A Future of Despair, Suffering and Medicine Despoiled
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The are two paths ahead to the future of medicine. The high path sees rapid, growing, unfettered progress towards new knowledge and biotechnologies capable of curing all disease and reversing age-related damage. The low path leads to stagnation, progress spurned, opportunities squandered and suffering and death for all.

We are presently heading for the low path, thanks to ignorance, short-term greed and the rule of regulation, politicians and bureaucrats. Your prospects for future health and longevity are being squashed and wasted away; present legal and regulatory systems hand control of your well-being to people who don't care for you one way or another, and are in no way incentivized to help you.

How Government Medicine Really Works - British Edition:

Now the NHS wants to limit access to various drugs for Alzheimer's disease patients on the grounds that they are not cost-effective. Actually, there is a lot of research that suggests that delaying the cognitive decline that comes with Alzheimer's saves money because it delays much more costly care, such as admission to assisted living facilities. In any case, the NHS is engaged in pure and simple rationing.

Proponents of government health insurance will reply that private insurers might not cover the cost of such drugs and besides don't you know that there are 40, 50, or 60 million Americans without health insurance, so they wouldn't get the drugs anyway. So what? That response amounts to little more than that we should all get the same equally crappy care by government fiat. Just because extensive government meddling has screwed up private medicine in the United States surely doesn't mean that the solution to the problem is more government intervention.

Creating a commons - such as a socialized medical system in which no-one is permitted to make their own decisions about the deployment of their own resources, but rather everything is pooled at the whim of unskilled government employees - will always result in a tragedy. Here, the tragedy proceeds as rationing, waste, suffering and death - all of which are avoidable.

The US medical system is already two of three steps down this sorrowful road, and we all suffer for it already. Writ large, decades more of this will destroy any hope you and I have of a medical research and technology infrastructure rising to the level of defeating aging in our lifetimes.

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State of Werner Syndrome Research
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Accelerated aging conditions are teaching us more about the biochemistry of normal aging; progeria is yielding its secrets, and Werner syndrome will most likely soon be next: "If WRN function is lost (as exemplified in cells from Werner patients), problems with replication and DNA damage processing arise, probably resulting in an increased number or persistence of strand breaks. In turn, these events lead to chromosomal and telomeric abnormalities or activate checkpoints that bring about early senescence or increased apoptosis. Thus, elevated cancer incidence associated with Werner syndrome is due to increased chromosomal changes, while the accelerated aging characteristics probably stem from telomere dysfunction leading to accumulation of non-functional senescent cells or excessive apoptotic cell death over time. More research is needed to determine whether these specific DNA-dependent mechanisms contribute to development of aging characteristics in normal individuals."

Link: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=16720342

Better Than Exercise
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Another take on recent human calorie restriction (CR) research arrives via EurekAlert: "both calorie restriction and endurance exercise protect [mice and rats] against many chronic diseases including obesity, diabetes, cardiovascular disease and some types of cancer. However, the research has shown that only CR increases the animals' maximum lifespan by up to 50 percent. These animal studies suggest that leanness is a key factor in the prevention of age-associated disease, but reducing caloric intake is needed to slow down aging. ... [this human study] suggests that CR has some specific anti-aging effects that are due to lower energy intake, rather than to leanness ... Primary aging determines maximal length of life. Secondary aging, on the other hand, refers to diseases that can keep a person or an animal from reaching that expected lifespan. ... By slowing primary aging, CR may increase maximal lifespan." But don't skip the exercise - add both exercise and CR to your lifestyle and reap the benefits.

Link: http://www.eurekalert.org/pub_releases/2006-05/wuso-cra053106.php

A Switch For Blood Vessel Growth
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Better control over the growth of blood vessels, or angiogenesis, is required for continued progress in tissue engineering. It could be a novel avenue for regenerative medicine. Reversing blood vessel growth will be most useful in fighting the growth of cancer in the body. Here, Medical News Today reports on progress towards that control: scientists have discovered "a switch inside blood vessel cells that controls angiogenesis ... Angiogenesis is an important natural process that can be both good and bad for the body. It restores blood flow after injury [and] increases circulation in a damaged heart. But, it can also nourish cancer tumors and damage delicate retinal tissues when uncontrolled. ... Understanding this process opens a whole new avenue for treatment of angiogenesis-related diseases. For instance, drugs could be designed to decrease [a switching enzyme] in cancer patients or those with proliferative diabetic retinopathy or macular degeneration, or designed to increase it in a damaged heart."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=44199

Antisense RNA Therapies
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If I'm going to discuss the future power-house technology of RNA interference (RNAi) in the context of fighting cancer, I should probably also mention closely related research into antisense RNA therapies - so says Charles Dorman in an email:

You've mentioned RNAi to cure cancer. Maybe I just missed it, but I haven't seen you mention [antisense RNA (aRNA)] applied to cancer. These articles are old, but this company has gotten its glioma drug through Phase III trials and has many more in the pipeline:

http://www.biospace.com/news_story.aspx?StoryID=19879020&full=1
http://www.engelpub.com/News/index.cfm?articleid=342460&categoryid=21

The results of its Phase IIb glioma trial was that 72 of 75 patients taking their drug were still alive at the time that the whole control group had died -- achieved essentially without side effects.

Both antisense and RNAi therapies are - comparatively speaking, at least in comparison to other technologies readily available today - precision methods of silencing the expression of particular problem genes. This could be thought of as a very limited way of reprogramming the biochemical engine in the nucleus of your cells.

One could say an antisense therapy is more of less half of an RNAi therapy, a comment that makes much more sense after reading this article:

When antisense RNA (aRNA) is introduced into a cell, it binds to the already present sense RNA to inhibit gene expression. So what would happen if sense RNA is prepared and introduced into the cell? Since two strands of sense RNA do not bind to each other, it is logical to think that nothing would happen with additional sense RNA, but in fact, the opposite happens! The new sense RNA suppresses gene expression, similar to aRNA. While this may seem like a contradiction, it can be easily resolved by further examination. The cause is rooted in the prepared sense RNA. It turns out that preparations of sense RNA actually contain contaminating strands of antisense RNA. The sense and antisense strands bind to each other, forming a helix. This double helix is the actual suppressor of its corresponding gene. The suppression of a gene by its corresponding double stranded RNA is called RNA interference (RNAi), or post-transcriptional gene silencing (PTGS). The gene suppression by aRNA is likely also due to the formation of an RNA double helix, in this case formed by the sense RNA of the cell and the introduced antisense RNA.

The Wikipedia entry might be a more gentle introduction:

Antisense therapy is a theoretical form of treatment for genetic disorders. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA produced by that gene, effectively turning that gene "off".

This synthesized nucleic acid is termed an "anti-sense" oligo because its base sequence is complementary to the gene's messenger RNA (mRNA), which is called the "sense" sequence (so that a sense segment of mRNA " 5'-AAGGUC-3' " would be blocked by the anti-sense mRNA segment " 3'-UUCCAG-5' ").

In essence, you can accomplish a great deal by interfering in the messenger RNA that genes use to accomplish their job of creating proteins. The comments I made in relation to the future of RNA intereference apply just as much here.

Cancer must be dealt with if we are to enjoy much longer, healthier lives, but let's tie this to another topic of great interest to those who follow healthy life extension research. You may recall that researchers have recently discovered that the Lamin-A mutations underlying the accelerated aging of progeria - mutations that lead to malformed cell nuclei and resultant failure of function - are also a part of "normal" aging:

In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew ... The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot. Critically, blocking production of this deviant protein corrected all the problems with the nucleus. ... You can take these old cells and make them young again.

So then, there is the possibility that any successful therapy for progeria will also be of use to repair these age-related cellular defects. At PubMed, we can find a full text paper reporting on research using antisense RNA technologies:

The fact that the antisense [RNA] reduced prelamin A levels in cells and improved nuclear shape is exciting, raising the possibility that systemic administration of these antisense compounds might ameliorate disease phenotypes in Zmpste24-/- mice or newly created mice with a targeted Hutchinson-Gilford mutation in [Lamin-A].

The next ten years in applied genetics are going to be most interesting.

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Stem Cells Inside the Heart
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(From the New Scientist). Present first generation stem cell therapies for heart damage involve obtaining stem cells from elsewhere and introducing them to damaged heart tissue. As it turns out, there is an existing population of heart stem cells that might be used instead: "Leri and her colleagues have now removed tiny numbers of cardiac stem cells from people undergoing heart operations, grown them in the lab and then transplanted them into the damaged hearts of rats and mice. The results are promising, says Leri, and may eventually give better heart-healing results than bone-marrow derived stem cells. ... We think that these are the cells that normally provide new heart tissue and will most likely be better suited for repair of diseased hearts." Scientists have been finding stem cell populations throughout the body in past years - this will hopefully speed the maturation of early regenerative therapies.

Link: http://www.newscientist.com/article/dn9239-heart-may-be-home-to-its-own-stem-cells.html

Indian Stem Cell Heart Therapies
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Express Pharma examines the present state of first generation stem cell therapies in India: "Hurkisondas hospital, under the guidance of Shah has treated seven to eight patients with stem cells so far ... Four patients have been re-studied after a period of six months and we have found that their cardiac indices have improved ... Stem Cell Research centre located at Manipal Hospital is actively involved in stem cell research and currently focussing on both adult and embryonic stem cells. Currently, Phase I clinical trial for safety and efficacy studies of bone marrow derived mesenchymal stem cells is going on [for] myocardial infarction ... [the All India Institute of Medical Sciences] too has conducted a study on 35 cardiac patients, who have been injected with stem cells and have been monitored at six, 12 and 18 month intervals. ... Six months later, 56 percent of the dead muscle area injected with these cells had shown improvement. After eighteen months, this went up to 64 percent."

Link: http://www.expresspharmaonline.com/20060531/research01.shtml

A Look At Korean Public Funding
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Via The Korea Times, an update on public funding for stem cell research in South Korea for those who like to keep up with such things: "The Korean government Monday set up a plan to channel roughly 430 billion won ($454 million) of taxpayers' money into stem cell research over the next decade. ... The big budget earmarked for the stem cell sector will be spent both on adult and embryonic stem cells ... Included in specifically targeted areas are a study of the stem cell's differentiation mechanism, establishment of a clinical test database and a system to set up stem cell banks." This compares in size and timeline to existing and proposed state funded programs in the US - and will no doubt be just as inefficient as every other government program, sad to say.

Link: http://times.hankooki.com/lpage/200605/kt2006052917331610160.htm

People Who Happen To Be Alive Want To Be Fixed
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In a recent LiveScience article on Aubrey de Grey, the MPrize for anti-aging research and the SENS Challenge, Methuselah Foundation co-founder Dave Gobel neatly encapsulated the reason behind a prominent quirk in the MPrize structure.

The MPrize has been divided into two prizes since launch in 2003; the names have changed with time, but they are presently known as the Longevity and Rejuvenation prizes.

A fund exists to provide the money for the Longevity and Rejuvenation prizes. This fund is open to contributions from anyone; donors can contribute to either or both prizes as they see fit.

...

The Longevity Prize is won whenever the world record lifespan for a mouse of the species most commonly used in scientific work, Mus musculus, is exceeded. The amount won by a winner of the Longevity Prize is in proportion to the size of the fund at that time, but also in proportion to the margin by which the previous record is broken.

...

The Rejuvenation Prize rewards successful late-onset interventions and has been instituted so as to satisfy two shortcomings of the Longevity Prize: first, that it is of limited scientific value to focus on a single mouse (a statistical outlier), and second, that the most important end goal is to promote the development of interventions to restore youthful physiology, not merely to extend life.

Donors have always had the free choice of which prize to bolster. Without any prompting from the organizers and volunteers, the vast majority of donated funds have been applied to the Rejuvenation Prize. Dave Gobel sums up why this is so:

People who happen to be alive want to be fixed.

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Self-Loathing and Death Worship
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Why do some people vociferously oppose the idea of living a longer, healthier life? Some thoughts via sci.life-extension:

Somewhere along the line and very early on, we self-conscious creatures made some inevitable observations about our existence. It is painful to come in to, for both mother and child, and it is generally painful to leave (and can take a long and torturous time), for the individual and everyone else who's left.

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Since there seemed to be so little (if anything) we could do about it, we mistakenly concluded that this was all somehow our own fault, a punishment inflicted upon us by some creator(s) for something very bad that we had done a long time ago. Accepting this as fact then became a societal imperative, and a sign of having achieved adulthood, maturity, a cold and realistic view of the "nature" of life on this planet. Accepting this view then became a point of pride.

The very prospect, the mere suggestion, of the extension of the human lifespan on a scale that Aubrey de Grey says is possible and worth persuing results in reactions from some people which reveal how deeply they actually loath themselves, their own lives, and the rest of humanity as a whole. This is one profound reason for the vociferous objections to de Grey's ideas.

The reactions of Nuland, Pontin, Hayflick, and countless others, reveal such individuals for what they really are: people acting upon a fundamental, archaic self-loathing that they have accepted, and consider part of their virtue, experience, and expertise.

I don't think self-loathing or a distaste for aspects of life has to be particularly archaic or Jungian to provide the basis for opposition to healthy life extension. Plain old misanthropy or the lessons learned from a catalogue of unfortunate experiences probably serves just as well for some. While people grow and change continuously from day to day and year to year - and usually for the better - it is often hard to see a better future from a position of misery. Strong religious beliefs are another common root; people may like life, but like the idea of what they believe comes after death even more. That the grass is greener on the other side is a hardwired trait for us primates; a pity it supports things like this in addition to more beneficial practices.

Whatever our varied opinions, whatever the contribution of our genes and personal history, ultimately it is - and should be - the choice of the individual as to whether to extend his or her healthy life span. Respect that choice and others will be much more likely to respect yours. The people who should be stepped on, and with great vigor, are those who extend their opposition to block your freedom to attempt to live a longer, healthier life. Where I come from, we call that murder - it may take longer than more traditional methods, but the end result is just the same.

Healthy life extension is, at the most fundamental level, all about choice. Specifically, it is a matter of engineering a choice that cannot presently be made. We are attempting to create a new freedom; the freedom from age-related suffering and death for as many as choose to work towards that goal.

Moving on from the self-loathing a little, why do those folk who stand in opposition to longer, healthier lives receive so much press? What is the fascination with people who want to die, versus those of us who want to live in good health? Is this simply another aspect of "good news is no news?" Or perhaps it is a modern outlet for the hardwired impulses that lead to death worship and other mystery cults; a facet of the curiosity over people who do bad things to themselves, or those who "explore" (and I use that word advisedly, since all who go there cease to exist) what some people will always regard as the unknown.

Take this Cosmic Log entry at MSNBC, for example, which follows up on the trail of anti-life-extension LiveScience articles (first, second and third) from the past week:

This week, a series of stories from LiveScience laid out the potential problems with immortality - or, more realistically, medical advances that could extend normal life spans well beyond the 100-year mark.

The typical response from MSNBC.com users shouldn't come as a surprise: We should all have such problems. But the dissenting opinions were, if anything, more interesting.

In a world in which we have moved quite rapidly in the past five years from healthy life extension in the fringes to the typical response to negative articles on healthy life extension being "let's get out there and do it," why does this fixation with the pro-death and suffering camp exist?

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Repairing Humans via Brain Prosthesis
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From ABC12, an unexpectedly transhumanist look at the near future of medical research: "Over the years, we've heard miraculous stories about people getting artificial arms, legs, even hearts. Some doctors say they can create artificial [brain parts] that may help millions of people with diseases like Alzheimer's, Parkinson's, and epilepsy. ... neuroscientist Theodore Berger has developed the first artificial brain part - a hippocampus to help people with Alzheimer's form new memories. ... There's no reason why we can't think in terms of artificial brain parts in the same way we can think in terms of artificial eyes and artificial ears ... Information would come into the brain the same way, but would be re-routed to a computer chip, bypassing the damaged area of the hippocampus. ... What we're hoping to do is replace at least enough of that function, so there's a significant improvement in the quality of life."

Link: http://abclocal.go.com/wjrt/story?section=healthfirst&id=4184600

Inducing a Regenerative Environment
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(Via Newswire Today!). One possibly viable alternative to stem cell based regenerative medicine is to alter the local biochemical environment to stimulate healing that would not normally take place: "The main finding of our study is that you can deliver growth factors to the environment around injected cells using nanofibers ... Most past studies inject proteins directly into tissues like the heart. Many proteins delivered this way don't stay in the tissue very long. Our new technology allows the growth factor to be delivered for many weeks in a highly controlled way ... We think this is just the beginning of how we can design the local environment around cells to encourage them to do things that can help the injured tissue. We just delivered one factor, but there's no reason you can't deliver many factors that are needed."

Link: http://www.newswiretoday.com/news/5678/

Two Interesting Calorie Restriction Papers
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While browsing sci.life-extension, I noticed two papers on calorie restriction (CR) that you might find interesting. Scientists are increasing our understanding of the mechanisms by which a calorie restricted diet brings impressive health benefits - and extended healthy and maximum life spans in most species - much more rapidly in this decade than the last. Perhaps this has as much to do with growing numbers of higher mammal and human studies as with the relentless advance of biotechnology.

Effects of caloric restriction are species-specific:

This article addresses two questions: (1) 'can caloric restriction (CR) extend the life spans of all species of experimental animals', and (2) 'is CR likely to slow the human aging process and/or extend the human life span?' The answer to the first question is clearly 'no', because CR decreases the life span of the housefly, Musca domestica, and fails to extend the life span of at least one mouse strain. The answer to the second question is unknown, because human CR has not yet been shown either to increase or curtail the human life span. However, recent efforts to develop insect models of CR have been unsuccessful and/or relatively uninformative, so any insights regarding the relationship between CR and human aging are more likely to arise from studies of established, mammalian models of CR.

I think that the health benefits of human CR (in terms of resistance to age-related disease) are in the proven box now, with open questions regarding which populations benefit most or least. Life span effects seem probable, if only from a consideration of the reliability theory of aging. If you use CR to reduce cellular damage at the root of - or resulting from - age-related diseases, and aging is just an accumulation of this damage, then you should be slowing aging.

A few intriguing studies on inadvertent CR and human life span exist, as well as a number of scientific arguments against significant gains in maximum life span in humans, but nothing conclusive as yet. Don't expect "conclusive" to arrive any time soon either - for all of modern biotechnology, we're still stuck with extrapolation based on prevention of age-related disease, or waiting for people to die and counting the years. With that cheerful thought in mind, onto the next paper.

Effect of Long-term Calorie Restriction with Adequate Protein and Micronutrients on Thyroid Hormones:

Calorie restriction (CR) retards aging in mammals. It has been hypothesized that a reduction in triiodothyronine (T3) hormone may increase lifespan by conserving energy and reducing free-radical production.

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low serum T3 concentration was not associated with an increase in inflammatory cytokines in our CR subjects. In fact, markers of systemic inflammation, serum CRP and TNF-α concentrations, were low in our CR subjects. These findings are consistent with data from CR studies conducted in rodents and monkeys, which showed that CR caused a marked decrease in markers of inflammation and a reduction in serum T3 concentration. The combination of decreased serum T3 and reduced systemic inflammation could alter the aging process by reducing metabolic rate, oxidative stress and systemic inflammation

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Long-term CR with adequate protein and micronutrient intake in lean and weight-stable healthy humans is associated with a sustained reduction in serum T3 concentration, similar to that found in CR rodents and monkeys. This effect is likely due to CR itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging.

The full PDF version of this paper is available. This human study confirms an observation of one distinct effect of CR in other mammals; this is now a more viable mechanism for further investigation, especially since the researchers seem to have eliminated the weight loss that accompanies CR as a possible cause. I find the reduced markers for inflammation more interesting than T3 levels, though that may be a bias resulting from the past few months of news on that topic - chronic inflammation is quite the bugbear in terms of its long-term effects on your health.

Clearly, calorie restriction is accomplishing a range of beneficial changes to biological processes across the board. Good stuff.

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Free Radical Theory of Greying
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Some interesting ideas are coming out of further investigations of the biochemistry of greying hair: "Intriguingly, the continuous melanin synthesis in the growing (anagen) hair follicle generates high oxidative stress. We therefore hypothesize that hair bulb melanocytes are especially susceptible to free radical-induced aging. ... We found evidence of melanocyte apoptosis and increased oxidative stress in the pigmentary unit of graying hair follicles. The 'common' deletion, a marker mitochondrial DNA-deletion for accumulating oxidative stress damage, occurred most prominently in graying hair follicles. ... We conclude that oxidative stress is high in hair follicle melanocytes and leads to their selective premature aging and apoptosis. The graying hair follicle, therefore, offers a unique model system to study oxidative stress and aging and to test antiaging therapeutics in their ability to slow down or even stop this process."

Link: http://www.fasebj.org/cgi/content/abstract/fj.05-4039fjev1

Another Blow For Programmed Aging
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How much do genetic programs contribute to degenerative aging? If they contribute greatly, then fighting aging would be a matter of understanding and changing these programs - but the job is much harder if degeneration predominantly results from the accumulation of random damage. Here, Medical News Today reports on another nail in the coffin of programmed aging theories: "One long-standing observation concerning the physiological decline that accompanies aging is its variability - some people age better than others. However, there has thus far been little or no evidence supporting the existence of similar [variability] at the level of gene expression. ... Using a wide range of expression data from both humans and rats, the researchers showed that levels of gene expression become more variable with age. Furthermore, they found that the tendency toward increased variation is not restricted to a specific set of genes, implying that increased [variability] is the outcome of random processes such as genetic mutation."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=43893

Handbook of Models for Human Aging
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Leonid Gavrilov just recently pointed out the hefty Handbook of Models for Human Aging It's also on Amazon if you're interested in a less hefty price tag.

This Handbook is designed as the only comprehensive work available that covers the diversity of aging models currently available. For each animal model, it presents key aspects of biology, nutrition, factors affecting life span, methods of age determination, use in research, and disadvantages/advantes of use. Chapters on comparative models take a broad sweep of age-related diseases, from Alzheimer's to joint disease, cataracts, cancer, and obesity. In addition, there is an historical overview and discussion of model availability, key methods, and ethical issues.

...

Readership: Researchers interested in the mechanisms of aging, gerontologists, health professionals, and allied health professionals and students

The index of contents certainly reads like a who's who for half of modern gerontology. Some of what caught my eye:

2. Species Selection in Comparative Studies of Aging and Anti-Aging
Joao Pedro de Magalhaes

5. Models of Systems Failure in Aging
Leonid A Gavrilov, Natalia S. Gavrilova

17. Telomeres and Aging in the Yeast Model System
Kurt W Runge

20. Strongyloides Ratti: A Nematode with Extraordinary Plasticity in Aging
Michael P. Gardner, David Gems, Mark Viney

34. Life Extension in the Dwarf Mouse
Andrzej Bartke

41. Mitochondrial DNA and Aging
Mikhail Alexeyev, Susan P. LeDoux, Glen L. Wilson

45. Therapeutic Potential of Stem Cells In Aging Related Diseases
Shannon Whirledge, Kirk C.L. Lo, and Dolores J. Lamb

66. Human T Cell Clones in Long-term Culture as Models for the Impact of Chronic Antigenic Stress in Aging
Graham Pawelec, Erminia Mariani, Rafael Solana, Rosalyn Forsey, Anis Larbi, Simone Neri, Olga Dela Rosa, Yvonne Barnett, Jon Tolson, Tamas Fulop

80. Werner Syndrome as a Model of Human Aging
Raymond J Monnat, Jr

A thought: if you can reasonably claim to cover the diversity of scientific approaches to aging - we'll take it that the diversity of experimental classes (or models) scales with the diversity of the science - in one fairly hefty book, that seems to be to indicate that nowhere near enough resources are presently focused on this very complex topic. I don't believe one could adequately tour models for cancer research in 1075 pages, for example. That's something to think about when looking at what must be done to ensure a future of large-scale, effective, well-supported longevity research.

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Funding For MRL Mouse Research
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Research into regenerating MRL mice is attracting more attention and more funding these days; a better understanding of the biochemistry involved in mammalian regeneration of organs may just lead to impressive therapies for injury and some forms of age-related damage in humans. "Although most mammals cannot restore tissue efficiently [the] MRL mouse can regenerate a portion of the ear as well as its heart tissue following injury. ... researchers aim to prove that mammals can form the required progenitor cells for regeneration just as a salamander does. By studying salamanders and MRL mice, the researchers hope to identify the specific types of cells, molecular signals, genes and cellular scaffolding required for regenerative cell growth. In essence, they seek as comprehensive an understanding as possible of the mechanisms and processes - to obtain the blueprint for regenerative growth."

Link: http://unews.utah.edu/p/?r=050306-6

LiveScience on the MPrize
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LiveScience redeems itself somewhat for the past few days of anti-life-extension nonsense with a straightforward piece on the MPrize for anti-aging research and the SENS Challenge: "Anyone debating the scientific feasibility of extending the human life span will find that it's only a matter of time before the name "Aubrey de Grey" comes up. The controversial Cambridge University researcher has been making news in recent years by claiming that humans could soon enjoy thousand-year lifetimes and by helping to establish two contests: one to spur anti-aging research and another to debunk his own audacious claims. In 2003, de Grey helped establish [with entrepreneur Dave Gobel] the Methuselah Foundation and create the M-Prize, a $1.5 million award available to any scientist who can slow or reverse the effects of aging in mice. Private donations made since 2003 have bumped the prize value up to nearly $3.5 million."

Link: http://www.livescience.com/humanbiology/060526_aging_contests.html

Progress Towards Cavity Vaccines
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Lumping the mechanisms of tooth decay under "damage that accumulates with age" is pushing the definition a little, but it's an interesting thought experiment. Other systems in the body rack up damage as they run - some will be comparatively easy to suppress, low-hanging fruit for modern medicine. "Researchers at The Forsyth Institute have made significant advances in research to develop a vaccine against cavities. [A research team] discovered key molecules that can stimulate a human immune response and has successfully conducted immunization trials in animal models. ... Forsyth's strategy is aimed at stimulating the production of antibodies that inhibit the enzyme that allows bacteria to accumulate on teeth. The researchers believe that the best way to protect against caries over the long term is to vaccinate children at about the age of one, after teeth have begun to emerge, but before [bacteria] have begun to colonize the tooth surfaces."

Link: http://www.forsyth.org/news_disp.asp?content_id=100535

Oxidative Stress, Neurodegeneration
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(From Medical News Today). Scientists are increasing their understanding of the biochemical mechanisms by which oxidative stress causes neurodegeneration: researchers "have discovered a mechanistic link between cellular stress caused by free radicals and accumulation of misfolded proteins that lead to nerve cell injury and death in neurodegenerative disorders such as Alzheimer's and Parkinson's Disease. That link is Protein Disulphide Isomerase (PDI) ... The accumulation of misfolded proteins is a common pathogenic mechanism in many diseases, including neurodegenerative disorders. In normal circumstances, PDI levels increase in response to accumulation of misfolded proteins due to cellular stress. ... molecules related to the free radical NO, which is present in elevated levels in neurodegenerative diseases, [alters PDI's structure to block] its normal neuroprotective function, which ultimately leads to nerve cell injury and even death."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=43994

RNA Interference as the New Gene Therapy
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It's easy to draw parallels between work on RNA interference (RNAi) today and gene therapy circa 1986. Both have demonstrated tremendous potential as platforms for building therapies to treat - or cure - a wide range of conditions that presently lack effective therapies. Both are powerful tools for changing our genes and biochemistry; a comparative lack of understanding can harm the recipients of therapies:

Long-term use of RNA interference (RNAi) can be fatal in mice, scientists report in this week's Nature. However, some short hairpin RNAs (shRNAs) suppressed viral infections without killing the mice, suggesting that the technology may still be useful -- if used carefully.

...

Irvin Chen at the University of California at Los Angeles, also not a co-author, noted he also has found that some shRNAs directed against CCR5 for HIV-1 therapy proved toxic with long-term use in primary human T-cells and chimeric mice, while other shRNAs were not toxic in the same setting. "The more data we accumulate about what shRNAs and siRNAs are and are not toxic, the better we can get at the mechanisms and in the future hopefully be able to predict toxicity," he said.

Much the same was said about gene therapy in its infancy, and rightfully so. These are some of the most challenging areas of modern biotechnology - but then building powered aircraft that could actually fly was challenging a century ago. The challenges of the present day are the foundations of medicine far more capable than most researchers envisage.

Gene therapy has advanced greatly in the past 20 years - dozens of clinical trials are presently underway or in planning. RNAi medicine will advance more rapidly, as today's enabling biotechnology is (quite literally) a thousand times more capable than that of 1986. Still, the human factor is the eternal sticking point; no matter how powerful your bioinformatics, it still takes much the same time to sort out funding, organize research efforts, fill out paperwork, pay a cut to government wastrels, and so forth.

A central target for RNAi research - and much gene therapy research for that matter - is cancer:

RNAi Versus Cancer:

RNAi is so new only three companies are experimenting with drugs based on it, but none are targeting cancer. Unlike other drugs on the market, SanoGene's experimental drug targets multiple cell origins of brain tumors, blocking the invasion of cells into other tissue. So far, it has shown extremely positive results for the drug in animal models, according to its founders

More RNAi Versus Cancer:

scientists were the first to use what are known as 'small interfering RNAs' to block the spread of human colorectal cancer cells implanted in laboratory mice. ... Over the last couple of years people have talked a lot about cell-culture studies of siRNAs, but only a handful of labs have pushed it to animal models, which we need to do before going on to clinical trials."

Revolution in the fight against cancer & viruses:

"We've exploited this process by creating short interfering RNA, or siRNA, that are being developed into drugs to fight viruses and cancer," he said. "We've now taken this a step further and worked out how we can create siRNA with different cellular properties to target different diseases."

...

"By 'tweaking' the structure of siRNA to target specific diseases, we can dictate whether we want a particular siRNA-based drug to block or promote an immune response, to increase the effectiveness of the treatment," he said. "While our research is at an early stage, human trials using siRNA are currently underway in the USA and Europe. We're confident our have a significant impact on the way siRNA is being developed as a weapon in the fight against viruses and cancer," said Professor Williams.

Medical revolutions tend to be slow-burning affairs of a decade or more - but RNAi will be the next gene therapy, I'll wager. Ten years from now, there will be dozens of trials, just as for gene therapy in the present day. Like gene therapy, RNAi is a powerful technology with great application to many age-related conditions - and ultimately to making adaptive alterations to human biochemistry to better withstand or repair the cellular damage at the root of aging.

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A Switch For Muscle Atrophy
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Via AScribe, news of a possible new approach to preventing age-related muscle atrophy: "muscle weakness caused by atrophy during aging can lead to serious falls and bone loss. Exercise is the most beneficial strategy to treat atrophy. However, many individuals are too ill to adequately participate in exercise programs. We've found a chemical 'switch' in the body that allows us to turn atrophy on, and, from that, we also have learned how to turn atrophy off ... The Merg1a protein is a channel that normally passes a small electrical current across the cell. The researchers implanted a gene into the skeletal muscle that resulted in a mutant form of this protein that combines with the normal protein and stops the current. The researchers found that the mutant protein would inhibit atrophy." Nice work; other groups are also looking into ways to halt or reverse age-related muscle loss, or sarcopenia.

Link: http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20060524.111825

Doleful Idiocy
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The last of the set of anti-life-extension articles at LiveScience is now up; more handwaving and psychobabble to try and justify suffering and death that could be prevented in the decades ahead. What to make of an "ethicist" who is so sure that you would be bored as a healthy, active, limber 100-year-old, he would see you die in pain from any number of presently incurable age-related conditions rather than support healthy life extension research? "I don't believe that if you give most people longer lives, even in better health, they are going to find new opportunities and new initiatives. They will want to come and play more golf maybe, but they aren't going to contribute lots of brand new ideas, at least the ones I know." I think I join many, many people in saying "speak for yourself" and "you don't know what you're talking about."

Link: http://www.livescience.com/humanbiology/060524_immortality_psychology.html

Artificial Parts Versus Tissue Engineering and Regenerative Medicine
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Competition is good at all stages of the research pipeline; it's the alchemy by which base human fears and desires are transformed into technological progress and better lives. More competition means a greater chance of more efficient, effective new medical technologies; the more competition the better, I say.

One contest of note is that between the development of artificial replacements for body parts and the progression of tissue engineering (or regenerative medicine - the line blurs when the body parts under discussion are small, such as a handful of cells in the eye). Given equal funding and a standing start for research and commecialization, it seems plausible to imagine either a minaturized, implantable kidney-shaped lifetime dialysis machine or a fully functional kidney grown from your own cells arriving at the finish line first. We live in exciting times: the same advancing biotechnology that enables tissue engineering also makes it possible to replicate biological functions in other systems - and at ever smaller scales.

It's all in the early stages now when talking about recreating the functions of entire organs, of course. A good example of present day research cropped up in the MIT Technology Review recently:

There are several different approaches used today in the attempt to develop retinal prosthetics. But the basic principle underlying all of them is the same: by stimulating cells within the retina, vision sensations can be elicited in the visual cortex. This is possible because for some common eye diseases, like retinitis pigmentosa and macular degeneration, only the light-sensitive photoreceptor cells in the retina are damaged. This means other types of cells in the retina and visual cortex in the brain remain intact and fully functional.

Until now, the method of choice for repairing these cells has consisted of using arrays of electrodes placed near the retina to stimulate the cells electrically. The trouble with this technique is that, apart from the electrodes being larger than the cells they're trying to stimulate, there is no way to isolate the electric fields in order to trigger individual neurons without triggering their neighbors.

Encouraging the cells to grow tentacle-like dendrites between the cell and an electrode [gets] around this problem by creating a communication channel that stimulates the cell without invading or disrupting the structure of the retina.

The real payoff with this method, though, is the ability to make use of the preprocessing of the [retina]. Until now, most research has focused on stimulating the retinal ganglion cells, the large cells that feed signals directly into the optic nerve. But this bypasses all the motion-detection and edge-detection processing carried out in the retina itself by a network of neurons called bipolar cells.

My one complaint about all this is that, for all the rapid advance in capabilities, this type of work is directed at patching up the end results of age-related biochemical damage - plugging holes in the crumbling dam rather than preventing or repairing the root causes of those holes.

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More RNAi Versus Cancer
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Age-related cancer must be efficiently and effectively stopped in its tracks as a part of the first decades of the healthy life extension revolution; no sense in fixing all the other age-related damage if that just means ever more cancer and little more life. RNA interference (RNAi) seems like the next tool for the job based on present research: "scientists were the first to use what are known as 'small interfering RNAs' to block the spread of human colorectal cancer cells implanted in laboratory mice. Small interfering RNAs (siRNAs), first described in 2001, are tiny bits of genetic material that can prevent the translation of genes into proteins - including specific proteins involved in biochemical reactions that promote cancer and other diseases. ... Over the last couple of years people have talked a lot about cell-culture studies of siRNAs, but only a handful of labs have pushed it to animal models, which we need to do before going on to clinical trials."

Link: http://www.eurekalert.org/pub_releases/2006-05/uotm-ris052306.php

Stumping for Death and Suffering
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Part two of the LiveScience presentation on radical life extension isn't any better in tone than part one. This seems to be turning into a tour of all the hoary old arguments for doing nothing to stop the present toll: 100,000 deaths due to aging every day. Every day. Think about that. The words of sense in this article come from interviewees, such as John Harris or Richard Miller: "When you save a life, you are simply postponing death to another point. Thus, we are committed to extending life indefinitely if we can, for the same reasons that we are committed to life-saving. ... If you’re really interested in increasing healthy lifespan, aging research is more likely to get you there in a quick and cost-efficient way than trying to conquer one disease at a time."

Link: http://www.livescience.com/humanbiology/060523_immortality_moral.html

Piling in on Lipofuscin
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Lipofuscin is one of the many different types of extracellular aggregates that contribute to aspects of age-related degeneration. It's one of the targets for the LysoSENS work funded by the generous donors who have given to the Methuselah Foundation. LysoSENS is a bioremediation approach - we know that all this junk in and around our cells in ultimately digested by soil bacteria, so we should get out there and identify the enzymes involved. This is a big job, but more hands speed the work.

LysoSENS is not the only program looking into tackling the accumulation of toxic byproducts of our biochemistry. Most of the others are characterized by a focus on one particular disease and its associated intracellular or extracellular accumulations. Thus, back we come to lipofuscin, via a release at EurekAlert:

Harvard Medical School announced today that is has signed a multimillion-dollar license agreement with Merck & Co., Inc. to develop potential therapies for macular degeneration ... Under the terms of the agreement, Harvard will receive a $3 million up-front payment, significant milestone fees and downstream royalties on any marketed products that result from this agreement.

...

Dr. Rando's approach is to prevent toxic substances called lipofuscins from forming in the eye. "Lipofuscin accumulation appears to be a major risk factor for macular degeneration, including the age-related type," said Dr. Rando. Toxic constituents of lipofuscin are generated as byproducts of the visual cycle, a complex chemical pathway that is required for the maintenance of the light gathering components of the eye called retinal photoreceptors.

When light hits the retina, which is packed with photoreceptor cells, a complex chemical process occurs that stimulates the optic nerve. ... The most common by-products of the vision cycle comprise the lipofuscins, which are very stable toxic substances, and not readily eliminated from the eye.

...

One of the worrisome issues with the lipofuscins is that they are insoluble and form aggregates akin to plaques, suggested Dr. Rando. In addition, he noted the lipofuscins and their readily formed oxidation products are highly retinotoxic for a variety of reasons, which includes their propensity to react with DNA and other macromolecules.

...

Dr. Rando, members of his research team, and collaborators at Columbia University, selected small molecule antagonists that they had previously synthesized and showed that they can also stop production of the retinotoxic lipofuscins.

The more the merrier, and good luck to their team. As I've no doubt noted in the past, most of the seven pillars of Strategies for Engineered Negligible Senescence (SENS) are already engaged by the mainstream scientific community in connection with various age-related conditions. Progress towards lengthening the healthy human life span is being made, just not in a directed and efficient manner.

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A Brain for the Long Run
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I'm somewhat overdue in pointing out a piece by Natasha Vita-More entitled "The Strategic Sustainable Brain":

People are living longer; there is a notable increase in the number of activists supporting life extension technologies; economic reporting predicts an increase in research and development of molecular manufacturing and nanotechnology; programming engineers are reveling in the increase in research and development of superintelligence; and conservative organizations are publishing warnings indicating an increased awareness of the potential threats of superintelligence. These events will directly or indirectly affect the brain, resulting in a set of expectations for the brain to function over a longer period of time and operate at a higher level of quality than it has ever achieved in the past.

While I wouldn't have approached the topic in quite the same way, being more of a first things first type, I'm basically in agreement. It should be of interest to those of us looking at the long haul who are most concerned about neurodegeneration and the long term maintenance of the brain. You are your brain; the rest of your body could, at worst, be replaced via future regenerative medicine, but we will need to be very good at repairing the brain in situ - or building a better alternative.

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More DNA Repair Research
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As a follow-on to DNA repair research from last week - a good example of the power of modern bioinformatics - ScienceDaily reports on work from another team: "For the first time anywhere, [scientists] have succeeded in observing and describing how damaged DNA is naturally identified. ... Proteins triggered by the bacteria that are similar to the protein that has been revealed in our laboratory are found in all species, including humans, and therefore one can conclude that the way in which the bacterial protein scans the DNA for lesions is similar among many forms of life. This understanding of the molecular basis of the DNA repair is a basic step in furthering our ability to understand those illnesses stemming from DNA damage, for example cancerous growths." Accumulated damage to DNA is one root cause of age-related degeneration - so the more we know about DNA repair, the better.

Link: http://www.sciencedaily.com/releases/2006/05/060519235555.htm

Trying So Hard To Find Fault
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Part one of a series on radical life extension at LiveScience tries hard to find fault with the idea of less suffering, less frailty and more healthy years. Makes you wonder what planet these people live on: "While scientists go back and forth on the feasibility of slowing, halting or even reversing the aging process, ethicists and policymakers have quietly been engaged in a separate debate about whether it is wise to actually do so. ... If scientists could create a pill that let you live twice as long while remaining free of infirmities, would you take it? If one considers only the personal benefits that longer life would bring, the answer might seem like a no-brainer: People could spend more quality time with loved ones; watch future generations grow up; learn new languages; master new musical instruments; try different careers or travel the world. But what about society as a whole? Would it be better off if life spans were doubled?" Be very wary of those who invoke that mythical entity "society" - they are trying to steal something from you.

Link: http://www.livescience.com/humanbiology/060522_immortality_social.html

Sunday Science and Research Links
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Here are a few links of interest for you to peruse this Sunday; thanks go to the busy infomorphs of the sci.life-extension group for the first few. These folks perform a very useful service for the rest of us, taking their valuable time to sort through a great deal of data in search of connections and items of note.

Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan:

Uncoupling proteins (UCPs), which dissipate the mitochondrial proton gradient, have the ability to decouple mitochodrial respiration from ATP production. Since mitochondrial electron transport is a major source of free radical production, it is possible that UCP activity might impact free radical production. Free radicals can react with and damage cellular proteins, DNA and lipids. Accumulated damage from oxidative stress is believed to be a major contributor to cellular decline during aging. If UCP function were to impact mitochondrial free radical production, then one would expect to find a link between UCP activity and aging. This theory has recently been tested in a handful of organisms whose genomes contain UCP1 homologs. Interestingly, these experiments indicate that UCP homologs can affect lifespan, although they do not support a simple relationship between UCP activity and aging.

The plasma membrane redox system in aging:

Oxidative stress over time leads to the accumulation of damaged macromolecules and to profound physiological changes that are associated with several age-related diseases. The plasma membrane redox system (PMRS) appears to attenuate oxidative stress acting as a compensatory mechanism during the aging process. The PMRS appears to play a protective role during mitochondrial dysfunction to provide cells with a survival mechanism by lowering oxidative stress.

Plasma membrane redox systems across various species form a big topic - big enough for their own conference. As you might note from the papers above, or indeed from pretty much anything I post here on the topic of mitochondria, metabolism is a fearsomely complex system. Greater understanding of the biochemistry of metabolism could lead to technologies of optimization - meaning least amount of age-related damage generated - that are demonstrably better than the practice of calorie restriction. Don't hold your breath there, however; this has the look of a topic that will still be hotly debated and the subject of ever-deeper investigation in 2016 and 2026. Meanwhile, calorie restriction is as simple a matter as putting thought into eating less in the right way. More to the point, tinkering with metabolic optimization seems to be a far less effective path forward than to aim at directly and effectively repairing what we know to be the root biochemical causes of aging.

To finish up, you'll find a set of sizeable videos of a Brian Wowk presentation on cryonics and vitrification in a thread over at the Immortality Institute.

Dr. Brian Wowk's presentation on Suspended Animation by Vitrification at the Life Extension Conference is now available ... It is recommended that you choose to "Save" the files rather than stream them online

Vitrification, as I've noted before, is a fascinating topic in and of itself. It shows potential to become the spin-off, revenue-generating infrastructure technology that the cryonics industry needs in order to support further growth. Alcor has been moving forward with this; a good thing in my book. If you're interested in learning more, one of the papers in the latest Rejuvenation Research was co-authored by Wowk:

Until recently, the cryopreservation of organs has seemed a remote prospect to most observers, but developments over the past few years are rapidly changing the scientific basis for preserving even the most difficult and delicate organs for unlimited periods of time. Animal intestines and ovaries have been frozen, thawed, and shown to function after transplantation, but the preservation of vital organs will most likely require vitrification. With vitrification, all ice formation is prevented and the organ is preserved in the glassy state below the glass transition temperature (TG). Vitrification has been successful for many tissues such as veins, arteries, cartilage, and heart valves, and success has even been claimed for whole ovaries. For vital organs, a significant recent milestone for vitrification has been the ability to routinely recover rabbit kidneys after cooling to a mean intrarenal temperature of about -45°C, as verified by life support function after transplantation. This temperature is not low enough for long-term banking, but research continues on preservation below -45°C, and some encouraging preliminary evidence has been obtained indicating that kidneys can support life after vitrification.

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What Is Known About Brain Aging?
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What is known about brain aging and what can be done about it? Comparatively little at this point, sad to say. Obviously, neurodegenerative conditions - based on what are essentially structural or infrastructural failures in the brain and supporting organs - must be understood and prevented or cured if we are to enjoy much longer, healthier lives brought on by advancing medical technology. Real progress is being made in that arena, though not yet in the realm of preventing the known roots of age-related damage. Beyond that, however, there are the poorly understood ways in which a lifetime of thought and activity changes the structure and wiring of our brains - sometimes for the worse. At the end of the present day, as illustrated by this Washington Times piece, we are left with a proven "use it or lose it" and the knowledge that much more research is required.

Link: http://washingtontimes.com/functions/print.php?StoryID=20060517-111239-1612r

People Die Too Young
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Methuselah Foundation volunteer April Smith writes an obituary, making the points that should always be made: "When we talk about the possible lifespan gains from [calorie restriction (CR)], people often ask if the five or ten or even twenty years that we might gain from CR are worth the trouble. When I think about what Jaroslav Pelikan could have done with five, ten, or twenty more years, I have to answer a resounding YES! ... what books would he have written between 82 and 85? Between 85 and 90? Between 90 and 100? What lectures would he have given, what students would he have inspired? The world has lost a great thinker, teacher, and writer, and I believe he died too young. It's a classic example of how bodies begin to deteriorate at just the point when experience and education combine to form tremendous wisdom. Death steals wisdom from the world, and I don't think we should quietly accept this theft."

Link: http://www.mprize.org/blogs/archives/2006/05/people_die_too.html

Aging, Immunodeficiency, Inflammation
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Via the open-access journal Immunity & Aging, a look at how the aging immune system harms us by doing both too little and too much (a full PDF is available): "Aging is associated with a paradox of immunodeficiency and inflammation (an evidence of hyperactive immune system). Apoptosis is associated with cellular depletion and suppression of inflammatory response. In this brief review, we will present evidence for the role of increased apoptosis in immunodeficiency and paradoxical increased inflammation associated with human aging. In particular, a role of apoptotic antibodies in failure to generate anti-inflammatory responses in dendritic cells will be discussed."

Link: http://www.immunityageing.com/content/3/1/5

Reprogramming T Cells
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This Medical News Today piece on reprogramming the activity of T cells in our immune system is focused on HIV and hepatitis as applications, but this misses the most obvious use for those of us interested in healthy life extension. We know that - as a result of past chronic infections "using up" capacity - the ability of T cells to react to new threats declines with age. The declining immune system plays a large part in age-related frailty, suffering and eventual death. If scientists have a way to reprogram this part of the immune system, then new therapies could rejuvenate its effectiveness. From the article: "The concept that T cell deletion and inactivation is neither an inevitable nor permanent consequence of persistent viral infection - that it is reversible - and that its reversal leads to control of viral infection, should have important implications for the future design of therapeutic approaches to resurrect T cell responses."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=43695

Rejuvenation Research, Volume 9 Number 2
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The latest Rejuvenation Research is out, following closely on the heels of volume 9, number 1. I pointed out some of the items I found most interesting in that previous issue last month; this new issue is a sizeable one. My picks below hardly scratch the surface, and you'll find a lot to read.

From Disease-Oriented to Aging/Longevity-Oriented Studies:

Aging should be considered a major risk factor for life-threatening degenerative pathologies including atherosclerosis, cancer, neurodegeneration, diabetes type II, osteoporosis, and sarcopenia. ... Currently predominant disease-oriented paradigm should be reconsidered toward aging/longevity oriented.

This is a very important topic at the infrastructure and cultural levels of medical research; the present "discover and patch" methodology is inefficient - and ultimately ineffective - in comparison to a focus on repairing and preventing the root causes of aging.

Factors That Might Affect the Allotopic Replacement of a Damaged Mitochondrial DNA-Encoded Protein:

The human mitochondrion contains a small circular genome that codes for 13 proteins, 22 tRNAs, and 2 rRNAs. The proteins are all inner membrane bound components of complexes involved in the electron transport system and ATP formation. Mutations to any of the 13 proteins affect cellular behavior because energy production could be decreased. Investigators have attempted to find methods to correct these mutated proteins. One way is to express the mitochondrial gene in the nucleus (called allotopic expression). The newly synthesized protein would have to be imported into mitochondria and assembled into complexes. This paper reviews some of the successful attempts to achieve allotopic expression and discusses some issues that might affect the ability to have the proteins properly inserted into the inner membrane.

More researchers are looking into ways to alleviate or prevent age-related damage to mitochondrial DNA - this is one area of basic anti-aging science in which funding from traditional disease-focused sources is plausible, given the strong (and growing) weight of evidence associating mitochondrial dysfunction with widespread and well-known age-related conditions.

Other groups are making progress in methods of replacing damaging mitochondrial DNA (mtDNA), a different approach to the SENS proposal of moving these genes into the comparatively well-protected nucleus. Competition and variety are good signs - may the best methodologies win.

Following on from this, a couple of papers demonstrate the positive effects of calorie restriction (CR) on mitochondrial function; not too surprising considering the relationship between the metabolic processes and damage to mitochondria. This sort of result lends strength to any claim that CR "slows aging" by showing a portion of how it does so - in this case by reducing the rate of one class of changes at the root of degenerative aging.

Tissue-Specific Effect of Age and Caloric Restriction Diet on Mitochondrial DNA Content

A decrease of the mtDNA content occurs with aging in liver and soleus muscle, whereas there is no age-related significant change of mtDNA content in brain. CR fully reverses the age-dependent loss of mtDNA in liver and soleus, whereas it results in a significant increase of mtDNA amount above the value of aged ad libitum fed rats in brain.

Caloric Restriction Protects Mitochondrial Function with Aging in Skeletal and Cardiac Muscles

The present results show that CR largely prevents the age-associated decline in mitochondrial function in heart and skeletal muscles, and suggest that this is secondary to a better-maintained drive on mitochondrial biogenesis.

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On Sepsis and VEGF
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An overview of recent research into sepsis and its role in age-related mortality, via Senior Journal: "Vascular endothelial growth factor, or VEGF, was initially identified as a potent stimulator of endothelial permeability, causing 'leakiness' in the endothelial cells that line the body's blood vessels. ... [VEGF] thus serves as a key mechanism behind the onset and perpetuation of [sepsis]. ... [researchers] treated animals with protein inhibitors of VEGF or neutralizing antibodies against VEGF receptors, and demonstrated significant protection against morbidity (as measured by cardiac dysfunction, inflammation, coagulation and permeability) and mortality." Sepsis is an end-stage failure due to age-related damage; we must invest more in ways to ensure that no-one accumulates that level of cellular damage in the first place. Plugging holes in the failing dam is not a viable path forward to healthy life extension.

Link: http://www.seniorjournal.com/NEWS/Health/6-05-19-NewSepsisTreatment.htm

Analysis of the Moral Imperative to Engineer Radical Life Extension
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As of earlier this month, Russell Blackford is starting in on an analysis of a position I agree with, albeit in my own way: that there is a moral imperative to aid the development of medical technologies that will bring radical life extension to as many people as possible.

I owe an account of why I am slightly sceptical about an argument offered by Aubrey de Grey, who has defended the strong claim that there is a moral imperative to "cure" the process of human aging. (I'll henceforth drop the scare quotes around the word "cure", but I intend to signal that I am well aware of the controversies that surround whether the word is apt in this context.)

...

By the end of this post, I will still owe a proper account of what doesn't entirely convince me, but I'll have made a start. My main purpose at this stage is to take a first stab at getting the logic of the argument clear. This will help us see where, if anywhere, it might be vulnerable to attack. It may also help us see whether better formulations of the argument possible - perhaps my formulation does not do de Grey justice, or perhaps it is possible for him to do some further shoring up.

It makes for an interesting read, though as you will note, Blackford is intuitively unhappy with the sum of the parts he rebuilds. I will venture a guess as to the source of this unease with Aubrey de Grey's position: no-one likes to be told they are a part of the problem. That's Good Advocacy 101; even in the unlikely event it is absolutely true that everyone who doesn't help out is a part of the problem, you won't make much headway by using this fact as a blunt implement of persuasion.

Another way of looking at this might be the obligation that is taken to be implied by what is now commonly meant by "a moral imperative." It's plain old human nature to dislike to be told by a third party that you are obliged to expend effort. But if you're of a mindset to find truth and guidance in law and philosophy provided by other people, you're going to find yourself obliged - if only by yourself - in all sorts of ways. In that view, and in a world in which tens of millions die each and every year, your understanding of morality could lead you to place yourself as part of the problem for failing to devote 100% of your life to advancing healthy life extension. That is no doubt an uncomfortable position to find oneself in.

The key here is a libertarian one: you don't owe anything to anyone that you haven't contracted and chosen to provide. No philosophy can create an obligation - only choice made of free will can do that. I have decided that I should act in support of healthy life extension research, for reasons both selfish and altruistic. This is my moral imperative, home-crafted and unique. I think that we demonstrate ourselves better people for helping to advance anti-aging research - but this is a choice each person must make for his or herself. Find your own moral imperative: I persuade, you decide.

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Mapping DNA Repair
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Like all things, your DNA accumulates damage over time; complex, highly efficient biochemical systems are in place to repair that damage, but some still leaks through. This accumulation is one root cause of aging, and so the more we know about DNA repair, the better. Here, The Scientist notes that researchers have "used a systems biology approach to create a map of transcriptional networks that are activated when yeast DNA is damaged. We now know an order of magnitude more pathway connections than were known before, as far as how information is transmitted through the cell in response to damage ... Looking at cellular processes from a wide-angle view -- rather than the one-gene, one-protein approach of classical biology -- permits the construction of 'a complete wiring diagram' of transcriptional interactions, [which] will help scientists control cellular response to DNA damage."

Link: http://www.the-scientist.com/news/display/23466/

Still the Knee-Jerk Opposition
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(From the Palm Beach Post). While advocates are generating wider support for healthy life extension research, all too many people still knee-jerk in opposition to the idea: "Humans instinctively strive for longer life. Doctors and scientists who make medical breakthroughs are heroes. ... But what happens when science messes with one of nature's fundamentals: that the older generation will die off to make way for the younger generation? ... life as designed by modern medicine is bound to come into serious conflict with life as designed by nature. If future generations are going to have a right to life, those who already have life will have to recognize an obligation to die." Aging is just as much one of "nature's fundamentals" as anthrax, living in caves, and dying, parasite- and disease-ridden, in your 20s. I look forward to seeing a follow-up article to advocate these wonderful, natural concepts.

Link: http://www.palmbeachpost.com/opinion/content/opinion/epaper/2006/05/18/a16a_versteegcol_0518.html

Looking to the Future
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Worthwhile thoughts from Gregory Stock can be found in this press release: "Evolving science and technology, including genomics and nanomedicine, will radically alter healthcare in a way that will 'transcend biological limits that other generations have only dreamed of,' ... The next frontier is not space, it's our own selves. We are reworking our biology. This will change the way we have children, change the way we manage our emotional states and will even alter our life spans. ... These developments are not only going to reshape medicine and healthcare, they are going to alter the fabric of humanity. ... We have entered a new millennium and long before the next one arrives, future human beings will look back and see it not as a horrible moment in time when we trashed this environment, but will see it as a glorious moment that laid the very foundation for our future."

Link: http://biz.yahoo.com/prnews/060518/phth042.html

Two New Non-Profit Incorporations
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Via the Gerontology Research Group mailing list, we have this from Stanley Primmer, president of the Supercentenarian Research Foundation:

As Dr. Coles informed you last night the Pennsylvania Department of State has accepted the Articles of Incorporation of the Supercentenarian Research Foundation(SRF) effective as of May 2, 2006. Our first Board meeting was held this morning, consisting of Dr. Doros Platika, Dr. Stephen Coles, David Gobel, and myself. Dr. Platika is the Chairman; Dr. Coles is the Treasurer; and I have been asked to serve as President.

The SRF is dedicated to promoting scientific research into the causes and effects of aging, with initial emphasis on those who are at least 110 years of age. Until we obtain 501(c)(3) status as a tax exempt foundation the Methuselah Foundation (MF) has kindly agreed to be our Fiscal Sponsor. Tax deductible donations can legally be made to the MF with the designation that they are for the SRF. Please see our website at www.Supercentenarian-Research-Foundation.org for additional information about our mission and plans.

In other news, the Cryonics Society has obtained 501(c)(3) status:

"Cryonics used to be seen as science fiction," said Pavlica. "Now it's becoming science fact. People want to learn more about it. We're here to help."

Pavlica pointed out that recent research experiments have broken new ground in eliminating freezing damage in cryogenic conditions. Whole organs have been removed, stored at extreme low temperatures, then restored and used successfully in transplants.

"That used to be impossible." said Pavlica. "Now it's reality. Cryonics is like that too. It's just over the horizon. And when it arrives, it could save a lot of lives. Provided we can break the cycle of unthinking criticism and build more public support.

That's the job of the Cryonics Society, he added.

Incorporation and 501(c)(3) status are far from necessary hurdles placed in the path of earnest folk; regulation never achieves anything other than making progress slower and more expensive. It would be so much more pleasant to live in a world in which there was no need to sacrifice time to government employees before deciding how best to accomplish your goals. Not to mention further sacrifice to enable government employees to better waste your resources on corruption and other uses you'd never condone.

The standard libertarian objections aside, more non-profit incorporations in the healthy life extension community are definitely a sign of growth and progress, however.

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Why We Need to Change the Approach to Aging
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The present day mainstream approach to age-related degeneration, disease and frailty is a function and outgrowth of a historical lack of knowledge; if you don't know why the dam is crumbling, you get to plugging the holes and damn the expense. When plugging the holes is all you can do, then it's all you can do - it'll cost the moon and the dam will collapse only a little later than it would otherwise have done.

We can do better than this. Not right now, but soon. It will only be soon, however, if the research and funding communities stop piling the vast majority of their resources into plugging the holes. They need to start developing different, better approaches based on tackling what we know to be the root causes of aging.

While not recommending an article I noted recently as a paragon of common (or economic) sense, it's an eye-opener on the cost front:

The care of people with chronic illness accounts for more than 75 percent of all U.S. health care expenditures

So much of that chronic illness stems from age-related cellular damage - and the medical care is very much a matter of patching up holes in the dam.

As to the rest of that article, it comes back to matters of freedom and choice. The author talks about overspending and misallocation of resources - but who gets to decide? In a socialist medical system such as that under construction in the US, the decision maker is not you, the one who desires treatment. That's a fundamental problem of another stripe, and one that will doom medical research and commercialization if it proceeds.

To obtain the future of medicine we would like - in which low-cost, effective healthy life extension technologies exist - we must fight for freedom in medicine and better approaches to anti-aging research with every step of the way.

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More Telomere Shortening In Men
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Via FuturePundit, news of a study on telomere differences by gender: "This new study [shows] significantly shorter telomeres and higher erosion rates in men than in women, which likely causes a shorter life expectancy of male cells and tissues. Human telomeres form the terminal structures of human chromosomes and play a pivotal role in the maintenance of genomic integrity and function. During aging, telomeres gradually shorten, eventually leading to cellular senescence." The telomere theory of aging is on the way out, however, and there is some uncertainty as to just what short telomeres mean for health and longevity for any given individual. Like so many things in human biochemistry, it's a very complex question asked about a very complex system.

Link: http://www.futurepundit.com/archives/003461.html

Aging and Amyloidosis
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An interesting piece on amyloidosis from the e-journal of the Age Management Medicine Group: "The diseases with which amyloid has been most commonly associated, type 2 diabetes and Alzheimer's disease, are notable for their contribution to decreased quality of life, and mortality, in the elderly. But even among supercentenarians - those living to 110 or more - amyloidosis has emerged as a prime suspect for eventual cause of death. ... What, then, is the connection between amyloidosis and aging? To some extent, this depends upon who you ask - as does the question of whether amyloid buildup can be prevented or reversed. This illustrates the large amount of research being conducted in this area, and constantly emerging knowledge that results."

Link: http://www.agemed.org/p/10,42.html

Mitochondria and Parkinson's Again
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(From EurekAlert). A number of research groups have published recently on the relationship between age-related mitochondrial DNA damage and Parkinson's disease. Here is another: research "shows that oxygen free radicals are damaging proteins in mitochondria, the tiny cellular 'batteries' of brain cells. This damage may be one main cause of Parkinson's Disease (PD), the chronic movement disorder that affects at least one million Americans. [Scientists] believe the damage is taking place in a large protein structure called complex I, the first stop in the electron transport chain, which produces an electrical charge inside mitochondria. Mitochondria then use this electrical charge to make energy. ... complex I assembly in Parkinson's had 50 percent more damage from oxygen, [showed] evidence of not being properly assembled and had reduced electron flow." A good thing that methods of replacing damaged mitochondrial DNA are within sight.

Link: http://www.eurekalert.org/pub_releases/2006-05/uovh-dfo051606.php

On Longevity, Stagnation, and Freedom
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As I'm sure long-time readers are aware, there are all too many people in the world who would force you and I to suffer greatly and die from old age for no better reason than they want to and they can - concentration of power is the enabler of great horrors.

Politicians and government employees - with or without the tacit approval of the governed - have done far worse than force old age upon people in the past; the power to cause death and misery is only restrained by the threat of the same. Those with power insulate themselves from the consequences of actions that would bring just retribution upon others, however. There is no good cause for believing that an ugly future of mandated and enforced limits on life span could not occur -complacancy for our freedoms and tolerance of the abuse of power are the first steps down that sorry path.

A blog entry by Nydra at Betterhumans prompted this line of thought. It's a response to the stagnation objection to healthy life extension, a particularly poorly formed objection amongst many poorly formed objections - but this one touches on (or rather tramples over) the topic of freedom more than most.

The entire fulcrum of this comment seems to be the notion that individuals must necessarily be sacrificed so that some central tenet of nature may be upheld for the "greater good". I question the notion that a maximally "good" and ethical society must condemn people to death, despite the possibility of developing healthy life-extending technologies. Though some people certainly garner meaning and motivation from awareness of their own mortality, this is not true of all people. I do not see why the "death is meaningful" folks should get to decide the lifespans of those who disagree. As far as I am concerned, people who want to die are welcome to do so, but those who would rather stay around longer should have that option.

Freedom, in other words, in the form of self-ownership; the freedom to do as you see fit with your own body. But the trampling in the stagnation argument occurs earlier in the quote above, in the assumptions underlying a "greater good." Who gets to decide, and how do they get to force that decision upon others? Words like "we," "society" and the like - indeed, any assumptions of unity or of speaking for groups - are tricky pieces of camouflage for people who are employing force to have things their way, usually at your expense.

Further discussion on this matter would be greatly appreciated, since the "stagnation" argument against radical life extension seems to be nearly as frequently encountered these days as the "overpopulation" argument.

Agreed. More discussion is the way to show these arguments to the world as the nonsense they are. People change, and long-lived people will likely change more. If people refrain from change, that is their choice, and I would like to live in the sort of society where choice without harm is respected. What sort of person calls for institutionalized murder when faced with a free choice that does not impact him or his possessions?

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Novel Gene Therapy Delivery Method
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The New Scientist reports on a novel method of targeting gene therapy to a particular location. In this case the aim is to treat diabetes: "The team injected microscopic spherical shells into rodents, and using a directed ultrasonic pulse they caused the bubbles to break and release their genetic contents in the target organ. ... cells producing important proteins - such as insulin - lie inside remote structures in the pancreas organ, which itself sits beneath the stomach. It is difficult for foreign particles – such as gene-therapy viruses – to get there from the blood. Without a more sophisticated and targeted approach, cells throughout the body might pick up the gene and begin producing insulin. Since only pancreatic cells are fine-tuned to release insulin in response to food, other cells would over-produce the protein with no regard to food intake."

Link: http://www.newscientist.com/article.ns?id=dn9174&print=true

Reading the Immortalist
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The Immortalist is a cryonics-focused community magazine; the latest issue is now online: "Why is so much attention given to the subject of 'immortality' by cryonicists? Why all the philosophical ruminations about the meaning of death and the meaning of living forever? Why all the provisions for money after reanimation in contrast to the sparse attention paid to the real problems of being cryopreserved under good conditions, or ensuring that cryopreservation will be maintained? I think that the chances of failing to be cryopreserved are over a trillion times greater than the chances of living a trillion years. I think that the chances of cryonics not working at all are over a trillion times greater than the chances of living a trillion years. And the chances of being cryopreserved under terrible circumstances (dementia, autopsy, bad ischemic damage) are over a trillion times greater than the chances of living a trillion years."

Link: http://www.cryonics.org/immortalist/may06/index.htm

State of Alzheimer's Research
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From SFGate.com, a look at the present state of research into Alzheimer's disease: "I think there is really hope that something will work in the next two to five years. It will not completely prevent the disease or reverse it, but it will have an effect on the disease process ... I think with Alzheimer's, we're now at where we were with cancer in the '70s. We have a sense of the problem, we know where we'd like to be in 20 years, but we don't know how we're going to get there. ... What we're seeing now is an explosion in understanding Alzheimer's that is underpinned by the last 30 years or so of very, very fundamental, basic science ... a lot of the major [pharmaceutical] companies [see] that clearly there's a market out there now. They are getting involved, and the venture capitalists are looking for good opportunities."

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2006/05/15/ALZHEIMERS.TMP

What Do Failing Stem Cells Contribute to Degenerative Aging?
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Stem cell populations power healing processes; declining effectiveness in this task will clearly cause degeneration, as wear and tear outpaces repair. What is the cause of this decline, and how much does it contribute to frailty, suffering and death versus other classes of age-related cellular damage? Scientists are investigating, but it doesn't even seem clear at this point as to whether biochemical changes or declining numbers of cells are the real culprit - it might be both or neither, or different for differing populations. Much more work is yet to be done, but this, for me, is one of the most exciting areas of stem cell research - how much more healthy life could we gain through repairing or replacing our failing stem cells?

A small collection of abstracts on changes in stem cell populations and effectiveness with age can be found in a recent post in the sci.life-extension group:

The deteriorating in vivo environment is thought to play a major role in reduced stem cell function with age. The capacity of stem cells to support tissue maintenance depends not only on their response to cues from the surrounding niche, but also on their abundance.

...

In the adult mouse brain, the subventricular zone (SVZ) is a neurogenic stem cell niche only 4-5 cell diameters thick. Within this narrow zone, a unique microenvironment supports stem cell self renewal, gliogenesis or neurogenesis lineage decisions and tangential migration of newly generated neurons out of the SVZ and into the olfactory bulb. However, with aging, SVZ neurogenesis declines.

...

It is widely believed that cellular senescence is a tumor suppressor mechanism; however, it has not been understood why it is advantageous for organisms to retain mutant cells is a postmitotic state rather than simply eliminating them by apoptosis. It has recently been proposed that the primary role of cellular senescence is in mitotic compartments of fixed size in which spatial considerations dictate that a deleted cell is replaced by a neighboring cell. In these situations, rather than eliminating the neoplastic clone, deletion of mutant cells can paradoxically lead to their increased turnover. If mutant cells become senescent, then the compartment is instead progressively filled by senescent cells until the mutant clone is eliminated. Since most of the genetic alterations responsible for malignancy arise in stem cells, this mechanism may have particular relevance to the stem cell niche. In this article the implications of this hypothesis are examined in detail and related to experimental results. It is further proposed here that blockage of stem cell niches by senescent stem cells may account for some of the functional alterations observed in stem cell compartments at old age.

...

Hair graying is the most obvious sign of aging in humans, yet its mechanism is largely unknown. Here, we used melanocyte-tagged transgenic mice and aging human hair follicles to demonstrate that hair graying is caused by defective self-maintenance of melanocyte stem cells.

...

We have shown previously that chronically injecting bone-marrow-derived vascular progenitor cells can effect arterial repair. This repair capacity depends on the age of the injected marrow cells, suggesting a progressive decline in progenitor cell function. We hypothesized that the progression of atherosclerosis coincides with the deteriorating repair capacity of the bone marrow.

...

Reduced number of circulating endothelial progenitor cells [EPCs] predicts future cardiovascular events ... Reduced levels of circulating EPCs independently predict atherosclerotic disease progression

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Update On Amniotic Stem Cell Work
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I've previously mentioned tissue engineering for the unborn or very young based on the use of stem cells from the amniotic fluid. Here is an update from the Boston Globe: "Fauza's work focuses on the trachea and the diaphragm because the structures needed to fix them are relatively simple. If all goes well, he said, he can imagine fixing birth defects that affect the intestines, the bladder, and blood vessels in the heart. He is trying to coax the amniotic fluid cells to make the type of neurons that could help fix spinal cord defects in patients with spina bifida." That progress is being made here should provide greater incentive to find - or create - viable, easily gathered sources of multipotent stem cells for those of us who have left our amniotic fluid far behind.

Link: http://www.boston.com/news/local/massachusetts/articles/2006/05/14/new_birth_defect_treatment_studied/?page=full

Growth Factor Regenerates Nerve Fibers
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Via AScribe, news of a promising discovery: scientists "have discovered a naturally occurring growth factor [called oncomodulin] that stimulates regeneration of injured nerve fibers (axons) in the central nervous system. Under normal conditions, most axons in the mature central nervous system (which consists of the brain, spinal cord and eye) cannot regrow after injury. ... Out of the blue, we found a molecule that causes more nerve regeneration than anything else ever studied. We expect this to spur further research into what else oncomodulin is doing in the nervous system and elsewhere ... there is another side to the nerve-regeneration problem: overcoming agents that act as natural inhibitors of axon growth. ... Now that Benowitz has isolated oncomodulin, he believes even greater regeneration is possible by combining it with agents that counteract growth inhibitors."

Link: http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20060510.061706

Roundup on the Singularity Summit at Stanford
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The Singularity Summit at Stanford took place this weekend. I noted earlier:

[The outlined topics for the summit are] of little direct relevance to the near future of healthy life extension and advancing medical technology - as it will take place while the development of [general, or strong, artificial intelligence] is still in its earliest stages - but it is of great relevance to the mid- and long-term future of all human endeavors. Tools that improve our ability to manage complexity will greatly speed the advance of biotechnology, a science that is already bumping up against the limits imposed by our ability to manage and understand vast datasets and complex biological systems.

The event garned a fair amount of blog coverage, much of it live - as it should given the speakers listed on the program and hard work from the publicists and volunteers behind the scenes. Sadly, the mainstream media process is apparently still at the stage of typing up notes. Meanwhile, out there in the blogosphere, a selection of the more relevant posts:

The great Singularity debate:

In this new world, there will be no clear distinction between human and machine, real reality and virtual reality. We will be able to assume different bodies and take on a range of personae at will. In practical terms, human aging and illness will be reversed; pollution will be stopped; world hunger and poverty will be solved. Nanotechnology will make it possible to create virtually any physical product using inexpensive information processes and will ultimately turn even death into a soluble problem.

...

Biotech is also key to Kurzweil's vision. He cited efforts to create artificial blood '[respirocytes]' by the late 2020s that would allow people to sit at the bottom of a swimming pool for an hour or sprint for 15 minutes without getting winded. By 2020, you should be able to have the power of the human brain in a personal computer for $1,000.

Singularity: Technology, spirituality and the close box:

On radical life extension - including immortality - mastering and reprogramming who we are in terms of health processes through biotechnology is on the horizon, Kurzweil said that biology and medicine in post information era are about reprogramming biology to eliminate health problems, he said. "Within 15 years add a year to life expectancy every year," he predicted, which supports the "real goal of life is to expand human knowledge."

He added that "creating communities is what holds people together and enhance human relationships, and I would like more time to partake of that."

Singularity Summit Opens:

Major kudos to Tyler Emerson, Director of the Singularity Institute, who led this effort in conjunction with Kurzweil. Not only has he been fabulous to work with, but he -- together with his team -- has managed to pull this off without a glitch. No small task, with 1,800+ seats filled, and another 1,000 on the wait list.

Summit End:

A VIP reception was held tonight at the Computer History Museum for speakers, press and friends of the Institute following the Singularity Summit at Stanford today.

...

I uploaded photos from today's event here. Most of them I took, however some were taken by Dan Farber and Mike McGrath. Dan's photo stream here

Singularity Summit LIVE! (5)

[Bill McKibben's] remarks are focused on his objection to "the immortalitists." He says that instead of aiming to live forever, we should aim to live. That's a remarkably shallow platitude, in my view, as I see nothing wrong with vigorously pursuing both aims.

Now he is reporting on how humans, as a whole, are less happy today than we were 50 years ago. He claims that the answer of technoprogressives is always "more is better." But I think that's: a) a strawman, and b) confusing cause with correlation.

It's a strawman because virtually all of the futurist thinkers that I know (and I know most of the leading ones) are just as interested in living now as they are in living forever, and they are just as connected with human interests and values as they are to technological goodies.

Singularity Summit Summary:

Humans are, by nature, conservative. In an auditorium filled with people attending an event focused on techno-change -- and in a university set in the middle of Silicon Valley, no less -- still the largest applause was reserved for those with the most reactionary views.

In the healthy life extension space, this conservatism is the greatest hurdle to be overcome. The development of large-scale infrastructure, investment and the culture of research can only happen in an atmosphere of widespread support and understanding. People don't like to think about aging, however, or any other future unpleasantness; people think that aging is set in stone, a fact of life that cannot be changed; people think that aging is not a medical condition open to the development of therapies; people believe overpopulation would result from longer lives; people think that living longer means being frail and sick for longer; people think that living longer means being bored. The list of errors and head in the sand mistaken thinking goes ever onward.

I'm a firm believer in the power of the suitable outragous extreme to shift the foundations of cultural debate in a favorable direction. Pick a point that's defensible in the facts, as far out as you can go, and stick a flag in the ground with great fanfare. By doing so, you advance the middle ground and bring forward the range of ideas that people consider "reasonable." Never engage opponents of progress in the present middle ground - doing so only supports that status quo and makes it harder to raise investment in developing advanced technology. The Singularity Summit at Stanford is a good example of bringing more fanfare to a pre-existing flag; the event will help to increase support for a range of important scientific and technological development - including that important to greatly extending the healthy human life span.

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Nothing Fails In Isolation
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Via Reuters, a good illustration of the interconnected nature of the body. It degenerates in the same general way as any complex system - nothing fails in isolation. "The results of a new study suggest that there is an association between heart failure and an increased risk of dementia or Alzheimer's disease in the elderly. ... it may be worth looking at possible biological pathways linking heart failure to dementia, specifically to Alzheimer's disease. The markedly impaired cerebral circulation that results from chronic heart failure, for example, may play a role in the neurodegenerative process, especially in the elderly population. Poor blood circulation in the brain could further promote neurodegeneration by depriving the brain of oxygen." This is why the most effective approach is to prevent or repair the root causes of failure, rather than to continually develop patches for the far greater range of resulting problems.

Link: http://today.reuters.co.uk/news/newsArticle.aspx?storyID=2006-05-11T191922Z_01_COL169482_RTRIDST_0_HEALTH-HEART-FAILURE-DC.XML

Another Side of Learning About Money: Hows and Whys of Research Funding
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I talked a little about money and personal finance in the context of healthy life extension yesterday. Economics is both the root and representation of society and human interaction; modest understanding of the flows and practicalities will bring you great advantage in your endeavors.

I imagine that many of the folk reading Fight Aging! are very interested in the rate and details of progress in medical research, and specifically in work that may lead to healthy life extension technologies. If you're interested in medical progress and don't understand the workings of investment and commercialization, then you are left largely blind. You will not understand why some work succeeds while other work does not; you will fail to grasp the full significance of many news stories; you will not have a realistic view of the near future of medicine; you will not understand how and why some actions, events and situations damage progress and hinder the advance of new medical technology from laboratory to clinic.

Medical research funding in the US is approximately 30-40% public, 50-60% private for-profit and 10% philanthropic; most to the hard work of bringing science from laboratory to market is accomplished with private funding. So best to learn a little about how that process and culture works, no? A good place to start, with respect to recent private investment in healthy life extension and related research, might be the book "The Quest for Human Longevity."

Most other popular books on human longevity are focused almost exclusively on scientific ideas and breakthroughs in life-extension research, and they typically avoid any money talks as inappropriate subject. ... This somewhat idealistic perspective is challenged in a new book, which describes in a great detail how important money is in modern entrepreneurial world of life-extension and anti-aging research business. The book provides an alternative, more realistic perspective that financial incentives are driving scientific innovations in anti-aging studies by stimulating researchers to take risks and to work really hard.

While thinking along these lines, I bumped into a short article on venture investment in biotechnology today that gives some insight into the way in which investors think.

While the public markets for biotechnology companies have historically been an opportunity for very significant returns, the recent past markets have not been as attractive. With significant downward pressure on public valuations for many biotechnology companies, venture capital investors have had to evolve some of their thinking.

...

With the markets valuing many new public companies in the range around $150 million (as opposed to $300 million), investors can no longer invest in companies that require $80-100 million to mature to the point where they can go public. This has forced companies and investors to be much more capital efficient and to pursue creative paths to product development and ultimately commercialization. This might manifest in the pursuit of more developed assets or the adoption of clinical development plans that can be abbreviated.

Investment environments are something like the weather - too many variables to predict well at the smaller scale, but big storms rarely come out of the blue. Investors react to this weather, which can make all the difference in funding of early stage companies, more speculative research, or research that will take longer to mature.

This is just a small slice of life from a broad, changing culture, however. I'm not familiar with the breadth of venture investment and private research funding, and neither do you need to be - the general basics, incentives and practicalities of venture investment, growth of companies and commercialization of products are all you need to gain a much better understanding of the world around you. This, like an understanding of money in the context of personal finance, is really nowhere near as hard as you might think. Much of it is intuitive, and the more you look at it, the easier it becomes to figure out the rest.

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Billion Dollar Proposals All Over
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Politicians trying to get elected are pretty free and easy with future public money; government always means bribes and corruption some sort, but for some reason buying votes isn't usually seen as such. In any case, following Spitzer's recent announcement in New York (and the 2005 precedents elsewhere in the country), here we have another billion dollars proposed for stem cell research: "Gabrieli will outline his plan Thursday for the Massachusetts Biotechnology Council. The proposal calls for the state to borrow 100 million dollars a year over ten years. The money will go into a fund that would provide grants to scientists selected by a board of experts." It seems clear that research infrastructure for regenerative medicine and tissue engineering will continue to grow - hopefully as little as possible will be of the inefficient, regulated, steered-by-the-ignorant public variety.

Link: http://cbs4boston.com/topstories/local_story_131073906.html

Register for TransVision2006
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TransVision2006, a gathering of transhumanist-minded folk from around the world, will be held in August in Helskinki, Finland. "This year the theme of the conference will be Emerging Technologies of Human Enhancement. We'll be looking at recent and ongoing technological developments and discussing associated ethical and philosophical questions." The event tends to reflect the biases of the World Transhumanist Association, so your milage may vary. Personally, I prefer a greater focus on the hard work of creating technological progress rather than inventing ways to slow and hinder advancement under the banner of "ethics" - how is it in any way ethical to attempt to slow down development and adoption of life-saving technologies, such as working anti-aging medicine? Early registration ends on May 31st, so you still have some time to read up on the early edition program and list of speakers.

Link: http://www.transhumanismi.org/tv06/

Why CR Would Work For Human Longevity
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The latest issue of Biogerontology contains a number of articles on calorie restriction (CR), reflecting the spectrum of positions with regard to its likely effects on human longevity. From the optimistic side of the fence: "To delineate the cellular and molecular mechanisms of CR's efficacy on human longevity, this review elaborates on the modulation of CR on the inflammatory process, a common risk factor for many chronic diseases. Discussions also include evidence from human data on the effect of CR in the loss of body weight, known to suppress inflammatory cytokines, subsequently leading to the reduction of chronic diseases known to compromise the functional longevity of humans." The strongly positive effects on human health have been handily demonstrated in recent years - you owe it to yourself to look into calorie restriction.

Link: http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1007/s10522-006-9009-y

Healthy Life Extension: Live Like You Mean It
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I thought I'd direct your attention to a few interesting thoughts I stumbled across while perusing the blogosphere a few days ago:

Also, with advances in biotech, I can easily see the 80-90 age getting pushed back to 100 or 110 by the time I reach it. My expectations for biotech really deserve their own article. The very-short version of my belief is that biotech is to this century as electicity & computers were to the last. Think about the advancements made during your grandparents' lifetimes and then apply that to biotech, and you have some clue as to how interesting the road ahead truly is for biotech and medicine.

So, with moderate advancement of medicine, I am probably only a third of the way through my lifespan. Therefore, it makes sense to think about how I wish to live this vast span of time.

...

Last year, I asked the question and came up with my most ambitious answer yet. "If I was going to live forever, I'd really rather not have to worry about money all that time. Besides, much of the medical technology that will make life extension possible will be very expensive. I intend to get and stay wealthy."

...

For me, fulfilling this dream will mean developing the skills, habits and the mindset needed to get and stay wealthy. The basics of this are to spend less than I learn, to drop all fear of money, and to learn how it really works and flows in society. The advanced part is to free myself from being dependent on wages which are in any way linked to hours. It really is an all out effort, since it will touch almost every area of my life.

I heartily endorse this way of looking at the world. You'll find a few posts expressing similar sentiments back in the Fight Aging! archives:

I cannot overemphasise the value of learning how money actually works - or better, the underlying culture, history and practice of human action, trade and endeavor. It's really not as intimidating as it sounds; most of the core concepts are in fact quite simple and intuitive, for all that too few people understand economics and the practice of wealth these days. Economic ignorance is not a sure root to poverty, nor a sure block to wealth, but it's a pretty large hurdle to getting ahead in the world in ways both large and small.

Writ large, economic ignorance is the death of cultures; why be a participant in the decline of your civilization when you could be so much more than that? Start with well-regarded self-help books on investment and money management - such as The Courage to be Rich - and move on to picking up the basics of Austrian economics from the daily articles and user-friendly introductory materials at the Ludwig von Mises Institute. It will make a difference.

Take a look at your life; if you're enjoying it now, why not do the very best you can to ensure that continues to be the case for a very, very long time? Support medical research for healthy life extension, and prepare your financial ground for a life lived in the future. You'll thank yourself for doing so.

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Nanoengineering, Cardiovascular Disease
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(From EurekAlert). The most notable effect of advancing biomedical and nanoscale engineering technologies is the sharp fall in cost of understanding biochemical processes - and of creating ways to intervene in those processes at earlier, more effective points: "researchers propose a way to combat clogged arteries by attacking how bad cholesterol triggers inflammation and causes plaque buildup at specific blood vessel sites. Their approach contrasts with today's statin drug therapy, which aims to reduce the amount of low density lipids, or LDLs ("bad" cholesterol), throughout the body. ... researchers propose a way to combat clogged arteries by attacking how bad cholesterol triggers inflammation and causes plaque buildup at specific blood vessel sites. Their approach contrasts with today's statin drug therapy, which aims to reduce the amount of [LDLs] throughout the body."

Link: http://www.eurekalert.org/pub_releases/2006-05/rtsu-nse051006.php

Human Enhancement and Longevity
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The New Scientist looks at the future of human health and longevity, amongst other enhancements that biotechnology could bring: "It is 2050, and Peter Schwartz is deciding what to do with the rest of his life. He has already had two successful careers and he wants another one before he dies, which he expects to happen in around 50 years. By then he'll be about 150, which isn't bad for a baby boomer, but he expects his son, now 60, to live a lot longer than that. The world that Schwartz lives in is radically different from the one he grew up in. The industrial and information age has passed into history, overtaken by a revolution in bioscience." This wonderous future of radical life extension is by no means a sure thing, however - a great deal of work is needed just to create the culture and infrastructure required for significant progress towards longer, healthier lives. If we do not stand up and help, we will certainly age, suffer and die all too soon.

Link: http://www.newscientist.com/channel/being-human/mg19025511.500.html

Nanobiotech Infrastructure Growing
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The nanomedicine of the future we'd like to see - medical nanorobots capable of repairing age-related cellular damage, for example - will grow from the union of the nanobiotechnology and dry nanotechnology research industries. A good example of present day dry nanotechnology research would be the work of Zyvex; building tools and basic capabilities that will later be turned to medical uses. As to nanobiotechnology, here are a couple of recent articles:

In medicine, small is about to become big :

One common approach to creating nano-therapies is to hitch a "targeting" molecule, which can find cancer cells in the body, to another particle that can identify the cell to doctors -- or kill it outright. A tiny ball of radioactive material, for example, could be carried to the tumor to irradiate it from within. Microscopic bits of metal could be used to dissolve tumor cells with heat, as with Triton's system, or highlight it on a body scan, so doctors can find growing cancers that would otherwise be impossible to detect.

Sangeeta Bhatia, a medical engineer at the Massachusetts Institute of Technology, has come up with a way to create iron particles small enough to sneak into cancer cells, and coated in such a way that they automatically clump together when exposed to certain proteins inside the tumor.

At Northeastern University, Mansoor Amiji and Vladimir Torchilin are investigating ways to pack capsules with chemotherapy, creating tiny drug bubbles that could sneak into tumors through their blood vessels and penetrate the cells before releasing their toxic payload. In the future, they say, the capsules could have additional functions, such as helping doctors track the size of the tumor as well as the drug's effect.

Aiming small, thinking big:

Johns Hopkins is preparing to aim enormous research and educational resources at some exceedingly small targets. Drawing on the expertise of more than 75 faculty members from such diverse disciplines as engineering, biology, medicine and public health, the university will officially launch its new Institute for NanoBioTechnology on Monday, May 15, with a celebration featuring prominent speakers.

...

Institute members will work within [key] research areas:

  • Diagnostics, including the development of molecular imaging probes that can relay information about the health of a patient's organs and other tissues without the need for a biopsy. Advances in this area promise to greatly enhance the way diseases are diagnosed and treated.

  • Therapeutics, including nanoscale forms of drug delivery, gene therapy, protein therapy and immunotherapy. These will be used to treat diseases such as cancer and asthma and conditions such as spinal cord injuries.

  • Cellular and molecular dynamics, including the use of powerful new tools to study the inner working of cells. This knowledge should help identify causes of disease and new molecular targets that could help cure medical disorders.
  • You can estimate the health of a field by concrete and conferences - buildings constructed, institutes founded, gatherings held. By that measure, the foundation of future nanomedicine in bioscience is well underway; a good thing too, given the vast potential for medicine, health and longevity.

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    A Reminder of the Cost of Aging
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    Kevin Perrott provides a reminder of the cost of degenerative aging - a cost we are doing far too little to mitigate: "our ability to reduce the suffering of the aging process will require the use of technologies that have yet to be developed ... The need for such technologies is great. In Canada, according to the Insitute on Aging, the cost of age-related disease is growing rapidly. In 1993, musculoskeletal degeneration led to costs of more than 20 billion dollars, exceeding those of cancer ($13b) or cardiovascular problems ($19.8b). In the U.S. over 220 billion dollars per year is spent on giving the dependent elderly some quality of life as they deal with debilitating conditions. ... The benefits to slowing or preventing the degeneration that eventually occurs to even those who live the healthiest of lifestyles are obvious."

    Link: http://www.healthextension.net/archives/2006/05/expensive_agere.html

    More Promising Cancer Immune Therapy Research
    Permalink | View Comments (2) | Post Comment | | Posted by Reason

    While we're on the subject of stomping all over cancer with sophisticated immune therapies, I should point out recent research that seems to be another step ahead.

    The idea of using the body's immune system to kill cancerous cells is already routinely deployed. Our immune system contains killer white blood cells called cytotoxic T lymphocytes (CTLs), which single out and destroy tumours. But the body's natural response to cancerous cells is often not strong enough to wipe out the tumour.

    ...

    The new therapy, called TrimAb (triple monoclonal antibody) therapy, may solve that problem. Mark Smyth, at the Peter MacCallum Cancer Centre in Australia, Kazuyoshi Takeda, at the Juntendo University School of Medicine in Japan, and colleagues used a cocktail of three different antibodies.

    The first attacks the tumour directly, by stimulating the receptor for a death-inducing protein on tumour cells, called TRAIL. The boost that strengthens the response comes from the other two antibodies which activate killer T-cells that pitch in to kill the tumour.

    TrimAb cleared large breast tumours in 80% of the mice that received the treatment, while the tumour disappeared in less than 30% of mice that got either single antibodies or double antibody combinations. And furthermore, the therapy induced a complete cure in 60% of the mice in which the breast cancer had spread to the lungs, liver, and brain.

    As John Schloendorn was quoted in yesterday's post, "I think immune therapy is the most promising anti-cancer approach we have." We certainly need something that's a leap and a jump ahead of present widely available cancer therapy technologies - radiation and drugs that harm you just a touch less than they harm the cancer. Cancer in mice is significantly different to cancer in humans, however; mice are more vulnerable to cancer in general, for example. It's worth getting excited when a promising therapy successfully makes the jump from mouse models to human trials, but many past examples have not.

    For my money, cancer is number two - after neurodegenerative conditions - on the list of complex, hard to handle age-related conditions that must be successfully tackled by medical science in the near term. Stepping stone advances in healthy life extension technologies will not be too helpful if they simply allow you to suffer and die from ever more cancer and neurodegeneration.

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    Understanding Blood Vessel Growth
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    Via Medical News Today, news of an advance in understanding of blood vessel formation: "Up till now, we've been looking for a 'missing link' in the process whereby blood-forming cells in the marrow head to the site of injury to rebuild and sustain the vasculature. [The protein stromal-derived factor 1 (SDF-1)] looks like it could be that missing link ... The finding could explain why [existing] therapies have only been partially effective in restoring proper blood flow to limbs affected by peripheral vascular disease. ... Without SDF-1, you've only got a part of the mechanism." Given the importance of blood vessel formation to tissue engineering and regenerative medicine, a full understanding of the mechanisms involved will assist a wide range of further research.

    Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=42977

    Transferring Cancer Resistance
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    Via WESH.com, a look at transferring cancer resistance between mice and what that could mean for human cancer therapies: "Three years ago, Wake Forest researchers discovered a mouse that could not get cancer no matter how hard they tried to give it the disease. ... white blood cells from that mouse's descendants were injected into ordinary mice with cancer and their disease was completely wiped out. The treatment worked with a variety of cancers, including those similar to end-stage human cancers. ... The goal now is to find a human treatment that could avoid the rejection problem by using a patient's own cells. White cells from a cancer patient would be combined in a test tube with the specific anti-cancer gene and then given back to the same patient." Scientists do not yet know how this cancer resistance works in mice - this is early stage work, for all its promise.

    Link: http://www.wesh.com/health/9178673/detail.html

    Conversing on Cancer-Resistant Mice
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    News of a form of immune therapy to transfer cancer resistance between mice has spawned a good conversation, presently taking place over in the Immortality Institute forums:

    http://www.pnas.org/cgi/content/abstract/0602382103v1

    I first read about the cancer resistant mouse in 2003 and I am very surprised that it has taken this research team 3 years to merely establish a simple fact (that a transplant of a component of its immune cells will mediate complete cancer recovery in a non mutant-mouse). The mutant mice should be distributed in research centres all around the world and millions of dollars of government funding be available to rapidly investigate the mechanism by which this effect is mediated and how it can be reproduced in humans. Since the mechanism remains to be discovered, pharma companies can also participate.

    These mice are the most valuable experimental animals in the world.

    ...

    To dampen your optimism a little bit, bear in mind that there are considerable differences between mouse and human tumors. The most important ones of them derive from the fact that human tumors have more time and more cells, so they have greater potential to evolve against any type of treatment.

    For example, a major histological difference between tumors in resistant mice and normal mice is that in resistant mice tumors were fraught with immune cells that killed them, while in normal mice there were litte immune cells in the tumor. Now in humans, it's actually normal to have tumors fraught with immune cells, but they are doing nothing, because the tumor has figured out some way to defuse them with various signaling molecules.

    ...

    Still, I think immune therapy is the most promising anti-cancer approach we have.

    You'll find more links and commentary by reading the whole thread. Modern medical researchers are bringing in more data than the research infrastructure can process these days - hence promising advances or discoveries like this, or regenerating MRL mice, take a while to rise to general notice on their merits. You can be sure there are, a present, a hundred other equally important discoveries already made and languishing for the right attention, the right connections to other research.

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    Senescence or Cancer: Pick One
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    A good popular science article on telomere biology from Innovations-Reports: "Without the enzyme [called telomerase] that 'regenerates' telomeres (the ends of DNA), stem cells lose functionality and the organism rapidly ages, while it acquires cancer resistance. ... the lack of telomerase causes a severe defect in the fundamental functions of stem cells. ... in genetically modified mice that did not express telomerase, stem cells lost their functionality and became unable to regenerate the damaged epithelial tissue. On the whole, these mice aged more rapidly than normal mice. But, there was a very interesting side effect: without telomerase, mice showed a marked cancer resistance. ... Further experiments on telomeres structure showed that every time the shortening process is altered, the result is either 'early aging and cancer resistance' (if shortening is boosted), or 'aging inhibition and more cancer occurrence' (if shortening is reduced)."

    Link: http://www.innovations-report.com/html/reports/medicine_health/report-58768.html

    Interview With Nick Bostrom
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    The Guardian is running a short interview with Nick Bostrom, author of The Fable of the Dragon-Tyrant, amongst other works: "Now the discussions tend to start from the position that, yes, it will be increasingly possible to modify human capacities. ... For healthy adult people, the really big thing we can foresee are ways of intervening in the ageing process, either by slowing or reversing it. ... what you would need to do is either slow the rate at which this damage accumulates, or, even better, go in after the damage has accumulated and remove it. Stem cells, for instance, can be used to regrow cells that we have lost. And we might develop new enzymes which could break down those substances that the body, unaided, cannot deal with."

    Link: http://education.guardian.co.uk/higher/research/story/0,,1770694,00.html

    A Little Less Means More
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    Even slight calorie restriction is good for you, as noted at ScienceDaily: scientists "have found that eating a little less food and exercising a little more over a lifespan can reduce or even reverse aging-related cell and organ damage in rats. ... even small reductions in calories could have big effects on health and shed light on the molecular process responsible for the phenomenon, which until now has been poorly understood. ... This finding suggests that even slight moderation in intake of calories and a moderate exercise program is beneficial to a key organ such as the liver, which shows significant signs of dysfunction in the aging process. ... feeding rats just 8 percent fewer calories a day and moderately increasing the animals' activity extended their average lifespan and significantly overturned the negative effects of cellular aging on liver function and overall health." File this under "how good health practices actually work."

    Link: http://www.sciencedaily.com/releases/2006/05/060508165053.htm

    Calorie Restriction, Growth Hormone and Insulin
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    To follow up on the calorie restriction research noted today at the Longevity Meme, here is more of the same:

    A number of studies have shown that restricting calories increases the lifespan of animals, but the biological basis for this has remained elusive. A new report hints that growth hormone, as well as insulin, are key factors in the life-extending effects of calorie restriction.

    "The implication ... for pharmaceutical development would be that the signaling pathways of growth hormone and insulin may be logical targets for development of anti-aging medicine,"

    ...

    Bartke's team tested whether growth hormone and insulin are tied to the life-extending effects of calorie restriction in a series of experiments with normal mice and mutant mice deficient in growth hormone.

    The mutant mice do not express the receptor for growth hormone (and are therefore growth hormone resistant), have profoundly suppressed insulin levels, and are known to live longer and age more slowly than normal mice ... in sharp contrast to its effects in normal mice, calorie restriction failed to increase lifespan in mutant mice lacking growth hormone receptor.

    ...

    Although it would be irresponsible to recommend that healthy people start using anti-diabetic drugs," said Bartke, "it is reasonable to suggest that treatment(s) causing an improvement in insulin sensitivity combined with modest reduction in insulin release would reduce risk of age-related disease and likely also delay aging.

    Most interesting. Calorie restriction researchers are pulling at strands of the tangled knot of metabolic biochemistry - everything affects everything else. It is possible that an extra decade or two of healthy life span for even the most healthy and long-lived amongst us could result from present research into the biochemistry of calorie restriction. It's also possible that nothing of the sort will materialize prior to this line of research being rendered obsolete by the advance of much more aggressive approaches to tackling aging.

    It seems to me that metabolic research cannot be more than a stepping stone to far better ways of extending the healthy human life span. Scientists should already be striding beyond these studies to tackle the repair of age-related damage in a more direct manner.

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    Damn Interesting on Calorie Restriction
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    The folk at Damn Interesting interviewed biomedical gerontologist Aubrey de Grey and some of the Methuselah Foundation volunteers last year - on the topic of healthy life extension, naturally. In their latest piece, Cynthia Wood paints a skeptical and somewhat incomplete summary view of the practice and science of calorie restriction (CR), concluding:

    At least some in the nutrition field seem to regard CR as little more than anorexia with medical sweetening to make it more acceptable.

    While the practice of CR is still very controversial, the level of hostility towards its practice seems quite odd. There are hundreds of diets on the market in America, many of them vastly unhealthy, and most intended for no more worthy goal than the loss of a few pounds. CR remains unproven thus far, but ultimately the only way to definitively prove or disprove its effects is to do exactly what the CR Society is currently doing - to give it a try.

    If you know folk in the calorie restriction community, or at least the normal go-to contacts for media, you'll recognize some individual quirks writ large as the practice of many people, as well as transient community concerns taken as firm history for all time. It's annoying, but such is the way media goes. The community contains some real characters, and in any case isn't large enough or uniform enough to be able to extrapolate much of the way in which CR is practiced from any small sample. Finding your way to a style of CR that suits you is something of a journey in and of itself. These thoughts are probably worth repeating to the next interviewer or journalist you happen to be talking to on the topic.

    In general, I thought the article to be appropriately skeptical on calorie restriction for increased maximum human longevity, but far too dismissive of health benefits resulting from the practice of calorie restriction. The studies performed to date are pretty conclusive on that count, and something on the order of $100 million or more is presently invested in attempts to replicate the biochemical effects of calorie restriction to treat or prevent some age-related conditions. I don't see it as in any way controversial at this point to say that CR is very good for you - up there with moderate exercise as quite possibly the most important thing you could be doing for your long term health if you are an average, healthy adult.

    Any uncertainty in whether you, a healthy person, should practice calorie restriction (for which read "whether you should stop damaging your long-term health and longevity by eating too much and having too much body fat") stems from the lack of the sort of large-scale studies needed to ferret out those subpopulations for whom CR isn't a good idea. But outside of medical conditions with Latin and Greek names, it's all pretty much the same common sense as you apply to any dietary choice - you can't support an athelete's lifestyle on a CR diet, the obese should seek recommendations from a physician before any diet change, and so forth.

    So ask your physician if there is any objection to cutting back the calories - while maintaining correct nutrition - and losing some fat as a result; in most cases, and unless you suffer from a small range of specific medical conditions, you'll be told to go right on ahead.

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    Short Telomeres and Dementia, Or Not
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    Via the Doctor's Guide, news of a study on telomere length and dementia: "Despite previous mixed reports, telomere length cannot be used to predict dementia, according to the largest longitudinal study ... The telomere hypothesis of aging is based on the notion that telomere shortening with each cell division, and therefore with age, results in cell senescence ... This thus led to the 'telomere hypothesis of dementia,' that asks whether telomere shortening contributes to the genesis of certain age-related diseases, such as dementia ... [but] telomere lengths in both the dementia and nondementia patients showed no significant decline with age. ... There was no association between telomere length and change in cognitive status." It would be wonderful progress to find a simple association between known mechanism and disease, but this is rare indeed amidst the vast complexities of human biochemistry.

    Link: http://www.docguide.com/news/content.nsf/news/852571020057CCF68525715A005411B2

    Further Insight Into Type 2 Diabetes
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    Type 2 (age-related) diabetes can usually be avoided through smarter lifestyle choices, but further insights into biochemical mechanisms and genetic risks associated with diabetes will lead to therapies to help people who did not make these choices. From EurekAlert, news of a gene that "likely influences the ability of the pancreas to recruit a type of cell essential for constructing the walls of blood vessels. The beta cells of the pancreas, which are the critical insulin producing cells of the organ, are found clustered together in structures called islets and are nourished by a complex network of small blood vessels. If there are changes in this gene [the] blood vessels within islets may not form properly. ... The hope is this will open up scientists' thinking to realize that there are other cells of importance (in diabetes) beyond beta cells."

    Link: http://www.eurekalert.org/pub_releases/2006-05/uow-sfg050406.php

    Popular Mechanics on Living Longer
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    A Popular Mechanics article takes a look at what the near future holds in terms of upgrades for we humans; biomedical gerontologist Aubrey de Grey is one of the featured scientists: "There's a difference between working on aging and working on a specific age-related disease. Curing one age-related disease might extend life by five or 10 years, but an awful lot of people who would have died from it will die of something else instead. Even if we fix only four or five of these things very well, we probably won't get more than an extra 10 or 20 years of life because the things that we can't fix will still be accumulating. ... Depending on funding, it will take another 10 years or so to get to the proof-of-concept stage in the lab. I'd say we have a 50/50 chance getting these therapies all working in humans 15 years after that."

    Link: http://www.popularmechanics.com/science/medicine/2713146.html

    How p53 Controls Cancer Rates
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    The gene p53 is central to biochemical processes governing cancer and aging. From EurekAlert, more on how p53 controls DNA damage: "The body's solution to minimizing mutations is to have no fewer than ten different 'careless' [DNA replication] enzymes. Although this may seem paradoxical - intuitively, more careless enzymes should mean more mutations - each of these enzymes is tailored to deal with certain specific types of DNA damage. This specialization is what keeps the level of mutation, and thus the cancer risk, low. But the existence of this variety of specialist enzymes implies precise regulation of the system - otherwise copying by the careless enzymes might get out of control and lead to an unhealthy proliferation of mutations. ... The main components in this system are the proteins p53 and p21. ... if the functioning of p53 or its relative, p21, is harmed, the activities of the careless enzymes can go into overdrive, leading to more mutations."

    Link: http://www.eurekalert.org/pub_releases/2006-05/acft-wis050206.php

    The Damage Done by Patents
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    Via the Paramus Post, an examination of some of the damage done by patents. "Along similar lines, San Francisco-based Athena Neurosciences holds the patent on a gene associated with Alzheimer's disease. Athena will not allow any laboratory except its own to screen for mutations in that gene. ... Doctors and laboratories across the country face a lawsuit if they try to determine whether one of their patients carries this genetic predisposition to Alzheimer's disease, even though testing can easily be done by anyone who knows the sequence of the gene, without using any product or device made by the patent holder." So one company patent holder blocks or exacts a toll on any and all work the rest of the world might do to improve this technology. The bottom line: restrict competition and you restrict progress. Industries without patents are far more dynamic than those stifled by them, in which short-termists profit at the expense of everyone else.

    Link: http://www.paramuspost.com/article.php/20060505203501939

    Google Health to Launch Soon
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    Via Digg, news of a new feature for health-related searching soon to be rolled out at Google.

    Google will launch a new feature Wednesday: Google Health, that will help you find treatments, symptoms or alternative medicine treatments. You can try it today (be sure to set your Google interface to English).

    I think a number of readers here will no doubt be using this in their research; try this link to a search on Alzheimer's to see the additions above the search results - and note that they change, expand and mutate depending on what you've chosen in the past. "From medical establishment" followed by "For health professionals" brings up whole list of helpful subcategories, such as clinical trials - I can see that being very helpful for many folk. But give it a whirl, see what you think.

    From spending a little time with this, it seems to address a number of issues that made Google less helpful for background research into age-related conditions - you can even dive in with aging itself, although it's clear that more general terms benefit less from this refinement than specific named conditions. All the more reason to continue carving up the roots and results of degenerative aging into smaller named packages.

    UPDATE: Looks like those links are already non-functional, or rather plain vanilla Google once more - we'll have to wait until the day.

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    Mitochondria and Sarcopenia
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    This paper from Aging Research Reviews discusses current scientific thought on the connection between accumulated damage to mitochondrial DNA and sarcopenia, the progressive loss of muscle mass and function with age: " Many key theories on aging describing the mechanisms underlying sarcopenia are now focused on the mitochondria because of their dichotomous role in controlling life and death processes within myocytes. ... Evidence supports that apoptosis occurring in aging skeletal muscle may be due, in part, to the progressive decline in mitochondrial function and the resulting energy depletion within the cell." Damaged mitochondria seem to play an important role in many of the conditions and failure modes relating to age-related degeneration - methods to repair or prevent this damage will be most welcome.

    Link: http://dx.doi.org/10.1016/j.arr.2006.03.002

    Recent Items at InfoAging
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    The informative and useful InfoAging website is worth visiting every so often to catch up on their schedule of updates. Here are a few from the past month:

    Nir Barzilai discusses longevity research:

    Infoaging: There has been concern regarding the implications of people living forever. In your opinion, is there a certain point beyond which people cannot age or is it possible for lifespan to be prolonged indefinitely?

    Dr. Barzilai: Centenarians die of the same causes as everyone else - only approximately 30 years later. This suggests that once we find the right switch - a longevity gene - we can increase the average life expectancy to 100 years. Getting beyond that, however, is something we don't yet know much about.

    Attacking the mechanisms of metastasis:

    "Solid tumors have a very ill-defined and poorly developed blood supply," Giaccia explains. In fact, many tumors become hypoxic, and experts have long noticed that hypoxic tumors are much more aggressive and prone to metastasis than more oxygen-rich cancers.

    The Stanford group discovered that the hypoxic state triggers a very high expression of the gene that produces the lysyl oxidase enzyme. That's important, because lysyl oxidase aids metastasis by building the collagen "matrix tracks" that cancer cells travel on as they migrate to other sites.

    But would inhibiting lysyl oxidase curtail this migration? ... While mice with normal cancer lines went on to develop metastatic cancer, mice with lysyl oxidase-disabled tumors showed no such spread.

    On calorie restriction:

    Whether CR can actually extend the natural limits of the human lifespan, however, is debatable. "It's my personal opinion that caloric restriction isn't actually going to have much of an effect on human lifespan," says Mobbs. "Over the millennia, there have been many, many people who have been subjected to caloric restriction, probably most or all of their lives. Many had it imposed on them, but there were also religious, monastic people who fasted all the time. Among all of them, there has never been any substantiated report - really, almost no claim at all - that such people live much longer than everyone else. Even the present-day Okinawans, who have exactly the kind of diet we're talking about, don't live beyond the maximum known human lifespan." However, Okinawans, on average, do live longer than any other group on the planet, and they suffer from far less heart disease, cancer, and neurological diseases such as Alzheimer's and Parkinson's as they age.

    Mobbs is a calorie restriction skeptic in the manner of Michael Rose and John Phelan or Aubrey de Grey, then. Given the increase in healthy life span and reduction of chronic disease in just the past hundred years, I don't think the quoted text above is a very robust argument - but there are better, more convincing arguments out there, such as those put forward by the other researchers mentioned above. As the article notes, the jury is still out on extension of maximum life span - well proven for animals - in humans, but the weight of evidence is overwhelming for greater health and resistance to age-related disease.

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    A Step Towards Replacement Lungs
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    Via BusinessWire, news of early stage progress in engineering lung tissue for regenerative therapies and similar applications: "The growth of functional three dimensional organ structures begins with proof of concept studies showing that organ subunits can successfully be generated. This work takes us a step closer to realizing this goal which we hope will be applicable to all organs in the future ... a combination of 3-D cell growth on a [hydrogel] support and the addition of tissue-specific growth factors can induce functional lung tissue development. In a paper entitled, "Engineering Three-Dimensional Pulmonary Tissue Constructs," the authors report on their success in creating pulmonary tissue with appropriate lung tissue morphogenesis, architecture, and branching, as well as specific gene and protein expression."

    Link: http://home.businesswire.com/portal/site/google/index.jsp?ndmViewId=news_view&newsId=20060505005082

    Anti-Aging, Elastin and a Clash of Cultures
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    I'm still pondering what the community might be able to accomplish - and whether any reasonable accomplishment is plausible - in creating some enclave for a wider online conversation related to anti-aging science, keeping it afloat in a sea of spammers, vendors of useless junk and other short-termist undesirables. A conversation on that topic is taking place at the Immortality Institute at the moment.

    So it was that the role of elastin in skin and aging came to mind again. A number of groups are working on engineering replacement elastin, or developing potential artificial replacements such as Elastatropin. This impacts wound healing, amongst other things, and finding funding in that area is a good deal easier than for aging-related research - so some progress has been made. But, of course, you can't draw breath to mention aging and skin in the same sentence without being buried by the output of the voluble "anti-aging" marketplace; ever volume over quality.

    Elastatropin is actually a good example of the way in which potential progress can be subverted by short term goals when commercial possibilities arise. Take this press release, for example - marketing babble at its finest. But behind the scenes, here you have interesting science and possibilities. A real clash of cultures, but you see this in all too many places; the focus turned away from progress in medicine. It's quite possible, and indeed essential, to combine progress with commercial success - but this doesn't have that look to it.

    Real freedom is the freedom to sigh about the way folk choose to spend their time and money; if too many people are short-sighted, we'll all suffer for it. The far longer, healthier lives we all desire will take large-scale resources and decades to develop - there is no free lunch, no short term fix. Far too many people would rather play make-believe, condemning themselves a future of suffering and death, than to accept the reality of effort and long-delayed gratification. The story of the modern anti-aging marketplace is very much the story of the cricket and the ant.

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    Standing Up To the FDA
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    (Via Marginal Revolution). It is pleasant to see someone within the present establishment standing up to FDA bureaucrats and what they stand for - suppression of freedom, removal of choice in medical treatment, and the systematic destruction of incentives for research and investment in new medicine. "A right of control over one's body has deep roots in the common law. The venerable commentator on the common law William Blackstone wrote that the right to 'personal security' includes 'a person's legal and uninterrupted enjoyment of his life, his limbs, his body, [and] his health,'...barring a terminally ill patient from use of a potentially life-saving treatment impinges on this right of self-preservation." We are all terminally ill; we are all suffering age-related degeneration that will ultimately kill us. Government obstruction of freedom of medical research must cease if we are to see significant advances in the future of healthy life extension medicine.

    Link: http://www.marginalrevolution.com/marginalrevolution/2006/05/fda_shock.html

    Gathering Data on Longevity
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    More studies are underway with the aim of gathering raw data on patterns in the genetics and biochemistry of aging: "An $18 million National Institute on Aging study examining families with longevity patterns gets under way in the next few weeks ... Over the next several years, hundreds of families [with] multiple members alive and functioning in their 80s, 90s or beyond will be interviewed, and have blood samples drawn. ... Given that these individuals pan out to be models of successful aging and have abilities to escape or delay age-related disease, or escape or delay disabilities, we want to find out how they do that ... and we don't believe it's because of any one single factor. ... the interest is not just in those who live a long time, but in those who do so with vigor." A point of contention in the gerontology community is that scientists already know enough to be working towards meaningful anti-aging medicine - not just gathering more data.

    Link: http://www.shns.com/shns/g_index2.cfm?action=detail&pk=LONGLIVE-05-04-06

    No Therapeutic Cloning in Australia
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    A few years ago, stem cell politics in Australia took the turn for the worse that was - and still is - threatened in the US and much of Europe. The Scientist looks at the present state of affairs: "The Australian government has come under pressure this week to respond to proposals that national laws should be amended to allow somatic cell nuclear transfer (SCNT) for research purposes. The changes, recommended late last year by a government-commissioned independent review, would permit therapeutic cloning under strict controls. But scientists fear the government will ignore the advice and decide to keep the current ban." Ultimately, the problem is not politicians - who are only more cruel, venal and callous than you or I because they have brought upon themselves the means and opportunities to be so - but that power has been centralized, ripe for abuse. In whose hands should your future health and longevity lie - yours, or those of bureaucrats who care nothing for your well-being?

    Link: http://www.the-scientist.com/news/display/23355/

    More On Parkinson's, Mitochondria
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    From Forbes, a nice follow-on to recent research on mitochodrial DNA damage in parts of the brain associated with Parkinson's, and oxidative stress in Parkinson's: "Our study, using Drosophila [fruit fly] model, revealed that two distinct gene products, Parkin and PINK1, converge in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopamine neurons. This clearly suggests that mitochondrial failure is the central mechanism in the pathogenesis of Parkinson's disease. ... If we can find drugs that can rescue these mitochondrial functions, that would be a much better drug than the current therapies that are targeted on dopamine replacement."

    Link: http://www.forbes.com/forbeslife/health/feeds/hscout/2006/05/03/hscout532484.html

    Chapter's End
    Permalink | View Comments (3) | Post Comment | | Posted by Reason

    As noted via Betterhumans, the Extropy Institute has announced its dissolution.

    ExI deems its mission as essentially completed. With this said, and in respect for Extropy Institute's legacy of achievement, the Board voted and has unanimously agreed to close Extropy Institute's doors.

    Extropy Institute's website is being memorialized by turning it into a reference "Library of Transhumanism, Extropy, and the Future," - the beginnings, currents, and future of Transhumanism.

    On behalf of our members, I would like to thank Max for authoring the philosophy of Extropy and for his many efforts in working with others to steer the philosophical development of transhumanism, which is truly treasured by so many people in so many places.

    From where I stand, this is a post-hoc official stamp on the end of a chapter in the ongoing growth of transhumanist ideas - such as, and most importantly in my view, the path to radical life extension. Chapter's end was effectively a few years ago, as it became clear that the Extropy Institute was not intending to attempt the same sort of expansive transition engineered by the Foresight Nanotech Institute. As I recall, around the time the Proactionary Principle was solidified, I wrote in a private email to Max More and Natasha Vita-More that "the Extropy Institute has essentially achieved its original goals." After all, look around. Topics such as radical life extension were only discussed in small groups and modest forums not so long ago; these same topics are now fodder for the evening news, while efforts aimed at large scale fundraising for research are underway. For radical life extension, we are moving beyond futurists and into the age of patient advocates and scientists. This was the point, and it has come to pass as the result of hard work from many, many people and organizations.

    For those new to the healthy life extension community - which will be many of you, given the growth in interest and number of organizations in the past couple of years - this is probably all ancient subcultural history. But it's important ancient history, because these folk worked hard to bring healthy life extension - and many other related concepts, such as nanomedicine - in from the fringes. If you weren't thinking adult thoughts back a decade or two, it might be a shock to see just how much more remote and ridiculed was any discussion of meaningful anti-aging and longevity science.

    You can draw lines of association between the open salon that was the Extropy Institute and almost everyone of note in the pro-healthy life extension community. While I can't claim to be "of note," and my support for a future of greatly extended healthy longevity came about as a bolt from the blue long before my involvement with the community, it was via the Extropy Insitute forums that I came to be involved. For that matter, those forums were how I came to needle myself into running a position platform website, leading to all of the meaningful involvements that came afterwards.

    As a final thought, you are defined more by what you choose to discard than by what you choose to keep, and there will be a time of discard for each and every thing you hold. Directed change is vital if the concepts developed in the past are to shape and inform the future, rather than hold it back.

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    Killing Cancer With Autophagy
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    (From EurekAlert). Cancer researchers are turning out some impressive technological demonstrations these days, building on ten years of rapid advancement in biotechnology. "An engineered virus tracks down and infects the most common and deadly form of brain cancer and then kills tumor cells by forcing them to devour themselves ... The modified adenovirus homed in on malignant glioma cells in mice and induced enough self-cannibalization among the cancer cells - a process called autophagy - to reduce tumor size and extend survival ... This virus uses telomerase, an enzyme found in 80 percent of brain tumors, as a target. Once the virus enters the cell, it needs telomerase to replicate. Normal brain tissue does not have telomerase, so this virus replicates only in cancer cells."

    Link: http://www.eurekalert.org/pub_releases/2006-05/uotm-tvc050206.php

    Insight Into the State of Induced Regeneration
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    While the lion's share of funding for regenerative medicine is in the realm of first generation stem cell therapies and old-school drug discovery - aiming to take advantage of newly discovered biochemical cues that spur stem cells to particular actions - the prospect of bringing salamander-like regeneration to mammals is now attracting real interest. As a rule, public funding is far more publicized than the larger movements of private funding, so take this press release as indicative of the general state of research and fundraising in this field:

    To some extent, humans already have the capacity for regeneration. For instance, certain cells, such as liver cells and red blood cells, can self-renew; and during embryonic development mammals and birds can regenerate such diverse tissues and structures as their skin and spinal cord. However, humans can't perform the same trick of regrowing a severed limb like salamanders or newts can. That is because in humans the cells that respond to the site of injury form scar tissue, whereas in salamanders the responding cells are genetically programmed to become the cell types of the lost structure, with full limb growth complete by two months.

    When a salamander loses a limb, the wound sends out molecular signals that prompt surrounding tissue to begin production of new progenitor cells, also referred to as precursor cells. These progenitor cells continue to divide and form a large pool of cells at the wound site, called a blastema, that will later specialize and mature to help form the bone, muscle, cartilage, nerves and skin of the regenerated limb.

    ...

    The researchers aim to prove that mammals can form the required progenitor cells for regeneration just as a salamander does. By studying salamanders and MRL mice, the researchers hope to identify the specific types of cells, molecular signals, genes and cellular scaffolding required for regenerative cell growth. In essence, they seek as comprehensive an understanding as possible of the mechanisms and processes - to obtain the blueprint for regenerative growth.

    This is, as noted, a form of stem cell research. It has a lot in common with efforts to understand the process of cellular differentiation, in that it is thought that salamanders are dedifferentiating their cells in some way to produce progenitor cells. This fits nicely in with the thought that cells are really finite state machines, and the right keys can unlock all sorts of transformations in any cell - this may or may not be the case, but it would be very good for the future of medicine (and all of us) should it be so.

    As for the past decades of cancer research, one of the greatest long term benefits to come from stem cell research will be a greatly increased understanding of human cellular biochemistry. Once you have the map, all journeys become that much easier.

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    Aging and Group Selection
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    Via ScienceBlog, an argument for aging as an evolutionary adaption rather than a tradeoff: "Aging is taken to be an adaptation, but one that benefits the community, not the individual. This is 'group selection,' and most theorists have been skeptical that evolution can work this way. ... Mitteldorf claims that population crashes constitute an exception to this rule. Animal communities can't afford to go consuming food and reproducing as fast as possible - they would end up starving their own children. This leads to a mechanism of group selection that is swift and ruthless. Aging has evolved as one way to limit population growth. Mitteldorf calls it the 'Demographic Theory of Aging.' It is the first theory to regard aging as an adaptation since August Weismann abandoned his ideas in the 1890's." Given the level of scientific backing for the present consensus view of evolution and aging, Mitteldorf has an uphill road ahead.

    Link: http://www.scienceblog.com/cms/old-ideas-about-aging-gain-new-respect-10521.html

    Reminder: Singularity Summit at Stanford
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    The Singularity Summit at Stanford will start on May 13th, and seems a worthy use of your time: "What, then, is the [technological] singularity? It's a future period during which the pace of technological change will be so rapid, its impact so deep, that human life will be irreversibly transformed. Although neither utopian or dystopian, this epoch will transform the concepts that we rely on to give meaning to our lives, from our business models to the cycle of human life, including death itself. Understanding the singularity will alter our perspective on the significance of our past and the ramifications for our future." To understand the consequences of exponential growth in the real world is to see the seeds of radical life extension in today's rapidly advancing biotechnology infrastructure, even allowing for plausible limits to the steepness of the upward curve.

    Link: http://sss.stanford.edu/

    Video of Aubrey de Grey at TED2006
    Permalink | View Comments (1) | Post Comment | | Posted by Reason

    The Methuselah Foundation volunteers have posted video of biomedical gerontologist Aubrey de Grey's presentation at TED2006 earlier this year. As always, TED was an interesting event attended by interesting people, though the reporting was pretty thin (by design).

    TED2006 is one of the premier gatherings of influential and forward thinking individuals in the world. At this conference you will find everything from the most esoteric design ideas to the most practical solutions to global problems, and it is certainly an occasion where the message of the need for eliminating age-related diseases resonates.

    Direct links to the video:

    Real Media format (77MB)
    MPG Format (107MB)

    Please be kind and help the Foundation by not using all their bandwidth. If folk in the community would like to sort out the organization of torrents, or posting these videos to YouTube, Google Video and the like, it would be most appreciated.

    Quite a few other interesting videos reside in the MPrize multimedia section; take the time to browse while you're there.

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    Alzheimer's as Feedback Loop
    Permalink | View Comments (0) | Post Comment | | Posted by Reason

    Most age-related conditions take place within feedback loops, if only the one in which progressive inability to exercise causes further physical decline. Via EurekAlert, a look at the biochemistry of Alzheimer's in this way: "mitochondria appear to be a site where significant disease progression takes place ... We believe that the disease produces mutant [amyloid precursor protein] and beta amyloid which in turn impacts mitochondrial function. This results in increased production of hydrogen peroxide, resulting in a progression of the disease and higher levels of beta amyloid. In other words -- this model appears to be a vicious cycle where damage to brain cells increases and in fact feeds upon itself." Present Alzheimer's research seems very much a case of blind men and the elephant - but scientists are close to understanding the whole shape of the disease.

    Link: http://www.eurekalert.org/pub_releases/2006-05/ohs-orr043006.php