the realistic hope of overcoming it within the lifetimes of those now living.


The program continued as I was fervently hoping it would, with a brief interview with none other than the bearded one, Aubrey de Grey himself, who explained his confidence that we will be able to repair enough of this damage to delay death long enough for rejuvenation therapies to improve, so that more damage can be repaired, thus buying enough time for further improvements, et cetera. He explained that, while biblical-style immortality would not be achieved using rejuvenation therapies (since humans could still be killed by other means besides aging), living for 1,000 to 2,000 years was definitely possible.

Meanwhile the folk at Advanced Nanotechnology are perusing the abstracts for the forthcoming SENS 3 conference organized by Aubrey de Grey. The gathering will be attended by the best and brightest minds from many fields of scientific endeavor relevant to the prevention or repair of age-related degeneration. You should take a look yourself; it's quite the large range of science from those who support the fight to defeat aging and age-related disease.

This presentation will describe steps for deciphering the molecular mechanisms by which age-specific inhibitory culprits of tissue repair exert their negative influence on stem cells. Additionally, we provide evidence that embryonic stem cell-derived factors indirectly enhance and rejuvenate the regenerative potential of satellite cells endogenous to old skeletal muscle, thus, delineating new promising venues for enhancing the regenerative outcome of cell replacement therapies in the old.


Considering the reversibility of cell potency and aged-phenotype, the next logical step toward the goal of organismal rejuvenation is to test the possibility of inducing the pluripotent state in somatic cells in vivo. Such an approach will not only provide enough autologous stem cells to replace old cells as in standard replacement therapy, but may also have the additional beneficial effects of (i) reversing the possible aged-phenotype of iPS and (ii) rejuvenating non- or slow-turnover tissues that otherwise would benefit less from standard replacement therapy.

Lastly, I notice that the Future Salon is hosting a Q & A session in the Bay Area on July 20th, featuring Aubrey de Grey and William Hurlbut, the latter being one of those deathists we keep hearing about.

To live forever is an age old dream of humankind. Aubrey de Grey thinks it is within our reach and we should go full steam ahead with the research to make death obsolete. Peter Thiel gives Aubrey's research more umpf by pledging up to $3.5 million for it. That is serious money.

Not so fast, says Stanford Neuroscience Professor William B. Hurlbut. Besides the biology that Aubrey de Grey is a bit too optimistic about, there are several ethical issues that should be thought through as we head into longevity research: The relationship between the generations, the meaning of embodiment in the pace and purpose of our lives, and perhaps questions related to ongoing adaptive evolution of our species.

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Signs of the Times

(Via CBS News). There are more positive views of radical life extension in the mainstream press these days: biomedical gerontologist Aubrey de Grey "feels that people can live to be 1,000 years old without suffering any of the bad things usually associated with old age. ... He went on to say, 'I think the first person to live to 1000 might be 60 already.' Hello! Get in line behind me. ... He is optimistic that the mouse trials, followed by the human trials, should only take another 25 years or so. In other words, if we can all just hang on for another 25 years, each of us might be able to live to be 1,000. Just try not to get hit by a car for the next quarter of a century. Needless to say, there are quite a few scientists who don't take de Grey very seriously. ... But let's give de Grey and those who believe in his theory the benefit of the doubt for a moment. ... Would we benefit from the wisdom of older people who had seen so much? Would human accomplishments be greater than today because everyone would be able to develop to his or her own potential? ... The interesting thing about this kind of speculation is that it brings up the idea of whether there is ever an age when people should be considered 'old enough' to die. A 20-year-old may feel that a person who is 94 has lived a long and full life, and that nobody should feel bad if he dies at that age. However, when that young person ages and becomes 93, he no longer feels that way about 94. Most of us probably think 1,000 is too old for a person to live. But will we still think that when we're 999?"

Link: http://www.cbsnews.com/stories/2007/06/27/opinion/garver/main2986036.shtml

Progress In Engineered Skin

The Telegraph reports on progress in producing replacement skin: "Scientists said that the successful tests, in which laboratory-made living human skin was fully and consistently integrated into the human body for the first time, marked a clinical breakthrough in regenerative medicine. ... Intercytex said the new skin - called ICX-SKN - appeared to incorporate itself much better with real tissue than any other skin substitutes tried in the past, which biodegrade in situ after a few weeks. The researchers hope it might provide an alternative to skin grafts, which are often used for victims of serious burns and large wounds. ICX-SKN is created from a matrix produced by the same skin cells that are responsible for synthesising new tissue in the body. Results show that the new skin had produced a closed and healed wound site after just 28 days. ... To have an off-the-shelf skin replacement product that can be used in large numbers of patients will revolutionise the treatment of burned and skin damaged patients."

Link: http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2007/06/26/nskin126.xml

Ageless Animals, the Lobster Edition

The unknown is always closer than you think. For example: what is the life expectancy of a given species of lobster, absent predators, disease and parasites? You're going to find wildly different answers if you go looking - anything from 50 to 100 years, which as good a way of admitting ignorance as any. An audio segment from NPR caught my eye today, which is why the topic is lobster longevity:

I imagine you know folks who are in their 80s, maybe in their 90s, who are sharp, lively and very active.

But here's the thing - if you were a lobster, and especially if you were a very old lobster, all your colleagues, or almost all of them, would be sharp as tacks. (Can lobsters be tacks?)

Because, as best scientists can tell, lobsters age so gracefully they show no measurable signs of aging: no loss of appetite, no change in metabolism, no loss of reproductive urge or ability, no decline in strength or health.

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

Absent signs of aging have traditionally made it hard to determine age in zoological studies:

To date, there is no proven method to determine the exact age of a lobster. Scientists and experts can only guess at a lobster's age; this is based on water temperature, geographical location, and other factors. On average, it takes approximately 5-7 years for a lobster to reach 455 grams (the traditional 1 pound minimum legal size). It is believed, however, that in the wild lobsters can approach 100 years or more in age.

I believe that greater awareness of the many species that age very slowly or are of great longevity compared to their peers - turtles, tortoises, whales, rockfish, and so on - will help increase support for healthy life extension research in humans. Aging is not set in stone, immutable, and these are examples of that fact. Aging is radically different for different species, and therefore open to change. Other configurations of biochemistry can do far better than ours, which means that this modern age of biotechnology should be capable of enabling us to live longer in good health, if we but set our minds to the task.

Looking back in the medical research archives, I stumbled on research from a decade ago that suggests lobsters sustain their undiminished vitality through maintenance of long telomeres:

Longevity of lobsters is linked to ubiquitous telomerase expression

Mammals have high growth rates in embryonic and juvenile phases and no growth in adult and senescent phases. We analyzed telomerase activity in a fundamentally different animal which grows indeterminately. Lobsters (Homarus americanus) grow throughout their life and the occurrence of senescence is slow. A modified TRAP assay was developed and the lobster telomeric repeat sequence TTAGG was determined.


High telomerase activities were detected in all lobster organs. We conclude that telomerase activation is a conserved mechanism for maintaining long-term cell proliferation capacity and preventing senescence, not only in cellular models or embryonic life stages but also in adult multicellular organisms.

All most interesting, the things we don't yet know.

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Metabolic Rate and Free Radicals (Again)

Not to hammer on the point, but I find this worth looking at twice, given the importance of mitochondria and free radicals to aging: "increases in longevity during dietary restriction can occur together with lack of decreases or even increases in [oxygen (O2)] consumption. This is frequently interpreted as contradictory with the mitochondrial free radical theory of aging. But this is based on the erroneous assumption that increasing O2 consumption must increase the rate of mitochondrial oxygen radical generation. Here it is shown that the opposite occurs [during] aerobic exercise bouts, chronic exercise training, and hyperthyroidism, and notably, during dietary restriction. Mitochondrial oxygen radical generation is also lower in long-lived birds than in short-lived mammals of similar body size and metabolic rate. Total rates of reactive oxygen species generation can also vary between tissues in a way not linked to their differences in oxygen consumption. All this indicates that mitochondrial reactive oxygen species (ROS) production is not a simple byproduct of mitochondrial respiration. Instead, it is regulated independently of O2 consumption in many different physiologic situations, tissues, and animal species. Thus, the apparently paradoxical increases in O2 consumption observed in some models of dietary restriction do not discredit the mitochondrial free radical theory of aging, and they can further strengthen it."

Link: http://dx.doi.org/10.1089/rej.2006.0516

More Common Sense From Eliezer Yudkowsky

There's nothing more outlandish than people who think that working towards the defeat of age-related suffering and death is outlandish: "A transhumanist says unconditionally: 'Life is good, death is bad; health is good, death is bad.' Whether you're 5, 50, or 500, life is good, why die? Nothing more is required. Then why is there a widespread misunderstanding that transhumanism involves a special fetish for technology, or an unusually strong fear of death, or some other abnormal personal disposition? ... Correspondence bias can also be seen as essentialist reasoning, like explaining rain by water spirits, or explaining fire by phlogiston. If you kick a vending machine, why, it must be because you have a vending-machine-kicking disposition. So the transhumanist says, 'Let us use this technology to cure aging.' And the reporter thinks, How strange! He must have been born with an unusual technology-loving disposition. Or, How strange! He must have an unusual horror of aging!"

Link: http://www.singinst.org/blog/2007/06/24/transhumanists-dont-need-special-dispositions

Expanding the "Mitochondria Did It" Model, Piece by Piece

You might recall recent research suggesting that telomere shortening with age is caused by accumulated mitochondrial damage - always promising to see signs that two mechanisms associated with aging might be collapsed into one if you're interested in prevention and repair. Given that plausible methods of repairing mitochondrial damage using the biotechnologies of today are moving closer with each passing year, the more that would be fixed through mitochondrial repair, the better.

With that in mind, Chris Patil notes another possible link:

Why would DNA damage accumulate in aging cells? The trivial explanation is, simply, time passing: Unless repair mechanisms are 100% efficient, the passage of time will result in a slow, steady buildup of damage.

Another possibility is that DNA repair itself becomes less efficient with age, causing damage to accumulate with increasing speed over time. ... in both genomic and mitochondrial DNA, [aged] worms repair their DNA more slowly than young worms


The authors propose two speculative causes, the first of which is specific to mitochondrial DNA. Mitochondrial protein targeting and transport become less efficient in aged cells, so even if old cells are synthesizing nuclear-encoded repair enzymes at the same levels as in young cells, these proteins might not make it to their destination, resulting in a decrease in repair activity within the mitochondria.

The second hypothetical cause is more general: ... old cells might lack the energy to perform repair function at maximum efficiency: if ATP is limiting, then simply staying alive will require an increasing proportion of the available energy budget, and the DNA might be allowed to fall into disrepair.

ATP, the cellular fuel supply, is created in the mitochondria, of course. As the mitochondria become more damaged, less ATP is forthcoming - you can see what sort of downward spiral results from the intersection of these facts.

I jest with my fantasy "Mitochondria Did It" model; there's plenty more to the biochemistry of aging that seems very unlikely to be pinned on the ongoing degeneration of mitochondrial function. It is interesting, however, that we see these potential links as the tools of biotechnology grow more effective, and the store of knowledge grows ever larger. Fixing mitochondria looks ever more desirable at the same time as it is becoming ever more plausible.

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Regenerating From Deafness

(From EurekAlert!). Many stem cell therapies under development are in effect attempts to manipulating biochemical signaling systems into causing more regeneration than would otherwise happen. The stem cells used substitute for our present inability to directly and safely manipulate those signaling systems: "Hearing loss has many causes, including genetics, aging, and infection, and may be complete or partial. Such loss may involve damage to inner ear cells called cochlear fibrocytes, which are fundamental to inner ear function. Some natural regeneration of these cells can occur after acute damage, leading to partial recovery of temporary hearing loss. But could such restoration be enhanced by using bone marrow stem cells, which can differentiate into various tissue-specific cell types ... Stem cells injected into the inner ear survived in half of the injured rats, where they migrated away from the site of injection toward the injured region within the inner ear. These stem cells divided in the new environment and expressed several proteins necessary for hearing, suggesting tissue-specific differentiation. ... Importantly, transplanted rats exhibited faster recovery from hearing loss, particularly in the high frequency range, which is difficult to restore by natural regeneration."

Link: http://www.eurekalert.org/pub_releases/2007-06/ajop-cyh062207.php

Rejuvenation Research, Volume 10 Number 2

The latest Rejuvenation Research is available online, and as I said in this week's Longevity Meme Newsletter:

While we're out there fighting the good fight, remember that some segments of the biomedical research community are very willing to sign their names to the defeat of aging - and are publishing in a well-regarded, influential journal.

I've pointed out a couple of the more interesting papers as they came up in PubMed over the past few weeks, but here is one of the others - an important paper with an overly intimidating title. If you're feeling weak of constitution you might want to skip to the explanation, but this is really just a case of some science having a language and style all of its own.

Allotopic mRNA Localization to the Mitochondrial Surface Rescues Respiratory Chain Defects in Fibroblasts Harboring Mitochondrial DNA Mutations Affecting Complex I or V Subunits

The possibility of synthesizing mitochondrial DNA (mtDNA)-coded proteins in the cytosolic compartment, called allotopic expression, provides an attractive option for genetic treatment of human diseases caused by mutations of the corresponding genes. However, it is now appreciated that the high hydrophobicity of proteins encoded by the mitochondrial genome represents a strong limitation on their mitochondrial import when translated in the cytosol. Recently, we optimized the allotopic expression of a recoded ATP6 gene in human cells, by forcing its mRNA to localize to the mitochondrial surface. In this study, we show that this approach leads to a long-lasting and complete rescue of mitochondrial dysfunction of fibroblasts harboring the neurogenic muscle weakness, ataxia and retinitis Pigmentosa T8993G ATP6 mutation or the Leber hereditary optic neuropathy G11778A ND4 mutation.

What is this all about, and why is it relevant and interesting? Let's start with the mechanics: mitochondria are the powerplants of your cells, evolved from bacteria that brought their own DNA to the party. Some of your DNA is in the cell nucleus, and some is in the mitochondria. These researchers are taking genes normally found in the mitochondrial DNA and putting them into the cellular nucleus, to do their jobs there. This engineering feat is called allotopic expression.

The job of a gene is, in essence, to act as the instruction set for the production of proteins, the components of cellular machinery. A core problem in moving the factory from the mitochondria to the nucleus is that these proteins would then have to struggle their way back to the mitochondria where they are needed; this has been a challenge for a variety of reasons.

These researchers have demonstrated a way to overcome that challenge for at least a subset of mitochondrial genes - via what might be viewed as a rather clever hack to the programming of the cell - and thus can repair dysfunctional mitochondria that results from damage to those genes and a local absence of vital proteins.

So what's the big deal about that for those of us interested in healthy life extension? Well, evidence presently supports ongoing, accumulated damage to mitochondrial DNA as one contribution to age-related degeneration. All aging is damage, and this form of damage appears important, the root cause of free-radical propagation throughout the body. The engineering approach to dealing with this damage - and thus repairing or halting its contribution to aging - seems to have at least two viable paths forward at the present time:

  • Replace all damaged mitochondrial DNA with fresh, undamaged DNA, such as via protofection

  • Copy all the important mitochondrial genes into the nucleus, thus making damage in the mitochondria irrelevant

The second path would make damage irrelevant because the necessary proteins will be generated in the well-protected nucleus even if the mitochondrial genes are no longer functional. This is the path favored by biomedical gerontologist Aubrey de Grey and proposed in the Strategies for Engineered Negligible Senescence. de Grey suggested a different clever hack to move the proteins produced by these genes to where they need to be, but the overall scheme is much the same at the high level.

That is why this paper is interesting and important: it provides more concrete validation for allotopic expression as a means for eliminating one important contribution to the aging process.

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Presuming to Exist

A good piece from Anne C.: "Why must death, specifically age-related death (of all things) be singled out as some sort of cosmically significant defining factor of what it means to be a person? There are so many things in life that one might garner meaning from, after all -- art, beauty, love, friendship, creativity, excitement, learning, awe, wonder, and even the constant and unrelenting struggle to make meanings in a universe that frequently seems to be patently absurd. To deny the possibility of continued existence to full, valuable, loved individuals on the basis that this might somehow undermine the significance of life and personhood is beyond discriminatory. It is beyond presumptuous. Why not let people determine for themselves what it means to exist rather than presuming to decide for them on the basis of outmoded notions of everyone needing a guaranteed (probably age-related) end in order to truly appreciate and participate in life? This is perhaps one of the most confounding things for me in terms of arguments against the idea of healthy life extension -- the idea that somehow, the 'wisdom of nature' suggests that we are all part of some grand circle that demands our demise within but a few decades of our birth."

Link: http://rationallongevity.blogspot.com/2007/06/centenarian-birthdays-abstractions-and.html

Attacking the Mechanisms of Alzheimer's

The research here is illustrative of the improvement of present biotechnology over the past decades: precisely designed interference in specific, understood biochemical mechanisms of disease. "In 2000, Tang identified beta-secretase, a key enzyme in the progression of Alzheimer's that triggers the formation of amyloid plaques in the brain. Various stages in plaque formation produce toxic proteins that harm the brain, causing damage that eventually leads to dementia. Later that year, Ghosh built a molecule that binds to this key enzyme and inhibits its activity, a beta-secretase inhibitor. ... We created a molecule that fits with a key piece of the Alzheimer's disease puzzle. When the treatment molecule binds to the enzyme, it changes the shape of that puzzle piece so that it no longer fits in its original spot. This halts the chain reaction that leads to the devastating symptoms of Alzheimer's disease ... The molecule is both highly potent and highly selective, meaning it does not appear to affect other enzymes important to brain function or cause harmful side effects. ... The company expects to begin generating human clinical data by the end of 2007 and to begin phase II studies in Alzheimer's patients in 2008."

Link: http://news.uns.purdue.edu/x/2007a/070622GhoshTrials.html

Backup and Restore the Immune System

Researchers are already destroying and recreating the immune system to remove existing damage; the next logical step from there is reported by the New Scientist: "Imagine having a spare copy of your immune system on ice, ready to replace your existing one should you fall victim to AIDS, an autoimmune disease, or have to undergo extensive chemotherapy for cancer." Or indeed, perhaps, should you do no more than get old. "An Anglo-American company called Lifeforce has received permission from the US Food and Drug Administration to do just that. The firm collects 480-millilitre samples of blood from healthy individuals, extracts the white blood cells and stores them as an insurance policy against future disease. The service comes at a price, though: around $800 for taking the initial sample then $25 per month for storing the cells ... That sample would have the complete repertoire of all your white blood cells ... By taking some of the stored cells and exposing them to natural growth factors such as interleukin-2, whole new armies of white blood cells could be grown in the lab and reinfused into the patient. ... we can send them their 'pristine' system from 25 years ago." The normal cautions apply, but this seems to be a promising idea.

Link: http://www.newscientist.com/article/mg19426094.400-create-a-backup-copy-of-your-immune-system.html

Striking Back at Cytomegalovirus

Those of us with worn down, ineffective immune systems bloated with uselessly duplicated memory cells - at the expense of naive T cells ready to fight new invaders - can lay a large share of the blame at the door of Cytomegalovirus (CMV):

this appears to be the essential problem of design at the core of the aging immune system - you simply run out of space. Given the large degree to which immune system decay contributes to age-related frailty, suffering and death, it would be a big step forward to find a way to repair this mode of failure.

In recent years, it has become clear that this running out of space is not caused by a wide range of immunological threats - rather one type of virus is largely responsible for the entire problem.


CMV doesn't really hurt you at all in the short term; most people don't even show symptoms. But because you cannot clear it from your system, its presence chews up more and more of your limited immune resources with time.

This is what happens to all of us with increasing age, speeding the downward spiral: if your immune system isn't up to snuff, you're that much less able to resist further damage. Modern medicine is beginning to offer the opportunity to do something about that, however. I noted one approach to fighting CMV a little while ago, and here is more good news:

New vaccine prevents CMV infection and disease in mice

“Until now, scientists haven’t been able to develop a vaccine to protect against CMV,” said Deborah H. Spector, Ph.D., UCSD Professor of Cellular and Molecular Medicine and faculty member of the Skaggs School of Pharmacy and Pharmaceutical Sciences. “Using a two-pronged approach, we successfully created and tested a vaccine in a mouse model with CMV that shows enormous promise for re-directing the body’s immune system, enabling it to fight the virus.”

The mouse vaccine generates an immune response that protects against both infection and development of disease when the virus is present by completely disarming the virus’s ability to replicate and establish a persistent infection.


“Our approach generates an immune response that is different from the normal response to the virus, and we hope to have found an ‘Achilles’ heel’ in the defenses that the virus uses to evade the immune system,” said Spector. “The virus has evolved to persist in the host by evading the immune responses either by hiding or by misdirecting the host’s immune responses. We found a way to teach the host immune system to not be tricked by the virus.” She added that the next step is to apply this strategy to create a vaccine for use in humans.

Unfortunately, this is unlikely to help those aged folk already possessed of CMV-obsessed immune systems - you'd need something like a reboot of the immune system, or a therapy to target and eliminate specific memory T cells, or the ability to restore your immune system to an earlier version. While even the middle-aged would benefit greatly from eliminating all ongoing effects of CMV, it is good to see that the potential options are expanding for those already damaged. It is in all our interests to see the options for repair improving more rapidly than the options for prevention.

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Ever More Stem Cell Therapy Trials

Trials of stem cell therapies are rolling out more rapidly as the years pass, often alongside with existing techniques. Here's another one from EurekAlert!: "60 patients who have recently suffered a major heart attack will be injected with selected stem cells from their own bone marrow during routine coronary bypass surgery. The Bristol trial will test whether the stem cells will repair heart muscle cells damaged by the heart attack, by preventing late scar formation and hence impaired heart contraction. ... In a heart attack, part of the heart muscle loses its blood supply (usually due to furring up of the arteries with fatty material) and cells in that part of the heart die, leaving a scar. This reduces the ability of the heart to pump blood around the body. While the blood supply to the heart can be improved with coronary bypass surgery or angioplasty, thereby reducing the risk of further heart attacks, these techniques do not restore the viability and function of the area already damaged. ... Current treatments aim to keep the patient alive with a heart that is working less efficiently than before the heart attack. Cardiac stem cell therapy aims to repair the damaged heart as it has the potential to replace the damaged tissue." These are yet the early days on a path that soon leads to the complete regeneration of organs.

Link: http://www.eurekalert.org/pub_releases/2007-06/uob-sct062007.php

Straightforward Fears

People don't fear being old, they fear being decrepit. The two are so linked in our culture, experience and education that any discussion of life extension is doomed without carefully explaining that you mean extension of healthy, vigorous life. "There's only one thing that scares me more than death. It's the thought that I might live to be 100. The idea that 60 years from now I might still be pulling my arthritic limbs and degenerating mind out of bed is daunting. The sagging skin, wasted muscles, false teeth and declining memory, vision and hearing will be only half my worries - will my superannuation last that long? ... I'm taking a deep interest in the science of ageing - know your enemy, I say. And as medical science improves, living to 100 may not be as terrifying as you'd think. .... Quality of life rather than sheer length is what most of us want. John McCormack has studied Australians aged over 110 and found all of them reported health problems from chronic arthritis and diabetes to constipation. ... Forty per cent rated their ability to do things for themselves as fair/poor. But only six per cent said they were not satisfied with life and only 10 per cent thought it was not good to live to 100." Healthy life extension means to use the science and medicine to come to separate "old" from "decrepit" - to choose to repair the damage of aging in order to live longer in wisdom, health and vigor.

Link: http://www.news.com.au/dailytelegraph/story/0,22049,21944853-5001021,00.html

A Small Slice of Parkinson's Research

Looking in to the energetic world of research into Parkinson's disease, it's easy to see progress in the works. Parkinson's is a "simple" condition in that it stems from the degeneration of a small, specific population of neurons - in that, it is better understood than a good many other neurodegenerative conditions. It is also probably closer to being prevented and cured; "all" that has to be done is to find some sustainable way to restore these cells, or prevent this specific damage from happening in the first place. That would seem to be a task well matched against the first generation of truly effective regenerative medicine, and I'd be willing to wager on a cure leaving the labs within the next decade.

Here are a couple of pieces illustrative of the present state of research:

Promising results from first gene therapy clinical trial for Parkinson's disease reported:

The study of 11 men and one woman with the progressive neurodegenerative illness found that the procedure -- in which surgeons inject a harmless gene-bearing virus into the brain -- was both safe and resulted in improved motor function for Parkinson's patients over the course of one year.


"In Parkinson's disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement," Dr. During explains.

The researchers' bold idea: to insert the GABA-producing gene GAD back into an area of the brain called the subthalamic nucleus, a key regulatory center within this motor circuit.

"Our hope was that with a single operation to this single site, we could boost GABA production and thereby normalize the function of the entire circuit," Dr. Kaplitt says. "Not only would this alter the chemical balance in the subthalamic nucleus; it should also provide GABA to other parts of the network that weren't getting enough of the neurotransmitter."

Bigger Is Better; A New Therapeutic Approach For Parkinson's Disease:

The study shows how inhibition of SIRT2 - a member of the sirtuin family, which is linked to aging - prevents the toxicity of the protein aggregates that are believed to be behind the neuronal death characteristic of [Parkinson's disease]. Interestingly, and contrarily to "classic" approaches that try to eliminate these aggregates, SIRT2 inhibition appears to work by "fusing" many small protein aggregates into larger (apparently less neuro-toxic) ones.


SIRT2 is a member of the sirtuin family recently described as "the anti-aging proteins" as they seem to be capable of increase the life span of a multitude of organisms. In fact, SIRT1, one of its best-known members, is increased in the presence of anti-oxidants and during caloric restriction, both conditions known to increase longevity. SIRT2, however, seemed to have the opposite effect since its inhibition diminished the number of dead dopaminergic neurons in the presence of toxic alpha-synuclein aggregates.

I pointed out research on calorie restriction and alpha-synclein not so long ago. Given all the evidence linking calorie restriction to resistance to a number of age-related diseases, it should not be surprising to find that sirtuins have their hands in a lot of molecular mechanisms.

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Justified By Who, Now?

This Gulf Breeze News piece illustrates a real problem with the present level of centralized control over the provision of medicine: "After adjusting for non-medical factors in longevity such as reduced smoking rates and declines in death rates from accidents, suicide and homicide, the researchers conservatively estimate that 50 percent of the increase in life expectancy can be attributed to medical care. ... 70 percent of the gains from health care came from better treatment of heart attacks and other cardiovascular disease, and 19 percent was the result of improved medical care for newborns. ... The rising cost of health care has been the source of a lot of saber rattling in the media and the public square, without anyone seriously analyzing the benefits gained. But the dramatic increase in life expectancy that we've seen over the last decades shows that rising medical costs have been largely justified. The increased spending has, on average, been worth it." Justified by who, now? Worth it to who? It's a nonsense that anyone other than the individual has any say over what the medical costs of that individual happen to be. Let everyone find their own comfort zone. Remaining alive and in good health has a cost associated with it at any age; whether and how to pay that cost - and whether and how to help reduce that cost in years to come - should always be up to the individual.

Link: http://www.gulfbreezenews.com/news/2007/0621/health/067.html

Metabolic Rate and Longevity - Not Linear

While one might think that metabolic rate and longevity are linked - run faster, wear out faster - that isn't the case. Nothing is ever simple in biology, and the actual situation points once more to the significance of mitochondrial free radical generation: "In animals, longevity (maximal lifespan) is inversely related to mass-specific basal metabolic rates. However, contrary to expectation, in several mammalian taxa, exceptional longevity is associated with high basal metabolic rate, and also fast evolution of mtDNA-coded proteins. The association of these traits was suggested to result from adaptive selection of mutations in mtDNA coded proteins, which accelerates basal respiration, thus inhibiting the generation of reactive oxygen species that constrain longevity. In Serinus, a genus of finches (canaries) that exhibits the highest rate of cytochrome b evolution, and the highest values of exceptional longevity and lifetime expenditure of energy in all birds, many of the substitutions in cytochrome b are clustered around Q(i), a ubiquinone binding site adjacent to the mitochondrial matrix, apparently selected to increase the rate of ubiquinone reduction. We therefore suggest that, in songbirds, the accelerated evolution of cytochrome b involved selection of mutations that reduce the generation of reactive oxygen species, thus contributing to the evolution of exceptional longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17562891

There Is No Healthy Life Extension Secret

Healthy life extension, making money, losing weight, learning a new skill. You name it - if it requires hard work, you'll find any number of people who think there are hidden secrets to it all; knowledge held by the few that will enable you to succeed if you can but uncover the key.

No such thing, however. There are no secrets.

You can find the high level synopsis - and a fair stack of details for later reading - of everything presently known or proven to be of use relating to extending the healthy human life span in a single afternoon online. You'll have to wade through a moat of nonsense and idiots who don't know what they're talking about, but no-one is hiding anything. All the latest knowledge is right there, out in the open.

The general health matters, those line items that seem to attract the most attention, are trivial in the grand scheme of things. They are also very simple. Eat right, eat little, exercise, take supplements. You're never going to know whether you're at 70% or 80% of the best you can do, but you're still going to age and die on roughly the same timeframe regardless of all of that. It doesn't matter how much effort you spend - unless you look beyond those horizons to science and research:

Or you could just keep on thinking of the world as a patchwork of cults and their secrets, deluding yourself into avoiding the work required to achieve anything of value. It's your choice.

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Biomarkers in Longevity Science

Chris Patil looks at gene expression profiles as a biomarker of aging: "The discovery (and approval) of anti-aging pharmaceuticals is hindered by at least one major practical impediment: Measurement of the simplest biological endpoint of interest - length of lifespan - takes a long time. ... Consequently, much attention has been paid to the idea of aging biomarkers, i.e., phenotypes that can be measured throughout the lifespan and that reflect the percent of lifespan that has elapsed. ... essentially, anything quantifiable that correlates biological age with chronological age is fair game. ... Gene expression measurements are excellent biomarkers: they are both quantitative ('I am expressing three times as much of gene A at age 2 than I was at age 1'), and also robust - because one can measure all of the genes in the genome simultaneously, using microarrays or similar approaches, small perturbations in the levels of single transcripts don't obscure the overall picture. This might not be the case for biomarkers that focus on single phenotypes like bone density, since individual genetic variation might mask the aging signal in the data." For all that researchers are amassing data on gene expression changes with aging in various tissues, the only way to establish the relevance of a potential biomarker for sure is the long way - wait and watch.

Link: http://ouroboros.wordpress.com/2007/06/19/gene-expression-biomarkers-tools-for-developing-longevity-drugs/

SIAI Interview With Aubrey de Grey

The Singularity Institute for Artificial Intelligence (SIAI) interviews Methuselah Foundation chair Aubrey de Grey: "Dr. Aubrey de Grey is an SIAI Advisor and chairman and chief science officer of the Methuselah Foundation, a nonprofit focused on accelerating the development of evidence-based rejuvenation therapies to combat aging. In this interview, Aubrey discusses his role with SIAI, the relationship between Methuselah's work and SIAI's, the potential negative side of the singularity, the reasoning behind Friendly AI research, and more." There is quite the overlap between the younger strong AI research and healthy life extension communities - lots of transhumanists, for one, who formed ties in the earlier and more cohesive phase of online transhumanist groups. Those folk have gone on to make what each thinks is the best mark on the world; a great deal of the focus is on strong AI, nanotechnology, biotechnology and healthy life extension. I'm more of the opinion that full-on strong AI work is not as utilitiarian at this time as effort spent on healthy life extension, but that's just my take on the present state of progress.

Link: http://www.singinst.org/blog/2007/06/18/siai-interview-series-aubrey-de-grey-methuselah-foundation/

Ugly Reality, Deluded People

A reminder that (a) we have a lot of work to do in the engineering of longer, healthier lives, and (b) a lot of people just don't get it:

BABY Boomers are suffering a national delusion about ageing and expect government to deliver the good times when they are old.

They hold unrealistic expectations about health and lifestyle into old age and have little notion of how much it will cost and how to pay for it ... And they indulge in an "extraordinary conflation" of alternative remedies and western traditional medicines.

By "just don't get it" I mean that most people don't understand the true range of what is actually possible. Decades of relentless focus diets, skincare, wrinkles and supplements means that most people see "anti-aging science" as something from Revlon, or that nothing more is possible beyond adding a couple of years of health through diet and the next overhyped pill or fad. On the other side of the fence, the old-school drug pipeline and mainstream research targeting age-related disease is development forced into a regulatory straightjacket by unaccountable government employees who have declared they will not approve any therapy aimed at aging. It is largely run under the philosophy of patching up damage after the fact rather than preventing it or repairing it.

Most people don't see beyond the sorry state of what is, to visualize the cost of missing out on what is not.

Never mind the inability to tell the difference between the way the world actually works - the benefits and results of the scientific method - and the fantasy being pushed by any number of sellers in the "anti-aging" marketplace. Never mind the spread of the foolish idea that anything good comes from the centralization of government power and abrogation of personal responsibility for your own future health and longevity. The article goes on to illustrate exactly what happens in socialized medical systems: the inevitable rationing and the old thrown under the bus first of all:

She said in some overseas countries governments have already introduced rationing of operations. "There are rules that you cannot get a kidney transplant if you are over 75, for instance on the public health. You cannot get a hip replacement if you are over 80,' she said.

In some countries governments rationed radical health care for older people.

"In Australia we haven't done this, but we have long hospital waiting lists. If you are on the public hospital system and you want a knee transplant you could wait three years. In fact, people are going to need to pay for their own health, if they want that level of health provision," she said.

But the first quote of this post really does encapsulate a whole world of willful ignorance driving headlong for an entirely avoidable cliff. Until many more people understand that vastly more is possible than the narrow world of supplements and a few extra years of health, that we could be mere decades away from biotechnology capable of repairing the cellular and molecular damage that makes up aging, then progress towards that goal will remain slow.

That's an ugly reality: so much is possible, so little in the way of resources is being directed to see it through. We can either delude ourselves that things will get better on their own, or get out there and do something about it.

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Biochemistry of Stress and Alzheimer's

The advance of biotechnology is shedding light on the mechanisms underlying common sense on health - in this case, that chronic stress is bad for you: "A long-term study of about 800 members of religious orders had found that the people who were most prone to stress were twice as likely to develop Alzheimer's disease, but the nature of the link between the two has been elusive ... The group's findings [suggest] that the brain-damaging effects of negative emotions are relayed through the two known corticotropin-releasing factor receptors, CRFR1 and CRFR2, which are part of a central switchboard that mediates the body's responses to stress and stress-related disorders. ... Lee made available his mice that had been genetically engineered to lack either CRFR1 or CRFR2. ... In the absence of CRFR1, stress-induced tau phosphorylation was abrogated, while in mice missing CRFR2 the effect was amplified. Pharmacological studies with small molecule inhibitors replicated the effect. Currently, several companies are actively pursuing small molecule drugs that bind CRF receptors ... Such drugs could have a prophylactic effect or delay the progression of Alzheimer's disease."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=74308

The Simple Answer is the Right Answer

Straightforward thinking from the Singularity Institute Blog: "If a young child falls on the train tracks, it is good to save them, and if a 45-year-old suffers from a debilitating disease, it is good to cure them. If you have a logical turn of mind, you are bound to ask whether this is a special case of a general ethical principle which says 'Life is good, death is bad; health is good, sickness is bad.' If so - and here we enter into controversial territory - we can follow this general principle to a surprising new conclusion: If a 95-year-old is threatened by death from old age, it would be good to drag them from those train tracks, if possible. And if a 120-year-old is starting to feel slightly sickly, it would be good to restore them to full vigor, if possible. With current technology it is not possible. But if the technology became available in some future year - given sufficiently advanced medical nanotechnology, or such other contrivances as future minds may devise - would you judge it a good thing, to save that life, and stay that debility? ... If you believe professional bioethicists (people who get paid to explain ethical judgments) then the rule 'Life is good, death is bad; health is good, sickness is bad' holds only until some critical age, and then flips polarity. Why should it flip? Why not just keep on with life-is-good?"

Link: http://www.singinst.org/blog/2007/06/16/transhumanism-as-simplified-humanism/

SCNT In Primates, It Seems

Scientists are knocking down the hurdles to the full potential of stem cells, one by one. The latest to fall is the use of SCNT in primate cells:

In a world first Mitalipov of the Oregon National Primate Research Centre in Beaverton, USA, provided evidence that he had successfully achieved somatic cell nuclear transfer (SCNT) in a primate. This means he managed to clone a rhesus monkey embryo from adult cells. Previously it has proved impossible to derive embryonic cells from adult cells in primates. He then went on to derive two batches of embryonic stem cells from the cloned embryo.


And as Natalipov dramatically demonstrated in his presentation with a slide of beating cells, the CRES cells passed another test of stem cells and where able to transform into either throbbing heart cells or neurons.


Natalipov believes that standard cloning techniques have been the reason why experts have had such little luck in cloning adult primate cells before now. Removing chromosomes from the egg (to prepare it to accept DNA from the adult cell being cloned) relies on visualizing them using a dye and UV light - a procedure that damages essential factors that allow the resultant cell to reconfigure itself as an embryo, he said. Furthermore, said Natalipov, the use of electricity to fuse the donor skin cell to the chromosome-free egg, may cause the egg to activate or reconfigure itself prematurely. Natalipov’s alternative technique visualizes an egg's chromosomes without the dye or UV light, but through using polarized light to detect fibres that carry the chromosomes instead.

Such a simple thing in hindsight - crude tools mean crude results, and don't damage the raw materials. The ability to create, culture and modify totipotent cells from adult cells is a core feat of cellular reprogramming upon which a whole range of new medicine can be built. If Natalipov is correct in his identification of the problem, the whole field will speed up quite rapidly - the low efficiency of these processes to date has been a drag on progress.

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Calorie Restriction and Alpha-synuclein

Look hard enough and you'll find all sorts of interesting indications of the broad effects the practice of calorie restriction (CR) with optimal nutrition has on the progression of age-related damage: "Dietary restriction (DR) is one of the promising environmental interventions known to attenuate aging and decrease risk of age-related neurodegenerative disorders. The aim of this study was to assess the effects of DR on expression of alpha-synuclein, a presynaptic protein involved in pathogenesis of Parkinson's and some other neurodegenerative diseases, in the cortex and hippocampus of adult, middle-aged, late middle-aged, and aged rats. Using Real Time RT-PCR, the authors report that aging regulates the expression of alpha-synuclein in a tissue-specific manner and that long-term DR reverts the late age-related changes of alpha-synuclein expression." Which is interesting indeed, but not completely unexpected, given that CR slows the buildup of other forms of damaging protein aggregates in rodents.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17568432

Bioengineered Arteries Demonstrated

From ScienceDaily: "investigators have engineered artificial blood vessels from muscle-derived stem cells (MDSCs) and a biodegradable polymer that exhibit extensive remodeling and remain free of blockages when grafted into rats. The results of their study have potentially significant implications for the treatment of heart and kidney diseases, where there is a critical need for new sources of blood vessels for vascular grafts. ... these findings in a rat demonstrate the feasibility of developing MDSC-seeded tissue-engineered vascular grafts for eventual human application. ... The next step is to demonstrate the use of the tissue-engineered blood vessel in a larger animal model, such as a pig, which has a coagulation system more similar to that in humans. The advantage of our approach is that the graft could utilize the patient's own stem cells and be ready for implantation almost immediately or, at most, after a relatively short culture period. This suggests that we could make these available 'off-the-shelf,' which is an essential element for clinical translation."

Link: http://www.sciencedaily.com/releases/2007/06/070615145546.htm

Interesting Research on Cancer, Stem Cells and Microenvironments

If stem cells - or stem-like cells - of distinctive character turn out to be the heart and root of cancer, that'll be a lucky break in the world of complexity formed by our biochemistry. As scientists understand the workings of stem cells and the microenvironment of stem cell niches, more possibilities are coming to light - and just as the biomedical research community is becoming very good at safely killing specific cell types, too. Lucky indeed if it works out that way, as most of us have cancer in our future - especially if we plan on living many more years in health and vigor than our ancestors had the chance to enjoy.

Researchers Detect Small Set of Cancer Stem Cells That Are Similar To Normal Stem Cells:

Current cancer therapies often succeed at initially eliminating the bulk of the disease, including all rapidly proliferating cells, but are eventually thwarted because they cannot eliminate a small reservoir of multiple-drug-resistant tumor cells, called cancer stem cells, which ultimately become the source of disease recurrence and eventual metastasis. Now, research by scientists at the University of Pittsburgh School of Medicine suggests that for chemotherapy to be truly effective in treating lung cancers, for example, it must be able to target a small subset of cancer stem cells, which they have shown share the same protective mechanisms as normal lung stem cells.

CSHL scientists successfully target tumor microenvironment to stop cancer growth:

Cold Spring Harbor Laboratory (CSHL) researchers led by Daniel Nolan and Assistant Professor Vivek Mittal have found that bone marrow (BM) derived endothelial progenitor cells (EPCs) play a critical role in the early stages of tumor progression and that eliminating EPCs stops cancer growth.


Using antibodies developed for angiogenic cancer treatment, CSHL researchers collaborated with Memorial Sloan Kettering Cancer center (MSKCC) and were able to remove EPCs without harming normal blood vessels. This has significant clinical potential, particularly in fighting cancer re-growth after incomplete surgical resection or chemotherapy. “The exciting news is that targeting such a minor population of the BM-derived tumor microenvironment has such a dramatic impact on tumor progression,” said Mittal. The study makes clear that in addition to developing therapies that directly target cancer cells, it is also equally important to develop therapies that target critical non-cancer cells like EPCs.

Pre-cancerous blood diseases can be products of their environment:

When blood-forming stem cells misbehave, causing pre-cancerous conditions that can sometimes even progress to leukemia, the problem might not always lie with them. Rather, two studies in the June 15 issue of the journal Cell, published by Cell Press, reveal that a bad environment might be to blame.

Both reports show that defects in the bone marrow - where blood cells are made - can spawn such pre-cancerous blood disorders in mice. Previously, such myeloproliferative syndromes were thought to be rooted in the blood cells themselves.

“We show that the bone marrow microenvironment can make the blood cells become abnormal, like a type of pre-leukemic disease”

The more that researchers come to understand these systems and processes, the closer we come to truly effective medical engineering for prevention and cure. Cancer is just one of the most obvious targets - but once scientists have the knowledge and tools to defeat cancer, the field will long have been open to tackle many other systematic age-related changes in our cells and their interactions.

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Digging For Stem Cells

As ScienceDaily reports, scientists are making real progress in identifying useful stem cells in adult tissue. The regenerative medicine of 2017 will be a far cry from the early work taking place today: "Adipose tissue [requires] rapid adjustment in its blood supply and supporting connective tissue, or stroma. Based on previous reports that the 'stromal vascular' fraction of adipose tissue contains stem cells that give rise to pericytes - cells surrounding small blood vessels - [researchers] isolated the stromal vascular fraction from human adipose tissue ... Using a cell-sorting method known as flow cytometry, the researchers detected a broad spectrum of blood-forming, or hematopoietic, cells among the cultured cells at varying stages of differentiation ... Moreover, they detected CD34+ cells at approximately the same frequency as is present in freshly isolated bone marrow. In bone marrow, CD34+ expression indicates the presence of progenitor cells which give rise to all of the different types of blood cells. ... Since it has been shown in some cases that tumor cells contaminating bone marrow grafts are the source of recurrent malignancies after autologous transplantation, this might be a way of giving patients who need bone marrow reconstitution their own hematopoietic cells derived from a source other than their defective bone marrow."

Link: http://www.sciencedaily.com/releases/2007/06/070614164011.htm

Calorie Restriction and the Endocrine System

From innovations report: "Underfeeding an organism such as the ordinary roundworm alters its endocrine function, which regulates hormones instrumental in metabolism. But no connection between the longevity induced by calorie restriction and the endocrine system has been found - until now. ... a particular pair of neurons in the heads of underfed worms may play an essential role in their lengthy lives. When these two individual neurons were killed by a laser beam, the worms could not enjoy the longevity normally associated with calorie restriction. ... skn-1 genes expressed only in these two cells support dietary-restriction longevity; without the genes, the longevity increase on dietary restriction disappeared ... We suspect that the two neurons sense dietary restriction and secrete a hormone that increases metabolism - and life span - in the animal. ... calorie restriction activates the silenced information regulator (SIR2) gene, which has the apparent ability to slow aging. This gene makes a protein called Sir2, which Guarente has shown is integrally tied to extending life span in yeast and in the roundworm. Humans carry a similar gene. How Sir2 relates to the two neurons identified in the findings is not yet clear ... Guarente suggests that the first commercial products based on manipulating Sir2 to slow aging will appear in the next 10 to 20 years. It is only a matter of time, he said, before aging itself is declared a disease."

Link: http://www.innovations-report.de/html/berichte/biowissenschaften_chemie/bericht-85815.html

Revisiting "Glancing at the Opposition"

A little while back, I pointed out the rhetoric of the deathists quoted within an article on transhumanist goals written from a conservative religious / bioethical point of view.:

Who are these people who are trying to tell us to reject healthy life extension research and suffer and die instead? Here's a glance at some of the thought processes and opinions from that side of the line at Crisis Magazine: "The search for eternal youth is an ancient human impulse, going back to the world's earliest recorded epic, Gilgamesh. But with modern medical technology, we now seem closer to achieving that end than ever before. ... But does this go too far? Theological critics of anti-aging technology have pointed out that aging has long been considered a consequence of the Fall, and that we are undoing God's command when we radically extend life through medical means." At the base of it, these folk are trying to sell a deeply hostile message: suffer and die on their schedule, when you don't have to, because that's the only thing they can come up with that doesn't require them to utterly abandon their present positions. It's always very clear when someone sets out a hierarchy in which the maintenance of his or her own intellectual comfort zone is way and above whether the rest of us live or die.

Not nice people. I'm surprised that more folk don't treat them with the contempt deserved by anyone who aims to cut short your life. The author sent me an email yesterday, reproduced here with permission, in which it seems he thinks I'm referring to him rather than the quoted deathists:

I'm afraid you may have misinterpreted my intent in writing the article for Crisis you mention (http://www.crisismagazine.com/may2007/pavlat.htm). In your review, you quoted merely a counter-claim that I rebut a few paragraphs later; in other words, you quoted my opponents' arguments. In fact, once the argument in that section of the article has been fully developed, the final line of the section on anti-aging technologies reads:
Although we can give a cautious "thumbs up" to some anti-aging technologies, we need to be cognizant of just how many questions currently have no answers."

In addition, the article quotes extensively from a Catholic priest and bioethicist who not only supports anti-aging technology, but is an active participant in the research field (working on immortalizing yeast for the purpose of later applying the results to humans). So calling the article a glance "at the opposition" hardly seems fair, as I, and all of the Catholic-minded bioethicists I talked to, actually *support* anti-aging research. I apologize if the article was unclear on that point.

Your review states, "At the base of it, these folk are trying to sell a deeply hostile message: suffer and die on their schedule, when you don't have to, because that's the only thing they can come up with that doesn't require them to utterly abandon their present positions. It's always very clear when someone sets out a hierarchy in which the maintenance of his or her own intellectual comfort zone is way and above whether the rest of us live or die." This completely mis-states the Catholic position, and I think it much too harsh for someone who, in the final analysis, agrees with your position on anti-aging.

In sum, you're creating an enemy when there is none. I would appreciate a re-wording of your review that states the position of the article more accurately. If you wish, you may also include my apology for not having stated my position more clearly.

So off I went to reread the thing, and I find it rather interesting that the author believes his position to be essentially positive and supportive. That's not the way it comes across to me at all, but then I have a long history of grinding my teeth over the posturing of bioethicists, and a long history of grinding my teeth over those who believe their views give them power over others. I suppose that an argument of "my hierarchy wants to control your life in a much better way than that hierarchy over there" is doomed from the start with folk like me. If folk like Leon Kass and other outright deathists rate a 10 on the scale of trying to be obstructive to progress in healthy life extension, most mainstream bioethicists and regulators are about a 5, and the mainstream of gerontology - laboring away on and promoting the slow boat in this race - are a 2.

Go and read the article again, taking care to keep the quotes distinct. Sounds like a mainstream bioethicist to me, in tone and content. There is something to be said for the rising tide that floats all boats, but I'm more of the opinion that you get things done by getting things done. If you're not working on A, you're not working on A, even if you're working on B that is related to A. The present gaggle of bioethicists, regulators and scientists - determinedly plugging away on the inefficient path, creating problems and hurdles where none exist, shying away from real progress or opportunity, and sabotaging one another by committee - form a mess. A big, horrible, slow mess that won't go anywhere fast enough to help you or I, and will swallow up untold resources in that failure.

And meanwhile here we are, aging and dying just as fast as we were last year. Things have to be made to change, and change rapidly. Those ethicists gently dipping their toes into the water of "maybe we should be telling you to do something that might just, maybe, extend the schedule on which I am comfortable for you to remain alive" are helping not one jot. I don't think they get it, at root: the visceral understanding that death by aging is a greater horror than any other. When you truly understand that, you can't write gentle articles on incremental movements in policy anymore.

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A Glance at Mainstream Longevity Research in the UK

Where the aging research community merges gently with longevity research, the present day sees the development of initiatives such as the Longevity Dividend. The mainstream of aging research is all about genes and metabolism, and so their approach to longevity research is - broadly, and within several camps - to understand and manipulate genes and metabolic processes in order to slow down the accumulation of damage that causes aging. The past decade in the US-centric research community has seen some very interesting technology demonstrations of extreme healthy longevity in animals, an increasing understanding of the biochemistry of calorie restriction, and hundreds of millions of dollars in venture funding aimed at the development of therapies for specific age-related conditions based upon this research.

This is not the winning path forward, nor is it the fast path forward to extended healthy human life spans - but I've talked enough about that elsewhere. In short, for very basic and sound reasons, reworking a complex system to slow the accumulation of damage can never be as effective or as good a use of resources as identifying and repairing that damage without changing the system. If you want to live longer, rather than dying knowing that your children or grandchildren will benefit, then you have to support the faster path.

As I might have noted recently, the situation is starting to look similar across the pond in the UK; a very Longevity Dividend-like tone is emerging:

Professor Partridge and colleagues will look at the cellular and biochemical mechanisms of ageing in fruit flies, nematode worms and mice, and in particular the role of insulin signalling. Recent research has revealed that changes to single genes can make animals live longer, by maintaining health and delaying the onset of ageing-related diseases, such as cancer, diabetes and cardiovascular disease.

"What is particularly exciting about this approach is that altering an animal's genetic make-up seems able to slow down many diseases of ageing simultaneously," says Dr David Gems, a co-recipient of the award. "For example, mice remain youthful for longer and have glossy fur with slowed appearance of grey hair. Their eyes are unclouded by cataracts, and they are more active, both physically and sexually."

The researchers hope to explore how their findings in the animal models relate to the human ageing process, in particular neurodegenerative diseases, such as Alzheimer's disease.


Key to the success of the Institute of Healthy Ageing will be the focus on multi-disciplinary collaboration. The research will receive inputs from subjects ranging from biogerontology (the study of biological processes giving rise to old age), human gerontology, and the study of ageing-related diseases through to chemistry, epidemiology and social policy studies.

"By encouraging collaboration between the Institute itself and leading groups around the UK, both clinical and basic scientists, we hope to be able to move towards developing a broad spectrum of medicines to prevent the biological damage that ageing causes," says Dr Gems.

While it is a large step up from a decade ago to see funding come to gerontologists who speak openly about the desirability of engineering longevity, it is a pity that the community has not settled on the faster path first. That means time will be taken in demonstrating the merits of that path before funding will accelerate greatly to the levels required for broad, rapid, sustained progress.

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Yet More on Aging, Stem Cells and Cancer

Chris Patil has been rolling out the good posts of late, here continuing the general theme of the week: stem cells, aging and cancer. "The rate of aging may be evolutionarily determined as a balancing act between maintenance of regenerative capacity and prevention of cancer ... The idea is that the same mechanisms that stop our cells from proliferating out of control might also prevent them from dividing in order to repair damage. Like all theories of aging, this one has its advocates (of which I am one) and its detractors (whom I'm certainly willing to hear out). ... On the 'pro' side is an article by Christian Beausejour, who's worked in the field of cellular senescence for quite some time. He reviews evidence that senescence, which evolved as a tumor suppressor function, may contribute to age-related decline in the hematopoetic stem cell (HSC) compartment. ... In the other corner we have a review from Aranda-Anzaldo and Dent, who propose that the evolutionary history of p53 makes it unlikely that it's even an important tumor suppressor gene in short-lived species like the mouse, much less an antagonistically pleiotropic gerontogene."

Link: http://ouroboros.wordpress.com/2007/06/13/battle-of-the-reviews-do-tumor-suppressors-contribute-to-aging/

The Moral Imperative to Combat Aging

Is there such a thing as the moral imperative to fight aging through biomedical research? From In Search of Enlightenment, a look at what the philosophers are thinking in these days of socialism and redistribution: "Aging has an enormous impact on the health of a population. It not only affects the wellbeing of individuals (making us more frail and susceptible to disease, causing loss of mental acuity, etc.), but aging also puts pressure on healthcare resources, has costs to our productive capabilities, etc. The stakes are thus very high. So the status quo is certainly not one that says 'aging, how trite and trivial!'. ... Should we not invest in biomedical research that could help us better promote the aims of extending healthy living? I believe we should. Such an aspiration is ingenious and noble, not trite or trivial. ... When it comes to health we do not say that benefits to people above some threshold (like 'normal functioning') have no moral weight whatsoever. So while the sufficiency view may have some intuitive appeal when the good in question is wealth, it is not a defensible principle to invoke in the context of debates about health extension." It seems the threat of illness and death might be more motivating than the threat of poverty when it comes to shifting away from the abyss of control for the sake of control. When you read these passages think to yourself "who do these people think they are, telling me what I can do with research and longevity medicine?"

Link: http://colinfarrelly.blogspot.com/2007/06/rejuvenation-research-paper.html

More on Aging and Stem Cells

Scientists are constantly breaking new ground in their consideration of the biochemical changes that lead to diminishing function of stem cells with age - which in turn diminishes the ability to resist further age-related degeneration: "factors influencing bone marrow-derived cell proliferation and functions are likely to have a broad impact. Aging has been identified as one of these factors. One hypothesis is that aging directly affects stem cells as a consequence of exhaustive proliferation. Alternatively, it is also possible that aging indirectly affects stem cells by acting on their microenvironment. Cellular senescence is believed to have evolved as a tumor suppressor mechanism capable of arresting growth to reduce risk of malignancy. In opposition to apoptosis, senescent cells accumulate in tissues. Recent evidence suggests their accumulation contributes to the phenotype of aging. Senescence can be activated by both telomere-dependent and telomere-independent pathways. Genetic alteration, genome-wide DNA damage, and oxidative stress are inducers of senescence and have recently been identified as occurring in bone marrow-derived cells."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17554505

The Aging Brain

When you can start asking "why does this no longer work?" in detail, then progress towards progress and repair can begin earnest: "The brain represents the primary centre for the regulation and control of all our body activities ... Most importantly, it is also the seat of consciousness, thought, emotion and especially memory, being in fact able to encode, store and recall any information. Memory is really what makes possible so many of our complex cognitive functions, including communication and learning, and surely without memory, life would lose all of its glamour and purpose. Age-associated mental impairment can range in severity from forgetfulness at the border with pathology to dementia, such as in Alzheimer's disease. In recent years, one of the most relevant observations of research on brain aging relates to data indicating that age-related cognitive decline is not only due to neuronal loss, as previously thought; instead, scientists now believe that age-associated functional changes have more to do with the dysfunctions occurring over time. Within this context a prominent role is certainly played by signal transduction cascades which guarantee neuronal cell to elaborate coordinated responses to the multiple signals coming from the outside and to adapt itself to the environmental changes and requests."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17553691

Topic for the Day: Stem Cells and Aging

The role of stem cells in aging, as well as the changes in stem cell populations and capacities that come with aging, would seem to be the topic of the day. I've touched on it before; the presently ongoing research is fascinating to watch. For example, the debate over whether, how and how much changes in the surrounding environment and signaling of other cells is responsible for the decline in stem cell activity with age. Or is it that stem cell populations become worn out and decline in numbers? It's an important difference for those seeking to safely repair this age-related degeneration.

One hypothesis is that aging directly affects stem cells as a consequence of exhaustive proliferation. Alternatively, it is also possible that aging indirectly affects stem cells by acting on their microenvironment.

On this topic, a good post from Ouroboros today:

A good deal of recent work suggests that the environment in which a stem cell resides (the "niche") is at least as important to regenerative capacity as any property of the stem cell itself. A recent paper by Carlson and Conboy expands our knowledge of the deleterious effect of old niches on young cells; provides some tantalizing evidence of a mechanism, involving regulation of gene expression in the stem cells; and underscores the fundamental importance of studying the interaction between cells and their microenvironment.

Scientists on the "microenvironment matters and here's why" side of the debate look to be presenting their case ever more convincingly in the past year. As Chris Patil points out:

The most straightforward implication of Morgan and Conboy's findings is that we will need to address the tissue microenvironment/niche/cell-cell signaling issues in order to optimize the therapeutic potential of [human embryonic stem cells (hESCs)] introduced into an aged patient.

An obvious corollary is that identifying, targeting and inhibiting the "dominant" factors that decrease hESC pluripotency and proliferative capacity should be a major priority for scientists interested in developing stem-cell based solutions to the treatment of age-related disease.

You can't just drop stem cells into a patient and expect quality results if their local tissue is actively suppressing and sabotaging the rescuers.

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Sacremento Bee on CR

You'll find a balanced, if not entirely accurate piece on calorie restriction (CR) in the Sacremento Bee: "Most studies of calorie restriction have been done in lab animals, including rodents and worms. So far, reduced chronic disease (including cancer and Alzheimer's) and increased life spans have been observed in just about every living organism tested. Studies in humans are much fewer in number, however. In humans, calorie restriction generally leads to weight loss and reduced blood pressure, blood glucose and lipids. These are great benefits in and of themselves, leading to reduced diabetes, hypertension, heart disease, etc. However, there seems to be something more going on than just the benefits of weight loss. There are numerous theories why [calorie restriction with optimal nutrition] not only reduces chronic disease and extends life span but also delays aging and extends the 'health span.'" The tone is about right, but I'll leave sifting out the factual inaccuracies as an exercise for the reader. It's a good reminder that journalists suffer little for their inaccuracies, but are penalized for taking time to research rather than rolling out the copy to fill the news hole. The results of those incentives are fairly predictable.

Link: http://www.sacbee.com/107/story/210036.html

Early Registration Deadline For SENS3

Via the Methuselah Foundation: "this coming Friday, June 15th, is the deadline both for abstract submission and for registration at the early rate for the third "Strategies for Engineered Negligible Senescence" conference (SENS3), which will be held on September 6-10 2007 at Queens' College, Cambridge, UK. Please see the website for the fabulous program of speakers, as well as forms to submit an abstract or to register. Please note that there are numerous slots for short oral presentations, which will be selected from the submitted abstracts. Please also note that the registration fee includes accommodation and all meals, so it's really very good value. Finally, I can confirm that authors of short talks and posters will, like the invited speakers, be invited to submit a paper summarising their presentation for the proceedings volume, which will be published in the high-impact journal Rejuvenation Research early in 2008. ... I look forward to welcoming you to Cambridge in September!" A lot of very interesting stuff in the program already - this should prove to be just as engaging and productive as SENS2 in 2005.

Link: http://blog.methuselahfoundation.org/2007/06/early_registration_deadline_fo_1.html

A Matter of Degree

The difference between you and a trained technician when it comes to a recalcitrant computer is just a matter of degree - the technician knows more about the internals than you do, and has the tools to get in and look around - but quite profound. Knowledge of the internal processes and mechanisms of any system brings with it a completely different way of viewing and resolving problems. You see confusing symptoms at the most obvious level, and perhaps you have one or two experience-taught tricks that might or might not help; the technician can dive in and obtain a true picture of the situation.

So too with medicine; where the scientists are today is a matter of degree distant from the near past and near future. The past few and next few decades form a transition from the non-technical to technical for the complex, drawn-out conditions and transitions that come with aging. Therapies move from chance discoveries that may or may not work for individuals to precise attempts to understand and address specific dysfunctions in the complex systems of your cells and tissues.

A good example of this process can be found in a recent release describing one strand of rheumatoid arthritis research:

Early on in the rheumatoid arthritis research game, when HLA popped out as a major genetic player in the condition in the 1980s, Dr. Gregersen discovered that there was a shared bit of DNA that traveled in the disease. What took two years to identify in the laboratory -- shared bands of genetic material -- would take two days today. And that speed is what excites Dr. Gregersen. "We have the tools to get at these genes rather quickly now," he said. "The more patients and controls that we have, the more power we will have to pull out new genes and make associations."

In another major breakthrough, scientists have discovered the importance of a substance called citrulline as a target for immune attack in rheumatoid arthritis (RA). This immune system antibody associated with rheumatoid arthritis recognizes citrulline, which seems to be a key player in the condition. Indeed, the HLA associations with RA have now been shown by Dr. Gregersen and others to directly regulate the immune response to proteins containing citrulline. Citrulline is formed when a specific enzyme comes in contact with arginine, one of 20 common amino acids in proteins. When one of the enzymes is present, nitrogen is removed from the chemical structure of arginine and it converts into citrulline.

Laboratories have developed a test to measure for anti-cyclic citrullinated peptide antibody, or anti-CCP. It is now being used as a diagnostic for rheumatoid arthritis. Scientists are now finding that patients have CCP antibodies months or years prior to the illness, suggesting a way to identify the disease before it starts and perhaps offer treatments to stave off the symptoms. It turns out that those with these antibodies who also have a particular variety of HLA, a complex of genes that regulate immune function, have a 30 times higher risk of developing rheumatoid arthritis than those without these genetic risk factors.

This is, of course, one small sample of the wider space of work on arthritis. In the years ahead, the changes of aging will be laid open at the most fundamental level under the light of modern biotechnology - each moving piece available on the bench for study and manipulation.

Just how well you can repair an aging system is all a matter of degree - how much you know, the quality of your tools. Medicine and biotechnology are accelerating rapidly on all counts in these early days of the 21st century; the future is promising indeed. The flying cars may be late, but the life of years is coming down the line faster than many thought possible.

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Prediction Markets for Longevity Medicine

Prediction markets, like all markets, are extremely useful in those places where they have taken root. In a manner of speaking, all markets perform the function of a prediction market: they measure the ever-changing opinions of the participants on a range of topics. Prediction markets in the present definition are slanted to the generation of specific, clear, useful - and therefore valuable - information.

James Miller suggests prediction markets for the reliability of presently available medical and health techniques wherein the science is still uncertain; distillation of confidence for any given outcome is a classic type of prediction market.

The chemical resveratrol might slowdown aging. Taking large doses of vitamin D supplements might drastically reduce your chances of contracting cancer. It's possible, however, that taking either supplement could worsen your health.

Some would argue that the prudent thing to do is wait for more research to be published. But, for example, if resveratrol really does slowdown aging then if I wait five years to take it I might lose two years of life. Similarly, if taking large quantities of vitamin D really does drastically cut the risk of cancer then waiting five years to start taking it in supplement form might cost me my life.

In ten years we will know far more about the health effects of taking these and many other supplements. What should we do in the meantime? What most of us are forced to do is rely on the advice of experts as presented in the popular press. Instead someone should create prediction markets in the benefits and costs of health supplements.

If resveratrol fulfills its promise then in ten years tens of millions of Americans will be taking it. We could therefore create a prediction market that predicts how many Americans will be taking resveratrol in ten years.

I'm in the prudent waiting camp, personally, but that's just my choice, and one I am fortunate enough to have the time to take.

I wouldn't be tracking opinions of the penny-ante medical technologies mentioned above were I participating in a prediction market on medical science. I'm more interested in using such a market to more accurately determine the change in awareness and support over time for ambitious research such as the Strategies for Engineered Negligible Senescence. Why endlessly analyze the hypothetical performance of supplement A versus supplement B when neither is going to do much for you in the grand scheme of things, and when there are plausible paths forward to add decades to healthy life over the next few decades of research? Supplements and the possibility of a year here or a year there are not the future; overexamination of supplements is a good way to mire yourself in the past while missing the opportunities to help build the longevity medicine of tomorrow.

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Understanding Type 2 Diabetes

Progress on the mechanisms of age-related diabetes is noted at the PENN Medicine newsroom: "When a type 2 diabetic eats a meal, insulin cannot stop the manufacture of glucose in the liver, but it can stop the burning of fat stores. This gives the diabetic person a 'double whammy:' fatty acids accumulate from food and from the liver. Consequently, more fat is deposited in tissues and obesity worsens. Until now there was no clear connection between insulin and the control of fat metabolism. This study shows that when insulin is present, as it is after a meal, the protein Akt2/PKB adds a phosphate group to its molecular partner PGC-1a. When this happens, PGC-1a cannot activate the genes needed for fat metabolism. ... if a drug could induce Akt2/PKB to add the phosphate group (phosphorylation) to PGC-1a, then the liver of a diabetic might be 'fooled' into stopping the oxidation of fat stores." This sort of "finger in the growing crack in the dam" approach to medicine is inefficient in comparison to methods of prevention - type 2 diabetes is very avoidable, after all. Relying on the medicine of the future to rescue you from conditions you could have prevented or minimized doesn't strike me as a good strategy - the medicine of the future already has a mountain to climb in the defeat of unavoidable age-related degeneration.

Link: http://www.uphs.upenn.edu/news/News_Releases/jun07/diabetes-protein-target.html

Engineering Fly Longevity

The better the tools, the easier it becomes to precisely alter the operation of complex biochemical systems. From EurekAlert!: "Receptors are proteins that transmit signals across a cell membrane. [Researchers] manufactured short proteins that blocked a receptor involved in fruit fly aging ... Flies with a blocked receptor saw their lives extended by a third, with no apparent side effects. ... [scientist] literally threw trillions of peptides at the receptor and saved the ones that stuck. ... We let the molecules themselves decide if they bind, rather than trying to design them rationally ... After multiple cycles, the researchers had a group of peptides that stuck to the receptor and not to any other protein. Fruit flies genetically altered to produce such peptides lived longer, suggesting that the peptides were interfering with the receptor's normal function. Why these particular peptides work, and why the receptor they target plays such an important role in fruit fly aging, remain the bigger and as yet unanswered questions." Precision of operation doesn't necessarily mean you immediately know what the result is going to be, or why, of course. We'll see where this goes, but it's a long road from flies to humans, littered with techniques that don't work for mammals. The real story here is the new technology platform for blocking receptors - that'll be generating progress across the board for a decade.

Link: http://www.eurekalert.org/pub_releases/2007-06/uosc-sff060707.php

Myostatin Versus Sarcopenia

Researchers are making progress in developing therapies for sarcopenia based on manipulating myostatin: "A reduction in muscle mass and strength is often observed with aging, and this phenomenon is known as sarcopenia. This age-related atrophy frequently correlates with insufficient levels of muscle regeneration resulting from impairment of satellite cell involvement and myogenesis brought about by the aged environment. Using myostatin-null mice, we recently showed that negative regulators of muscle mass such as myostatin play an active role in the regulation of myogenesis during aging. The present study specifically tests the therapeutic value of a myostatin antagonist in sarcopenia. We report here that a short-term blockade of myostatin, through stage-specific administration of a myostatin antagonist, significantly enhanced muscle regeneration in aged mice after injury and during sarcopenia. ... In addition, the antagonist demonstrated a high degree of efficacy, as only minimal doses during the critical period of regeneration after injury were sufficient to restore the myogenic and inflammatory responses in the aged environment."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17551508

Diabetes and Dementia

This paper is a good reminder of the merits of taking care of your health: "Recent evidence suggests that the molecular defects associated with the development of diabetes also contribute to an increased risk of all types of dementia, including Alzheimer's disease, vascular dementia and Pick's disease. Indeed, the presence of type II diabetes mellitus results in a two to three fold higher risk of developing dementia ... There are currently 250 million people [worldwide] diagnosed with diabetes, and this number is predicted to double within the next 20 years, therefore the associated risk translates into a potential explosion in the appearance of dementia in the population. This review primarily focuses on the proposed molecular links between insulin action, Diabetes and Alzheimer's disease, while discussing the potential for therapeutic intervention to alleviate these disorders." Diabetes is a lifestyle condition for most - it can be avoided, minimized or reversed to a surprisingly large degree. Little that medical science can do today is better than taking care of your health over the years when it comes to metabolic disorders and their impact on your life span.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17544131

The Obvious Future

The "obvious future," to my eyes, consists of those achievements in technology not barred by the known laws of physics and which lie that the end of paths already funded and commenced. The only uncertainty is when these achievements arrive, and whether they enjoy the popularity and demand needed for commercialization, widespread usage, and consequent improvement. The devil is in the detail - look at what came of visions of flying cars from the Gernsbeck 50s. Possible, plausible, presently existing, but still a curio rather than mass market of transport. Other achievements, such as the development of computing capacity, have far surpassed popular predictions, reshaping our lives and prospects along the way.

So to medicine, a technology like any other. Greatly increased healthy longevity and near-absolute control over disease is the obvious future of medicine. The laws of physics allow it, the research community is slowly turning to this goal, and all that scientists and medical engineers lack today is the necessary knowledge. The future of medicine is one of increasingly capable, fine-grained control over cells, biomolecules and genes - manipulation at these levels of detail will become ever more accurate and ever more automated. Some hints of that future:

The Future Biological:

Garage Biology and Open Source Biology: Twenty five years ago, kids flocked to computers, pushing the limits of what they could do. Similarly, the next generation of genetic engineers won't need laboratories or even PhD: they'll have laptops, cheap mail order DNA synthesis, and, thanks to Google and Wikipedia and open journals like PLOS Biology, access to mountains of free biological data. They'll work in basements, garages, and cafes, and they'll trade ideas and collaborate on genetic designs the same way open source programmers now write computer code. Keep in mind that it was only 30 years ago that a little company called Apple started out of a California garage.


Engineered biology is going to allow us to make and test drugs far faster than ever before, particularly if they are based on DNA, RNA (a chemical cousin), or molecules that can be made by cellular factories. Examples of synthetic drugs already include RNAi-based therapeutics, aptamers, gene therapies, custom viruses, hormones, and monoclonal antibodies. As biotechnology booms, expect the drug pipeline to get a lot fatter and for bio-products become cheaper. A billion dollars to create a drug? That's just ludicrous. Life is cheap. The lower limit of bio-drugs should be the price of a sneeze.


Immortality: Biogerontologist Aubrey de Grey argues that here's no absolute reason why biological machines should break down and die. Theoretically, bits and pieces that break down can be continually regenerated and replaced, like keeping a vintage car in showroom condition. As biological engineering becomes more powerful, expect a plethora of age modulation drugs and treatments to appear.

Nanotechnology: Toward matter programmable to atomic precision:

I view nanotechnology in the larger context of making our world physically programmable. Ultimately, this means that making individual atoms act and move exactly the way we like should be as simple as writing a computer program. As the physical world becomes more programmable, many problems of daily life, from fixing broken computer parts to keeping medical implants from corroding, should become more tractable.


In recent experiments, I showed that the dielectrophoretic effect could be used to position, test, and assemble nanoelectronic devices into larger circuits. Such dielectrophoretic manipulation undermines the “fat fingers” argument against atomically precise nanosystems since field enhancement allows force field precision smaller than an electrode tip. In a computational study, I predict that certain diamond surfaces can locally raise the melting temperature of ice above human body temperature. Such surfaces may be useful in resolving the defrosting problem of cryonics, since they may enable atomically precise manipulation, in vivo, of biomolecules using “tweezers” of high-temperature ice.

The biotechnology of 2007 is much akin to the computational technology of 1957. There is a great road ahead of us, and even the nearest visible waystations promise gains in longevity and health unlike any seen before.

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On Antagonistic Pleiotropy

As noted at Ouroboros, evolution is a harsh designer. Benefits are front-loaded for optimal fitness in early life, with no regard to just how much damage, pain and suffering the underlying biological machinery will go on to cause later. Hence aging: "Oft-quoted examples include the prostate and breast, where robust proliferation improves early-life fitness (via effects on reproduction and child-rearing, respectively) but can increase cancer risk (and thereby mortality rate) in old age. One might, therefore, expect to find that gerontogenes (genes whose wildtype function promotes or accelerates aging) are enriched among what are sometimes referred to as 'housekeeping genes': genes with run-of-the-mill functions in metabolism, whose efficacy is intimately linked with the success of fundamental processes like cell division, protein production, etc. ... Unfortunately for this theory, it's particularly hard to identify mutations in these genes, where loss of function means loss of life. In order to investigate the hypothesis outlined above, one would need to allow these essential genes to function throughout development, and then turn them off at maturity." Which researchers can now accomplish - and are turning up interesting results.

Link: http://ouroboros.wordpress.com/2007/06/06/conditioned-for-aging/

Aging Stem Cells and DNA Damage

It's comparatively easy to produce results that look like premature aging - anything that raises the rate of biochemical damage to your cells should do the job. Diabetes has been used as a model for aging in animal studies for some time, for example. Deliberate changes leading to what appears to be premature aging are not always relevant to "normal" aging. From EurekAlert!: "Normally, a few stem cells are enough to completely replenish the bone marrow of mice and produce normal amounts of blood and immune cells. However, error-filled blood-forming stem cells taken from the mutant mice were much less effective at colonizing the depleted bone marrow than normal stem cells, and became even less effective when taken from older mutant mice. ... these results suggest that mutations accumulating in stem cells as they age were preventing them from doing their normal job of producing new blood and immune system cells. ... young stem cells from normal mice contained [little] or no DNA damage. Older stem cells, on the other hand, showed extensive [DNA damage]. ... blood-forming stem cells do accumulate DNA damage with age even though they rarely divide, and that damage is passed on to the blood and immune system cells they make. Weissman said these findings could explain the origin of blood cancer (leukemia) and immune dysfunctions that occur as people age."

Link: http://www.eurekalert.org/pub_releases/2007-06/sumc-asc060407.php

Progress In Controlling Cells, and Thus Controlling Health

Your cells are machinery; complex, but no less mechanical for that complexity. Each cell contains all the information needed to create any type of cell in the body, and the only thing preventing researchers from being able to do just that, given a cell and some raw materials, is a lack of knowledge. That lack of knowledge won't last.

The tools of modern biotechnology and the funds pouring into cell-focused fields like stem cell or cancer research will lead to a complete knowledge of our cells sooner than you might expect. People tend to overestimate what can be done in a decade and dramatically underestimate what can be accomplished in two decades - the state of regenerative medicine in 2027 will be impressive, I'll wager, and cancer will be a shadow of its former threat. In the process of getting there, scientists will learn enough about the mechanics of the human cell to create cells of desired types and properties from adult DNA and raw materials. Quite possibly from scratch, too, without the need for anyone's DNA to use as a starting point.

We can see the start of this road today, in the news that turns up every other week in the popular science press:

A twist of fate -- Reprogrammed fibroblasts resemble embryonic stem cells:

Stem cell biology takes another exciting leap forward as scientists report that normal tissue cells can be reprogrammed to exhibit many of the properties that are characteristic of embryonic stem cells, including the ability to give rise to multiple cell types and contribute to the germline. These findings [provide] strong support for the rationale that it may be possible to generate stem cells with nearly unlimited potential directly from a patient’s own cells, an idea that has significant implications for regenerative therapeutics.

Fertilized eggs yield stem cells:

For the first time, scientists have successfully performed somatic-cell nuclear transfer (SCNT) using fertilized mouse eggs, producing stem cell lines and cloned animals

The defeat of aging, or indeed any medical condition of note, is "just" a matter of replacing, reconfiguring and rearranging cells. The are no obstacles presented by the laws of physics in this matter; a future of perfect health without degenerative aging is "only" a matter of obtaining knowledge and developing the necessary medical technologies. The sooner we start aiming for this goal in earnest, the better.

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Embryonic Stem Cells Versus AMD

Regenerative strategies for the treatment of age-related macular degeneration (AMD) are proceeding apace: "Around 25 per cent of over-60s in the UK have some degree of visual loss due to AMD, and some 14 million people in Europe currently suffer blindness through the condition, caused by defects in the retinal support cells. There is currently no treatment that prevents the treatment of dry AMD. There has been some success in controlling new blood vessel formation in wet AMD, but these approaches are only suitable for certain patients and are often only temporary. ... The London Project's approach will involve production of a cell replacement therapy from human embryonic stem cells, which are effective in replacing dysfunctional [retinal pigment epithelial cells] and photoreceptors found in AMD, leading to a surgical therapy capable of stabilising and restoring vision in the vast majority of patients. Surgical procedures already developed and trialled in a number of patients using the patients' own cells have illustrated that a cell replacement therapy can work."

Link: http://www.eurekalert.org/pub_releases/2007-06/ucl-uss060507.php

Biogerontology: the Mainstream View Of Itself

Ouroboros looks at a position paper from the mainstream of UK biogerontology: "Ageing is a highly differentiated and malleable process. Therefore, the commitment must be to develop interventions that can affect the ageing process or the experience of ageing in order to extend healthy life expectancy, independence and well-being in old age. ... Investments in ageing research should be significantly increased as they are likely to produce immense gains to both the economy and society, in particular to the quality of life, productivity and self-sufficiency of the rapidly growing older population group." Which is a good start, but after that it lapses into calls for more of the slow path - metabolic manipulation to slow aging rather than medical engineering to repair aging, the phantom goal of compressed morbidity (increased years of health without increased life span), government control over research and unimpressive aims for the magnitude of healthy life extension. Too few years, and too long to attain them; not a good goal when we can plausibly do far better. In that, it mirrors the Longevity Dividend initiative on the other side of the pond.

Link: http://ouroboros.wordpress.com/2007/06/05/thou-shalt-not-fear-the-reaper/

Notes From the Advances in Human Cryopreservation Conference

The author of Arcturan Times attended the Advances in Human Cryopreservation conference held last month in Florida, and returned with copious notes. Great stuff for those following progress towards economic viability and scientific progress in the cryonics industry. The holy grail is a company that can grow large through sale and licensing of cryotechnologies for general medical use, while producing profit enough to continue the work of offering cryonic suspension - and a chance at a future - to those who will not live into the coming age of greatly extended longevity.

Part One:

Next, Greg Fahy, of Twenty-First Century Medicine (21CM) talked about his unpublished 2007 research, partly funded by an NIH grant, to use vitrification to preserve corneas for transplantation after long-distance transport. Vitrified corneas transplanted with better results than unvitrified corneas in a monkey model.


Greg also updated us on the study of the vitrified and thawed rat hippocampal slices. Looking for the ability to display electrical activity, he found 70% neural firing at up to 45 days, about the same as would be found in slices that had not been vitrified. He thus concludes that vitrification has no effect on neural firing or viability.

Part Two:

Ben Best spoke about the Cryonics Institute and the recent public release of its vitrification formula.

Stephen Van Sickle gave us the numbers about Alcor - founded in 1972, 820 members, and 76 patients, and $2.5 million in the Patient Care Trust. Alcor’s current research plans include cardiovascular bypass studies using a rat model. Operating on rats’ vasculature is obviously a challenge in itself. The research is intended to aid whole body vitrification work.

Part Three:

Rudi Hoffman kicked off a new sort of panel, one focused on the financial implications of cryonics. Rudi is the most prominent life insurance agent and financial planner for cryonicists. (Most cryonics arrangements are funded by an ordinary life insurance policy.) Rudi reminded us that dead people, in US law, have no legal standing.

Part Four:

An anonymous donor has funded a multimillion-dollar grant proposal by Greg Fahy to work toward successful reversible suspended animation. The 3-year project, staffed with half a dozen scientists in a new facility, will extend over 3 phases:

Phase 1 will identify an optimal method for vitrifying the body from a physical point of view in rabbits. Phase 2 will verify and extend Phase 1 results in larger mammals and possibly human cadavers donated for non-cryonics medical research. Phase 3 will work toward true suspended animation (biologically reversible whole body vitrification).

Well now - that's a big deal, and a lot of money from a perspective of cryonics funding to date. Congratulations are due to the donor and the rainmakers; the cryonics folk are clearly catching up with those other portions of the healthy life extension community to have engineered fundraising success in the past few years. Vitrification has the look of a technology with valuable spin-off applications; this development has a chance of building the base upon which a more self-sustaining, growth-oriented cryonics industry can form. All to the good, and best of luck to those folk doing the heavy lifting.

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Commonalities In Cancer Stem Cells

EurekAlert! reports on the discovery of another variety of cancer stem cells. Intriguingly, there are similarities between a number of those types found so far: "Researchers [have] identified the cancer stem cells that propagate tumors in colon and rectal cancer ... We have brought together a team of scientists and clinicians who will help find the weak points in cancer, devise new immune and molecular diagnostics and therapeutics, test them in mice that carry the cancer stem cells and, hopefully, in a few years begin to test them in our patients ... A protein called CD44 that has already been found dotting the surface of both breast and head and neck cancer stem cells also turns up on the colorectal cancer stem cells. ... that finding could simply reflect the fact that all of those tumors arise from similar tissue. It could also mean that a similar therapy could target all three cell types." Similar biomarkers means a lower cost of developing therapies - but it remains an open question as to whether cancer stem cells are the quick path to victory. We can hope, because a highly effective cure for cancer will have its part to play in the longevity medicine toolkit.

Link: http://www.eurekalert.org/pub_releases/2007-06/sumc-srf053107.php

Alzheimer's is a Very Gradual Process

The neurodegeneration state we call Alzheimer's is not a sudden onset at all, but rather builds up very slowly over time. This is becoming more clear as scientists more effectively detect biochemical markers early on: "Our findings show that beta-amyloid is associated with brain dysfunction - even in apparently normal elderly individuals ... PET is a highly specialized, noninvasive imaging technique that uses short-lived radioactive substances to produce three-dimensional images of those substances functioning within the body. ... We found that apparently normal elderly subjects with positive PIB PET scans do have mild - but significant - reduction in memory test scores, and this is related to the amount of amyloid present ... Besides providing an accurate diagnosis of early Alzheimer's disease, this research is helpful in providing the possibility of early diagnosis and intervention for individuals who are minimally impaired ... Additionally, 20 percent of the normal volunteers in our study whose average age was 72 had a positive scan. In subjects with mild cognitive impairment (MCI) - a condition that leads to Alzheimer's dementia in about 60 percent of cases - we found positive scans in 60 percent of the subjects. The amount of amyloid present, measured by the PIB scan, related to the severity of memory impairment in these subjects." Much like diabetes, early detection may mean a chance to change course.

Link: http://www.eurekalert.org/pub_releases/2007-06/sonm-wca052707.php

Aubrey de Grey's Google TechTalk Presentation

As noted at the Methuselah Foundation blog, in the latest Longevity Meme newsletter and over at the Immortality Institute, biomedical gerontologist Aubrey de Grey recently presented to a crowd of folk at Google as a part of the Google TechTalk series. The talk is online at Google Video:

It's longer than many of de Grey's other presentations, and delves more deeply into the details of presently ongoing research aimed at repairing the damage of aging, as well as the science behind the Strategies for Engineered Negligible Senescence.


I really enjoy the way that Aubrey went into a lot of detail about the SENS approach they are funding/currently working on. I suppose it is because he had a lot more time than he usually does in his lectures, but it was really interesting the way he explained everything.


What did everyone think, while Aubrey was answering one of the questions, that he suggests there really is nothing in supplemental form that can slow down aging?


He's correct. There are no supplements proven to make an appreciable increase in human longevity.


Yeah, you might slightly increase your lifespan if you did everything exactly right, but compared to the stuff he is working on it is so minute not even to be a blip on the radar.

Which is a good point. The "anti-aging" marketplace, or perhaps plain old human nature, has conditioned people to think about what they can ingest right now. If no-one moves beyond that, we'll all age, suffer and die just like our ancestors. Guaranteed healthy life extension of years and decades requires - absolutely, no doubt about it, requires - research and development in nascent, exciting new fields in biotechnology and medicine. The future of healthy life extension is gene therapies, nanomedicine, bioremediation, viral vectors for targeting specific cell populations, regenerative medicine, rebuilding the immune system, protofection of mitochondrial DNA, and so on - it is in engineering medicine, deliberately identifying and repairing the damage that is aging. The future of healthy life extension is not pills, diet and exercise.

If you're not supporting rapid progress in the most modern medical science, then you're not helping to extend your life in any meaningful way; you're just along for the ride, and rolling the dice on the efforts of other people.

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Retiring the Weekends

Going forward, I've decided to undertake the experiment of retiring weekend posting here at the Longevity Meme and over at Fight Aging!. This is something of a "less is more" decision: posts can always be better or more relevant to the topic at hand - the hows and wherefores of healthy life extension - than the stock standard of a link, comment and related thoughts. Taking a couple of days out of the schedule will help in that regard. I do not believe that this will significantly impact the contribution of Fight Aging! and the Longevity Meme to the online conversation about healthy life extension and longevity science - five times a week is plenty enough to talk up a storm. The time saved by dropping two days can be profitably diverted to other matters. I'm far past time on bringing the Methuselah Foundation blog up to spec with the rest of the Foundation site redesign, for example, and the Longevity Meme newsletter requires some technical attention behind the scenes. The list is always a long one.

Link: https://www.fightaging.org/archives/001232.php

Retiring the Weekends

Going forward, I've decided to undertake the experiment of retiring weekend posting here at Fight Aging! and over at the Longevity Meme. This is something of a "less is more" decision: posts can always be better or more relevant to the topic at hand - the hows and wherefores of healthy life extension - than the stock standard of a link, comment and related thoughts. Taking a couple of days out of the schedule will help in that regard.

I do not believe that this will significantly impact the contribution of Fight Aging! and the Longevity Meme to the online conversation about healthy life extension and longevity science - five times a week is plenty enough to talk up a storm.

The time saved by dropping two days can be profitably diverted to other matters. I'm far past time on bringing the Methuselah Foundation blog up to spec with the rest of the Foundation site redesign, for example, and the Longevity Meme newsletter requires some technical attention behind the scenes. The list is always a long one.

Working on Telomerase Gene Therapy

A number of groups are working on gene therapies for aging and age-related disease based on manipulation of telomere length. Here is some insight into what that work looks like: "Degeneration of the intervertebral disc is an age-related condition in which cells responsible for the maintenance and health of the disc deteriorate with age. Telomerase can extend the cellular lifespan and function of other musculoskeletal tissues, such as the heart, bones, and connective tissues. Therefore, extension of the cellular lifespan and matrix production of intervertebral disc cells may have the potential to delay the degeneration process. ... nucleus pulposus cells were lipofectamine transfected in vitro with a human telomerase reverse transcriptase (hTERT) expression construct ... hTERT transfection enabled a 50% extension in mean cellular lifespan and prolonged matrix production of collagen 1 and 2 for more than 282 days. ... Telomerase can extend the cellular lifespan of nucleus pulposus cells and prolong the production of extracellular matrix. Safety is still unresolved, as karyotypic instability was detected but no loss of contact inhibition, mitogen dependency, or G1-cell cycle checkpoint control was evident." That last meaning it is unclear as to whether the risk of cancer is increased by this process.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17495775

Systems Biology and Understanding Cells

The NYAS looks at efforts to better understand our cells - this is key to the most important potential advances in medicine foreseen for the decades ahead, such as extending the healthy human life span. "Thinking of the cell as a factory and biologists as engineers, [a] geneticist might unscrew every pipe inside the factory, one at a time for controlled experiments, of course, and determine the effect that the change has on the factory's operation, or the cell's function. A structural biologist might focus on the shape and size of one particular valve and try to determine how it contributes to the cell-factory's overall functioning. A biochemist would grind up the whole factory and then try to purify and analyze each of its various parts. ... But as scientists and engineers well know, a strictly reductionist view limits one's ability to see the big picture. A zoom-in-zoom-out process is often necessary to make significant progress in the quest for knowledge. This is the perspective of a systems biologist, who seeks to model the mechanistic details of the inner workings of a cell without losing sight of the larger experimental picture. These are the factory's engineers who create blueprints of the building, annotated in excruciating detail with its key industrial processes, and then step back to admire the plans as a whole."

Link: http://www.nyas.org/ebriefreps/main.asp?intEBriefID=637

Research From the Old School

The research noted by Newswise here does not strike me as the future of longevity science: "Aspirin didn't pan out. Neither did two other potential anti-aging agents. But a synthetic derivative of a pungent desert shrub is now a front-runner in ongoing animal experiments to find out if certain chemicals, known to inhibit inflammation, cancer and other destructive processes, can boost the odds of living longer. ... scientist Richard A. Miller reports early results from a mouse study his lab and two others are conducting for the National Institute on Aging. The study, now in its fourth year, will test as many as two dozen possible anti-aging agents in animals in the next five years." Discovering potentially interesting mechanisms in metabolism by testing ingestion of various chemicals is an inefficient journey along an inefficient path. We can do better than this, both in our methodology for identifying interesting mechanisms, and in the methods by which we attempt to extend healthy life span. Crude manipulations with chemicals from the environment can never hold a candle to the directed use of biotechnology to identify and repair the damage of aging. Which would you prefer scientists worked on for the next couple of decades?

Link: http://www.newswise.com/articles/view/530544/

Neural Regeneration Via Stem Cells

Picking their test cases carefully, researchers are making progress towards a technology base for repairing nerves and brain cells: "Rats paralyzed due to loss of blood flow to the spine returned to near normal ambulatory function six weeks after receiving grafts of human spinal stem cells (hSSCs) ... We demonstrated that when damage has occurred due to a loss of blood flow to the spine's neural cells, by grafting human neural stem cells directly into the spinal cord we can achieve a progressive recovery of motor function ... Three of the nine rats injected with hSSCs returned to walking at six weeks, and three others had improved mobility in all lower extremity joints. All nine animals grafted with hSSCs achieved significantly better motor scores than those in the control group, and showed a consistent presence of transplanted cells in the spinal area. In all the rats grafted with the stem cells, the majority of transplanted human spinal stem cells survived and became mature neurons ... Other human stem cell transplants in the spinal cord have focused on repairing the myelin-forming cells. In this study, we succeeded at reconstructing the neural circuitry, which had not been done before."

Link: http://health.ucsd.edu/news/2007/5-31-stemcell-marsala.htm

Another Look at the Mainstream View of Aging Science

Today, another reminder that we have plenty of work left to do in spreading a modern understanding of the potentials of healthy life extension science. So much of the public discussion of aging is based on the scientific understanding of yesteryear, and the talking points of a gerontological community whose members have historically been extremely reluctant to discuss ambitious, realistic goals in increasing longevity. One of the Immortality Institute folk posted links to the transcript of an Australian popular science show on aging very illustrative of these points:

Far too many people find the idea of understanding the mechanisms of aging and engineering a decade or two of additional healthy life to be too much of a change from their present ingrained view of threescore and ten and aging as a mysterious fact of life - never mind the real possibility of an ageless society created through advanced medical science well before the next turn of the century. But widespread understanding and support of the greater, more ambitious goals is needed in order to create an environment in which the necessary work is funded at a sufficient level for rapid progress. So the advocates and forward-looking scientists must continue to work hard to change this state of affairs.

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