Brightening Prospects For Muscle Regeneration
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Continued signs of progress in regenerative science from EurekAlert!: "so-called satellite cells in muscle actually include a mix of cells already committed to their muscular fate and others that behave like more versatile stem cells. The cells had widely been considered by scientists as a homogeneous population of dedicated muscle progenitors. Moreover, [researchers] showed that injection of the 'satellite stem cells' into the muscles of mice successfully replenished the animals' regenerative reservoir of cells. ... We've found that there are two types of satellite cell - 90% that are already committed to becoming muscle and another 10% with characteristics normally attributed to stem cells. It's not been shown yet, but these muscle stem cells might even have the capacity to make other tissues, such as bone and fat ... We've also shown that these satellite stem cells, when transplanted into muscle, can repopulate the regenerative cell niche. This is a very significant advance in our understanding of satellite cell biology that will require us to rethink decades of research. It also opens new avenues for therapeutic treatment of muscular diseases."

Link: http://www.eurekalert.org/pub_releases/2007-05/cp-eom052507.php

Aging Stem Cells and What Can Be Done
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Why do the regenerative capacities of stem cells diminish with age, and what can be done about it? This paper looks at some of the specific mechanisms as they work to suppress young transplanted cells: "aged differentiated [stem cell] niches dominantly inhibit [certain important gene expression] in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic [hESCs] and tissue-specific adult stem cells (ASCs). ... the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. ... hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo; thus, suggesting that the regenerative outcome of stem cell-based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell-replacement therapies for aged degenerating organs."

Link: http://www.blackwell-synergy.com/doi/full/10.1111/j.1474-9726.2007.00286.x

The Norm Is a Hurdle
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Cultural norms of knowledge, belief and intent bear no necessary relationship with fact, sanity and sense. Humans are hardwired to respect the norm: any set of concepts widely held are valued highly for that fact, while new or rare ideas have a real hurdle to acceptance. One aspect of this facet of the human condition is illustrated by Russell Blackford: science is by its nature a process of generating new ideas that are not widely held by the world at large, even when those ideas have come to be generally accepted within the scientific community. Hence demonstrating truth through science is by necessity a great deal harder than it might be in a more just universe:

Bloom and Weisberg conclude that resistance to scientific thinking will continue beyond childhood into adulthood if the scientific claims are contested within the individual's society. The resistance will be epecially strong if a non-scientific alternative (1) has currency in the society, (2) is rooted in intuitive understandings, or common sense, and (3) is championed by people who appear to be reliable and trustworthy.

He goes on to talk about magical thinking - of which we see a great deal in any broader discussion of longevity and health - but let's stick with the power of the norm for today. We advocates for healthy life extension should not lose sight of the fact that we're delivering a message that is still far from the norms, and thus appears deeply strange to a great many folk - for no other reason than it is unusual in their experience, novel to them. "Deeply strange" is going to get you rejected out of hand, no matter what the merits.

Raising awareness and generating an environment of support for funding successful longevity research requires a certain amount of raising the water level so that boats can float. Steady repetition, restatement and messaging through many channels and in many different ways are the coin of the realm; this has been taking place for some years now, and the results are beginning to be apparent. Take a look at a recent article on cryonics from a popular perspective, for example; it should remind us that there's a whole world of outsiders looking in out there, but it's far less negative than similar items from past years.

"I drive by the place twice a week," said Helgeson, "and I just can't believe Ted Williams's head is hanging in there. Either someone in his family is a lunatic or has a lot more faith in science than I do."

Cryonics is eminently sensible, yet, like all ideas that are not presently the norm, it must leap the hurdle of being something new for most people. This is one example of many I could draw for those of us interested in living much longer, healthier lives. The biggest challenge we face is not the medical research and development yet to come, but convincing a sufficient number of people to support that effort - in effect to make working towards healthy life extension a norm.

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Disposing of Disposable Soma Theory
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"According to the disposable soma theory, a cost for reproduction could exist in human beings and other species and, thus, longevity could decrease when women have a higher number of children. The purpose of this article is to review the evidence in populations living or not living under natural fertility conditions, i.e. when fertility is near its biological maximum. The results indicate that in natural fertility conditions longevity does not decrease when the number of children increases but, in modern populations, mortality could slightly increase when women have more than 5 children. Complete data for these modern cohorts will tell us, one day, whether these results are still observed when the variable of interest is longevity and not only mortality." The disposable soma theory of aging, arising from evolutionary considerations, has moved through a number of interations to its present form. It is not highly regarded in comparison to other theories, largely because of this sort of evidence. The model of the body as a self-repairing machine subject to an accumulation of characteristic types of damage it cannot repair far better fits the observed facts.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17532269

Pondering the Nature of an Ageless Society
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The economists of the blogosphere are pondering the nature of a post-mortal society, an activity that strikes me as thinking hard about what to do with the pits before you've planted the cherry tree. A great deal of work lies between here and there - we are barely starting on the serious effort to defeat aging through medical science.

The basic consequences of living longer are fairly straightforward, in the economic worldview at least: your time preference extends outwards. In theory that means that individuals are increasingly less likely to trash the future for the sake of the present; a long time preference looks a lot like wisdom when seen from the side. What that means for a society of like-minded and very long-lived folk is anyone's guess; no simple trend in individual averages extrapolates out to group dynamics. But it seems to me to be the case that the last factor of two increase in life expectancy produced changes in human society more remarkable for their subtlety than anything else.

Or at the very least, it's hard to pick out what is longevity versus other technological advances and wealth creation.

Would Ageless People be Libertarian?

If aging were curable, would people feel less inclined to expand government?

These days, I tend to think of the issue of the size of government as essentially a power struggle between capitalists and anti-capitalist intellectuals. I don't see how a cure for aging resolves this conflict.

...

If an ageless 150-year-old behaves like an old person, then he or she will have a goal of stability. That might mean a very non-libertarian attitude. But I am not sure that ageless people will have attitudes that are elderly or not.

Would immortals be libertarian?

If we assume monotonicity (and why shouldn't we?), we can draw inferences from societies with short life expectancies. They are extremely superstitious, willing to entertain tyranny, and hardly libertarian. Try teaching Henry Hazlitt in the Congo. More generally, pending death makes us think of honor, patriotism, and in-group solidarity.

The Risk of Immortality

Immortals would have far more to lose by dying in an accident than the average guy who kicks the bucket at before passing the century mark--particularly so, since the immortal never experiences age-related decline--which will make them far more risk averse. Risks that seem quite tolerable to normal human beings, like driving on the freeway or allowing aircraft to fly over your house, will be completely reckless (even insane) to an immortal.

Put more effort into making longevity medicine a reality, and increase your chances of being able to debate this sort of thing for as long as you care to. Not to mention living to see what a post-mortal society actually looks like. From where I stand, that's a much more interesting brand of economics as human action.

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Skeptical on Sir2
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As noted at Ouroboros, there's still plenty to debate in calorie restriction science. Well-funded companies are developing therapies and human studies have been taking place for years, but discussions continue on the basic research in lesser species: "In the last decade, research into the molecular determinants of aging has progressed rapidly and much of this progress can be attributed to studies in invertebrate eukaryotic model organisms. Of these, single-celled yeast is the least complicated and most amenable to genetic and molecular manipulations. ... Activation of Sir2-family proteins in response to calorie restriction (CR) has been proposed as an evolutionarily conserved mechanism for life span extension. This idea has been called into question with the discovery that Sir2-family proteins are not required for life span extension from CR in yeast. ... Several specific cases where the Sir2 model of CR is inconsistent with experimental data are noted. These shortcomings must be considered along with evidence supporting a role for Sir2 in CR in order to fully evaluate the validity of this model." A number of other possible candidate genes and proteins have been put forward in the past year; as scientists continue to investigate, the situation will become more clear.

Link: http://ouroboros.wordpress.com/2007/05/30/skepticism-about-sir2s-role-in-yeast-cr/

Regulation of Medicine Will Kill Us
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Have you noticed how much slower medicine seems to move than other fields of development? It takes a decade to move from news out of the laboratory to first therapies commercially available; compare that to the hectic rush and invention of the computer hardware industry. You can lay every last day of delay and cost down to regulation; just look at the gauntlet that has to be run:

Although some people talk of an anti-aging pill, it is more likely that research will yield therapies that target specific age-related diseases - a vaccine to prevent Alzheimer’s disease, for example. In either case, the road to such a medicine is long and often fraught with wrong turns, dead ends, and detours. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), it takes 10 to 15 years and up to $1 billion to develop one new medicine from the time it is discovered to the time it is made available as an FDA-approved therapy. Why does it take so long and cost so much? Because drug discovery and development is a time- and labor-intensive process involving thousands of people, from researchers at colleges and universities, to scientists and professionals at pharmaceutical companies, to participants in clinical trials.

Drug discovery and medical research is in fact no more inherently costly or time-consuming than research into new forms of computer hardware - a field that is just as exciting at this present time. But medical research and development is made costly by the heavy boot of regulation for the sake of regulation: an institution of rules and rule-makers that has come to stand for nothing beyond its own self-propagation.

If anything is to be the death of us in this era of potential and revolution in biotechnology, it will be that regulation scared away the innovators, suppressed the discoveries that might have been, and kept disruptive, effective new technologies away from the marketplace for years past their time. When progress is made costly, progress becomes slow - but worse, an entire range of invention and endeavor simply vanishes, priced out of existence.

But most people can't see the invisible cost - the cost of things that might have been. Most people suffer a great failure of the imagination when it comes to anything the government has a hand in; they can't imagine it any other way, even when presented with thriving examples from other industries. Medicine could be as dynamic, inventive and productive as the computer hardware industry, or the fashion industry. But it is not, and so we will suffer because progress will be slow and the delivery of goods funneled through organizations so regulated that their employees and owners have no incentive to do a good job.

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Thoughts On Exercise and Gene Profiles
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Randall Parker comments on recent research on the biochemical effects of exercise on aging tissue: "The reversal isn't complete. Aged muscles are still weaker and their gene expression patterns are still different than youthful patterns. We need to know why the aged muscles do not fully regain youthful strength when exercised. ... The resistance training exercise does not simply substitute for a lower level of exercise in the elderly. Younger control subjects who did not exercise much had youthful gene expression profiles even though they didn't exercise much. ... We need a gene therapy delivery mechanism that can deliver replacement mitochondrial DNA (mtDNA) into muscle tissues. Such a therapy would help us answer the question of whether accumulated mtDNA damage is a substantial cause of muscle aging. I hope the answer is 'yes' because methods to replace mtDNA will be much easier to develop than methods to replace nuclear DNA (i.e. the DNA in chromosomes in the nucleus of cells). Why the difference in difficulty? The nucleus contains over 2.9 billion base pairs of DNA whereas the mtDNA contains about 15,000 base pairs. So development of methods to deliver replacement mtDNA should be a relatively simpler task."

Link: http://www.futurepundit.com/archives/004279.html

Yet More Harm From Cytomegalovirus
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(From EurekAlert!). Adding insult to injury: as if the destruction of your immune system over the years was not enough, cytomegalovirus also causes further direct harm to your body: "Atherosclerosis is the main cause of morbidity and mortality worldwide. ... Recently inflammation and infectious agents have been shown to play an important role in the onset of acute cardiovascular events. ... Cytomegalovirus infection can be responsible of the initial vascular lesions typical of the atherosclerotic process. The mechanism involved in the vascular lesion is of autoimmune origin: antibodies directed against particular proteins of the virus are able to bind molecules expressed on the surface of the cells that line the arterial walls (endothelial cells) and to cause their death (apoptosis) through a mechanism called 'molecular mimicry.' ... This new study therefore confirms that antibodies directed against Cytomegalovirus-derived proteins purified from patients with coronary artery disease induce endothelial cells damage and support the hypothesis that virus infection plays a crucial role in mediating the atherosclerotic process."

Link: http://www.eurekalert.org/pub_releases/2007-05/plos-cea052907.php

Metabolic Rate and Free Radical Damage
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The mitochondria in our cells take in food and oxygen and use it to produce ATP, a chemical used as fuel to power the rest of the cell. This is known as mitochondrial respiration, or cellular respiration. In the process, oxygen radicals - also generally known as free radicals or reactive oxygen species (ROS) - are produced. These damaging byproducts go on to wreck other molecules and cellular mechanisms in a drawn-out process that is one part of degenerative aging. This is the essence of the mitochondrial free radical theory of aging - that we are slowly slain by the accumulated toxic byproducts of essential metabolic processes. Evolution cares not, because we've long passed the test of reproductive fitness by the time our bodies are choked with metabolic pollutants.

One might think that the faster metabolism runs, the worse the situation becomes: more oxygen consumed means more ROS unleashed to cause harm. This is not in fact the case, as the relationship between the metabolic rate - the rate at which oxygen is consumed - and the rate at which ROS are created is not linear. Rather like cars, levels of fuel efficiency and average time to next breakdown for the engine vary widely depending on speed and circumstance - and cars can neither repair themselves nor change significantly to adapt to new circumstances, both of which complicate the picture for human metabolism.

For humans, most of the simple things that reduce the rate at which ROS are generated also speed metabolism. Exercise and calorie restriction with optimal nutrition, for example, raise metabolic rate and are demonstrably good for healthy longevity - better for most folk in the long term than anything yet produced by medical science. Here's a paper that provides a succinct overview of the situtation:

Various recent investigations relevant to the study of aging mechanisms have recently found that increases in longevity during dietary restriction can occur together with lack of decreases or even increases in [oxygen, or O(2)] consumption. This is frequently interpreted as contradictory with the mitochondrial free radical theory of aging. But this is based on the erroneous assumption that increasing O(2) consumption must increase the rate of mitochondrial oxygen radical generation. Here it is shown that the opposite occurs in many important situations. Strong decreases in absolute and relative (per unit of O(2) consumed) mitochondrial oxygen radical production occur during aerobic exercise bouts, chronic exercise training, and hyperthyroidism, and notably, during dietary restriction. Mitochondrial oxygen radical generation is also lower in long-lived birds than in short-lived mammals of similar body size and metabolic rate. Total rates of reactive oxygen species generation can also vary between tissues in a way not linked to their differences in oxygen consumption. All this indicates that mitochondrial reactive oxygen species (ROS) production is not a simple byproduct of mitochondrial respiration. Instead, it is regulated independently of O(2) consumption in many different physiologic situations, tissues, and animal species. Thus, the apparently paradoxical increases in O(2) consumption observed in some models of dietary restriction do not discredit the mitochondrial free radical theory of aging, and they can further strengthen it.

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Know the Opposition
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Daniel Callahan is the deathist's deathist, working away to equate bioethics with suppression of healthy life extension technology and glorification of death and suffering. He and others like him are the intellectual opposition to advocates for longevity research. Here, Commonweal profiles Callahan: "The seventy-three-year-old Callahan was emphatic: It is a mistake, he told the council, to think that we have an obligation to pursue stem-cell work-or medical research generally, for that matter. Medical progress is certainly an important social good, but it must be weighed against competing social goods, such as education or decent housing. What's more, Callahan insisted, many of the diseases that stem-cell research might address, like cancer and heart disease, are illnesses of the old, and we must ask whether extending the human life span by a few more years through new treatments for these diseases is worth the cost. ... Callahan has sought to explore the folly of what he calls the 'gospel of medical progress'-namely, the idea that medicine brings the good news of liberation from death and dying." We should feel no shame in treading underfoot calls for the death of billions as we move towards the technologies that enable longer, healthier lives for all who so choose.

Link: http://www.commonwealmagazine.org/article.php3?id_article=1951

Repairing Muscle With Stem Cells
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Work on urinary incontinence is demonstrating that reconditioning and repairing even more subtle damage in muscle function is within the present bounds of regenerative medicine. Via Medical News Today: "Previous studies in animal models [demonstrated] that injecting stem cells into the urethral muscles increases leak point pressure, leading to the restoration of the deficient muscles. The results of these studies formed the basis for the clinical trial. [Researchers] took biopsies of skeletal muscle tissue from eight female patients and isolated and expanded the stem cells from the tissue in culture. In an outpatient setting, the patients then received injections of the muscle-derived stem cells into the area surrounding the urethra. ... Five of the eight women who participated in the study reported improvement in bladder control and quality of life with no serious short- or long-term adverse effects one year after the initial treatment. ... A multi-center study in Canada and a study in the United States are currently underway and will allow researchers to determine the optimal dose of muscle stem cells."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=71735

More Mice Full of Amyloid Beta
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Interesting animal model research from earlier this month I managed to miss, via ScienceDaily: "Tau is made normally by brain cells and regulates the stability of their internal skeleton. In [Alzheimer's disease (AD)], tau is altered in a way that makes it aggregate into clumps, called tangles. A lot of effort has been devoted to finding ways to specifically eliminate these abnormal forms of tau, but this has been difficult. ... Many investigational therapies for AD aim to reduce levels of amyloid-beta proteins (AB) because Amyloid-beta builds up to abnormally high levels in the brains of people with AD and is widely suspected to cause the disease. ... We wanted to pursue a complementary strategy and try to make the brain more resistant to A-Beta without having to change the levels of A-Beta itself. Amazingly, even partial reduction of tau prevented memory problems and premature deaths in our Alzheimer mice, even though their brains were full of amyloid beta." This looks to be related to Buck Institute research from last year, which also demonstrated healthy mice full of amyloid beta.

Link: http://www.sciencedaily.com/releases/2007/05/070503165315.htm

A Look at Nanomedicine
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Following up on some of their previous articles, Nanowerk looks again at nanomedicine: "Nanotechnology promises us a radically different medicine than the cut, poke and carpet bomb (think chemotherapy) medicine of today. The two major differences of nanomedicine will be a) the tools it uses - the main workhorse will be [multifunctional nanoparticles] - and b) it will enable a perfectly targeted and individual treatment: organs and bones, really any body tissue, can be diagnosed and treated on a cell by cell basis with precise dosing and monitoring through the use of biomolecular sensors. ... Looking into the future, Freitas envisions 'biocompatible surgical nanorobots that can find and eliminate isolated cancerous cells, remove microvascular obstructions and recondition vascular endothelial cells, perform noninvasive tissue and organ transplants, conduct molecular repairs on traumatized extracellular and intracellular structures, and even exchange new whole chromosomes for old ones inside individual living human cells.'"

Link: http://www.nanowerk.com/spotlight/spotid=1975.php

August Calorie Restriction Research Fundraiser
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The folk of the Calorie Restriction (CR) Society are continuing their efforts to raise funds to broaden human CR research with a fundraising event in August. As for many successful health-oriented organizations, the Society prospers through close ties with the research community - just look at any of their conferences in recent years. As Mary Robinson relates:

At last year's CR Conference, we all told Dr. Spindler that we would raise the money for him to do a human study on gene expression in CR - on us. This is a cool idea in so many ways. From all the moaning and groaning from the calorie restriction researchers at the conference, it is very clear that they are having a hard time getting funding from NIH. It's not a disease, after all - aging. Or is it? Spindler also thought it would be hard to get subjects. We all had quite a chuckle over that one. Told him that he was looking at a room full. Dr. Fontana vouched for us - and was just as amused, I think. So, we decided as a group to give him no excuse not to study us. He's too fond of rats, IMHO. It seems to me that most biologists are very fond of rats, mice, or worms or yeast.

April Smith has more details on the fundraiser:

People from all over the world will converge from Friday, August 10 through Sunday, August 12 on the village of Tarrytown, New York, near Sleepy Hollow, where Washington Irving spun his yarn of "The Headless Horseman." But this is a meeting of facts, not fiction. It is a workshop on calorie restriction, the only scientifically proven way to slow aging .

...

The workshop is a benefit for the continuation of a milestone research project on the effects of calorie restriction on humans. Initiated in cooperation with the Calorie Restriction Society by Drs. Luigi Fontana and John Holloszy, of Washington University Medical School in Saint Louis, the first two phases of the research have discovered new knowledge that allows people everywhere to better understand how to prevent disease associated with aging.

A highlight of the workshop will be presentations by Dr. Fontana and by Dr. Stephen Spindler, whose genetic analysis of calorie-restricted animals has garnered worldwide acclaim. Dr. Spindler will lead the exploration of the genetic and cell signaling patterns of human calorie restrictors in Phase Three of the research whose funding is spearheaded by the Calorie Restriction Society.

Contributions of $1,000 or more for the research project are requested for anyone wishing to register for the workshop. As a special "thank you" for this support, workshop attendees will receive a glucose control kit that includes a glucometer, testing strips, and stylus. A copy of NutriBase, the leading dietary tracking software, will be available for participants to use while they are at the workshop and to take home to try. Participants will also receive a bibliography and copies of the charts presented at the workshop.

All who are interested in slowing the ravages of aging are invited to take part in the warm, friendly immersion experience of the Calorie Restriction Workshop, where they can meet kindred spirits, exchange ideas, and make friendships that may last for a very long lifetime. Attendance is limited so that a personal experience can be provided to all attendees.

The practice of calorie restriction and exercise is most likely going to do more for your chances of avoiding many of the common age-related diseases than any drug presently in the pipeline. This isn't the future of longevity medicine - it won't take too many more years for research to actually repair age-related molecular damage rather than just slow the accumulation, a huge jump in potential effectiveness - but it is free and it is available now. Anyone can do it.

Taking better care of your body makes a real difference over the long term, and increases your chances of being alive and in good health when the real longevity medicine becomes available - some decades from now, when adding decades of rejuvenated health to the lives of those already aged will be a realistic proposition.

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What is this "Anti-aging" Thing Anyway?
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Around the time I was penning the first version of the anti-aging topic page over at the Longevity Meme, Binstock had already put out a much more eloquent paper on much the same themes. There are no unique ideas or approaches in a world full of people paying attention:

This article interprets the contemporary war on anti-aging medicine as largely an attempt by established gerontological researchers to preserve their hard-won scientific and political legitimacy, as well as to maintain and enhance funding for research on the basic biological mechanisms of aging. First, it recounts the difficult struggle of U.S. biogerontologists to join the scientific mainstream in terms of legitimization and public funding. Second, it examines how elements of a contemporary anti-aging movement seem to threaten the hard-won public legitimacy of established gerontological researchers and practitioners. Third, it looks at the "boundary work" responses of the gerontological community to the anti-aging movement. Finally, it assesses the consequences of the war on anti-aging medicine to date.

The public at large, led by a media with economic incentives to be ignorant, doesn't tend to distinguish all that well between two similar topics. Human nature at work, but that means that scientists find their funding threatened by the branding of "anti-aging" in the marketplace. Here are a couple more papers on the same topic, further illuminating the ongoing battle over understanding, support, legitimacy and funding:

Contentious terminology and complicated cartography of anti-aging medicine:

Serving as an introduction to the cultural significance of the contemporary emergence of anti-aging medicine, this article outlines some of the distinctions and controversies regarding the usage of the term "anti-aging medicine." By sketching out the complex field of researchers, practitioners, organizations, companies it is clear that "anti-aging medicine" is a highly contentious term that means different things to different groups. Thus, analysis demands a keen attention to contextualizing its usage. However, despite the critically important distinctions in how "anti-aging medicine" is used and what it connotes both to the user and the audience, the core principle of anti-aging is the notion that aging can be targeted for biomedical intervention. It is the orientation toward this explicit goal that marks anti-aging medicine. While neither advocating for/against anti-aging medicine nor excavating the large body of biological literature, this ethnographically researched article explicates the cultural use of "anti-aging medicine" and maps out its main varieties, controversies, stakes, and challenges.

Anti-aging medicine and research: a realm of conflict and profound societal implications:

Biogerontologists have recently launched a war of words on anti-aging medicine. They seek to discredit what they judge to be fraudulent and harmful products and therapies, and to distinguish their own research from what they regard as the pseudoscience of anti-aging injections, special mineral waters, and other services and products. Yet, many of these biogerontologists are themselves trying to develop interventions that will actually slow or arrest the fundamental processes of human aging and substantially extend average life expectancy and maximum life span. Achievement of these biogerontological goals would drastically alter the nature of individual and collective life, radically transforming virtually every social institution and norm. Biogerontologists who are engaged in anti-aging research need to undertake more active leadership in helping the public to understand their goals, to deliberately consider the implications of their fulfillment, and to begin thinking about ways to shape those ramifications in constructive fashions.

The paper above and the social study below cut very much to the core of it: the end goal of extended healthy life - giving more time to develop technologies to extend life even further - is profound and of greater value than any other grail of the immediate future. People who grasp and internalize that value are driven; understanding that moving along the wrong path means the difference between life and death for billions lends real weight and passion to differences of opinion.

Anti-aging medicine: a patient/practitioner movement to redefine aging:

Anti-aging medicine is a broad term that may comprise groups selling remedies over the Internet, companies touting the "anti-aging"ness of their products, practitioners who work outside of scientific medicine, and practitioners of anti-aging medicine in clinics who believe that their work is strictly scientific. This article, drawing from more than 3 years of ethnographic interviews, participant observation in clinics and conferences, and a review of the literature, considers the last group. It examines the involvement stories of anti-aging medicine practitioners in two Western United States metropolitan cities. These stories reflect the practices of anti-aging medicine practitioners and the accompanying rationale for involvement. Often originally patients themselves, practitioners frame their involvement with the anti-aging movement in three ways. First, they describe aging as it is currently experienced as a time of decline, suffering, and weakness. This anguish is not inevitable, they argue, and their work toward treating aging biomedically is situated as clearly moral. Secondly, intense frustration with the current biomedical environment has motivated practitioners to look for other ways in which to practice: anti-aging medicine is their chosen alternative. Finally, with dramatic expectations of future biotechnologies and disdain for current medical treatments of old age, anti-aging practitioners embrace a scientific revolutionary identity.

The mainstream of genontology does not publicly share whatever private enthusiasm its members have for rapid progress in developing therapies for aging, for they have - perhaps inadvertently - constructed a community in which that enthusiasm is the instant death third rail for funding. On the other side of the fence, enthusiasts and believers of the anti-aging marketplace (as opposed to the pure businessmen and frauds) are invariably taking the all too human shortcut of belief over science, and pushing things that don't work or otherwise cannot be shown to do much good.

As is so often the case, neither of the big bulls kicking up dust and butting heads is where you should be looking if you want to find the best path forward. Change must happen for either side to be the source of more rapid, sweeping progress. At the present time, attention and funds are better pointed elsewhere.

The better path I have in mind is support and growth for that presently small part of the scientific community that is interested in rapid progress in extending the healthy human life span, not afraid to talk about it, and in no danger of falling into the pit of the marketplace by jumping the gun and pushing products that don't work. Should this group succeed in gaining more influence, they will lead both the mainstream of gerontology and the anti-aging markplace into the needed changes that will produce more positive contributions to the future of healthy longevity - this much has been demonstrated from progress to date.

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More Signs of the Obvious
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Via the Winnipeg Sun, more signs of the incidental healthy life extension brought by advances across the board in medicine: "A new study on aging and retirement -- the largest study of its kind ever undertaken -- says that people are living longer and better health than ever before ... The HBC study -- conducted with the Oxford Institute of Ageing, which surveyed 21,000 people in 21 countries including Canada -- found that people the world over now able to live the lives the age of 70 that previous generations would have enjoyed at 50. People in their 60s and 70s generally feel in good health, and there are only small differences between people of this age and those in the 40s and 50s in terms of control and quality of life. ... older workers and retirees are better able to significantly contribute to society because they are more fit and active than ever before. They also feel they are in control of their lives and are generally looking forward to the next 20 to 30 years of their life. ... People in their 60s and 70s are a tremendous asset to society, not generally a burden." Showing the world that healthy longevity is increasing is only one part of the education process, however: we also have to help people understand that progress depends on action; that each and every one of us can step up to make the process move faster.

Link: http://winnipegsun.com/Business/2007/05/26/4209582-sun.html

Alliance For Aging Research Seeks Director of Development
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The Alliance for Aging Research is seeking a director of development: "This 20-year-old healthcare non-profit is recognized as the leading authority and advocate for healthy aging research. It is backed by a strong and diverse Board of Directors, representing companies, foundations, and patient advocates which supports scientific and medical discoveries to maximize healthy aging, independence and quality of life for older Americans. The organization is seeking a Director of Development who will be passionate about the potential of medical research to improving the lives of older Americans. ... The Director of Development works closely with the Executive and Deputy Director and is a senior member of the leadership team. Working closely with the Board and staff, this individual is responsible for formulating, implementing and directing the fundraising strategies for the organization. S/he will lead their team in carrying out a comprehensive development plan incorporating all levels of fund raising." The Alliance is one of the backers of the Longevity Dividend initiative; if you support that direction for longevity research and development, there are few better opportunities to step in and help directly.

Link: http://asi.careerhq.org/jobdetail.cfm?job=2575072

A Review of Primate Calorie Restriction
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A reminder, in the form of a review paper, that the evidence for calorie restriction (CR) as the best presently available method of increasing health and longevity is compelling: CR "is the only intervention repeatedly demonstrated to retard the onset and incidence of age-related diseases, maintain function, and extend both lifespan and health span in mammals, including brain and behavioral function. In 70 years of study, such beneficial effects have been demonstrated in rodents and lower animals. Recent results emerging from ongoing studies of CR in humans and nonhuman primates suggest that many of the same anti-disease and anti-aging benefits observed in rodent studies may be applicable to long-lived species. Results of studies in rhesus monkeys indicate that CR animals (30% less than controls) are healthier than fully-fed counterparts based on reduced incidence of various diseases, exhibit significantly better indices of predisposition to disease and may be aging at a slower rate based on analysis of selected indices of aging. The current review discusses approaches taken in studies of rhesus monkeys to analyze age-related changes in brain and behavioral function and the impact of CR on these changes."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17223278

Arthritis, Pain and a Gene Therapy
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From EurekAlert!: "Early-stage research [in mice] has found that a new gene therapy can nearly eliminate arthritis pain, and significantly reduce long-term damage to the affected joints ... If all goes well with a follow-up study currently underway, researchers will apply [to] begin human trials next year. ... researchers used gene therapy to increase by about one thousand times the number of opioid receptors expressed on the surfaces of nerve cells that carry pain messages back and forth between an osteoarthritic jaw joint and the spinal cord. ... nerve cells involved in pain transmission [became] drastically more responsive to the naturally occurring painkiller ... [this] work has contributed to the emerging theory that pain is not a symptom of osteoarthritis, but is instead part of the disease. According to this new paradigm, pain is composed of nerve messages that over time cause permanent chemical changes in the pathways they travel along, making them more sensitive to pain and encouraging inflammation. This two-way 'crosstalk' may mean that arthritis in one joint can spread, through the central nervous system (CNS), to other joints. Worse yet, joint arthritis may export inflammation to the brain, where it plays a role in neurological conditions (e.g. Alzheimer's disease, dementia and multiple sclerosis)."

Link: http://www.eurekalert.org/pub_releases/2007-05/uorm-egt052507.php

As Though the 70s Never Ended
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There is a small but rich vein of science fiction (or alternate history now, take your pick) set at various times in a past couple of decades that might have been - had the look and feel of the 70s continued unabated, as though the decade never ended, and the world in fact worked the way it was thought to back then. One might look at Bug Jack Barron, for example, or some of Spinrad's other works.

This was brought to mind by Alexy Olovnikov and his "chronomeres," which I stumbled over today in their glorious entirety. While I'm sure this fellow is quite serious in his endeavors, plugging away at his theory in isolation and managing to make his way into serious journals, it has all the look and feel of an alternate history of aging science taken from a world in which the 70s never ended - and in which aging actually works the way it was thought to back then. A world in which growth hormone, pineal glands and lunar cycles mesh with DNA science, aging is a programmed phenonenon regulated at the level of organs rather than cells and molecules, and the discoveries of the 1990s and 2000s never happened.

Hypothesis: Lifespan is Regulated by Chronomere DNA of the Hypothalamus

As the basis for the lifelong clock and as a primary cause of aging, a process of shortening of hypothetical perichromosomal DNA structures termed chronomeres is proposed in the [central nervous system]. The lifelong clock is regulated by the shortening of chronomere DNA in postmitotic neurons of the hypothalamus. Shortening of these DNA sequences occurs in humans on a monthly basis through a lunasensory system and is controlled by release of growth hormone discharged from the anterior pituitary directly into the hypothalamus via local blood vessels. In adults, this process is under control of the pineal gland. It is further proposed that different forms of Alzheimer's disease (AD) are caused by somatic and inherited deletions of chronomeres followed by a further abnormally accelerated decrease in their activity, resulting in failures of neurotrophic and neuroendocrinal activities and in various cellular imbalances.

Lunasensor, Infradian Rhythms, Telomeres, and the Chronomere Program of Aging

According to the redusome hypothesis, the aging of an organism is determined by the shortening of chronomeres (small perichromosomal linear DNA molecules). In this paper, a presumptive role for infradian hormonal rhythms is considered. Endogenous infradian rhythms are supposed to actively interact with those hormonal shifts which are governed by an exogenous infradian gravitational lunar rhythm. As a result of this interaction, the so-called T-rhythm is formed. Peaks of T-rhythms are used as the pacemaker signals to keep the life-long "clockwork" of the brain running. The "ticking" of this clock is realized by the periodically repeated shortening of chronomeres in postmitotic neuroendocrine cells, which occurs just at the maxima of T-rhythms. Shortening of telomeres in mitotic cells in vivo is a witness of the aging of the organism, but not the cause of aging. The primary cause of aging is shortening of chronomeres, the material carriers of a temporal program of development and aging. To recognize exogenous gravitational infradian rhythms, a special physiological system - the "lunasensor" system - evolved. It is assumed that it is a necessity to have a lunasensor as a particular variant of sensors of gravitation.

I'm rather hoping that second abstract above jumps out at you as absolutely alien to most of the aging science you've seen in the past few years. Here's an article from a few years back that's an easier read:

There are no genes of ageing, but there is a program for it

Early in the 70s of the 20th century, Russian researcher Alexy Olovnikov forecast existence of the chromosomes' end sequences - telomer, which shorten after each cell division. Aa lot of scientists believe now that telomere shortening leads to cell ageing. However, A.M. Olovnikov is convinced that telomer shortening is only the witness of ageing, and special DNA molecules - chronomeres - are responsible for ageing processes. Chronomeres are located in non-dividing cells of the cerebrum. So far, this is only a hypothesis based on the tremendous experimental material collected by Russian and foreign researches within the recent years.

It has to be said, this all triggers my crank sensors (and then some), for all that these papers appear in respected journals. Go hunt the scientific internet for signs of chronomeres and you'll meet with little but Olovnikov and the sound of crickets. A hypothetical component to the well-mapped cellular nucleus just isn't going to fly in this day and age, and the rest of it is all quite amazing - glands and hormones as giant controlling levers that can explain away aging. It seems like the aging science equivelant of building a working Babbage machine, or a computer constructed with miniaturized valve technology as it could be built today - a work of speculative art, but of little use to progress.

If you'd like to look at more modern and useful theories of aging, you might start with the Strategies for Engineered Negligible Senescence, which is built upon those theories with the best evidence and most active research communities behind them.

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Better Biochemistry in Centenarians
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As scientists continue to explore centenarian biochemistry, they are uncovering the details of its better performance: "Oxidative DNA damage has been implicated in the aging process and in some of its features such as telomere shortening and replicative senescence. Poly(ADP-ribosyl)ation is involved in many molecular and cellular processes, including DNA damage detection and repair, chromatin modification, transcription, and cell death pathways. We decided to examine the behavior of poly(ADP-ribosyl)ation in centenarians, i.e., those subjects who represent the best example of longevity having reached a very advanced age avoiding the main age-associated diseases. ... Our data show that cells from centenarians have characteristics typical of cells from young people both in their capability of priming the mechanism of repair after [oxidative damage] and in poly(ADP-ribosyl)ation capacity, while in cells from old subjects these phenomena are delayed or decreased. ... Our data support the hypothesis that this epigenetic modification is an important regulator of the aging process in humans and it appears to be rather preserved in healthy centenarians, the best example of successful aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17518695

Mechanisms of Alzheimer's Immunotherapy
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A snapshot of some of the present work on developing an Alzheimer's vaccine can be found at Medical News Today: "One of the things those earlier immunotherapy studies taught us was that antibodies can reduce amyloid plaques, which are a hallmark of the disease. The next logical question was -- how does it do that? ... Instead of working outside the cell, we discovered that these antibodies to beta amyloid bind with a specific part of amyloid precursor protein (APP) -- a precursor molecule to beta amyloid -- as it lies on the outside of the affected cell. This complex then gets internalized within the cell, where it works to decrease levels of amyloid peptides, the building block of plaques that are found outside and between cells ... How might antibodies working inside neurons decrease exterior plaque levels? The researchers still aren't sure, but they have already ruled out some of the most obvious answers ... What is clear from the study is that immune-based therapy does work to rid brain cells of amyloid -- giving new impetus to the search for a safe, effective Alzheimer's vaccine."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=71862

A Preview of Aging
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We've all experienced a preview of what it's like to suffer the effects of aging, even those of us who haven't tried on the aging simulator suit. What preview is that? Well, think back to the last time you were significantly ill - home from work, in pain, feeling sorry for yourself, and struggling with the list of simple tasks that still absolutely had to be accomplished regardless. Every simple thing seems like a mountain in such miserable times, never mind the hard stuff.

Now imagine all of that stretching forward for years; unending medical costs and no real prospects for improvement. That is the present end state of degenerative aging in a nutshell. Why aren't you doing more to help avoid this fate?

We live in an age of near-unlimited potential in the advance of biotechnology and medicine, yet very little in the way of resources is directed towards repairing the damage of aging. Potential is worth nothing if few are working on it.

So help yourself out by helping to bring forward the date on which humanity defeats aging. If we miss that boat, and consequently suffer years of the ugly realities of aging, then we only have our own inaction to blame.

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More On the Path to Brain Regeneration
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As reported by The Scientist, researchers continue to work on better understanding the mechanisms by which new neurons are created in adult brains: "Not only are the new neurons connected up early, but they are showing a form of synaptic plasticity that we know is associated with learning very early on ... It's a different environment but basically [adult cells] do exactly the same thing normally a young cell would do in fetal development ... That is very interesting to show that after let's say two months, the newborn neurons could become identical to preexisting neurons. That was not known. ... he plans to investigate the molecular mechanisms that determine how young cells incorporate into old circuitry. The findings may ultimately help reveal how stem cell therapy can repair the brain. Ideally, a few new neurons will rejuvenate the system, he said. ... the idea is emerging that adaptation of old circuitry or increasing plasticity of the old circuitry can help with recovery."

Link: http://www.the-scientist.com/news/home/53238/

Telomolecular Aims at Mitochondrial Repair
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This is most interesting: "Telomolecular Corporation [recently] acquired a new technology from Stanford Leland Jr. University. The technology, called Mitofusin 1, allows for the repair of damaged mitochondrial DNA. Damage to mitochondrial DNA leads to forms of aging and a variety of diseases. By combining this tool with other portfolio products Telomolecular hopes to reverse certain symptoms and signs of human aging. ... The correction of damaged mitochondrial DNA may have applications in human aging. An unfortunate side effect of aerobic respiration in mitochondria is that unstable molecules called reactive oxygen species (ROS) begin to accumulate in the mitochondrial DNA compartment and cause damage to mitochondrial DNA. The intentional mutation of mitochondrial DNA in lab animals causes premature aging ... Additionally, mitochondrial DNA mutations are found to accumulate with age in humans." Telomolecular has been focused on working with telomeres in the recent past, but is now joining a select few groups aiming to block the mechanisms of the mitochondrial free radical theory of aging.

Link: http://www.checkbiotech.org/orphan_News_treatmentandhealth.aspx?infoId=401

The Continuing Spread of Research Prizes
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Research prizes for medicine work, which is we're seeing more of them these days. It's very hard to institutionalize innovation, to build a conveyor belt for radical new ideas, but the contest model has traditionally worked well for this purpose. If you look back at the history of prizes for scientific and technical achievement, they draw healthy multiples of the prize purse in funding for novel lines of research, and empower worthy developers who would traditionally not have made much headway in the mainstream. The Mprize for longevity research is perhaps the most familiar initiative for readers here.

a scientific competition designed to draw attention to the ability of new technologies to slow and even reverse the damage of the aging process, preserving health and wisdom in a world that sorely needs it.

All this considered, I'm not too surprised to see research prizes launched in areas of medicine traditionally considered well-funded:

Medical researchers teamed up with hedge fund managers on Wednesday to offer a new million-dollar prize for the best new idea for cancer research in the hopes of kick-starting innovative approaches.

...

"I have seen firsthand how many ideas with incredible potential never reach fruition," Curhan said. "We will only make significant progress in cancer research by learning from each other's successes and mistakes, and by building on each other's knowledge."

People who want to make individual contributions to a particular researcher, as opposed to making a general donation to a charity, are also invited to look at the site.

Curhan stressed he does not believe the NIH is unimaginative in funding research.

"Most of the work is incremental just because of the long tradition and because people tend not to pick risks. And you tend to write grants to what you think will get funded as opposed to your most innovative idea," he said.

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The False Hopes of Recent Centuries
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Evidence of the quest for extended healthy longevity can be found for any period in human history; it is a tragedy that only now are we comparatively close to success. Each of us stands near the peak of a mountain of death, suffering, ignorance and failed hopes; any glance at the history of medicine should remind us of that fact: "During the 19th and early 20th centuries there was great interest in antiaging remedies. This search for the eternal fountain of youth stemmed from the concept of aging as a pathological condition that destroyed the body and mind. In addition, great emphasis was placed on the economic challenge that the elderly presented to society. ... The history of antiaging medicine includes a variety of remedies. E. Metchnikoff advocated a diet rich in lactic acid which he thought would eradicate the body of intestinal putrefaction and decay. Others believed the fountain of youth lay within the endocrine system. ... The early 20th century was marked by a number of surgical attempts at the restoration of youth. L. L. Stanley reported on more than 643 inmates at the San Quentin prison on whom he had performed testicular transplantation. This idea of gland grafting gained international interest and led others such as S. Voronoff to experiment with the transplantation of various animal glands into humans."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17509279

Exercise, Mitochondria and Gene Expression
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One result of the ongoing biotechnology revolution will be precise answers as to how and why exercise is good for healthy longevity. From EurekAlert!: a study "involved before and after analysis of gene expression profiles in tissue samples taken from 25 healthy older men and women who underwent six months of twice weekly resistance training, compared to a similar analysis of tissue samples taken from younger healthy men and women. ... The gene expression profiles involved age-specific mitochondrial function; mitochondria act as the "powerhouse" of cells. Multiple studies have suggested that mitochondrial dysfunction is involved in the loss of muscle mass and functional impairment commonly seen in older people. The study was the first to examine the gene expression profile, or the molecular 'fingerprint', of aging in healthy disease-free humans. ... in the older adults, there was a decline in mitochondrial function with age. However, exercise resulted in a remarkable reversal of the genetic fingerprint back to levels similar to those seen in the younger adults. The study also measured muscle strength. Before exercise training, the older adults were 59% weaker than the younger adults, but after the training the strength of the older adults improved by about 50%, such that they were only 38% weaker than the young adults."

Link: http://www.eurekalert.org/pub_releases/2007-05/bifa-era051507.php

A Report From the Glenn Aging Symposium
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Via the Gerontology Research Group list, Pete Estep reports from the 2007 Harvard / Paul F. Glenn Symposium on Aging. Hyperlinks are added by my hand for general edification, as usual:

I attended the Glenn Symposium on Aging today at Harvard Medical School. The speakers in order were Elizabeth Blackburn, Doug Wallace, Marcia Haigis, Nir Barzilai, Pere Puigserver, Tom Prolla, Marc Tatar, Rick Weindruch, and David Sinclair. Overall, it was pretty good. I missed Blackburn and Wallace but I saw Blackburn talk earlier this year and her latest research on telomeres is very interesting.

Barzilai talked about their centenarian study. He is calling it the LonGenity study! I told him I let the Longenity domain expire just recently--which was grabbed immediately. He was a bit perturbed not to have gotten it but I didn't know he had started using the name. Anyway, they are doing some SNP studies which he did not report on. He talked mostly about LDL and HDL particle size, and he showed data suggesting that both centenarians and their offspring have larger LDL and HDL relative to controls. They also found some IGF1-R allelic variants in some small centenarians. He also talked a bit about some work in rats. They surgically removed the visceral fat in ad lib fed young rats which lived longer and showed increased insulin sensitivity relative to ad lib fed controls.

Prolla talked about the Polg mutant mouse and some recent results they've gotten on measuring mtDNA deletions (in addition to their recently published work on point mutations). It seems that deletions increase in Polg -/- homozygotes but not in heterozygotes, which might explain why homozygotes experience accelerated aging but hets do not.

Weindruch gave an update on the Wisconsin primate [calorie restriction] project. The ad lib fed animals and CR animal mortality curves appear to be diverging but the result is not statistically significant yet.

Dave Sinclair gave an update on his lab's work on Sir2 and small molecule sirtuin activating compounds (STACs). Both resveratrol and SIRT1 overexpression reduce intestinal and other cancers. Sirtris, the company Sinclair founded with Christoph Westphal, has several compounds that are both stable and activate Sir2 at 1000x lower concentrations compared to resveratrol. I asked David about the switch to knotweed extract from China and he said it is a real concern. He stopped taking resveratrol a while back in order to participate in a Sirtris pre-clinical trial.

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Towards Molecular Automata For Medicine
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In the same vein as artificial cells as medical machinery for the 2010s and 2020s, EurekAlert! reports on researchers developing molecular machinery for similar purposes: scientists "have made a crucial step toward building biological computers, tiny implantable devices that can monitor the activities and characteristics of human cells. The information provided by these 'molecular doctors,' constructed entirely of DNA, RNA, and proteins, could eventually revolutionize medicine by directing therapies only to diseased cells or tissues. ... Each human cell already has all of the tools required to build these biocomputers on its own. All that must be provided is a genetic blueprint of the machine and our own biology will do the rest. Your cells will literally build these biocomputers for you ... The biocomputers' 'input' is RNA, proteins, and chemicals found in the cytoplasm; 'output' molecules indicating the presence of the telltale signals are easily discernable with basic laboratory equipment. ... These biocomputers can translate complex cellular signatures, such as activities of multiple genes, into a readily observed output. They can even be programmed to automatically translate that output into a concrete action, meaning they could either be used to label a cell for a clinician to treat or they could trigger therapeutic action themselves." It's a whole new century out there.

Link: http://www.eurekalert.org/pub_releases/2007-05/hu-iaf051707.php

Life, Death and Progress
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Via Betterhumans, Anne C.'s essay on attitudes towards fundamental truths and our ability to enact change: "Given the current (nascent) state of true longevity research, it remains to be seen whether tangible advances in life extension medicine will result in the depopularization of the 'death is natural' argument. Either people will decide that their sense of identity requires the 'aging into death' story lest they risk profound existential confusion, or they will concede that, now that we can actually 'do something' about aging, they're not actually all that keen on undergoing senescence. From the standpoint of longevity advocacy, the second outcome is certainly the preferred one -- for the same reason that most of us would consider it better for a friend contemplating suicide to determine that life is worth living after all and not go through with the act of killing himself. When a person has spent enough time in the healthy life extension community, it is quite likely that even poetic-sounding arguments like 'death is natural, it's part of the circle of life' will start to sound indistinguishable from statements like, 'I have a death wish for myself and everyone else in the world.'"

Link: http://betterhumans.com/blogs/anne/archive/2007/05/20/trends-in-attitudes-toward-life-death-and-progress.aspx

Aging of the Genome
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Researcher Jan Vijg's profile at the Buck Institute for Age Research includes a link to the first chapter of his recent book, "Aging of the Genome" in PDF format. Vijg stands in the school that believes stochastic corruption of the genome is at the root of aging:

Instability of the genome has been considered as a possible cause of aging since the late 1940's, when it was discovered that low, daily doses of radiation accelerated symptoms of normal aging in rodents. A connection between damage to the genome and aging was strongly supported by the discovery that heritable defects in genome maintenance are associated with premature aging - as shown in Werner syndrome and Hutchinson Gilford Progeroid syndrome. The defects present in those conditions, and other defects, have been engineered in mice and shown to cause premature aging in these animals as well.

In the past, my laboratory has generated a transgenic mouse model harboring plasmids containing the bacterial lacZ gene. These plasmids can be recovered from genomic DNA and subsequently transferred into E. coli to positively select for colonies representing a mutant lacZ-plasmid. The ratio of colonies of lacZ mutants over lacZ wildtypes is a measure for the mutation frequency in the mouse. In this way we demonstrated that, as predicted, the frequency of mutations increases with age in most tissues and cell types. Our present work is focused on unraveling the mechanisms through which aging-related mutations are induced and obtaining insight as to how increased genomic instability can give rise to some of the most common aging-related phenotypes.

The contribution of random mutations in nuclear DNA to aging is up for debate, however. Aubrey de Grey, amonst others, argues that the rise in mutation rates over time - effectively damage to the operating instructions of cells - does not contribute meaningfully to the progression of aging, at least not in comparison to the other forms of biochemical damage that accumulate over time. Why worry about something that will cause issues when you're 200 if any one of a dozen other processes will finish you off long before that?

Both sides can marshall a decent argument; areas like this are usually where science is at its most interesting.

I'm not completely following along with the argument that progeria and Werner syndrome support the contribution of stochastic damage to the genome as a meaningful cause of aging. Both conditions seem to have very specific causes: mutation in Lamin A for progeria and something buried in the kinases for Werner syndrome. Similar issues are seen - to a much lesser degree - in the "normal" old. Does that mean that the contribution of stochastic mutations to degenerative aging is made by how often damage hits a couple of very important genes relating to structural integrity of the cell? That seems implausible given the rate of damage, the sheer number of genes and sheer number of cells involved. But perhaps damage is more likely to happen to structural genes than in other places; maybe stochastic mutation in the nucleus is not quite so stochastic as some might think.

Research continues, and we shall see.

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Dendrimers and Lasers
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The power of dendrimers as a technology platform for precisely targeted therapies is in the reduction in time and cost to develop and test a new therapy. Hook up the biomolecular keys, seekers and tools you need to the dendrimer, and set it loose. From EurekAlert!: "A nanocomposite particle can be constructed so that it has a mix of properties that would not otherwise happen in nature. By combining an organic matrix with metallic clusters that can absorb light, it is possible to incorporate such particles into cells and then destroy those targeted cells with a laser. ... A laser can be used to kill cells indiscriminately, but it is really a blunt instrument. High powered lasers do so much damage that the tissue becomes opaque to further light. Yet, lower-powered lasers do not deliver enough energy to kill cells. By labeling cells with [composite nanodevices like loaded dendrimers], light absorption can be selectively and locally enhanced wherever composite nanodevices are present. Irradiation of the mix of labeled and unlabeled cells by laser light, causes tiny bubbles to form that disrupt and damage the labeled cells, but leave unlabeled cells unaffected. This technology holds promise as an alternative therapy for cancer patients." Any widespread, low cost, efficient method of identifying and killing specific cells is a medical revolution in and of itself.

Link: http://www.eurekalert.org/pub_releases/2007-05/ehs-nlc051707.php

Programmed Versus Non-Programmed Aging
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The debate over the degree to which aging is programmed into our biochemistry still continues. An example from ScienceDaily: " To date, there are two basic concepts of reasons for ageing. The first one is death as a result of damage accumulation, and the second is death as a suicide program. There are multiple arguments in favour of both concepts. A new - astrocytic - hypothesis has been put forward ... In the framework of this hypothesis, ageing is treated as a result of changes in cerebrum cells. The key role is played by transmutation of cells of the radial neuroglia into stellate cells - astrocytes. Since such cell transmutation is a programmed process, the researcher is inclined to the opinion that ageing and following death have been programmed." The SENS approach, treating all change as damage and working to fix it, somewhat sidesteps this debate. It doesn't matter why change happens with age: just figure out what it looks like at the biochemical and cellular level, and then develop a fix for it. Engineering, especially medical engineering, is all about working around the unknowns to attain a good result.

Link: http://www.sciencedaily.com/releases/2007/05/070519131142.htm

The Prospects For Controlling Regeneration and Growth
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A broad swathe of modern medical research is aimed at greater and more precise control over regeneration and growth. With the aid of technology, a body is capable of a great deal more regeneration than is naturally the case - latent capabilities lurk in the system, left over from the task of growing that body in the first place. Cancer, after all, is no more than uncontrolled growth as the result of damage in regulatory biomechanisms. It is also a demonstration of the capacity for growth and repair that will be turned to good use as scientists develop the understanding and tools needed for the job.

Regeneration of bulk parts and replacement of damaged tissue is not rejuvenation, but it should lead to a fair degree of healthy life extension. If life extension of 10 to 20 years is plausible from a simple extrapolation of systems biology, then a far better control over regeneration should add to that. It certainly won't hurt our prospects.

Here's an example of early use of techniques for nerve regrowth that will grow in sophistication in the years ahead:

Researchers at the University of California, Berkeley have developed a technology that has the potential to serve as a better alternative than currently available synthetic nerve grafts. The graft material is composed entirely of aligned nanoscale polymer fibers. These polymer fibers act as physical guides for regenerating nerve fibers. They have also developed a way to make these aligned nanofibers bioactive by attaching various biochemicals directly onto the surfaces of the nanofibers. Thus, the bioactive aligned nanofiber technology mimics the nerve autograft by providing both physical and biochemical cues to enhance and direct nerve growth.

This technology has been tested by culturing rat nerve tissue ex vivo on our bioactive aligned nanofiber scaffolds. When the nerve tissue was cultured on unaligned nanofibers there was no nerve fiber growth onto the scaffolds. However, on aligned nanofiber scaffolds, they not only observed nerve fibers growing from the tissue but the nerve fibers were aligned in the same orientation as the nanofibers. Furthermore, when there were biochemicals present on the nanofibers, the nerve fiber growth was enhanced 5 fold. In a matter of just 5 days, nerve fibers had extended 4 millimeters from the nerve tissue in a bipolar fashion on the bioactive aligned nanofiber scaffolds. Thus, this technology can induce, enhance and direct nerve fiber regeneration in a straight and organized manner.

The use of biodegradable guide materials in conjunction with signaling chemicals is in the very first stages today, but I'm sure you can see just how sophisticated this could quickly become. For example, the growth of entire organs or complex tissue can be envisaged: researchers a decade from now will use rapid prototyping technologies to build three-dimensional guide material frameworks, layered with chemicals known to produce the right growth and cellular differentiation characteristics, and add stem cells to get the job started. These initiatives and technologies exist today at varying stages of progress and sophistication; the path to this future is a straightfoward matter of development and already planned.

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The Slow Spread of Ideas
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I'm always pleased to see the basic concepts of healthy life extension - and its relationship to scientific research and development - out there in the wild, as it were. Even if folk have it a little wrong, or are overenthusiastic, or overly pessimistic, they are still talking about longevity and the prospects and scope of progress. Facts a little askew are a whole lot easier to correct than the complete absence of interest, opinions and knowledge.

The normal way of looking at life is to believe that death comes closer as we grow older. This seems quite logical because it is usually old people rather than young ones who die. We talk of life expectancy as if life were like a clock that was counting down our allotted time on earth.

Very depressing.

Until one realises that life expectancy increases as one grown older.

...

By the time today's twenty year old had reached sixty (in 2047) your life expectancy will have reached one hundred.

In other words, when you were born you could look forward to sixty years of life- but at the age of sixty you find yourself in almost the same position! You now have forty years ahead of you- possibly more.

Here is where it gets really strange.

A man who is sixty in the year 2047 can expect a further forty years of life- until 2087. This will mainly be due to 'survivorship bias' and improvements in conventional medicine. It will be about this time that stem cell therapy becomes viable. This is a process by which stem cells may be injected into an injured area and will form themselves into a new organ just as they do in the womb.

Initially this will be used to repair people who have been injured but the main role will eventually be life extension.

There is indeed a great deal wrong with this at the detail level - regeneration is not rejuvenation, for one, and I'll be greatly surprised if tissue engineering of whole organs, immune systems and the like for replacement is not commonplace in the 2020s. Even the conservative scientists are looking to 2050 for these sorts of medical technology. But there's much more to the repair of aging than replacement of parts in this manner.

The concept of ever increasing life expectancy with time and progress is an important one, however, and I'm pleased to see it repeated more often. This is why we should strive for incremental improvement now even when we know that complete victory over aging will take decades more - the early gains, if large enough, will see us through to that victory. Our life expectancies will increase into the far future, marching alongside progess in bio- and nanotechnologies, if we beat the curve.

Which brings me to the most important error in this piece - it treats this future as a given, when it is not. The future is built by our actions, and if we fail to advocate, support and fund large-scale longevity research, then we will degenerate, suffer and age to death just like our ancestors.

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More On Stem Cells Versus Parkinson's
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You'll find a fair degree of interesting work taking place in India these days, often in connection to medical tourism, as illustrated here by Express Healthcare: "Stem cell research seems to be promising in regenerating hope to cure [Parkinson's disease (PD)]. This will motivate innumerable patients across the world to explore this new modality. However, we need to observe the long-term clinical effects in large number of patients to decide its role in the treatment of the degenerative diseases ... After stem cell therapy last year, Andrew has shown remarkable recovery in his symptom as he has started walking without support, there has been significant reduction in the tremors [and] his medication for PD has been withdrawn since the last months. ... The successful clinical outcomes from our stem cell research programme have given us the confidence to share this new hope with the public at large so that a greater number of people can participate in the clinical research for getting relief from major diseases and disabilities." The economics dictate that you'll see progress being driven in less prosperous countries by the flow of comparative wealth from outside, driven on by the high cost of regulation in places like the US.

Link: http://www.expresshealthcaremgmt.com/200705/market14.shtml

Towards Brain Regeneration
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I've long said that repairing and sustaining the brain is a vital goal for longevity, and that we will see overcoming myriad neurodegenerations as the greatest challenge to healthy life extension two or three decades from now. Progress is being made, however, as reported by ScienceAlert : "neuroscientists have identified the stem cell population responsible for production of neurons, and the mechanism which drives this process. ... For the first time, we've been able to identify a mechanism that's able to regulate production of nerve cells, a step that's crucial to our understanding of memory and learning. The same mechanism helps regulate growth of healthy brain tissue, so identifying this process is essential for the development of therapeutics to treat conditions such as dementia. ... With this knowledge, we are well placed to further develop our understanding of the basic mechanisms that regulate the generation of healthy, new nerve cells in the brain. Our long-term goal is to develop new therapies whereby nerve cells can be generated to replace those lost or damaged in disease or trauma."

Link: http://www.sciencealert.com.au/news/20071705-15883.html

The Financial Industry and Longevity
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From SmartMoney.com, another reminder that those with the most money on the table are betting on increasing healthy longevity: "Think you'll make it to your 100th birthday? Your insurance company does. And so does most of the financial world around you. ... That's presented a new challenge for financial planners, who traditionally have been able to follow the old models of folks retiring at 65 and dying within a good 10 years after that. The old approach of an advisor sitting down with you to make sure you had transitioned to a safe, yield-based portfolio the day you rode down your office elevator for the last time is out of date. And dangerous. Without a rethinking of longevity into the picture, a financial plan can become a recipe for running out of money well before you physically run out of steam. ... The life insurance companies have raised their actuarial tables to account for lifespans of 115 years. When we hear things like that, we think about it, and we now calculate our retirement plans to age 100. ... living longer can pose problems if there's inadequate financial planning, and the expectation of a longer life in retirement can pose some challenges for today's aging boomers. But 'it's a problem I hope to have myself.'"

Link: http://www.smartmoney.com/beyond/index.cfm?story=20070518

An Interview With Michael Anissimov
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RU Sirius interviews Michael Anissimov at 10 Zen Monkeys, discussing radical life extension and other topics: "Think of ten possible lives you could live, and then think that you don't necessarily need to choose between them. You could live them back to back. ... Recently Peter Thiel, former CEO of Paypal, offered three million dollars in matching funds for projects related to [repairing aging]. And [the Methuselah Foundation] started coming up with ways to actually use over a million dollars, I believe. They have the MitoSENS project and the LysoSENS projects. ... lysomal junk is this stuff that builds up between cells. And our natural metabolism doesn't currently have any way of breaking it down. So researchers are trying to exploit the law of microbial infallibility - the notion that no matter what organic material you’re talking about, you're going to be able to find a microbe that can eat it. ... some of these researchers have even gotten permission to get soil samples from the people that run graveyards because that's where you'd expect to find the bugs. Basically, they're looking for specialized microbes that can dissolve that lysomal junk."

Link: http://www.10zenmonkeys.com/2007/05/18/give-me-immortality-or-give-me-death/

Grey is the New Gold: Podcast Interview
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I found "Grey is the New Gold" from the Kronos Longevity Research Institute interesting chiefly because it presents a viewpoint merging the Longevity Dividend position of modestly slowing aging with support for more direct-to-the-end-goal research aimed at radical life extension. That's a position not seen too much in the wild to date; mention of reversing aging and Aubrey de Grey next to the pitch for $3 billion in government funding for Longevity Dividend research.

You'll find a podcast interview over at Eons:

Eons: What kind of breakthrough is longevity science on the verge of? Have you guys discovered the Fountain of Youth, yet?

Dr. Harman: No, we haven't, but what I think we are very close to is discovering some of the basic processes that are involved in aging, really understanding how they work, but also understanding how certain of our genes modulate our rate of aging. It's absolutely clear that we can alter the aging process in experimental animals. There's no doubt about that any longer, and we've identified genes in those animals that we have very good evidence are involved in that modulation, in that slowing of cellular and tissue aging that leads to greater longevity and also an increase in the healthy part of the lifespan in these animal models. Well, it turns that people have got the same genes.

...

Eons: I see the conversation going on, in our community. I saw somebody ask about growth hormone the other day.

Dr. Harman: Exercise is a much better intervention, I believe. You can lose the same amount of fat and gain the lean mass, and it's functional. You'll improve your, if you do the right kinds of exercise, you'll improve your balance. You'll improve your strength. You'll improve you ability to do the things that you really want to do, like go to the grocery store and carry a couple of bags of groceries up a flight of stairs without finding that you're exhausted or puffing at the top.

Which I think illustrates that Kronos is much more on the side of optimizing health and the modest Longevity Dividend approach to extending healthy life - by tinkering with metabolism to slow aging rather than reversing aging by repairing damage - than "Grey is the New Gold" makes out.

Still, a rising tide raises all boats. If the backers of the Longevity Dividend continue to broaden their campaign, and by doing so bring more people to support and understand that healthy life extension is possible, then some of those people will make the leap to see that the Strategies for Engineered Negligible Senescence and the work of the Methuselah Foundation are a much better template for the future.

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The Micronutrient Camp
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I see the exploration of micronutrients and other supplements as an aspect of the mainstream direction of aging research - interested in optimizing and tinkering with metabolic processes to gain only very modest, incremental gains in healthy life span. Slowing aging a bit, in other words, rather than any more ambitious project based upon modern biotechnology. From ScienceDaily: "The evidence suggests that lipoic acid is actually a low-level stressor that turns on the basic cellular defenses of the body, including some of those that naturally decline with age ... Researchers at LPI are studying vitamins, dietary approaches and micronutrients that may be implicated in the aging or degenerative disease process, and say that lipoic acid appears to be one of those with the most compelling promise. The goal of LPI research, Hagen said, is to address issues of 'healthspan,' not just lifespan -- meaning the ability to live a long life with comparatively good health and vigor, free of degenerative disease, until very near death. The best mechanisms to accomplish that, scientists say, have everything to do with diet, exercise, healthy lifestyle habits and micronutrient intake." Which is true - if you ignore the entirety of the modern biotechnology revolution. Live in the past, or live in the future? Not a hard choice for me.

Link: http://www.sciencedaily.com/releases/2007/05/070517130823.htm

Towards Cell Therapy For Diabetes
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As noted at Genetic Engineering News, Geron continues to show progress in the manipulation of embryonic stem cells (hESCs): "the paper describes studies showing how the researchers differentiated hESCs into cell clusters containing the main cellular components of the islets of Langerhans. The islets of Langerhans are structures in the pancreas that are responsible for regulating and producing insulin in response to changing glucose concentrations and are targets for autoimmune destruction or dysfunction in Type I Diabetes. ... These studies show that the islet-like clusters contain the major cellular components of islets and are sensitive to glucose, the key sugar to which they must respond to be therapeutically beneficial. Our major goal moving forward is to improve the purity, yield and maturational status of these cells ... The protocol to produce the ILCs drives hESCs through a series of cell culture steps that mimic the progressive differentiation stages during development of the pancreas in humans. Other pancreatic cell types resembling those of the exocrine pancreas were also observed during the differentiation process."

Link: http://www.genengnews.com/news/bnitem.aspx?name=17569445

Defining Success Upwards
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If you want to get ahead in the world, there's a very simple trick to it - every time you succeed, redefine "success" to a higher level and keep at it. This always springs to mind whenever I read about the present concept of "successful aging."

The literature on successful aging reveals a wide range of definitions, generally reflecting the academic discipline of the investigator. Biomedical models primarily emphasise physical and mental functioning as successful aging; socio-psychological models emphasise social functioning, life satisfaction and psychological resources as successful aging. Several studies also identify these factors as the precursors of successful aging. Moreover, research shows that older people consider themselves to have aged successfully, but classifications based on traditional medical models do not. Fewer studies have explored lay views, and most of these have been exploratory or restricted to specific groups of areas. A model of successful aging needs to be multi-dimensional, incorporate a lay perspective for social significance, use a continuum rather than dichotomous cut-offs for "success" and lack of, and distinguish clearly between predictor and constituent variables.

"A little less degeneration than that guy over there and still dead at 80" has never seemed to me to be a goal worthy of the word "success." We can do so much better than this - but only if we haven't prematurely declared victory and shut up shop.

If you want to fail in life, there's an easy trick to it: just keep defining success down every time that a goal looks like it might take work. Declare yourself a winner right now - after all, there's always someone, somewhere you can point to as an example of your comparative success.

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Advances In Human Cryopreservation
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The Advances in Human Cryopreservation conference, sponsored by Suspended Animation Inc, starts on May 18th. As I noted at the end of last year, some bold claims are being made, and I'm pleased to see signs of progress in the cryonics field: "Major scientific breakthroughs will be revealed [followed] by demonstrations of advanced cryopreservation equipment ... This event will feature the first details about a revolutionary research project to achieve perfected human cryopreservation. In the short-term, this research will lead to advanced methods of cryopreserving terminal patients for future revival in good health and vigor. In the long-term, it will lead to human suspended animation. ... conference banquet on Saturday night will feature internationally acclaimed cryobiologist Gregory M Fahy, PhD, who will announce a major grant to fund research to perfect whole body vitrification, which is a method of cooling organs, tissues, and entire organisms to super-low temperations without damaging ice formation." No-one wants to die, but all too many of us are going to do just that before real longevity medicine arrives. The choice between cryopreservation and the grave should be an obvious one.

Link: http://www.prlog.org/10016890-advances-in-human-cryopreservation-first-cryonics-conference-in-south-florida.html

Delving Into Mammalian Regeneration
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Scientists continue to work on the nuts and bolts of regeneration in mammals: greater understanding will lead to greater ability to improve upon what we have. From EurekAlert!: "Researchers previously believed that adult mammal skin could not regenerate hair follicles. In fact, investigators generally believe that mammals had essentially no true regenerative qualities. (The liver can regenerate large portions, but it is not de novo regeneration; some of the original liver has to remain so that it can regenerate.) ... In this study [dormant] embryonic molecular pathways were awakened, sending stem cells to the area of injury. Unexpectedly, the regenerated hair follicles originated from non-hair-follicle stem cells. ... We've found that we can influence wound healing with wnts or other proteins that allow the skin to heal in a way that has less scarring and includes all the normal structures of the skin, such as hair follicles and oil glands, rather than just a scar ... By introducing more wnt proteins to the wound, the researchers found that they could take advantage of the embryonic genes to promote hair-follicle growth, thus making skin regenerate instead of just repair. Conversely by blocking wnt proteins, they also found that they could stop the production of hair follicles in healed skin."

Link: http://www.eurekalert.org/pub_releases/2007-05/uops-fdo051407.php

Attitudes On Death and Aging: Poll Results
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Over at Existence is Wonderful, Anne C. is embarking upon a four part essay, starting with the results of her recent poll on attitudes towards death and aging:

What sorts of attitudes are developing as emerging technologies make it possible for more and more people to live longer, healthier lives? Are people holding unyieldingly to old, possibly outmoded attitudes, or adopting new ones? What sorts of news items and/or scientific breakthroughs help to shape people's attitudes regarding how long they might live, and what they imagine the shape of their future will be?

...

While this was not a scientific poll, its results still proved very interesting, and will be taken into account in considering future philosophical writings and advocacy efforts. In any advocacy movement, it is important for the movement to self-examine continuously in order to avoid ideological "tunnel vision" and alienation of newcomers or persons unfamiliar with the idea of healthy life extension. Hence, as well as considering a primary respondent demographic of pro-longevity individuals, the poll also included several items deliberately intended to prompt responses from those not necessarily in favor of life extension. It was thought that in this way, a maximally representative sample pool could be obtained -- one consisting of people likely to read about longevity research and advocacy, or who are at least willing to follow links to sites that discuss these topics.

Head on over and take a look at how it turned out.

From where I sit, I see the world to be broadly divided into two groups: those who think that aging and death are terrible things, and those who realize too late that aging and and death are terrible things. You can only do something about your stately drive towards toward the cliff if you care to look ahead to see the impending drop. Trite, but true.

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Healthy Life Extension Scenario Planning
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Anders Sandberg searches for scenario planning resources for healthy life extension and finds the cupboard comparatively bare: "Yesterday I held a ExtroBritannia scenario planning event with the theme of life extension. As a warm-up I did a quick survey of papers related to scenarios of life extension. Overall, I was surprised by the lack of good scenarios: this ought to be a great area to explore, but likely many researchers shy away from the imagined radicalness of life extension. That will likely change over the next years. Right now most people are making scenarios merely of current demographic trends, not willing to assume any effective life extension." Sandberg lists a selection of papers and works that are probably worth your time, or at least worth being aware of. Not that I see this absence of policy-forming work as a bad thing. The less policy making, the more room for progress - there's nothing quite like getting government involved early to flatten the growth and inventiveness of a prospective field of development.

Link: http://www.aleph.se/andart/archives/2007/05/life_extension_scenario_planning_bibliography.html

One Longevity Dividend Viewpoint
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In this PDF document, the Longevity Dividend viewpoint on aging research is filtered through the Kronos Longevity Research Institute: "Scientists are making discoveries every day about how aging works and how to keep it from slowing us down so that we stay healthier and feel younger longer. Dietary changes, genetic engineering and hormone activity can all play a role in the aging of the body's systems. Scientists are discovering that the aging of those systems can be delayed and thereby delay the onset of deadly diseases. Slowing the aging process is not a new idea, and there is no quick fix or magic mirror ... We're not trying to increase lifespan so we add 20 years of life at the end when you're frail. We want to increase the middle part - the healthspan. ... The belief that aging is an immutable process, programmed by evolution, is now known to be wrong. ... In 2002, Cambridge associate and biogerontologist Aubrey de Grey developed the radical idea that reversing cellular aging could extend life. De Grey predicted that the next great social debate would occur when aging research matures to the point that public funds can be used to speed effective aging treatments. That future is now."

Link: http://www.kronosinstitute.org/state_of_science.pdf

A Snapshot of Alzheimer's Research, From the Institutional Point of View
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Where are we with Alzheimer's research? I noticed a very institutional point of view today. Only the big, heavily funded consensus science is mentioned - none of the more exciting or speculative recent research. This is science patterned after lumbering organizations; slow to change direction, careful and extremely conservative in taking steps or drawing conclusions. Effectively, it's yesterday's science, the well-trodden and heavily regulated path. After extracting the three letter agencies and policy matters:

The body of data on Alzheimer's that has accumulated to date is substantial, researchers say, marking a pivotal point in the disease's history and transforming the perception of Alzheimer's as an isolating and inevitable consequence of aging to a potentially manageable, chronic disease that can be slowed or even prevented through a vaccine.

What scientists know so far is this:

-- the amyloid peptide -- which forms the plaques in the brain that prevent neurons from communicating -- is the primary culprit in the vast majority of cases, giving researchers a specific disease target to aim for;

-- less than 1 percent of Alzheimer's cases are caused by a single gene mutation;

-- anti-inflammatory drugs and estrogen don't seem to work, but antioxidants, the supplement DHA and cholesterol-lowering drugs called statins show promise;

-- lifestyle choices including exercise, diet, intellectual stimulation and social interaction all play a critical part in warding off brain-plaque formation.

Pharmaceutical companies are currently testing drugs that specifically target amyloid peptides and remove them from the brain, and vaccines that harness the body's own immune system to do the same job. Other experimental therapies go after Alzheimer's symptoms by, for example, correcting imbalances in brain chemicals like serotonin and dopamine that control communications among the brain's neurons.

The rest is worth reading for an insight into the mindset of those who see science as as a block-puzzle of large funding entities, legislation and regulation. From where I stand, nothing could be further from the actual process of creating new knowledge and new technologies; it's rather unfortunate that so many people "graduate" from useful, productive work into that airy realm of block-puzzles.

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A Look At the Wake Forest Institute
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Via WRAL, a look at the work of the Wake Forest Institute for Regenerative Medicine: "The Wake Forest Institute for Regenerative Medicine includes scientists and physicians in the fields of biomedical and chemical engineering, cell and molecular biology, biochemistry, physiology, materials science, nanotechnology, genomics, proteomics, drug delivery, surgery and medicine. ... we push forward in our efforts to develop more efficient ways to enhance cell growth and function in vitro and fabricate biomaterial scaffolds for tissue generation in three-dimensions. ... We have numerous ongoing and planned projects that represent the next phases of advancement toward the clinic as well as expansion into an increasing array of tissue types, ranging from organs such as kidneys, livers and heart valves, to tissues and cells for therapy, such as cartilage, bones and nerve cells. I would, however, recommend cautious optimism in this complex and nascent field of regenerative medicine. Our team, together with renowned scientists from other institutions, have been working on these or similar projects for almost two decades, and it could be years before commercial-scale production of engineered organs is viable."

Link: http://www.wral.com/business/local_tech_wire/biotech/story/1411813/

Calorie Restriction and the Hippocampus
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The function of the hippocampus declines with the ongoing accumulation of biochemical wear and tear in the body. As for so many aspects of aging, calorie restriction makes some modest difference here: "Caloric restriction (CR) extends life span and ameliorates the aging-related decline in hippocampal-dependent cognitive function. In the present study, we compared subunit levels of NMDA and AMPA types of the glutamate receptor ... Each of these parameters has been reported to be a potential contributor to hippocampal function. Western blot analysis revealed that NMDA and AMPA receptor subunits in [ad libitum (AL)] animals decrease between young and middle age to levels that are present at old age. Interestingly, young CR animals have significantly lower levels of glutamate receptor subunits than young AL animals and those lower levels are maintained across life span. ... These results indicate significant aging-related losses of hippocampal glutamate receptor subunits in AL rats that are consistent with altered synaptic function. CR eliminates that aging-related decline by inducing stable NMDA and AMPA receptor subunit levels."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17490652

The Economics of Repairing Aging
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How much do you think it will cost to defeat degenerative aging? Pick a number. It's almost certainly the case that the end result - medical technologies that can repair the accumulated cellular and molecular damage that is aging - will very quickly pay for itself.

For all that people try to make it complex, economics is really very simple at its root. All costs must be paid, and there are no free lunches, but new wealth and new resources can be created through investment. Illness, decrepitude and death are costs - deeply unpleasant aspects of the present human condition, but still costs that can be quantified and compared to other resources. Resources directed towards maintaining the aged are resources not directed towards technological advancement or the creation of wealth. The aged themselves are resources that fade in value - for people of health, capacity and vigor are the root of all progress.

Once you start to make this comparison between the cost of degeneration and other goals that could be achieved with the same use of resources, it quickly becomes clear that the level of resources we direct as individuals to medical research is low to the point of irrationality. To pick one example, from many, of the cost of failing biological systems:

By the year 2010 -- less than three years from now -- the annual cost to treat patients in the United States with Alzheimer's disease will reach $160 billion, researchers said Monday in Washington. But they said scientific discoveries to slow the disease could save society $1.2 trillion to $3.97 trillion a year by 2050.

...

"Our calculations, while preliminary, suggest it is more important than ever to understand the full economic value associated with new treatments for Alzheimer's, as for any other devastating disease," Vernon told United Press International.

In his report, "Alzheimer's Disease and Cost-effectiveness Analyses: Ensuring Good Value for Money?", submitted for publication by the NBER, Vernon suggests that a treatment for Alzheimer's disease that could delay the onset of the major symptom of the illness -- memory loss that affects activities of daily living -- for five years would be worth nearly $4 trillion a year.

Moreover, if a treatment could be found that would only delay the disease for one year, it still would be worth $1.2 trillion each year, Vernon said. His calculations are based on determining dollar values for productivity, longevity and quality of life.

That is for just one age-related condition amongst many. If you follow that line to the end, you will see staggering numbers:

According to the Lasker Foundation, a dozen or so studies since the mid-1970s have found the value for human life is in the range of $3 to $7 million dollars, using many different methodologies.

...

If you multiply the death rate at each age [by] the dollar value at each age [you] get the economic loss at each calendar age, due to natural death. The sum of these economic losses divided by the total number of deaths gives you the average economic value of a human life lost.

The result is an average value of about $2 million dollars for each human life lost. If we conservatively assume that the population age structure and the age-specific mortality is the same worldwide as in the United States, then the worldwide natural death toll of 52 million people in the Year 2001 represents an economic loss of about $100 trillion dollars. Every year.

How big of an economic calamity is this? Taking Federal Reserve figures for the total tangible wealth of the United States, including all financial assets, all real estate, and all consumer durables, net of debt, and applying the ratio of U.S. to world GDP gives us an estimate of total global tangible net worth of $91 trillion dollars. So this means that every year, natural death robs us of human capital equivalent in value to the entire tangible wealth of the world.

It is as if in the Year 2001, someone took out a giant broom and swept up all the physical assets of human civilization into a cosmic trash can, and then threw it all away. That's $100 trillion dollars of financial assets, real estate, and durable goods. Gone. And then in 2002, the giant broom sweeps again. Another $100 trillion dollars of human capital is destroyed, or three times larger than the $33 trillion dollars of annual economic activity represented by world GDP. Then it happens again in 2003.

It should be clear that no level of investment in longevity research - that could reasonably be mounted by the human race at this time - would ever be considered too much.

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A Reminder That Only Fools Rush In
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Via the PubMed listings, a reminder that for all the noise about growth hormone from the "anti-aging" marketplace, the scientific backing isn't there: "Growth hormone release and IGF-I synthesis decrease with increasing age. The regulation of the GH/IGF-I system is dependant on the integrity of the hypothalamus, pituitary and liver. During aging there are several changes which contribute to the decline in GH/IGF-I including changes in signal to the somatotrophs from growth hormone releasing hormone, somatostatin and other factors such as body composition, exercise, diet and sleep. ... The phenotypic similarities between aging and adult growth hormone deficiency syndrome combined with this decrease in GH/IGF-I with aging have prompted the question whether aging is a GH deficient state. The advent of recombinant growth hormone has led to a number of studies treating elderly patients with GH alone or in combination with sex steroids or exercise. The results of these studies would not back up the use of GH in elderly non-hypopituitary patients as they did not show efficacy, showed high rates of adverse events and there is also some evidence associating GH/IGF-I and risk of neoplasia. If GH therapy is to be used in this cohort of patients further long term efficacy and safety studies are required."

Link: http://www.ncbi.nlm.nih.gov/pubmed/17492509

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

Link: http://www.crisismagazine.com/may2007/pavlat.htm

Nothing So Cruel, Wasteful and Destructive as the Norm
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Take a look back at history, and see what has been endorsed, defended and welcomed as the norm of behavior in human society: violence, infliction of pain, incredible delusion, victim groups and mass murders (sanctified by religious hierarchies or the states that substitute for their role), enforced beliefs, abandonment to death, and much more.

Then look at today. The only things to have changed are the degree and the details - and don't kid yourself that the degree is all that great in the grand scheme of things. Most likely you hold one or more incredible delusions and consider a broad range of murders sanctioned, on the basis that this is "normal," for all that you're what would be described as a principled, kind, upright sort of person. It is entirely possible that I do also.

We humans are deeply flawed in this respect. Start out with decent-at-the-small-scale folk you'd be happy to have as neighbors and you'll wind up with a society that advocates and defends the most outrageous, irrational, cruel and terrible beliefs and actions. But there's no such thing as "society" - only individuals making individual choices. It is those decent-at-the-small-scale individuals who advocate, defend and ultimately carry out cruel and destructive actions.

I leave it up to the reader to fill in their personal specifics, but I'm sure you know where the worst is from my point of view: the acceptance and defense of degenerative aging, and the acceptance and defense of death and suffering due to aging. More than 100,000 people die due to the results of aging - of accumulated cellular damage that we are doing too little to try and repair - each and every day. Hundreds of millions suffer in one way or another. Every day, day in and day out, a tide of death that beggars the imagination. Think of that a moment.

Other human cruelties and irrational beliefs fade into the background in comparison to the defense of age-related suffering and death in an era of accelerating biotechnology and medical research. We are very close to a time in which aging can be repaired - but as for any goal, it will only come to pass if the desire is there. Yet the vast majority of people do nothing, and accept or support the suffering and death that is everywhere and all around.

This must change.

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Watching the Targeting Improve
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The cost of research into bio- and nanotechnologies for targeting therapies to specific cells is falling. I can tell this is the case because rapid progress is being made, especially in connection to cancer, but also in relation to immune system and other work. Prior to the point in the development cycle at which groups become completely channeled and weighed down by regulation, it is still possible for rapid innovation to florish. Here's one example:

Recent research into a new kind of photodynamic therapy has concentrated on using single-walled carbon nanotubes, combined with near-infrared light, to generate heat to kill cancer cells. Now, Chongmu Lee and colleagues from Inha University, Korea, have substituted the carbon nanotubes with a porous silicon nanomaterial, which they claim can generate as much heat as the carbon nanotubes, with the added bonus of producing much smaller amounts of reactive oxygen species.

Photodynamic therapy uses the same sorts of targeting and delivery mechanisms as other modern therapies, but the delivery is of an inert substance that can be efficiently heated with low-level radiation - killing specific cells without widespread tissue damage. Unfortunately, if you produce significant amounts of reactive oxygen species and other free radicals in the process of heating, then you do wind up causing some level of widespread damage. The incremental improvement reported above is one of many taking place worldwide in this broad field; let the engineers in and this is what happens. There's always room for improvement in every technology, and that improvement will be found by someone - provided the cost of experimentation is low.

The scientific paper is freely available also:

Photodynamic therapy (PDT) is a very useful approach for cancer treatment, but it has a few short-term and long-term side effects arising from reactive oxygen species (ROS) generation. Recently a new photodynamic therapy (PDT) based not on the ROS generation capability of photosensitizers but on the heat generation capability of carbon nanotubes (CNT) combined with a near-infrared (NIR) light irradiation technique has received significant attention. Our experimental results show that PSi can also be utilized as a therapeutic agent that generates sufficient heat to kill cancer cells without toxicity. The surface temperature of PSi increases as high and as quickly as that of CNT, but PSi was found to produce a smaller amount of ROS than CNT during NIR light irradiation. In addition, we developed a new method to effectively measure the amount of the ROS produced by nanomaterial photosensitizers including porous silicon (PSi) and CNT. The analysis results show that this method is reliable and reproducible.

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The Conservative View of Calorie Restriction
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The Mayo Clinic accurately reproduces the cautious, conservative line on calorie restriction. As for many such resources, it manages to be technically accurate while overstating the difficulty of practicing calorie restriction responsibly and safely, and missing some of the latest science: "Short trials of calorie restriction diets in people have shown some benefit. ... people who subscribe to calorie restriction carefully monitor their food intake to ensure they're getting all the vitamins and nutrients they need. ... Scientists have their doubts about the viability of the calorie restriction diet in a Western culture where overweight and obesity seem to be the norm. ... People undergoing calorie restriction, whether through a restricted diet only or through a combination of diet and exercise, typically have seen positive changes in their: blood pressure, blood sugar, body fat percentage, cholesterol levels, heart rate, weight ... Calorie restriction studies may help researchers better understand the aging process, and they may provide clues for developing new anti-aging drugs. Researchers hope to study how calorie restriction works on the body so that drugs may be developed to work in the same way."

Link: http://www.mayoclinic.com/health/anti-aging/HQ00233

A High Level View of Aubrey de Grey and SENS
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From the Daily Sundial, a high level profile of biomedical gerontologist Aubrey de Grey, the Strategies for Engineered Negligible Senescence (SENS), and the past couple of years of public discussion on the topic: "Speaking at conferences in Europe, the U.S. and China, and interviewing with major media outlets such as '60 Minutes,' the New York Times, and Popular Science, De Grey has sent ripples, and sometimes waves, through the technology and scientific community by claiming that he has developed an age-reversal model that may feasibly work in as little as a decade in mice and 20 to 30 years in humans." Conditional on large-scale funding and growing research community, which people often miss out. "I'm convinced that de Grey's strategy for achieving life extension is the best that has been proposed. We have a comprehensive list of the types of age-associated damage that kill people in a normal life span, and a corresponding list of therapies for treating each type, which are widely supported by experts in the relevant fields ... Scientists find things out for the sake of finding things out. Engineers find things out in order to solve some problem so they are always looking for ways to minimize how much they need to know to implement a solution or ways to sidestep their own ignorance. This is antithetical to the scientist's raison d'etre, so scientists constantly overlook it."

Link: http://media.sundial.csun.edu/media/storage/paper862/news/2007/05/07/News/Fantasy.Or.Fountain.Of.Youth-2896479.shtml

An Example of the Damage Done
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From Immunity & Aging, one PDF-format example of the way in which the cytomegalovirus-compromised aging immune system lets you down: natural killer (NK) cells "are a component of nonspecific immune response involved in the defense against viral and bacterial infections ... infections and pathogen burden have been considered as a potential risk factor for [coronary heart disease (CHD)]. The main suspects linked to the vascular disease are wide-spread organisms such as cytomegalovirus (CMV) and Chlamydia pneumoniae. ... as infections deteriorate the course of CHD and NK cells are the first line of defense against infections, there might be a link between development of CHD and NK cells. ... These data indicate that an active infection with specific pathogens
may affect NK cells functions. Vice versa, low NK activity may be one of the possible gates of spreading infection, and this may be a way of deepening of NK cell deficiency. Altogether, it creates a positive feedback loop leading to accelerated progress of diseases associated with chronic infections." When your system starts to run down, the process of degeneration accelerates - but the initial accumulation of damage is gradual, which is why the development of repair strategies can be a path to greatly extending healthy life span.

Link: http://www.immunityageing.com/content/pdf/1742-4933-4-3.pdf

Demyelination and Alzheimer's
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Commentary from FuturePundit on recent research into the mechanisms of Alzheimer's disease: "Myelin is the fatty sheath that coats the axons of the nerves, allowing for efficient conduction of nerve impulses. It is key to the fast processing speeds that underlie our higher cognitive functioning, including, yes, wisdom. Myelination continues sheathing axons until we reach the age of about 50, but in these later stages, the myelin becomes more and more susceptible to damage. ... [a report] suggests that it is the breakdown of this late-stage myelin that promotes the buildup of toxic amyloid-beta fibrils that eventually deposit in the brain and become the plaques which have long been associated with Alzheimer's disease. These amyloid products in turn destroy more and more myelin, [disrupting] brain signaling and leading to cell death and the classic clinical signs of Alzheimer's. ... Your myelin slowly breaks down after age 50. That, by itself, is thoroughly disgusting even before we consider the threat from Alzheimer's. The brain is our most powerful tool. Our brains become less powerful. In the process of its decay and aging we become less capable and lose parts of who we are. Shouldn't we try much harder with research funding to find ways to stop and reverse brain aging?"

Link: http://www.futurepundit.com/archives/004243.html

The Development of Stem Cell Medicine, Up Close
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A revolution looks like a real grind when you're up close and living it. Every little thing has to be done for the first time at seemingly great expense and endeavor, every new tool and technique built from scratch. Fast forward ten years and the first decade of this new century will look like a steep, rapid climb to new heights in hindsight - but working in the trenches today can be a matter of one step after the other.

Some articles illustrative of this theme today; compare where we are with where we'd like to be in our use of stem cells and knowledge and control of biochemistry. Fast doesn't always look like fast when you're the guy turning the crank.

Embryonic stem cells trial on track to start:

The first clinical trial of embryonic stem cells is on track to start early next year on patients with spinal cord injury. Geron, the California-based biotechnology company, will carry out the study on accident victims in six trauma centres across the US.

...

Geron’s product will have been tested in 2,000 animals before it goes into its first patient, Mr Okarma said. It consists of immature oligodendrocytes - specialised nerve cells - grown from human embryonic stem cells. The animal tests show that these can repair spinal cord injuries in rats, by growing new nerves with the myelin sheaths they need to work properly. Paralysed rats can walk again.

Mr Okarma said the product was designed to repair recent spinal damage and would need to be injected into patients within two weeks of the accident. It could not help people with long-term paralysis such as the late actor Christopher Reeve who did so much to champion stem cell research for spinal injury.

Amorcyte Cardiac Cell Therapy Trial Completes Second Of Four Phases:

Amorcyte, Inc. (Amorcyte), a privately funded biotechnology company developing cell therapy products to treat cardiovascular disease, announced today the completion of the second of four dose cohorts in its phase I clinical trial.

The trial will now await review of the data by the data safety monitoring board (DSMB) in accordance with the protocol.

"All treatment patients in the second cohort received intra-coronary artery infusion of a specified number of stem cells. The DSMB will review the data on this second treatment group and determine whether to give approval to start accruing patients in the next cohort at an increased pre-specified number of stem cells infused", said Dr. Thomas Moss, Amorcyte's Chief Medical Officer.

At the stem of medical change

From its dockside laboratories at Fells Point - once the settlement ‘‘stem” of Baltimore - Osiris Therapeutics Inc. has quietly grown into a leader in stem cell science and technology, with five treatments in clinical trials.

...

Osiris, with 120 employees, raised nearly $130 million in 2005 and 2006, through its initial public offering and several private financing rounds. It had sales of $9.5 million in 2006 from its only commercial product so far, Ostelocel for regenerating bone mass.

...

The company completed five clinical trials in 2006, leading to Phase 3 trials this year for treatments for Crohn’s Disease and a life-threatening condition called Graft vs. Host Disease, or GvHD, of some bone marrow transplant patients. Revenues for the fourth quarter ending Dec. 31, 2006 were $3.1 million compared with $1 million for the same period in 2005. Quarterly loss was $12.7 million compared with $8 million for fourth quarter 2005.

For all the promise, it's early days yet. Of course, a decade from now we'll be looking at similar hard work, trials and commercialization for the early stages of tissue engineering complete organs. Advancing biotechnology and medical research only looks slow and incremental if you stand up close to the workers.

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Towards Very Early Disease Detection
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Catch cancer very early on - or any one of a range of other age-related, progressive conditions - and much more effective options for dealing with the problem exist, even today. Just like precision targeting, the impact of biotechnologies of very early detection is not to be underestimated. It's not as flashy as cures, but will save just as many lives. Judging by the low cost of entry into the tool development field these days, we'll have bioscanners in every clinic a decade from now: "the simple and inexpensive system, which can be built from off-the-shelf components, can rapidly detect the presence of cancer biomarkers - telltale proteins in body fluids that can signal the presence of malignant tumors - at very low levels. ... With this technology, a future scenario might be that you go to the doctor every year for an annual checkup; he draws about 10 cc's of your blood and runs it through our machine. The machine is equipped to detect the biomarkers for all the common types of cancer. Half an hour later it produces a list of the biomarkers that it has found. And then either a software program or the physician examines this list to determine whether you have any cancers that need treating. ... The researchers are focusing on lung cancer as an initial application because there is currently no adequate way to detect it at an early stage."

Link: http://www.azonano.com/news.asp?newsID=4087

Fighting Cytomegalovirus
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Age-related degeneration is sped along by the failing of the immune system, due in part to the cellular troops all facing the wrong way - geared up to fight cytomegalovirus (CMV) to the exclusion of all other tasks. Here, EurekAlert! reports on progress in eliminating CMV: scientists identified "the critical molecular targets controlling virus persistence, and two ways in which we can modulate immunity in vivo with the desired result of blocking virus spread to uninfected individuals. The potential excitement in the findings is that we may be able to one day use this kind of treatment in humans to block or significantly reduce the spread of cytomegalovirus and other chronic virus infections ... IL-10 is a messenger molecule which suppresses the protective T cell response that would normally attack the cytomegalovirus. By blocking the ability of the IL-10 molecule to bind to its receptor, then you allow these T cells to do their job and reduce or eliminate this virus. ... It significantly reduced the virus load in all the animals and in 50 percent of them it completely eliminated it." Sadly, this would only prevent ongoing damage if made to work in humans - it won't restore a CMV-focused immune system from its dysfunctional state. Other potential strategies are on the table for that task, however.

Link: http://www.eurekalert.org/pub_releases/2007-05/ljif-lsm051007.php

"...is not a part of natural aging"
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If I had a dime for every time I saw the phrase "is not a part of natural aging," or words to that effect, in connection with a named age-related disease ... well, I'd have a nice big stack of dimes. Here's one:

[Rheumatoid arthritis] is not a normal part of aging. It is a specific condition with symptoms that can't be cured, but can be managed.

"Arthritis should not be considered just a part of the aging process or a normal part of getting older"

Except that arthritis was absolutely thought to be a part of the "normal aging process" - until it wasn't. The dividing line between solemnly named condition and mysterious process of aging is utterly arbitrary; the "normal aging process" only really exists if you want to define it into existence. When you say "normal aging," you are applying a name to a collection of changes, damage, diseases and medical conditions, some of which have their own well-worn taxonomy, and some of which don't. But all changes can be identified, and medical technology developed to repair, prevent and reverse them.

Whether and what we name these undesirable changes for the worse is rather beside the point.

The mantra of "not a part of the normal aging process" is irrational. It's an irrational response to the irrational acceptance of aging as normal - folk slowly carving off one piece of "normal aging" at a time by giving it a new name and repeatedly asserting its individual nature as a thing apart from aging. It works with the funding sources and regulators, so scientists have made something of a habit of this over the years.

This is all very silly, and has to break down at some point. The Strategies for Engineered Negligible Senescence (SENS), for example, takes a good stab at breaking down the whole of degenerative aging into seven categories of condition, damage and change. All are named and known by the scientific community, if not by the average household, and anyone can jump up and say "this decay right here - that's not a part of normal aging, because we can see it, understand it and fix it!"

What's left of "normal aging" after the researchers and medical development groups have done that? Not much, and good riddance to a bad idea.

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Most Likely a Common Viewpoint
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Via the Synapse, what is most likely a common view of calorie restriction: "Obviously the idea of living disease free into old age is desired by most, but few people would seriously consider making the sacrifices required of such a complex diet. ... Since hundreds of people are restricting caloric intake [there] is sure to be an abundance of data about the long-term effects of calorie restriction on humans in the (not too distant?) future. This means that [we] can wait and see where this research leads and then change our minds later ... But before you have your cake and eat it too, consider that there may be an additional take-home message from this research. I would make the case that the potential benefits of short-term caloric restriction reported here seems to underline the prudence of eating in moderation." The human tendency to laziness at work: if there's the possibility of benefits later for work later, wait and see how it turns out rather than working now. But maybe you can get something for a little work now, since the results of the work look pretty compelling - but not compelling enough to propel you to action. It should be said that you can only call calorie restriction complex in comparison to a diet of "whatever, whenever, no attention to nutrition given" - and if you haven't actually tried it.

Link: http://www.ucsf.edu/synapse/content/51007/calories.html

Profile Of an Anti-Cancer Virus
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The Scientist profiles one of many initiatives to engineer viruses to destroy cancer: "He had been studying ways in which pox viruses evade the immune system and looking at ways to disable them. ... He had pox viruses from China and from Russia and India that were used as vaccines. He had elephant pox, camel pox, you name it; so we could immediately tap into that treasure trove and try to identify the best anticancer strains ... Of particular interest [was] a form of vaccinia known as extracellular enveloped virus (EEV), which appears tailored for long-distance travel through the blood stream and seems resistant to complement and neutralizing antibodies. He saw EEV as a key to achieving systemic spread of a therapeutic virus, in order to hunt down distant tumor metastases. ... Advances in bioengineering have provided the means to sharpen viral activity, fine tuning its targeting and adding transgenes that might aid in the destruction of cancer. Kirn is eager to get these infectious agents into humans. ... Even with more than a century of work on oncolytic viruses that hasn't spurred a major breakthrough, Kirn says that things are different now. The goals of research are more sharply defined, and the questions being asked in trials are more specific. Instead of merely documenting the effects of available or slightly-modified viruses, new candidate viruses can meet specific criteria."

Link: http://www.the-scientist.com/article/home/53142/

LysoSENS Work on CML Targeting
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As I'm sure you recall, LysoSENS is one form of longevity research funded by the Methuselah Foundation. Broadly, it is directed towards the use of bacterial enzymes to degrade harmful metabolic byproducts that build up over time. These byproducts are associated with age-related degeneration and a range of diseases related to the failure of the lysosome, the overwhelmed cellular garbage collector. Keep these byproducts below the level of causing damage, and you'll shut down one of the root causes of aging - so is the theory. Easier said than done, of course, as is any worthwhile goal, but folk are working on it now.

In every case, it is thought that the selective removal of the respective substances would be extremely beneficial, although obviously nobody has directly tested this. LysoSENS is an attempt to do just that, in the worst case paving the ground for rethinking what age-related storage diseases are all about, and in the best case providing a cure for them.

There are many different types of damaging metabolic byproduct, and thus many threads of research to find the keys to degrade them. Over at the Methuselah Foundation forums, you'll find one such line of work outlined for the layman:

CML (Carboxymethyllysine) is a chemical modification of lysine residues on proteins. It forms as a result of a sequence of reactions that begin with sugar molecules. In general such reactions can lead to the formation of Advanced Glycation Endproducts (AGEs), and CML is one of these.

...

A lot of AGEs cause chemical crosslinking between proteins. Your intuitive ideas of how this could be bad are probably accurate. Imagine if you started randomly soldering pieces together under the hood of a car. Now imagine that there are a million times as many types of pieces and spread out the soldering over a hundred years.

...

the circumstantial evidence linking CML to age-related diseases, nevermind the mechanisms, is pretty strong.

One reason we're excited about the possiblity of finding enzymes to remove CML from the body (actually, we probably want to find a way to just remove the "CM" part) is that CML might be low-hanging fruit as far as AGEs go - primarily, because it's not a crosslink. Because it's not a crosslink, it might be much more physically accessible to enzymatic remediation.

As for the cleverness of our particular schemes to find enzymes that specifically remove the "CM" from the "L", I'll leave that for someone else or for another night...

It's exciting to watch this sort of work underway - even more so if you're one of the forward-looking folk who helped to fund this research. This is your generosity at work, enabling young scientists who support healthy life extension to work towards creating more healthy years for all of us.

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More State Funding For Stem Cell Research
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As for New York, New Jersey and California, Massachusetts continues to move towards large-scale funding of stem cell research from public monies: "Gov. Deval Patrick on Tuesday unveiled a $1.25 billion proposal intended to help the state maintain its status as a pre-eminent place for stem cell research and other life sciences. The money would provide grants for university and hospital scientists, establish special research centers to make their work faster and more efficient, and train workers for biotechnology businesses. It would also establish the first stem cell bank, a repository of all the stem cell lines created in Massachusetts laboratories, which would serve as a kind of stem cell lending library to scientists around the world. ... Mr. Patrick's plan involves $1 billion in state money over 10 years, some borrowed through bond issues, plus $250 million in matching money from private business." Nothing like massive centralization to remove the accountability and incentives that lead to efficient use of funds - not to mention the terrible waste of resources spent on fighting for control of the purse.

Link: http://www.nytimes.com/2007/05/09/us/09stem.html?pagewanted=print

New Look For the Methuselah Foundation
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You might have noticed the reworked Methuselah Foundation website: "The golden age is before us, not behind us." Quite true, albeit in ways that Sallust could only have dreamed of; the ancients had a keen vision for longevity and health, but never the tools to attain it. This new design places a sharper focus on the mission and present activities of the Foundation: "a non-profit 501(c)(3) volunteer organization dedicated to raising public awareness of the near-term potential for evidence-based interventions in the aging process. To this end, we perform research focused on repairing the damage that accumulates at the cellular and molecular level with time causing age-related dysfunction, and offer the multi-million dollar Methuselah Mouse Prize (Mprize) for significant, scientifically reproducible life extension in already aged lab mice." Degenerative aging will one day be defeated through the development of more advanced biotechnology, and the Foundation serves as a rallying point for those willing to help make it happen sooner rather than later.

Link: http://www.methuselahfoundation.org

On Queen Bee Longevity
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Those of you of a certain age will no doubt recall a good example of "anti-aging" magical thinking in the advertisement of royal jelly. Queen bees live far longer than workers, queen bees are associated with royal jelly, therefore...

Magical thinking is that state wherein you invent your own logic; the human gift for pattern recognition run amok, let loose by the human gift for laziness. Reality, unfortunately, cares little for what you think - this is why those who follow the scientific method prosper. Prosper so well, in fact, that a horde of lazy crickets can practice magical thinking and other frivolous pastimes, supported by the vast wealth produced by those who practice science.

So what's the reality of queen bee longevity, and what does it mean for medical science? As it turns out, the bees might one day be up there with flies, yeast and nematodes as a model to study certain important processes in aging.

Researchers at Illinois explore queen bee longevity:

Expression of Vg was high in the abdomen in the young queen and declined over time, but increased with age in the head and thorax. Old queens showed much higher Vg expression than young queens.

Worker bees had much lower levels of Vg expression than queens, and Vg in worker heads was also low compared with queens. Previous studies in workers had shown that Vg reduced oxidative stress in honey bees by scavenging free radicals that can lead to aging or illness. Not surprisingly, queens were more resistant to oxidative stress than workers.

Whether this is the actual mechanism by which queens achieve both fertility and long life remains to be seen, Robinson said. In any event, this study suggests that vitellogenin plays a vital role in queen bee longevity, he said, particularly since the honey bee lacks many antioxidants commonly found in other species.

Oxidative damage again as the determinant of longevity differences - perhaps naked mole-rats and their imposing resistance to oxidative stress would be a better companion species to the bee, insofar as longevity studies go.

I fully expect to see serious attempts to greatly alter the processes, amount and results of oxidative damage in humans make progress in the next two decades; the weight of evidence for potential benefits is far too great to ignore. The results of supplements, diet and calorie restriction are not "greatly alter" - here I mean repair biotechnologies such as protofection to remove a source of oxidative damage, or gene engineering to introduce effective, targeted antioxidants to where they will actually work. Some paths are more effective than others, but the attempts will be made, and more power to those folk who get them off the ground and flying.

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Pseudocells As Targeted Delivery Vector
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Building medical technology from biological components is the new black, and a great deal of very inventive work is presently taking place out there in the world. From the New Scientist, here is one that continues the cellular micromachine theme: "When bacteria divide, they normally do so at their centres. But [researchers] have found a way of forcing them to divide at their ends, producing small buds of cytoplasm each time. They have also discovered that a range of different drugs could be packaged into these particles. These 'mini bacteria', or EnGeneIC Delivery Vehicles (EDVs) as the company has dubbed them, are cheap and easy to produce, and can be used as targeted drug delivery vehicles. ... They look like bacteria but they have no chromosomes and are non-living. And because they have a rigid membrane they don't break down when injected, so they carry their payload happily to the target site ... The EDVs are able to selectively target different tissues thanks to [antibodies] attached to their surface." Hopefully we all recall just how revolutionary good targeting technologies are in medicine - they will be the difference between life and death for millions every year.

Link: http://www.newscientist.com/article/dn11797-minicells-could-stop-sideeffects-of-chemotherapy-.html

Repairing Blood Vessels With Stem Cells
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News of the latest technology demonstration from Advanced Cell Technology: "hemangioblast precursor cells derived from human embryonic stem (hES) cells can be used to achieve vascular repair ... When the cells were injected into animals that had damage to their retina due to diabetes or ischemia-reperfusion injury (lack of adequate blood flow) of the retina, the cells homed to the site of injury and showed robust reparative function of the entire damaged vasculature within 24-48 hours. The cells showed a similar regenerative capacity in animal models of both myocardial infarction (50% reduction in mortality rate) and hind limb ischemia, with restoration of blood flow to near normal levels. ... These cells were able to generate functional blood vessels in the presence of severe tissue injury, as well as in chronic disease states. These cells have a robust vascular reparative ability under what is typically considered very adverse growth conditions making them potentially ideal for treatment of diabetic vascular complications where profound tissue compromise exists and healing is typically severely compromised."

Link: http://www.advancedcell.com/press-release/precursor-cells-generated-from-human-embryonic-stem-cells-show-ability-to-repair-vascular-damage-in-animals

Pre-orders Available For "Ending Aging" - Spread the Word
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As you might have noticed, you can now pre-order the forthcoming Strategies for Engineered Negligible Senescence (SENS) book by Aubrey de Grey and Michael Rae, "Ending Aging: The Rejuvenation Biotechnologies That Could Reverse Human Aging in Our Lifetime." Aimed squarely at folk who want to know more about the science of repairing the molecular damage that causes aging, but find navigating the wild waterways of scientific publications too intimidating or time-consuming, this is a step by step, detailed explanation of how we could achieve radical life extension within our lifetimes, as best we understand from our present knowledge of our biochemistry.

If you're used to the "eat this, take supplements and exercise" longevity bookshelf, Ending Aging is a big step up - very much more "research this science to develop this specific therapy based upon that sound basis established over the past two decades." You'll be seeing more of that in the years ahead, and this exactly where your attention should be focused if you care about your own longevity.

Kevin Perrott of the Methuselah Foundation was kind enough to run up a banner for pre-ordering Ending Aging whilst redesigning the Foundation website. Here it is: right click, save picture as, and use it as you will to spread the word:

If those of you with artistic tendencies want to pitch in, we'd all be happy to see a more interesting selection than can be produced by those of us blessed with too little time (or too little artistic talent in my case). Have at it!

In any case, I'm sure you all know the drill of self-interested altruism here: publishing companies like pre-orders; it makes them happy and more likely to go the extra mile beyond established plans when it comes time for active promotion closer to launch. Promotion of "Ending Aging" means promotion of the Strategies for Engineered Negligible Senescence, which in turn means that more people will come to learn about and support serious efforts to extend our healthy life span soon enough to matter for you and I. That is a big deal; we have to build the widespread understanding and support for large-scale research into longevity, and the only way that happens is one step at a time.

Besides, stepping off the soapbox for a moment and speaking as someone who edited drafts, it's a damn good book on exactly why we age and die - and what we can actively, materially do about it in the years ahead. So get out there and pre-order if you intend to read it after it comes out.

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The Humble Nematode
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A fair amount of modern research into aging, longevity and the manipulation thereof starts in studies of the nematode Caenorhabditis elegans. Scientists start with short-lived lower animals such as nematodes, flies and yeast for all the obvious economic reasons; if you're going to pitch an expensive study in mammals - and studies in mammals are always expensive, never mind the ones in which a team carefully monitors the mammals for year after year - you had better have cast-iron support. No-one will fund out of the blue, and working with short-lived, easily managed creatures allows researchers to explore much more of any given problem space at a given level of funding.

One of the benefits of the way the world works - in this case that we all evolved from a common ancestor - is that you can produce value for the development of human medicine from a study of a creature with 1000 cells and lifespan of weeks. There are common mechanisms, shared biochemistry, cellular structures and processes. Here are a couple of recent papers; food for thought, and an insight into some of the work presently underway in the scientific community.

Public and private mechanisms of life extension in Caenorhabditis elegans:

Model organisms have been widely used to study the ageing phenomenon in order to learn about human ageing. Although the phylogenetic diversity between vertebrates and some of the most commonly used model systems could hardly be greater, several mechanisms of life extension are public (common characteristic in divergent species) and likely share a common ancestry. Dietary restriction, reduced IGF-signaling and, seemingly, reduced ROS-induced damage are the best known mechanisms for extending longevity in a variety of organisms.

Dietary restriction in the nematode Caenorhabditis elegans:

The nematode Caenorhabditis elegans has proved to be an excellent model organism for the study of development and aging. Many aging mutants have been discovered in the past two decades, and much has been discovered about the physiology of long-lived mutants. It therefore seems surprising that dietary restriction (DR) has not been extensively studied using C. elegans. The main reason for this is the lack of an ideal method to subject C. elegans to DR. However, several authors have tried to study the effect of DR on the metabolism and physiology of C. elegans, and epistasis-type interaction studies have been carried out in order to detect genes that might be involved in DR effects. These studies show that DR life extension is not caused by a reduced metabolic rate, consistent with results in other species. Moreover, the well-known insulin/IGF-1 pathway seems not to mediate life-extending effects. One possibility is that target of rapamycin signaling mediates the effects of DR on life span in C. elegans.

Some folk seem a little skeptical of the whole "target of rapamycin" work, but the proof is in the pudding. Resources continue to pour into the study of calorie restriction biochemistry and the related more general topic of metabolism and longevity - I can't imagine that the most pressing unanswered questions will remain unanswered for too many more years.

The way the mainstream research community is following through on doing something with this new information, on the other hand, seems inefficient - as I've been saying for a while. Greater knowledge eases all future research and development, but some paths forward are better than others:

Practicing calorie restriction is free, but research is not. The present purposing of the aging research community to metabolic manipulation is expensive, but money isn't the real concern. An opportunity is being lost: the real cost is the slowdown in developing a research infrastructure that is instead purposed towards identification and repair of aging damage, a more efficient way forward to extended healthy lives. This is the difference between tuning your engine and taking it to a mechanic: tuning gets you so far and so far only; at some point, you're going to have to repair the components.

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More on Cellular Micromachines
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Via the Cantonsville Times, another look at the near future of medical devices - make them small, make an army of them, and build them exactly like cells: "Imagine not having to go to the doctor when you are sick. No medicine, no popping pills. Instead, tiny cell-like machines in your body would manufacture medicine and deliver it exactly where it is needed. University of Maryland researchers said these 'nanofactories' may not be that far away. Nanofactories are pseudo-cells that are swallowed, inhaled or absorbed through the skin and travel to a specific location in the body. What's unique about these tiny biochemical factories is that they could potentially use materials already in the body to manufacture medicine at the first sign of infection or disease. ... You actually take components and make something that wasn't there before. It takes things from their environment and puts them through the factory and generates something important." Our cells are tiny, complex machines - varied, efficient, autonomous robots in effect. Since we want more of the same, but tailored to our design, why not start with the blueprint that's right under our noses?

Link: http://news.mywebpal.com/news_tool_v2.cfm?pnpID=351&NewsID=803814&show=localnews

The Fading Ability to Heal
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(From ScienceDaily). Diabetes is often used as a model for aging by researchers, as some of the underlying mechanisms or consequences are similar. Here, researches examine the mechanisms by which healing works, and then ceases to work with disease progression. " Endothelial progenitor cells (EPCs), which derive from bone marrow, normally travel to sites of injury and are essential for the formation of blood vessels and wound healing. ... The authors examined diabetic mice and found that increased oxygen levels (hyperoxia) enhanced the mobilization of EPCs from the bone marrow to the peripheral blood circulation. The high oxygen levels increased the activation of the bone marrow enzyme eNOS, which stimulated nitric oxide production, helping to produce greater numbers of EPCs. However, local injection of the chemokine stromal cell-derived factor 1 alpha (SDF-1alpha) was required to recruit these EPCs from the circulation to the wound site. The increased presence of EPCs at the wound site resulted in accelerated wound healing. The authors concluded that impaired eNOS activation and decreased SDF-1alpha expression in diabetes are responsible for the defect in diabetic wound healing." Failures in this healing process exist in aging due to the accumulation of damage in vital components of our biochemistry. We should hurry to repair that damage just as we hurry to cure diabetes.

Link: http://www.sciencedaily.com/releases/2007/05/070504141456.htm

Linking Telomere Shortening and Mitochondrial Damage?
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I bumped into a great paper just the other day that illustrates the rewarding side of keeping up with scientific publications. Every so often you see something that might just be very important if correct, linking together disparate but significant areas of exploration and indicating that the way forward might be more straightfoward than imagined. The mapping of complex systems often looks like this - sail the rivers first, and then find the roads between. All becomes clear in hindsight, and those moments at which clarity arrives are easily remembered.

In any case, have a look at this PloS Biology publication claiming telomere shortening to rest on the shoulders of mitochondrial damage:

After a limited number of cell divisions, somatic cells lose the capacity for proliferation, called cellular replicative senescence. Senescence, which is triggered by the loss of DNA sequences at the ends of chromosomes (telomeres), is often seen as an example of a regular “biological clock.” However, cell senescence is heterogeneous, with large differences in lifespan between individual cell lineages. This heterogeneity is clearly related to stress, specifically oxidative stress. It was not known, however, whether stress-induced “premature” senescence involves telomeres or is caused by telomere-independent DNA damage responses. Mitochondria are the most important source of reactive oxygen species (ROS) in cells under physiological conditions. We found that mitochondrial function deteriorated while cells approached senescence, leading to increased ROS production. Delaying mitochondrial dysfunction led to postponed replicative senescence and slowing of telomere shortening. Prematurely senescing cells sorted out of young cultures displayed mitochondrial dysfunction, increased oxidative stress, and short telomeres. We propose that replicative telomere-dependent senescence is not “clocked,” but rather is a stochastic process triggered largely by random mitochondrial dysfunction.

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

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

Keep an eye on the funding for research into cures for mitochondrial diseases in the next few years; the mainstream funding system is steered by regulation into supporting only the search for cures for specific named conditions, but the technologies employed in repairing dysfunctional, malformed mitochondria may also be applied to age-damaged mitochondria.

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A Look Inside the CALERIE Study
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From the Daily Reveille: "Pennington Biomedical Research Center conducts what Assistant Communications Director Alan Pesch called an 'exciting' two-year study on the effects of calorie restriction. The new study, CALERIE II, marks the second phase of a $12.4 million, seven-year study launched in 2002. ... Pennington researchers and others have already successfully linked caloric restriction to longevity in small animals and organisms. ... We know it's been working for flies, worms, yeast and then mammals like rats and mice. All the data are consistent, and the question is: Do we have any evidence that it can work in humans? ... Pennington will use a variety of techniques to analyze test subjects' metabolism, which may affect longevity. Researchers will also examine genes they believe may control bodily responses to caloric restriction. Though the study examines the effects of caloric restriction, Pennington plans to test whether subjects can realize a longer life through increasing activity levels. ... There is something we don't understand totally that keeps your cells in the body younger ... Pennington will accept 100 qualified men and women for the upcoming two-year study. Enrollment begins in late summer."

Link: http://www.lsureveille.com/home/index.cfm?event=displayArticlePrinterFriendly

An Interview With Guarente And Butler
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Via the transhumantech list, an interview with researcher Lenny Guarente and Robert Butler of the International Longevity Center, folk from the longevity dividend camp: "I dont think of life span as the gold standard. The gold standard is health span. All the indicators from the laboratory are that the genes were studying and the kinds of drugs we would be developing would extend health span. If you can extend health span, and you also happen to extend life span, so be it. Thats a side benefit. ... Why does 50 percent of all cancer occur after 65? Why does 80 percent occur after age 50? As we age, there are changes at the cellular molecular level that predispose us to disease and disability. But so far, no government, no foundation, no corporation anywhere in the world has fully embraced the importance of longevity science. If we could target aging, that would have an impact on diseases." He means no foundation of massive size of course - the Methuselah Foundation is way ahead of the longevity dividend position. It is interesting to note that Guarente puts a timeline of 10-15 years on the arrival of drugs to replicate the effects of calorie restriction on healthy longevity.

Link: http://postbiota.org/pipermail/tt/2007-May/000469.html

Nuts and Bolts of Naked Mole-Rat Longevity
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While we're on the subject of oxidative stress, here's a paper looking at just how resistant naked mole-rats are to oxidative damage. This seems to be the root of their eight-fold longevity over similarly sized rodent species. "The naked mole-rat (NMR; Heterocephalus glaber) is the longest-living rodent known (maximum lifespan potential [MLSP]: >28 years) and a unique model of successful aging showing attenuated declines in most physiological function. This study addresses age-related changes in endothelial function and production of reactive oxygen species in NMR arteries and vessels of shorter-living [rats]. ... long-living NMRs can maintain a youthful vascular function and cellular oxidant/antioxidant phenotype relatively longer and are better protected against aging-induced oxidative stress than shorter-living rats." The short version of the story is that - by a whole range of biochemical measures - naked mole-rats just don't show much evidence of this aspect of degenerative aging, an aspect that causes great suffering for we humans. As for several other species of mammal, the mole-rats indicate there is great room for improvement in the human model. Which is interesting, but certainly not the fast path to greatly extended lives, for all that we live in the midst of a revolution in biotechnology - it's much easier to learn to fix damage in the present model than to rework our biochemistry to resist that damage.

Link: http://dx.doi.org/10.1152/ajpheart.01287.2006

CR Makes For Efficient Mitochondria
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Via PLoS Medicine, a look at the benefits calorie restriction (CR) brings to mitochondrial function - and hence to your long-term health: "A calorie-restricted diet provides all the nutrients necessary for a healthy life but minimizes the energy (calories) supplied in the diet. ... A major factor in the age-related decline of bodily functions is the accumulation of 'oxidative damage' in the body's proteins, fats, and DNA. Oxidants - in particular, chemicals called 'free radicals' - are produced when food is converted to energy by cellular structures called mitochondria. One theory for how caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria. ... The induction of these efficient mitochondria in turn reduces oxidative damage in skeletal muscles. Consequently, this adaptive response to caloric restriction might have the potential to slow aging and increase longevity in humans as in other animals. ... CR and CR [plus exercise] both increased the number of mitochondria in skeletal muscle. Both interventions also reduced the amount of DNA damage - a marker of oxidative stress - in the participants' muscles." The normal caveats are given, but the more we learn about the mechanical operation of calorie restriction, the better it looks, given that it costs nothing but thought and time to try.

Link: http://dx.doi.org/10.1371/journal.pmed.0040076

Go Vote
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From Anne C.:

I am currently working on an essay on the subject of attitudes toward death and aging, and would appreciate it greatly if readers could take a few moments to fill out the poll in this post.

Given the quality of her work, you should all head over and help the creative process. Pass the word along, too - no such thing as too many passers-by for poll.

Attitudes towards death and aging, and changes in those attitudes, shape the future of healthy life extension and the longevity research it depends on. If everyone was perfectly comfortable with aging to death (and the inevitable frailty, helplessness, pain and suffering), then it seems self-evident that there would be little or no funding for meaningful anti-aging science. If everyone desired health and longevity, and acted rationally on that desire, then the aging research community would be afloat upon a sea of banknotes.

Neither extreme reflects reality of course; attitudes are complex and contradictory. Opinions depend on how you ask the question. People faun over the worthless trinkets of the "anti-aging" marketplace, looking for the silver bullet that doesn't exist, while refusing to believe that science to actually repair the damage of aging is comparatively close at hand. Folk defend the existence of death and aging, while seizing upon straws in the wind to mask their wrinkles.

It's a strange world, populated by strangers - and it'll be the death of us all if we don't get our act together. Real, working technologies that can rejuvenate the aged - exactly, literally, rejuvenate - are only a few decades away. If the science is funded, if the research community forms, if the public support and understanding exists.

Or we could all keep giving money to the makers of wrinkle-reducing products and sellers of magical thinking about aging - I'm sure they'll be glad to take our funds, as they age to death alongside the rest of us.

As always, the choice of which future you want to live in, and how much of it you see, is very much up to you.

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"Ending Aging" At Amazon
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The Methuselah Foundation notes that the forthcoming SENS book is now available for pre-order at Amazon: "Which means we all now know the title: Ending Aging: The Rejuvenation Biotechnologies That Could Reverse Human Aging in Our Lifetime. Having edited drafts earlier this year, I'm in a position to say: buy it. 'Ending Aging' provides a far richer introduction and overview of SENS science, of the real prospects for progress in extending our healthy life spans, and of the nuts and bolts of getting there, than any other material published to date. If you are in the demographic who finds the information at the SENS website too little, but the interlinked world of scientific papers on longevity science too much, and have A Brief History of Time in your collection, then this book is for you." Ending Aging arrives in September, and is well worth the wait. Michael Rae, Aubrey de Grey and the Foundation volunteers have done a superb job.

Link: http://blog.methuselahfoundation.org/2007/05/ending_aging_available_for_pre.html

Manipulating NAD For Longevity
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Scientists continue to try and recreate aspects of the biochemical changes brought on by calorie restriction, in an effort to generate the health and longevity benefits via medicine. An example can be found at ScienceDaily: "a newly discovered vitamin activates the yeast anti-aging gene product Sir2, which resembles sirtuins found in humans. ... NR (nicotinamide riboside), a natural product found in milk. Like the B3 vitamin, niacin, NR is a precursor to a versatile cellular factor that is vital for all life. The factor, called NAD, short for nicotinamide adenine dinucleotide, is elevated by calorie restriction. So the researchers set out to develop an intervention to elevate NAD, using yeast cells, whose genes are easy to manipulate. ... It's surprising that no one was be able to elevate NAD with a small molecule before ... The team discovered two pathways that allow yeast to raise NAD levels with NR, improve their control of gene expression and live longer in the presence of high glucose." Some folk in the gerontology community are skeptical, pointing out that no success has been obtained in mammals through the use of other precursor biochemicals in this pathway - this may be one of the many differences rather than similarities between yeast and people.

Link: http://www.sciencedaily.com/releases/2007/05/070503125741.htm

Autophagy
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Autophagy is, broadly speaking, the process by which your cells recycle damaged components. Cells are packed full of building blocks dedicated to specific tasks, and few of them are designed to last. The average cell is a little powerhouse of dynamic destruction and construction, tearing down and rebuilding organelles left and right. Like all important cellular processes, autophagy is complex, regulated by a web of genes and proteins. The Wikipedia entry gives a good introduction:

In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process which plays a normal part in cell growth, development, and homeostasis, where it helps maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more essential processes.

A variety of autophagic processes exist, all sharing in common the degradation of intracellular components via the lysosome. The most well known mechanism of autophagy involves the formation of a membrane around a targeted region of the cell, separating the contents from the rest of the cytoplasm. The resultant vesicle then fuses with a lysosome and subsequently degrades the contents.

But we can say that more autophagy appears to be a good thing. You don't want damaged organelles running wild in your cells; one only has to look at the mitochondrial free radical theory of aging to see where that can lead - a trick of biochemistry prevents mitochondria from being recycled, and ever more damaged cells spew toxins into your body, causing the degenerations of aging that follow.

Scientists believe that a number of the benefits of calorie restriction result from an increased level of autophagy, producing a lower level of damage in your cells at any given point in time. Over at the Immortality Institute forums, you'll find an educational reprint on the process of autophagy:

Autophagy often gets overlooked as "just housekeeping," says Beth Levine, professor of internal medicine at the University of Texas-Southwestern Medical Center at Dallas. In fact, she says, failures in keeping house likely contribute to diseases such as cancer and neurodegeneration. In addition, autophagy wanes with age for reasons that aren't yet clear, says Levine, and is "mechanistically important" in aging itself.

...

Other pathways have certainly been implicated in the lifespan extension induced by calorie restriction. Fasting upregulates expression of sir-2 in yeast and worms, and SIRT-2 in mice, and the resulting proteins may help mobilize glucose for use in the cell. At present, no one has tried to link autophagy to the sir-2 pathway, although Levine admits that she's pondered the notion.

Aging is ill defined and certainly multifactorial. The appeal of autophagy to ameliorate normal aging is its capacity as a jack-of-all-trades repair mechanism in the cell. "I believe that the induction of autophagy in caloric restriction-or loss-of-function mutation in insulin signaling-leads to increased degradation of damaged mitochondria and reduction of oxidative stress," says Levine. "And that's probably a downstream pathway that's in common to all these life extension phenotypes."

What interesting times we live in! A great new territory of knowledge and possibility is opening up around new biotechnologies, and aging is becoming open to intervention and ultimate defeat.

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More On PHA-4, Calorie Restriction and Longevity
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A better article on the latest calorie restriction gene via EurekAlert!: "After 72 years of not knowing how calorie restriction works, we finally have genetic evidence to unravel the underlying molecular program required for increased longevity in response to calorie restriction ... Loss of only one of the genes, a gene encoding the protein PHA-4, negated the lifespan-enhancing effect of calorie restriction in worms. And, when researchers undertook the opposite experiment - by overexpressing pha-4 in worms - the longevity effect was enhanced. ... So far, only one other gene, called sir-2, has been implicated in the life- and health-prolonging response to calorie restriction. Increased amounts of SIR-2 protein extend longevity of yeast, worms, and flies, but while loss of sir-2 disrupts the calorie restriction response only in yeast, it has no effect on other organisms, such as worms. ... We know three distinct pathways that affect longevity: insulin/IGF signaling, calorie restriction, and the mitochondrial electron transport chain pathway, yet it is still not clear where sir-2 fits in. It seems to meddle with more than one pathway. PHA-4 is specific for calorie restriction as it does not affect the other pathways."

Link: http://www.eurekalert.org/pub_releases/2007-05/si-srd042607.php

Towards a Progeria Therapy
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From Newswise, an update on progress towards treating progeria - and maybe "normal" aging too: "Scientists studying the genes of two infants who died of mysterious illnesses found the infants had mutations in LMNA, the same gene altered in patients with the premature aging condition progeria. ... when researchers treated cell samples from one of the patients with a drug targeted for progeria, they saw signs that the cells were improving. ... progeria treatment may not be as distant as we thought. If physicians can reduce production of bad lamin A by as little as half in progeria patients, we might see significant improvement. ... Progeria treatment also has potential implications for larger populations. The LMNA gene is involved in several other more prevalent disorders including forms of muscular dystrophy and heart disease. ... recent studies by other labs have shown that occasional errors in the production of lamin A may take place even in people with 'normal' copies of the gene. Scientists suspect that accumulation of these bad copies may contribute to aging. If so, treatments that work for progeria patients may one day be adapted to reduce the effects of aging."

Link: http://www.newswise.com/articles/view/529622/

Taming Tau
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As a companion to a recent NYAS meeting summary pointed out at the Longevity Meme, here is another on the same topic: the biochemistry of Alzheimer's disease.

In the modern history of drug discovery in Alzheimer's disease (AD), amyloid-β (Aβ) has played the diva's role: center stage, with top billing - and difficult to manage. Aggregates of this peptide, which form amyloid plaques, are evident in the brains of people who die of or with Alzheimer's disease, making it an obvious target for therapeutics. But simply reducing amyloid buildup in the brain hasn't been easy. Meanwhile, evidence mounts that the microtubule-associated protein tau is an equally important player in this disease process.

...

Right now, the prevailing idea is that tau, which under normal conditions stabilizes microtubules, becomes hyperphosphorylated and undergoes conformational changes in Alzheimer's disease. Tau is normally phosphorylated - it can undergo phosphorylation at up to 19 sites, affecting the kinetics of how it binds to microtubules - but in AD, phosphorylation expands to almost all possible sites, about half of which are serine/threonine residues followed by a proline. A cluster of pathogenic events is associated with this change: tau, normally highly soluble, accumulates in neurites and forms insoluble tangles. Tau also moves from the axons into the somatodendritic compartment of the cell. The protein appears to lose its ability to bind to and stabilize microtubules. Ultimately, cells stop working properly and die.

Why this happens, and how these various steps are causally linked, is a flourishing field of research.

From where I stand, admittedly far from the action, Alzheimer's has the look of a clump of related conditions or disease-causing processes. Many roots leading to a similar and unfortunate end state would explain a great many of the contradictory or seemingly unrelated lines of research to date.

Watching reports from the front is a good way to obtain an impression of the scale of our biochemistry - it's immensely complex. Equally, we should be impressed by the degree to which modern technology and the scientific community are up to the tasks at hand. The secrets of Alzheimer's, just as for the rest of our inner workings, won't remain secret for many more years. Along the way, scientists will have accumulated the working knowledge of the brain that we'll need to help extend healthy life span in the near future.

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A New Calorie Restriction Gene
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The Wall Street Journal reports on another gene that regulates the benefits to health and longevity produced by calorie restriction: "This gene is absolutely essential for the response to dietary restriction [in] prolonging life span ... we're still in the identification [of genes] phase and a long way from clinical trials. ... The gene [known] as PHA-4 was discovered in worms, where it plays a key role in the embryonic development of the intestine. However, PHA-4 also coordinates other genes that influence how the adult worm's body responds to a restricted diet. Humans possess three genes that are very similar to PHA-4. ... The gene is highly conserved in humans, mice and worms. So its function in humans could be similar. ... Other researchers have studied a different gene, SIR-2, which plays a role in extending longevity of yeast, worms and flies. However, its role isn't as specific in influencing the calorie-restriction response as PHA-4." So continues the process of narrowing down the focus: how exactly is it that calorie restriction extends healthy life? When that question is answered, engineering similar benefits for everyone through medical science becomes a plausible goal - albeit not as efficient a way forward as other plausible goals.

Link: http://online.wsj.com/article/SB117804593208188504.html

We Should View Aging As Curable
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Randall Parker lends his voice to common sense foresight for medicine and longevity: "I would [argue] that the general advance in biotechnology, with the continuing development of much more powerful tools to measure and manipulate biological systems at the molecular level, makes the idea of rejuvenation seem much more attainable. ... [we should] expect orders of magnitude more powerful tools in a couple of decades. Just as the shrinking size [of] computer technology allows computer chips, hard drives, fiber optics, and transceivers to go through long series of doublings in capability so does the miniaturized level at which biological instrumentation advances. Why shouldn't we treat aging as curable? The amazing physicist Richard Feynman gave a speech in 1959 entitled There is plenty of room at the bottom where he argued that we can develop the ability to manipulate matter at the molecular level. A continuing trend in technology since that speech has been the development of tools to better measure and manipulate increasingly smaller amounts of material. ... That trend is also going to lead to technology that allows us to make nanodevices that can repair human tissue at the level of individual cells and molecules."

Link: http://www.futurepundit.com/archives/004218.html

On the Aging of Stem Cells
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As Chris Patil points out, the latest Annals of the New York Academy of Sciences contains a number of interesting papers. The two that jump out at me today relate to the aging of stem cells, a topic I've touched on before. How and why do the capacities of stem cells to repair your tissue deteriorate with age, and what can medical research do about this degeneration in the near term? These papers are modest components in the larger picture: progress towards answers, and from answers to interventions.

A Dual Role of p21 in Stem Cell Aging:

A decline in adult stem cell function occurs during aging, likely contributing to the decline in organ homeostasis and regeneration with age. An emerging field in aging research is to analyze molecular pathways limiting adult stem cell function in response to macromolecular damage accumulation during aging. Current data suggest that the p21 cell cycle inhibitor has a dual role in stem cell aging: On one hand, p21 protects adult stem cells from acute genotoxic stress by preventing inappropriate cycling of acutely damaged stem cells. On the other hand, p21 activation impairs stem cell function and survival of aging telomere dysfunctional mice indicating that p21 checkpoint function is disadvantageous in the context of chronic and persistent damage, which accumulates during aging. This article focuses on these dual roles of p21 in aging stem cells.

This is essentially cancer versus aging, as is often the case in regulatory functions related to the cell life cycle. Do you want damaged stem cells churning away, raising the risk of the biochemical accidents that generate cancer, or do you want to damp down the repair function, thereby accumulating more damage that causes aging? No good choice there, but the future of medical science provides other approaches - such as repairing the damage via new technologies.

Age-Dependent Effects on Functional Aspects in Human Satellite Cells:

In humans aging is a complex process that determines many physical and metabolic alterations correlated to the accumulation of oxidative damage in different tissues. Sarcopenia is an age-related nonpathological condition that includes a progressive loss of mass and strength in skeletal muscle, associated with a decline in the fibers' functional capability. This condition could be correlated to abnormal reactive oxygen species (ROS) accumulation with consequent fiber oxidative damage. This complex situation is not only evident in mature muscle fibers but also in muscle resident satellite cells (involved in fiber damage repairing)

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These results suggest that during donor's life the satellite cells undergo an aging process similar to the one observed in skeletal muscle tissue, even if they are in a quiescence status for most of the time.

The failing capabilities of satellite cells in muscle have come up before here at Fight Aging! For example:

One small part of the whole, but it shows just how rapid, broad and deep the river of science runs. Even in the just the past few years, understanding has advanced in leaps and bounds. Where next? That's up to us.

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