On Longevity Insurance
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Pantagraph.com discusses longevity insurance in a piece that provides more of the nuts and bolts details than my recent post on the subject at Fight Aging! "In its simplest form, the premise of longevity products is that by making a one-time payment, you will start receiving guaranteed lifetime income at a designated point in the future. Your projected income stream is calculated at the time that you invest. ... The insurance companies rely on the fact that people aren't going to live that long to provide the payouts to the select few that will ... financial planners were critical because the investments, while similar to annuities, carried high commissions and lacked some of the flexibility traditional annuities offer, such as inflation protection and return-of-premium benefits ... Insurers have since added some of these options. But such features add considerably to the cost, which leads critics to still question whether such products are worth the investment." And of course, whether these insurers are going to be ambushed by rapidly rising longevity in the old, thanks to modern biotechnology, and thus rendered unable or unwilling to meet their obligations.

Link: http://www.pantagraph.com/articles/2006/12/31/money/doc45970259ec07b165223006.txt

FuturePundit On CETP VV
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Randall Parker of FuturePundit comments on the latest results from studies of the long-lived and centenarians: "CETP is on one of the 3 pathways that transfer cholesterol from HDL particles in the blood into the liver. So CETP is involved in regulating the amount of cholesterol in the blood. ... Work is underway to develop a drug that emulates the effect of this life-extending version of the CETP gene. But I'd much rather get a gene therapy that'd enhance my liver cells to express the genetic variant for CETP that slows aging. I've long thought the liver a key target for slowing whole body aging because it regulates blood lipid, lipoprotein, and cholesterol levels. This CETP gene variant (called CETP VV) is likely just one of many genetic variations waiting to be found that are expressed in the liver and can raise life expectancy." As I've said before, this sort of complex work to tweak metabolism to slow the rate of age-related damage does not seem to be the best use of scientific resources, at least when compared to the path of periodically repairing damage.

Link: http://www.futurepundit.com/archives/003990.html

Site Updates at Fight Aging! and the Longevity Meme
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As you might have noticed, I have enacted a number of updates - obvious and not so obvious - here at Fight Aging! and over at the Longevity Meme over the past week or so. The intent is to both to focus more clearly on the purpose and use of these websites as they stand today, and to clean up the laundry list of minor improvements, factual updates and bugfixes that have been languishing untouched or unnoticed for quite some time.

As I see matters, the Longevity Meme is a combination of news tracker and introductory reference library for healthy life extension and its activism, while Fight Aging! is equal part bullhorn at large and conversational market maker for the healthy life extension community. This is how matters have shaken out over the years, in any case. I'm happy to keep it this way and focus my attention to working on education and awareness by growing the audience.

Of note here at Fight Aging! is that I have finally set foot upon the link sharing enablement bandwagon. Better late than never; I am, as ever, the cautious late adopter. You'll see that posts here now come equipped with links to ease submission to the various aggregation and link sharing communities (StumbleUpon, Reddit Science, and so forth) that have helped discussion of healthy life extension reach a wider audience in the past. Feel free to use them if you feel a post is worthy of more attention.

As always, if you see anything untoward or outright broken as a result of recent changes, please do let me know.

Speculation on Solar Radiation and Longevity
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Speculation indeed:

The reasons for the link are not fully understood, but it has been suggested that the amount of solar radiation we are exposed to in the womb is a key influence. The amount of radiation varies according to where you are in the world, what time of year it is and cyclic changes in the sun’s behaviour. The Equator generally gets the most radiation, and in the northern hemisphere, the usual radiation peaks will be in June and July, but there will be variations from year to year according to “solar cycles”. Every 11 years the Sun goes through a cycle when the magnetic field changes and the number of sunspots grows and dwindles. This affects the amounts of radiation produced.

The Maine researchers suggest that high radiation levels either stress the immune system of embryos and foetuses or cause small mutations in their DNA, which can either predispose or protect from disease, mould brain characteristics and influence length of life.

So the reason that people born in December might live longer could be that they were conceived in March, possibly avoiding the most harmful affects of radiation early on, when the embryo is at its most vulnerable, but also avoiding very low levels of UVR that might predispose people to certain conditions.

The assumed general mechanism in biology is good, whatever you might think of the rest of the theory; it's essentially covered by the reliability theory of aging - biochemical damage, caused by radiation or otherwise, lowers remaining life expectancy by reducing or destroying the functionality of component parts in the machine that is you.

The reliability-engineering approach to understanding aging is based on ideas, methods, and models borrowed from reliability theory. Developed in the late 1950s to describe the failure and aging of complex electrical and electronic equipment, reliability theory has been greatly improved over the last several decades. It allows researchers to predict how a system with a specified architecture and level of reliability of the constituent parts will fail over time. But the theory is so general in scope that it can be applied to understanding aging in living organisms as well. ...

In reliability theory, aging is defined through the increased risk of failure. More precisely, something ages if it is more likely to fall apart, or die, tomorrow than today. If the risk of failure does not increase as time passes, then there is no aging.

Some interesting studies are quoted in the article on solar radiation, but it looks very much like a case of having a hammer and seeing nails in everything. It is logical to suppose that demonstrated variations in human longevity and disease by location of birth date in solar and seasonal cycles have something to do with the sun at root - but that certainly doesn't mean that the sun is the direct cause of the biochemical damage that leads to such variations. It might be solar radiation, or it might be one or more differences in other systems caused by variations in solar radiation - diet, weather, hormonal changes, behaviors ... just to rattle off a few. There are certainly many more.

Once the article starts in on the distribution of mathematical or creative ability by latitude, with an eye on solar radiation as a root cause, I think it's completely lost in the sea of secondary, cultural and population-level genetic effects. There really is nothing of use to be said about that; more hammers in search of nails.

But back to aging: the interesting part of reliability theory as applied to aging is that is suggests we are born with a certain level of damage already present. The Strategies for Negligible Senescence outline a list of classes of biomolecular damage that can be demonstrated to contribute to age-related degeneration, much of which falls into the camp of accumulated biochemical products of metabolism - which one would not expect to see to any meaningful degree in the newborn. That doesn't leave too many types of damage that might be present in infants, either as a result of developmental errors or some process with the sun at it's ultimate root - missing or malfunctioning cells in important populations (such as stem cells, for example), and genetic mutations, essentially.

Once we can repair these forms of damage in adults - as a part of the effort to develop working rejuvenation technologies - reliability theory suggests that humans would gain some modest benefit in the longevity (or at least life expectancy) stakes by applying the very same rejuvenation techniques to the newborn as well. Science is interesting, is it not?

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Funding and Progress in Alzheimer's Research
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Interesting views on the structure and progress of the Alzheimer's research community - and its funding - can be found in a recent BusinessWeek article: "A few years behind Alzhemed and Flurizan are promising treatments [that] provoke an immune response against the disease. Nearly 60 other drugs designed to modify the disease are also in clinical trials, including one from AC Immune of Switzerland that caught the attention of biotech giant Genentech Inc. best known for its cancer treatments. Genentech just announced plans to invest $300 million for the rights to AC Immune's drug. ... It's a whole new era. At least some of these medications are likely to work, and once we have disease-modifying drugs, we have opened the door to prevention. ... Certainly any disease could benefit from more funding, but with Alzheimer's the need for effective treatments is especially urgent. It is the only major cause of death in the U.S. where the numbers are getting worse, not better. That's because Alzheimer's is a disease of success. As people live longer and benefit from new treatments for common killers such as heart disease and cancer, the odds they will succumb to Alzheimer's increase."

Link: http://www.businessweek.com/print/magazine/content/07_02/b4016060.htm

More of the Right Attitude
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I am always pleasantly surprised to see a very positive, mindful article on healthy life extension in the media, especially coming from reaches of the community I was unaware existed. It's a sign of growth, that the concepts of progress in longevity science and support for research are spreading. From the American Chronicle: "History unequivocally demonstrates that money is essential for invention. It shows that the larger the share of the economy that goes into research and development, the larger the amount of discoveries. It is a very straightforward correlation. Therefore, the larger the amount of cash that goes into biomedical gerontology, the sooner will humanity possess a technology that will allow people to live to two hundred years. ... What could possibly be more important than that? What could be more relevant than that? There is obviously nothing worthier than life. Most people believe there is such a thing as the right time to die. There is no such thing. ... if what we have today is good, then living to two hundred will also be good."

Link: http://www.americanchronicle.com/articles/viewArticle.asp?articleID=18446

Being Aged is a Torment No-One Should Be Forced to Bear
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Wisdom, experience and the freedom that comes with financial security - with savings and investment over decades - are just a few of the benefits of being old, available for collection and accumulation with the passing years, should you make the modest effort to do so. The old are quite simply better at whatever they have set their mind to; time and effort can buy any form of mastery.

But being physically aged - and the death by a thousand cuts that takes place along the way - is a burden that no-one should be forced to bear. The cuts come slow over the years, and we humans, adaptable as we are, accomodate ourselves to each loss. Your arm acts up; a joint seizes; your immune system fails you; you don't remember quite so well any more; your friends die. Each new discovery of failing biology is a wealth of activities and potential crossed from your list - a change in your life that you did not choose, a closing in of the walls of the possible.

What is the natural response to a life lived within a shrinking set of walls? What good is all the wisdom and experience, what good the structure of a life carved out just the way you like, if shortly thereafter common communicable diseases, shrugged off in youth, will fell you?

The elderly are also less likely to notice they have pneumonia until it's too late. Younger patients will visit their doctor with symptoms like chills, shortness of breath, and chest pain, but elderly sufferers are often asymptomatic. This is because their immune response is already in a somewhat weakened state. For instance, younger people cough up sputum when congested, the body's natural way of clearing out the lungs. (It's unpleasant, but it is also a healthy response.) People tend to lose lung capacity as they age, which makes it harder for them to cough productively. As a result, they might build up a large amount of sputum without becoming symptomatic. Similarly, elderly patients are less likely to notice the symptoms they do have, since they're so used to feeling ill.

When left untreated, pneumonia is deadly; it's considered by the medical community to be as serious as a heart attack. After pus forms in the alveoli, it can spread to the bloodstream, the pleural cavity, or into implanted medical devices, such as a replaced valve or pacemaker.

Even if doctors do spot the disease in an elderly patient, it's often difficult to administer the necessary antibiotics. A younger person might be cured by taking azithromycin for seven to 10 days. But the ability of the kidneys and the liver to metabolize medications changes as we age: Older people are more susceptible to stomach upset and more sensitive to dosage. Many elderly people are also on a cocktail of medications for their other ailments, further vexing prescription.

Living is such a state of frailty is a torment, make no mistake. This is but a fraction of the disability and pain that being aged brings; you become ever more fragile, and chance will soon enough knock you hard enough to end your life. The young would do well to evisage themselves pitched headlong into the degree of disability suffered by the old - but we are not naturally given to look far into the future at what will come, and that is a great pity. By failing to plan ahead, failing to think about unpleasant matters in our future despite the reminders all about, we are failing to work together to ensure that our future is not limited and capped by decades of increasing torment.

We live in an age of possibility and wonder, of rapidly advancing biotechnology and nascent cures for cancer. Scientists understand enough about aging and the roots of degeneration to start on the work that will utterly remove frailty and degeneration from the human experience in decades to come. Progess in science during the years about the turn of the millennium had made clear possibilities that have been absent for the entire past history of humanity - it is both possible and plausible to build repair technologies for the biochemical wear and tear of living beings. We can work to cure aging!

How can we let the torment of being aged to frailty and suffering continue for hundreds of millions, when there is such a clear path forward to a scientific, medical solution?

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Reducing Stroke Damage
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EurekAlert! notes a demonstration of a comparatively straightforward method of mitigating stroke damage: "In one study, rats' brains were subjected to ischemia - severely reduced blood flow - for two hours in a model of stroke. Researchers then administered nicotinamide adenine dinucleotide, or NAD+, immediately after "reperfusion," or resumption of blood flow. Reperfusion is the time when stroke damage actually occurs because brain cells are suddenly exposed to highly reactive and unstable oxygen molecules, which are toxic. The researchers found that NAD+ reduced brain cell death from reperfusion by 70 to 86 percent compared with rats not given the treatment ... NAD+ plays a number of essential roles in cell metabolism. One role is supporting the activity of the DNA repair enzyme PARP-1, which normally repairs cell damage from brain infection. In response to reperfusion following ischemia or brain trauma, PARP-1 is overactivated. As a result, it quickly depletes all available NAD+, in a sense its 'fuel,' and is unable to repair cell damage, leading to brain cell death."

Link: http://www.eurekalert.org/pub_releases/2006-12/uoc--ntp122806.php

Thou Shalt Not Overhype
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From Genes&Aging, a justifiable note of complaint about the way the press has presented recent research: "researchers in the US have identified a gene which is reponsible both for longevity and for the retention of mental sharpness. 'Wow!', thinks I, 'my work has been done for me, we can all go home.' ... It's a nice paper, and the results are interesting and may direct research into useful areas. But: (1) It's a small study (158 people); (2) The results are only just statistically significant; (3) Other factors (other genes, environment, nutrition, exercise...) appear to be more important in influencing the phenotype than the gene itself; (4) "Cognitive function" was measured with a single test. ... Neither the general public, nor the researchers, nor science itself is done any good by hyping results such as these into news of supergenes which are going to turn us all into centenarian geniuses. It's never that simple." You have to read the popular science press with a critical eye.

Link: http://genesandaging.blogspot.com/2006/12/ageing-genes-back-in-news.html

Read the Popular Science Press With a Careful Eye
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A recent brief release over at EurekAlert! nicely illustrates the need for caution - and a little context - when reading through descriptions of new research:

Csiszar and collegues treated aged rats with etanercept to test the hypothesis that anti-TNFa treatment exerts vasculoprotective effects in aging. Etanercept (Enbrel) is an FDA-approved drug that binds and inactivates circulating TNFa. Recent studies have demonstrated that anti-TNFa therapies, including etanercept, may improve inflammation-related vascular disease, including heart failure.

Csiszar and colleagues made four notable findings in their study. First, they confirmed that in advanced aging, increased TNFa levels were associated with significant impairment of vessel relaxation, which is required for proper regulation of blood pressure.

Second, blocking TNFa via chronic etanercept treatment decreased cell death in aged vessels, demonstrating that increased TNFa levels likely contribute to age-related cardiovascular disease. Similar cell-protective effects were found when anti-TNFa antibodies were used in cell culture.

Third, not only was TNFa released into the blood, where it can have systemic effects, but it is also expressed within blood vessel walls, where it can exert specific local effects.

Lastly, administration of TNFa to young arteries reproduced the features of vascular aging, such as blood vessel dysfunction and cell death, further confirming the role of TNFa in the aging of the cardiovascular system.

The knowledge that cardiovascular disease is the leading cause of death for both men and women in the U.S. underscores the significance of these findings. This treatment could one day lead us closer to better heart health as we age.

Sounds great, right? Existing already-approved drug to help with an aspect of aging! Well, maybe. Very maybe. Hold your horses and back up to read the notes above again. You'll see a bunch of correlations, but they don't add up to a demonstration that Embrel addresses the physiological changes of interest, such as age-related imparement of blood vessel relaxation. You can be pretty sure that if the research team had that under their belt, they'd be trumpeting it from the rooftops in the advance releases - compare the release above with that for much more convincing work on vascular hardening from earlier this year:

The research, which was done in test tubes and animal models, needs to be confirmed in humans before it could form the basis for new therapies. But the fundamental findings reveal an important insight into how blood vessels change with age and lose much of their ability to relax, contract, and facilitate the circulation of blood in the body. ... Basically, we've learned that in older blood vessels, the cellular signaling process is breaking down. The vessels still have the ability to relax much as they did when they were younger, but they are not getting the message ... The laboratory studies were very compelling. We were able to make aging blood vessels behave as if they were young again ... This overall process, the researchers said, is linked to a low-grade, chronic inflammation that occurs with aging, in blood vessels and probably many other metabolic functions.

Making old components behave in a young fashion is much more convincing than vice versa in a demonstration of mechanisms - there are many ways other than aging to damage young biological systems and make them show desired characteristic failures of age, but very few ways to make old systems show young characteristics.

Csiszar's group is announcing additional carefully derived and presented evidence for the involvement of TNFa in the overall process at the biochemical and cellular level. This, however, doesn't necessarily mean that an anti-TNFa strategy will be helpful, even if the signs are pointing towards inflammation as the root problem. Suppressing TNFa might be a step too far down the line of cause and result, for example, and do little to help with the real biochemical cause of blood vessel hardening. Or it may actually help, given the experiments with young blood vessels given TNFa - but the researchers haven't shown that here, which seems surprising, all things given. I'll bet they tried.

And this is not even to talk about the plausible role of AGEs in tying the controlling biochemistry of blood vessel activity into knots.

Anyway, on to the context. I'm always slightly more careful of the bevy of papers involving the search for additional uses for an approved drug. The weight given to such work is very much a creation of the FDA's regulatory burden - it is much cheaper to search extensively for a hole that maybe, somewhat fits an approved peg than to develop new pegs to better fit the holes you find. There is tremendous pressure at all levels of the funding and research community to bang that newly-approved peg into whatever hole will fit closely enough - hundreds of millions of dollars are at stake. This means entire research groups, all their support structure, management and other necessities for a decade can hinge on an existing peg and a not-quite-right hole. That degree of carrot and stick tends to make people adjust their behavior, collectively and individually.

This is what the heavy hand of government does to organizations that are, in concept, the most well meaning you're likely to find in this world - people coming together to cure disease and eliminate suffering by building the future of medicine. Regulation twists that ideal, aligning the incentives of all involved away from competing through novel research, away from competing to produce the best possible solution, and towards shortcuts, recycling of existing ideas and comparatively worse solutions.

So when I look at the work of Csiszar's group here, I see good work on TNFa, nicely done, but visions of holes and pegs are floating before my eyes. TNFa is ubiquitous in many aspects of degenerative aging, because inflammation is ubiquitous in many aspects of degenerative aging - and so there are a lot of places to look for that new hole for etanercept that's more round than square. It has that cast to it so far, in any case - but I will be delighted to be proven wrong, in this as in many other cynical views of the world.

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Cryonics in Teen Fiction
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Via Existence is Wonderful, a look at spreading awareness of cryonics in unexpected places: "I grew up reading science fiction, so I am no stranger to the subject of suspended animation -- however, it is odd and strangely compelling to see this subject pop up in something so far removed from sci-fi as the bubblegum world of novels written for an audience of eighth-grade girls. Could it be that the cryonics meme is, in fact, propagating through mainstream culture? ... The book's overall tone is one that assumes that being alive is inherently good, and that freezing -- er, vitrifying -- people is a compassionate and proper thing to do in the event of fatal illness. ... It is more than refreshing to read a book, albeit one aimed at teen girls, that not only presents life extension technology in a positive light, but that is completely devoid of annoying, moralizing messages about how death is somehow 'natural' and that cryonics is some kind of abomination."

Link: http://rationallongevity.blogspot.com/2006/12/transhumanism-meets-teen-lit.html

A Look Inside Geron
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If you like to see how the sausage is made, Seeking Alpha takes a look inside Geron, a company representative of the messy business of developing the latest regenerative medicine and cancer therapies: "Geron has two telomerase-based cancer drugs in human trials, though both are early stage. For metastatic prostate cancer, the company is injecting telomerase into patients, hoping to provoke a more aggressive immune response - a therapeutic vaccine. ... On the stem cell front, Geron is testing GRNOPC1 to treat spinal cord injuries. The drug was given to rats with injuries that prevented them from using their legs, and GRNOPC1 helped them regain control of their legs. ... A second drug, GRNIC1, uses embryonic stem cell-derived islet clusters treatment to treat diabetes. ... Geron plans to begin its initial human testing of the drug in 2007 ... GRNCM1, the third stem cell based drug candidate, is a potential treatment for myocardial infarction."

Link: http://biotech.seekingalpha.com/article/23090

Computation as the Root of Physical Immortality
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Increasing capabilities and lowering costs of computation are driving modern biotechnology - since biology at the level of proteins and genes is essentially the business of processing information. One could argue that rapidly increasing abilities in computation lie at the root of advances in all fields of human endeavor across the past fifty years or so. Every human action of any significance or complexity involves information processing, or can be made more effective through processes that involve information processing - such as effective invention and design of better tools and methods, planning, prediction, and so forth.

Russian transhumanist Danila Medvedev posted a nice, simple diagram of the way many supporters of the development of radical life extension look at the tree of technology and enablement. One could quibble with the details, bearing in mind it's written by one of the folk behind the Russian cryonics group KrioRus, but it I think it captures the spirit of the long-term transhumanist viewpoint:

"Immortality" here is in the sense of physical immortality, a shorthand for vulnerable agelessness, or the defeat of aging - the development of technologies that will allow us to maintain a human body in a decent state of repair for so long as we expend the resources to do so. This is all somewhat close to one of my recent thoughts on the topic:

Consider that it is only in recent years, now that computing power per dollar has really started to take off, that major progress has been made in long-standing fields such as cancer research, genetics and immunology. Without advances in processing power, and the tools of bioinformatics built atop this foundation, scientists would have no hope of dealing effectively with the sheer complexity of human biochemistry.

With tools, understanding, hard work and funding we will be increasingly able to tackle the details of degenerative aging: replace failing mitochondria; turn cancer into a manageable, chronic condition; remove toxic byproducts that accumulate inside and around your cells with age; repair the aging immune system; build replacement tissue from our own stem cells; and much more. Every problem has an answer, if only the resources are applied to find it.

Danila has posted a number of other diagrams you might find interesting, such as his Arguments for Cryonics, assembled in the TruthMapping tool. Premise number one: "life is interesting."

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Apoptosis Drugs Versus Cancer
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To live longer, healthier lives, we must find safe, effective ways to defeat cancer - but for the most part, drugs to kill cancer cells also kill healthy cells. This is why better targeting via nanomedicine is a productive way forward. An alternative approach is to blanket the body with drugs that hurt cancer cells far more than healthy cells; progress in one such long-running attempt is outlined at ScienceDaily: "ABT-737 is a drug with a different strategy for attacking cancer. Rather than attempting to poison the rogue cells, the new drug attempts to reactivate the healthy and normal cell death program that failed to kill the unwanted cells on cue. ... Normally, the cell death machinery is switched on when damaged cells need to be removed. The failure of the machinery to be turned on when it should can lead to cancer. ABT-737 is a 'switch flicker' that kicks the cell death machinery into action. Much more remains to be done to assess the drug's safety and effectiveness in patients, but early results from the laboratory are promising. Our hope is that the new drug will prove to be more effective while having fewer side effects."

Link: http://www.sciencedaily.com/releases/2006/11/061116100836.htm

More On Wnt and Zebrafish Regeneration
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Via EurekAlert, more details on the role of Wnt signaling in the regeneration of complex organs in zebrafish: regeneration "involves creating cells that can take any number of new roles. This can be done by re-programming cells that already have a given function or by activating resident stem cells ... a particular kind of cell-to-cell communication, called Wnt/Beta-catenin signaling, regulates the fate of these as-yet undeveloped cells as an embryo forms. ... These streams of signals also tell stem cells in adult organisms what functions to undertake. Once tissue formation starts, something has to tell it to stop before growth gets out of hand. ... We show that Wnt/Beta-catenin signaling is activated in the regenerating zebrafish tail and is required for the formation and subsequent proliferation of the progenitor cells of the blastema ... It is most likely the inability of humans to form a blastema in the first place that renders us unable to re-grow arms and legs ... the same genes for turning on and turning off growth and development are found in humans, and drugs exist that can regulate this pathway."

Link: http://www.eurekalert.org/pub_releases/2006-12/uow-hda122606.php

If You Want the Job Done, Then Help to Get the Job Done
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Sage words from Anne C.:

However, there do seem to be some in the life-extensionist population specifically who have rather surprising amounts of confidence in their own future assured survival, and though there is a chance they know something I don't which somehow justifies this confidence, I have yet to see evidence of this knowledge. I do think there is a chance that some alive today will manage to prolong their lives indefinitely, but by no means do I think that, beyond a shadow of a doubt, aging is going to be "solved" by the time I turn fifty or anything like that. Progress is dependent on many variables, and there are too many "ifs" to make any kind of confident estimates of one's chances of "escaping" age-related death at this point. Quibbling about probabilities, placing bets, and arguing over whether one will or will not get to celebrate their 1000th birthday probably isn't worth a whole lot of time or energy. If enough people can agree that age-related decline deserves attention, then the proper course of action is to give it that proper attention -- directly, in the laboratory, in computers, in hospitals, in our homes, in doctor's offices.

All any of us can do is look to see which of those "ifs" we can influence, and perhaps support efforts like SENS, the MPrize and the development of AGI, or even become scientists ourselves, or come up with something we think is more likely to yield results than any existing organized effort. We can all help to author the yet-unwritten future so that, at the very least, it is more likely to yield longer, healthier lives for all who seek them.

Which ties nicely into my ruminations and exhortations on the subject of personal responsibility for the future. You have to think directly, action to result, if you want to change the world - and we all have that power, when we act in concert.

It is now the case that the right scientific programs backed by the right levels of funding could greatly extend the healthy human life span rapidly enough for us to benefit. We know enough to get started - this is not a time for modest goals and conservatism. This is a time to unleash the full potential of the biotechnology revolution on the cause of more death and misery than anything else in this world: age-related degeneration.

Folk like you and I don't have to stand on the sidelines and hope for more results, or for more scientists to get to work. Organizations like the Methuselah Foundation offer powerful ways for us to band together and fund or encourage effective research into defeating aging. The MPrize for longevity research is the best present way for you to place a dollar in the pot to inspire many more dollars of aging research funding. People like you and I have already pledged millions to this cause, and in doing so are changing the world.

The first step on the road to radical life extension is a big leap forward: to develop and make widely available technologies capable of extending healthy life span in the old by a good 20-30 years. Perhaps this will be some combination of SENS-like therapies for mitochondrial repair, immune system repair and regenerative medicine, plus a really good set of cancer therapies and a better handle on the aging brain. It will have to be some form of repairing the damage or replacing worn parts, unless the metabolic manipulators pull something amazing out of their hat - which I think is unlikely in the case of reversing aging or adding many years for the already old.

There's only so much you can do with slowing aging through metabolic manipulation - the elderly wouldn't benefit, for example - but a working repair mechanism for the cellular damage associated with aging could be used to restore the aged and hold off aging over and over again. It's more efficient and effective.

Twenty to thirty years of additional healthy life is, more or less, the minimum necessary for a new technology base to emerge from the laboratory into widespread use; the technology of interest here is whatever comes after SENS, the new medicine that will give the SENS-using old another 20-30 years or more.

But as I said, that first step is a big one. Once we are past it, we will already have widespread support, a self-sustaining infrastructure, massive funding, and a new and eager generation of researchers entering the field. The move from SENS to post-SENS will be much like the move in the cancer research community from chemo- and radiotherapy to the new biotechnology - an organic, ongoing change in focus and the quality of results, not the creation of a multi-billion dollar infrastructure from scratch. But today, we have no multi-billion dollar infrastructure dedicated to the defeat of aging - and if we don't band together to build it, who will?

Which comes back to the title of this post. If you have the slightest interest in living a long, healthy life, you must get up out of your chair and do something about it. It is not enough to assume that things will work out; if everyone makes that assumption, then, most assuredly, things will not work out. If everyone stays to the sidelines, nothing will happen. If a small group of workers continue in absence of widespread support, then their progress will be slow or negligible.

You are in part responsible for the future; your actions and inactions help to shape it, just as those of everyone else. So step up and do your part to make the years to come a place you would like to live in.

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A Year-End Message From the Methuselah Foundation
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A look back at 2006 and some of what is to come in 2007 from the Methuselah Foundation (MF) founders: "A major effort of the MF during 2006 will become public only in the fall: a popular science book describing [the Strategies for Engineered Negligible Senescence (SENS)] in depth for a general audience. It will be published by St. Martin's Press, a major New York publishing house. ... The book will be launched contemporaneously with the next Cambridge SENS conference, which will take place on September 6-10. ... We'll continue to expand our SENS research program, with more manpower at our main LysoSENS site (Arizona State University), additional LysoSENS work at Rice University, a probable doubling of effort on the MitoSENS project in Cambridge, and with several other projects lined up to begin as we obtain the needed funds. Our public outreach activities will be much enhanced in 2007 ... will be aiming to allocate substantial resources to building an organisation of the size needed to defeat aging, including hiring a professional fundraiser and making more frequent visits to meet key potential supporters."

Link: http://blog.methuselahfoundation.org/2006/12/a_yearend_message_from_the_met.html

Longevity Gene, Cholesterol
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Cholesterol metabolism remains a focus in the work of Nir Barzilai on the genetics of the long-lived. "A gene variant linked to living a very long life - to 90 and beyond - also serves to help very old people think clearly and retain their memories ... Known as CETP VV, [this] protein affects the size of 'good' HDL and 'bad' LDL cholesterol, which are packaged into lipoprotein particles. Centenarians were three times likelier to possess CETP VV compared with a control group representative of the general population and also had significantly larger HDL and LDL lipoproteins than people in the control group. Researchers believe that larger cholesterol particles are less likely to lodge themselves in blood vessels. So people with the CETP VV gene (and the larger cholesterol particles they produce) run a lower risk of heart attacks and strokes, which may explain their unusual longevity. ... CETP VV also protects the cognitive integrity of the brain - either through the same vascular 'anti-clogging' benefit that prevents heart attacks and strokes or through an independent protective mechanism that remains to be found."

Link: http://www.eurekalert.org/pub_releases/2006-12/aeco-gtt121906.php

Take the Money and Run?
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There is no doubt some increased interest in longevity "insurance" packages these days, hand in hand with the uptrend in media attention given to longevity research and increasing public awareness of the same. Enough so that mainstream articles on longevity insurance are surfacing here and there:

Insurers in the past year have rolled out a new product that aims to fill that need. It's a type of investment the industry refers to as "longevity insurance," which guarantees that you won't outlive your money.

These products aren't really insurance. With most, for one thing, your investment is lost if you die before the payouts begin. Longevity products are more like a mix of deferred and immediate annuities. Like a deferred annuity, you invest money now with the agreement to start receiving monthly payments later -- say at age 85 -- for the rest of your life. Like an immediate annuity, your projected income stream is calculated at the time you invest. The payouts are considerably higher than those of deferred annuities. But the costs can be high, too.

Here's what you need to know:

The premise of longevity products is that by making a one-time payment, you will start receiving guaranteed lifetime income at a designated point in the future. Your projected income stream is calculated at the time that you invest.

Compared with deferred annuities, longevity-product payouts are considerably higher. For example, if a 65-year-old man invested $10,000 in a deferred fixed-income annuity from MetLife, in 20 years he would start collecting $137 a month, assuming the investment grew at the minimum guaranteed rate of 3 percent.

But if that man instead invested in MetLife's longevity product, his monthly payout would be $665.

Why such a big difference?

For starters, this particular investment, like most basic longevity products, offers no death benefit. If purchasers don't make it to 85, their investment is forfeited. And the majority of today's 65-year-olds may not live that long.

Here is a knee-jerk response: unless these products are stunningly bad value for money under very conservative estimates for growth in life expectancy in the old, those companies to offer longevity insurance packages will be taking a bath twenty to thirty years from now. You might recall that the actuaries are wavering on their estimates for life expectancy, and a healthy debate is taking place in the actuarial community as to just how to account for the ongoing revolution in biotechnology and medicine. An insurer that offers fair valued, competitive products today based on the actuarial trends of the past few years will find themselves in trouble down the line if the efforts of groups like the Methuselah Foundation succeed, or even if the systems biologists have their more modest way.

It would seem to be the case that either:

a) enough people die at younger ages than you that the offering company makes money and stays in business. In other words, healthy life extension research did not succeed rapidly enough to help you either - you will age, suffer and die.

b) healthy life extension takes off and the insurer is left with a huge liability, which may or may not actually be paid. That depends on how well the insurer handled the funds, the level of economic growth across the years, and the level of interest in the original product, amongst other items. Bribing politicians to write new law to remove obligations is a very predictable out, however.

c) the product is of poor enough value that the company can offer it even though healthy life extension research succeeds - in which case you would likely have been better off placing your funds elsewhere.

The point of purchasing longevity insurance is, of course, to mitigate risk in your later life, when you are less able to earn or raise funds due to the effects of aging - assuming that healthy life extension technology does not arrive in time restore health and vigor. Whether that is worth the loss of investing those funds yourself for 20 or 30 years is between you and your level of comfort with risk. The removal of risk is, in essence, the product you are purchasing with that opportunity cost. Point (b) above is a potentially serious problem when looking at the exercise in that light. If healthy life extension advances rapidly, everyone lives, but your investment vanishes into political games and shirkmanship. If healthy life extension doesn't advance rapidly, your later life will be less financially risky - but you will age, suffer and die.

So as usual, a "take the money and run" strategy isn't going to work if everyone does it, or if everyone simply assumes that healthy life extension is coming, rather than getting out there to help make it happen.

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Who's Who in Gerontology
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Researcher Joao Pedro de Magalhaes maintains a number of interesting databases at his senescence.info website. One I haven't pointed out is a Who's Who of gerontology, with listings for better-known people and companies hard at work on the biology of aging. "I hope senescence.info can also make people aware of the problem that is aging. Aging will likely be the major cause of suffering and death of those you love. It is the main reason why great artists, scientists, sportsmen, and thinkers die. ... Even so, few resources are aimed at tinkering with the biological causes of aging and most people are not even aware of that research is done on the biology of aging. Rivers of money, both in the industry and academia, flow to fight specific age-related diseases, but not to fight the aging process. Less than 20% of the National Institute of Aging's budget goes to research the basic causes of aging, which pales in comparison with the resources available to other medical problems like neurodegenerative diseases or cancer. Hopefully, senescence.info can contribute to make the public aware of the work done by gerontologists."

Link: http://whoswho.senescence.info

LA Times on Longevity Science
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The LA Times takes a high-level look at longevity science that has attracted media attention this year: calorie restriction, resveratrol, centenarian studies and other metabolic manipulations intended to slow the accumulation of age-related damage. This is but one weak side of the coin; when thinking in these terms "Phelan says he doesn't think there will ever be a way to significantly extend human life span. 'Millions of years and billions of people living a variety of lifestyles that result in life spans that never exceed 122 demonstrate that it is unlikely that some new method will dramatically extend this.' Which might be true if you restrict yourself to manipulating metabolism - it's like tuning up a car; there are definite limits to performance within the present architecture and state of repair. But this leaves out the concept of using modern biotechnology to identify and repair the damage that causes aging. That is the real path forward - fix the failing engine, don't tune it.

Link: http://www.latimes.com/features/health/la-he-lifespan25dec25,1,77391,full.story

Stem Cell Funding In India
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(From RxPG News). Branches of the Indian government continue to move public funds into stem cell research: "A sum of [US$11 million] has been allocated for the proposed stem cell research centre. About 150 scientists from Pune's Cell Science Research Centre will be engaged in research and application. ... Admiral Singh, also chairman of Military Medicine Association, said funding would be made available to make it Asia's biggest state-of-the-art stem cell research centre as this was the future of medical treatment/therapy for various diseases and India could not lag behind. He said the longevity of humans could also be increased through stem cell treatment. ... It will be the futuristic treatment replacing drug therapy and surgery. Through stem cell treatment, heart diseases, diabetes, Parkinson's disease, epilepsy, multiple sclerosis, eye and muscle disease and various other diseases can be cured."

Link: http://www.rxpgnews.com/india/Military-college-to-set-up-stem-cell-research-centre_9733.shtml

Magical Thinking Abounds in the "Anti-Aging" Marketplace
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We humans have been shaped by past evolutionary processes to be very good at identifying patterns - and to enjoy doing so, such that we will spent significant investments in time and effort in this task. Pattern recognition was so important to evolutionary success back in the early days of humanity that it was acceptable to suffer the downside: our tendency to see patterns where there are none, and the limitations of our pattern recognition when applied to complex or random systems. We are adapted to pattern recognition in a "fire burns X, so it will burn Y", "the stars will do this next year as well" range of experience - we do not do well for much more complex situations.

Magical thinking - or "non-scientific causal reasoning" - is well-documented and understood consequence of the nature of our hard-wired ability with (and desire for) patterns. It can be found at the roots of magical activities in a wide range of traditions and cultures. These activities spring from common human urges, traits and societal structures, and so are remarkably similar at root, for all their varied details:

Magical thinking is a term used by some scholars to describe non-scientific causal reasoning (ie superstition). James George Frazer and Bronislaw K. Malinowski said that magic is more like science than religion, and that societies with magical beliefs often had separate religious beliefs and practices. Like science, magic is concerned with causal relations, but unlike science confuses correlation with causation. For example, someone may believe a shirt is lucky if he had won a bowling competition in it. He will continue to wear the shirt to bowling competitions, and though he continues to win some and lose some, he will chalk up every win to his lucky shirt.

...

According to Frazer, magical thinking depends on two laws: the law of similarity (an effect resembles its cause), and the law of contagion (things which were once in physical contact maintain a connection even after physical contact has been broken). These two laws govern the operation of what Frazer called "sympathetic magic", the idea that the manipulation of effigies or similar symbols or tokens can cause changes to occur in the thing the symbol represented. The use of voodoo dolls is a typical example of sympathetic magic. Others have described these two laws as examples of "analogical reasoning" (rather than logical reasoning).

The scientific method is the cure for problems caused by magical thinking, such as a lack of progress towards better lives, and all the limitations - dramatic or trivial - that stem from an incorrect understanding of the way in which the world works. To make progress happen, you must tackle complex systems in a methodical way: propose, explore, test, verify, record, repeat. But that requires more work than merely guessing, and so there will always be some market for those willing to take the "shortcut" to the wrong answer. When the wrong answer doesn't have clear, obvious and rapid bad consequences attatched to it, magical thinking will prosper. Such is the downside of human enonomic preferences - there is always a market for "incorrect" when "incorrect" is sold more cheaply than "correct."

So how does this fit in with the practice of medicine - in the broadest sense of the term, as any attempt to develop and apply technology or technique to health? Here's an article from way back in the Committee for Skeptical Inquiry archives:

To distinguish causal from fortuitous improvements that might follow any intervention, a set of objective procedures has evolved for testing putative remedies. Unless a technique, ritual, drug, or surgical procedure can meet these requirements, it is ethically questionable to offer it to the public, especially if money is to change hands. Since most "alternative" therapies (i.e., ones not accepted by scientific biomedicine) fall into this category, one must ask why so many customers who would not purchase a toaster without consulting Consumer Reports shell out, with trusting naivetë, large sums for unproven, possibly dangerous, health remedies.

...

The answer, I believe, lies in a combination of vigorous marketing of unsubstantiated claims by "alternative" healers, the poor level of scientific knowledge in the public at large, and the "will to believe" so prevalent among seekers attracted to the New Age movement.

It's a decade on from the date of writing - so much changes in detail, but people are still people. You don't have to wander far at all into the modern "anti-aging" marketplace to see magical thinking in the sales materials.

The wider business community - including a great many fraudulent and frivolous ventures - views "anti-aging" as a valuable brand and a demonstrated way to increase sales. At the worse end of the scale, this leads to snake oil salesmen, "anti-aging" cremes that may or may not make your skin look younger, and infomercials that tout the "anti-aging" benefits of exercise machines. Broadly, and very charitably, we can look at these varied definitions of anti-aging as meaning "to look and feel younger in some way" - which has no bearing on how long you live or how healthy you actually are.

Magical thinking is often accompanied and obfuscated by pseudo- or irrelevant science, so as to be made to appear more like the sort of work that comes out of the scientific community. Here is a good example of the type:

One key ingredient is a soybean cuticle extract that the company claims stimulates the body's production of a protein to slow aging. Orlane says its product is based on studies of the longevity of Okinawans, whose fish and soybean diets have been credited for the large number of centenarians on the Japanese island.

"They lived to their 100s and died wrinkle-free," said Naz Toloui, Orlane's vice president of sales and education.

...

Japan's Kanebo boasts an even more unusual ingredient. Its "Sensai Premier" eye cream - priced at $320 for 0.5 ounces - is infused with Koishimaru silk extract, from delicate silk cocoons that are half the size of normal silk cocoons. Kanebo, founded almost 120 years ago as a textile-manufacturing company, began producing soaps containing silk in the 1930s after noticing that silk workers' hands were soft. Kanebo claims that the Koishimaru silk extract stimulates the skin's production of hyaluronic acid, a component of connective tissue.

Those two above are examples of sympathic magic at its finest - A and B are somewhat the same, so it must work, right? Some people will believe enough in any new such proposal to spend resources, and other, better-educated people rightly estimate that they'll make money from investing in the beliefs of the the first group. Once it all gets going, you'll see a self-sustaining industry with the resources to expand the pool of consumers through (mis)education, and which comes to employ more and more true believers in key positions.

Many such interesting follies of human endeavor populate this world, growing organically from evolutionarily selected traits of the human mind. One might almost consider it a sort of species-level antagonistic pleiotropy - except that that would be magical thinking.

But none of this is going to help anyone to live a longer, healthier life. For significant healthy life extension you need the scientific method, modern biotechnology, a geared-up, dedicated and funded research and development community, and widespread recognition that the rapid development of real, modern medical science is the only viable path forward. Manipulating human biochemistry - identifying and repairing the root causes of aging - is simply too complex for any other way to succeed.

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LEF On Alzheimer's, Diabetes Link
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The latest issue of the Life Extension Foundation Magazine has an overview of the link between Alzheimer's and diabetes: this "is yet another compelling reason for those who value their health to address issues of impaired insulin sensitivity before it is too late. Although diabetes is an emerging epidemic, it is also wholly preventable and reversible through strategies that incorporate dietary changes, lifestyle modifications, and nutritional supplementation. ... While declining levels of acetylcholine and formation of beta amyloid plaques in the brain are characteristic of Alzheimer's, oxidative damage and the accumulation of advanced glycation end products occur in both Alzheimer's disease and diabetes. These biochemical similarities may be a telling link between the two seemingly different diseases. ... Now that diabetes appears to be associated with Alzheimer's, it is imperative to take action to protect against this burgeoning epidemic. The first two steps are ones that almost everyone can implement: eat a healthy diet and exercise regularly."

Link: http://www.lef.org/LEFCMS/aspx/PrintVersionMagic.aspx?CmsID=114514

Death (By Degenerative Aging) and Taxes
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Death and taxes, the age-old twosome. There are certain similarities between attitudes and possible approaches to the two; death by degenerative aging on the one hand and government theft backed by threat of force on the other.

The first similarity of note lies in behaviors of learned helplessness and rationalization of the unpleasant when faced with aging and taxation. Sure, people worm around and try to make their position as least uncomfortable as possible - but the majority are doing so within the rules laid down, within the firm belief that death by aging (and the resulting suffering) and taxation (and the resultant waste) are both set in stone.

The second item of note is that by banding together we can dramatically change or remove both death by aging (through the advance of biotechnology) and taxation (through changing our society). The only way the world changes is through human action, whether that action is the discovery of science or the changing of minds. Neither death by aging nor taxation is set in stone, but changing their solid present existence for everyone will first require sufficient ongoing education to change the expectations and level of understanding for most people - to change them from supporters of the status quo, no matter how bad, to supporters of a better future, and willing participants in bringing about that future.

On the one hand, we have the understanding of economics and expectations of government, and on the other hand we have the understanding of progress in biotechnology and the expectations of medical science. For most people, at this time, dearly-held beliefs and instinctive responses are widely divergent from reality:

These great tasks are very hard, but not impossible; distributed, co-operating groups of humans have attained equally challenging goals in the past. Societies and science can be made to change dramatically in half a lifetime. The development of a toolkit for the repair of age-related damage, and elimination of parasitic government and taxation, would lead to a society far less burdened by waste, both of lives and resources - a society in which growth, progress and individual lives are far greater than in the present time. That is well worth the tremendous, distributed, ongoing effort it will take to change minds and set people to working on a better tomorrow.

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Telomerase, Immune Senescence
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Beyond the reduction in number of naive T cells, the immune system also ages through an accumulation of senescent T cells that behave in suboptimal or damaging ways. Via Ouroboros, a look at the science of doing something about the latter problem: "Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age ... high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8+CD28- T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging."

Link: http://ouroboros.wordpress.com/2006/12/22/telomerase-as-a-cure-for-immune-senescence/

Characterizing Inflammaging
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From the open access journal Immunity & Aging: "The term "Inflammaging" has been coined by Claudio Franceschi to explain the now widely accepted phenomenon that ageing is accompanied by a low-grade chronic, systemic up-regulation of the inflammatory response and that the underlining inflammatory changes are also common to most age-associated diseases ... [researchers] postulate that both the ageing process and age-associated diseases are late consequences of evolutionary programming for a pro-inflammatory response mainly selected to resist infections and for a successful response to wound healing in early age, a view that has been discussed in the light of the antagonistic pleiotropy theory. Such a theory on the evolution of aging postulates that senescence is the late deleterious effect of genes that are beneficial in early life. Evolutionary programming of the innate immune system may act via selection on these genetic traits."

Link: http://www.immunityageing.com/content/3/1/12

On Brain Repair Mechanisms
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Via EurekAlert: "In mice, after a stroke was initiated in a part of the brain located far from the [subventricular zone], the researchers [tracked] newly formed neuroblasts (immature brain cells from which mature adult neurons form) as they traveled through healthy brain tissue to the stroke area. Once there, these immature neurons wrapped themselves around the immature vascular cells that were in the process of forming new blood vessels in the damaged area. ... two proteins, stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1), that are given off by these newly-forming blood vessels, are what trigger the thousands of immature neurons to the site of damage. ... the molecular mechanisms for neuronal regeneration hold the promise of regenerating and reconnecting brain cells near the area where stroke occurs." When scientists understand the mechanisms and signals by which the brain repairs itself, the door is opened to greatly improving the effectiveness of these processes - very much a needed advance.

Link: http://www.eurekalert.org/pub_releases/2006-12/uoc--cci122106.php

Following Through
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You might recall I had mentioned an up and coming young poker player at Fight Aging!, and his pledge to donate a percentage of his winnings to the Methuselah Foundation in support of SENS research. He's following through with a vengence: "I am also happy to say that as I promised a few months ago, I will be giving 5% of my winnings to www.Sens.org. I said this would include the two 5k events and the 15k events, but it seems silly to include only 3 of my 4 final tables, so I will be giving them 5% from all of these events. This comes out to $13,250 which I hope can make a difference. Peter Theil pledged to match 50% of all donations towards SENS research, so this will actually be a $20,000 donation thanks to his help. ... The plan at this point is to play as many events as possible in 2007, and try to win Cardplayer's Player of the Year. It will take a little bit of luck, but I like my chances a lot. Expect me to make AT LEAST top ten in 2007 for sure." Best of luck to you, and thank you for joining those who step up to make a difference.

Link: http://www.zeejustin.com/journal.php?journal_id=103

A Look At Incremental Progress In Alzheimer's Research
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Two recent releases on modest progress in Alzheimer's research are illustrative of the way in which this scientific community is driving the establishment of new biotechnology toolkits and a deep knowledge of brain biochemistry as a part of seeking a cure. Each new incremental advance adds a new piece to the biochemical puzzle and tool to the toolkit, there to be used in all research into the aging brain.

And, yes, we need all the research we can get - if we want to live far longer, healthier lives, we had better become very, very good at understanding and repairing the aging brain.

New Imaging Technique Identifies People At Risk For Alzheimer's Disease

Scientists are in the early stages of identifying biomarkers in the blood and spinal fluid to help with Alzheimer's diagnosis, but this new study is the first to report a real time "window into the brain" that identifies both of the major abnormal deposits of the disease in living people who may not develop Alzheimer's for years to come.

...

Researchers performed PET brain scans after intravenously injecting the volunteers with the new chemical marker called FDDNP, the molecule that binds to the plaque and tangle deposits found in Alzheimer's disease.

Scientists found distinct differences among people with normal brain aging, patients with Alzheimer's disease and people with mild cognitive impairment.

The PET imaging showed that the more advanced the disease the higher the FDDNP concentration in areas where the abnormal protein deposits typically accumulate -- in the temporal, parietal and frontal brain regions. Patients with Alzheimer's disease showed the most FDDNP binding, indicating a higher level of plaques and tangles than other subjects.

...

"This is the first time this pattern of plaque and tangle accumulation has been tracked in living humans over time in a longitudinal study"

Scientists Develop A New Way To Target Alzheimer's Disease

In a new animal study, the NYU School of Medicine researchers report that they have reduced by around 50 percent the aggregation of toxic amyloid protein in the brains of mice by blocking the interaction between a protein called apolipoprotein E (apo E) and amyloid. Apo E acts as a sort of biological chaperone, ferrying cholesterol and fats around the brain.

The researchers [created] a nontoxic, synthetic protein fragment or peptide that binds to apo E, preventing it from latching onto amyloid.

In a series of studies in transgenic mice, the peptide reduced the amount of plaque in the brain and the amount of amyloid in the brain's blood vessels. It did not cause any apparent inflammation or leaks in blood vessels in the animals' brains, according to the study. Finally, in another set of experiments, the treated mice did not exhibit any memory decline when they were put into a radial arm maze, which evaluates working memory based on the animals' behavior.

Even imperfect or partially effective therapies (or changes in lifestyle in many cases) can be of great benefit for age-related conditions if applied early on, in the very first stages - but to do that, you must have the ability to diagnose early. This ability has been greatly lacking for Alzheimer's patients until very recently, but none of the diagnostic work in progress is yet beyond trials and in widespread use:

The regulatory hurdles chew up years between laboratory and clinical practice these days - which is not to mention the many therapies and tests that are simply never developed because the regulatory costs are too high.

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More On DNA Repair and Aging
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Scientific American has an article on recent DNA repair research that is more clear on the point being made the scientists involved: "Do we get old due to the accumulation of damage over our lifetimes or due to the genetic blueprint we inherit? ... What we say is [that] both are valid and that, in particular, damage to DNA contributes to aging. Damage accumulates ... but it is modulated by your genetic makeup. If you have better repair and/or slower metabolism, you age slower. ... If we would be able to reduce the induction of DNA damage by triggering the survival response [to lower metabolism and allow less damage] or by boosting repair or, perhaps, by adding protecting compounds in food or medication the rate of DNA damage and consequently aging may be reduced."

Link: http://www.sciam.com/print_version.cfm?articleID=A5B0A265-E7F2-99DF-3EAC6E6864B2E70C

Of the Aging Body, What Might Be Easiest To Rejuvenate?
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There seems to be a case for believing that a number of the body's systems and cell types become less effective with age due to biochemical cues rather than any inherent deficiency of function. You might recall the ongoing debate over age-related decline in stem cells that maintain and repair muscle; back in 2005 a group demonstrated a rejuvenation of stem cell capacity by introducing young blood - i.e. replacing an "old" surrounding cellular environment with a "young" one, and all its attendent biochemical signals.

Recently, another group showed the mechanism by which capacity declines in neural stems cells with aging: they slow down, divide less often - but are still present in numbers. That might just be what aging muscle stem cells do also. Would a young environment wake up the neural stem cells also? What is it, exactly, about that environment that sets stem cells back to work?

While perusing PubMed, I came across another few recent examples of researchers investigating aging systems in the body that might be rejuvenated through changes in signaling. Stem cells feature prominently, even when discussing the rejuvenation of an aging immune system.

The molecular basis of ageing in stem cells

Here, we argue that cellular ageing is a reversible process, and this is determined by the balance of biological molecules which directly or indirectly control telomere length and telomerase activity, either through altering gene expression and/or modulating the epigenetic state of the chromatin.

Complexity of anti-immunosenescence strategies in humans

Immunosenescence is characterized by three main aspects: (i) the shrinkage of the T cell repertoire and the accumulation of oligoclonal expansions (megaclones) of memory/effector cells directed toward ubiquitary infectious agents; (ii) the involution of the thymus and the exhaustion of naive T cells; and (iii) a chronic inflammatory status called inflamm-aging. We present here possible strategies to counteract these main aspects of immunosenescence in humans ... the complexity of a rejuvenation approach is stressed, with particular attention to the inhibitory role played by the "old microenvironment" on the performance of progenitor cells, the best candidate to counteract the decline in regenerative potential characteristic of organs and tissues from old organisms.

Thymic rejuvenation and the induction of tolerance by adult thymic grafts

We report here that aged, involuted thymus transplanted as a vascularized graft into juvenile recipients leads to rejuvenation of both thymic structure and function, suggesting that factors extrinsic to the thymus are capable of restoring juvenile thymic function to aged recipients. ... These findings indicate that it may be possible to manipulate thymic function in adults to induce transplantation tolerance after the age of thymic involution.

Involution of the thymus is a whole interesting topic in and of itself - the body is a changing system from the moment the first cell divides.

A question still high on the list is "why are these systems turning themselves off with increasing age?" It's quite possible that this is because a dangerous fraction of the component cells are, in fact, damaged goods in later life. In the case of stem cells, for example, turning them all back on at full blast might just mean an orgy of cancer, due to a high level of random genetic damage accumulated over a lifetime.

As the second paper above points out, "easy" is a relative term. But we should be encouraged that researchers are thinking along the right lines - given an aging biological system that leads to frailty and suffering, what can we do to restore it to full functionality? That is a path towards longer, healthier lives, freed from the slow and inevitable breakdown of form and function that only exists because we are not yet capable enough to enact repairs.

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Dental Regenerative Medicine Progresses
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innovations report notes a recent technology demonstration in dental regenerative medicine: "Utilizing stem cells harvested from the extracted wisdom teeth of 18- to 20-year olds, [researchers] have created sufficient root and ligament structure to support a crown restoration in their mini-pig (animal) model. ... The technique relies on stem cells harvested from the root apical papilla, which is responsible for the development of a tooth's root and periodontal ligament. ... The apical papilla provides better stem cells for root structure regeneration. With this technique, the strength of the tooth restoration is not quite as strong as the original tooth, but we believe it is sufficient to withstand normal wear and tear. ... [Researchers hope] to move the technique to clinical trials within the next several years, a potential boon for dental patients who are not appropriate candidates for dental implant therapy or would prefer living tissue derived from their own teeth."

Link: http://www.innovations-report.de/html/berichte/studien/bericht-76330.html

Paul F. Glenn Backs Aubrey de Grey
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More good news from the Methuselah Foundation: "In response to the recent progress report from Methuselah Foundation chairman Aubrey de Grey, we are pleased to note that the Glenn Foundation for Medical Research has stepped forward in greater support of [Methuselah] Foundation-funded SENS research with the offer of an additional $50,000 donation ... Paul F. Glenn, founder of the Glenn Foundation, said, 'We have been following the progress of Aubrey de Grey's ideas with interest, and the Thiel matching pledge allows us to leverage our funds in a highly efficient way.'" This follows a (second) $55,000 donation from the Scott B. and Anne P. Appleby Charitable Trust just last week. Exciting times! We are entering an age of considered philanthropic support for real anti-aging science - just what is needed to loosen rusted gears and get moving.

Link: http://blog.methuselahfoundation.org/2006/12/continued_support_from_the_gle.html

The Role Of DNA Damage In Aging
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(From PhysOrg.com). What does DNA damage and change in DNA repair mechanisms contribute to aging? There are several camps in this debate; understandably, progeria researchers feel that it is an important factor: "These progeroid mice, even though they do not live very long, have remarkably similar characteristics to normal old mice, from their physical symptoms, to their metabolic and hormonal changes and pathology, right down to the level of similar changes in gene expression. ... it shows how important it is to repair damage that is constantly inflicted upon our genes, even through the simple act of breathing." Other camps argue that progeria is a grand exaggeration of one facet of "normal" aging, which may or may not contribute significantly to degeneration in most people. Anti-aging engineers would argue that any change is damage - we should start working on a fix now, rather than wait to fully understand how harmful this DNA damage is.

Link: http://www.physorg.com/news85846219.html

Let the Engineers Have At the Biotechnology
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Engineering is all about the rapid determination of effective uses for every new piece of information about the way in which the world works. Explore, test, combine, invent, improve, repeat - there's no need to protest the fact that understanding why often follows the demonstration that we can. Bridges and monuments were built well before the formalism of physics, materials science and architecture; the how was common practice long before the why. Humans excel at operating in an environment of less than perfect understanding, deciphering complex and poorly understood systems - and a good thing too.

In this era of biotechnology, the eager engineering mindset is turned towards genes, cells and biochemistry. If there's one thing better than engineering, it's engineering during the exploration of an enormously intricate system. Each new fact carved out from the unknown by researchers is a puzzle piece to be set with all the others, turned about and around, compared for new and interesting fits. The medical engineers take those pieces and gleefully work to build wonderful, effective new medical technologies.

An example of the sort of inventive progress presently taking place can be found in a recent press release from the cancer research community:

Most chemotherapy drugs affect both normal and cancerous tissue, which is why they also are toxic to naturally fast-growing cells in the body such as hair follicles and intestinal cells. Aboody and her colleagues have developed a two-part system to infiltrate metastatic tumor sites, and then activate a chemotherapeutic drug, thereby localizing the drug's effects to the tumor cells.

The technique takes advantage of the tendency for invasive tumors to attract neural stem cells. The researchers injected modified neural stem/progenitor cells into immunosuppressed mice that had been given neuroblastoma cells, which then formed tumors. After waiting a few days to allow the stem cells to migrate to the tumors, researchers administered a precursor-drug. When it reached the stem cells, the drug interacted with an enzyme the stem cells expressed, and was converted into an active drug that kills surrounding tumor cells. The precursor-drugs were administered for two weeks, then after a two-week break, a second round of stem/progenitor cells and drugs were administered.

One hundred percent of the neuroblastoma mice appeared healthy and tumor-free at six months. Without treatment, all the neuroblastoma mice died within two-and-a-half months.

Daunting cancerous death sentence? That's not a real showstopper - scientist-engineers will just take these here puzzle pieces and turn them into a therapy that uses existing cellular behavior and biochemical processes to do all the hard work. We don't fully understand those processes, but that's not the point; buildings were built - and built well - prior to Newton's contributions to science. This is engineering: taking the scraps of proven knowledge and putting them to good use.

It is this sort of workflow with an attitude that will get us to an era of far longer, healthier lives, one inventively solved problem at a time. In the modern age of biotechnology, medicine is engineering; that means look out below and mind the dust - big things ahead.

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Exercise For the Aging Brain
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Use it or lose it; a fair body of evidence stands in support of the modest improvements to be gained by exercising brain and body. From the Washington Post: "Ten sessions of exercises to boost reasoning skills, memory and mental processing speed staved off mental decline in middle-aged and elderly people ... honing intellectual skills can bolster the mind in the same way that physical exercise protects and strengthens the body. ... the benefits of the brain exercises extended well beyond the specific skills the volunteers learned. Older adults who did the basic exercises followed by later sessions were three times as fast as those who got only the initial sessions when it came to activities of daily living, such as reacting to a road sign, looking up a number in a telephone book or checking the ingredients on a medicine bottle ... the brief training sessions seemed to confer enormous benefits as many as five years later." Every little bit extra gets you closer to an age of real rejuvenation technologies.

Link: http://www.washingtonpost.com/wp-dyn/content/article/2006/12/19/AR2006121901431.html

Delivering on the Promise
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Here we have a look at the mess people have made of what should have been a good, solid decade of unrelenting progress in the foundation of regenerative medicine, via EMBO reports: "it is still unclear which human stem cells -whether embryonic [ESCs] or adult [ASCs] - will be developed and for which conditions. Given this, the focus of the NIH in the USA, and research organizations in other countries, should be on developing human research capacity in both ASCs and ESCs. Each type of research will take time to mature. The ethical debate will need to produce acceptable policy and regulatory compromises so that the regulatory burden can be reduced and investors' risk aversion can be overcome. If these things happen, the major remaining barrier to realizing the medical benefits of stem-cell research might be the lack of skilled scientists in the field."

Link: http://www.nature.com/embor/journal/v7/n12/full/7400861.html

From Around the Healthy Life Extension Blogosphere
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Herein find a brace of items of interest from the healthy life extension community, starting with a call to action from the Methuselah Foundation:

Great Happenings and the Next Level

I am writing to you to relate some momentous developments at the Methuselah Foundation. PayPal co-founder Peter Thiel has generously pledged $3.5 million to our research effort over the next three years. $500,000 of this sum will be immediately put to use with a view to securing near-term validation of the SENS strategy. The remaining $3,000,000 is offered in the form of a matching grant - Mr. Thiel will contribute 50 cents for every $1 that we raise for SENS-related research. (Note that donations to the Mprize do not attract this matching money.)

The Methuselah Foundation is now transitioning from its start-up phase to becoming a fully operational scientific research organization. Researcher John Schloendorn at Arizona State University has just been awarded a scholarship in recognition of his original work under our LysoSENS initiative in identifying bacterial enzymes that are particularly effective in breaking down intracellular debris. At Cambridge University, doctoral student Mark Hamalainen has begun Methuselah Foundation-supported work on mitochondrial DNA. And I have identified several more promising research projects that we can start work on as soon as funding is in place.

Next, researcher Attila Chordash interviews himself as a part of his series of discussions with the healthy life extension community - you have to be completist to be competitive in the world of molecular biology.

The story of my life&extension commitment

I have a sharp memory about the formulation of the argument that led me to this “aim” conclusion: I, A.Cs. would like to become a good scientist, but I need 50 years for biology, 50 years for physics, 50 years for mathematics and so on…and the only way to achieve this is not concurrently but consecutively, so I need more time, a lot much more than my evolutionarily fixed biology allows me to expect.

I like this logic; it is a very rational approach to life. There simply isn't enough time to achieve even a modicum of what we might. In past decades, we would simply have to cut our ambitions down to size - to become less than ourselves, in other words, to accept limits we have no choice in. But we are entering an age in which we can do far better than that: we can say "first things first" and invest our previous time to create much, much more time - to build the technologies that will greatly extend our healthy life spans. We have eliminated so many of the crushing limitations that weighed down our ancestors, destroying their potential amidst suffering and hard labor for the simplest tasks. The defeat of degenerative aging is a very logical, economical continuation of this process. We stand facing the world and our present limitations, knowing that we can do better. And so we should.

On to a couple of commentary posts on recent science:

Aged Neural Stem Cells Divide Less

Replacement of aged stem cells by younger stem cells will some day be a core component of rejuvenation therapies. So how many neural stem cells will we need to replace in our hippocampuses? Some human brains weigh 1400 grams as compared to 2 grams for a rat.. The difference is approximately a factor of 700 (though human and rat brain sizes vary considerably). So if we could create 700 times 50,000 or about 35 million human neural stem cells and inject them into a human brain's hippocampus we should be able to make our aging brains act younger again.

Think about that. We know one of the causes of lower brain performance as we age: A very small portion of all brain cells gradually lose their ability to divide. That portion of brain aging is a problem that seems solvable within a couple of decades at most.

Calorie restriction slows immune system aging

These findings have significant clinical ramifications: Resistance to infection decreases over the lifespan, especially among the frail elderly (many of whom exhibit a dramatic increase in circulating levels of inflammatory cytokines, possibly originating in part from senescent memory T cells). Finding a means of boosting immune function in these individuals - e.g. by finding a CR mimetic compound that could trigger the T cell improvements observed in this primate study - could help turn decades of decrepitude and chronic illness into more robust “golden years” for millions of human beings.

Calorie restriction has been racking up the points of late - the outcome of greater funding for research. You should look into it; your future self of decades to come will thank you for it.

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Neural Stem Cell Transplants
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Scientific American reports on a first generation stem cell therapy for the brain, now in early trials: "Just over a month ago, on November 14, orderlies at Doernbecher Children's Hospital in Portland, Ore., wheeled a six-year-old child with an incurable disorder of the nervous system into an operating theater. During the next eight hours surgeons used computers to guide a surgical procedure the likes of which the world has never seen: injections of neural stem cells directly into the brain of a human subject. In this phase I clinical trial, doctors affiliated with Oregon Health Sciences University (OHSU) are collaborating with scientists at Stem Cells, Inc. ... Their immediate goal is limited to healing children afflicted with Batten disease, a rare but fatal neurodegenerative disorder. In the coming decades, however, this work could lead to treatments for neurodegenerative disorders that affect millions, such as Huntington's, Alzheimer's and Parkinson's diseases."

Link: http://www.sciam.com/print_version.cfm?articleID=963605BF-E7F2-99DF-31C866B5D61C4463

Stem Cells and the Aging Brain
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(From DukeMedNews). Scientists appear to have reconciled the observed lower rate of neurogenesis in the aging brain with the fact that stem cells are still present: "as the brain ages, fewer new nerve cells, or neurons, are born in the hippocampus, the brain's learning and memory center. ... The common assumption had been that the brain drain was due to a decreasing supply of neural stem cells in the aging hippocampus ... in young rats, the hippocampus contained 50,000 stem cells - and, significantly, this number did not diminish with aging. This finding, the researchers said, suggested that the decreased production of new neurons in the aged brain was not due to a lack of starting material. ... The team now is searching for ways to stimulate the brain to replace its own cells in order to improve learning and memory function in the elderly." This sounds much like the debate over the declining ability of stem cells to repair aging muscle - stem cells are present, but they do less work.

Link: http://www.dukemednews.org/news/article.php?id=9979

"Raging Against Aging" Transcript
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Via transhumantech, we have a transcript of Anders Sandberg's presentation on healthy life extension in Second Life. I can't say I think these virtual spaces have gone far enough past prettified chatrooms and teleconferences to be a genuinely new thing, but not being there does mean you miss out on the slides - just like the first life we're all working on. You'll have to scroll down a ways (to the [10:22] mark) to get past the pre-presentation chatter. Some excerpts:

[10:27] Anders Nadir: The scientific study of the causes of ageing, biogerontology, is a young science that developed after WW II and was still often ridiculed by researchers from other field as late as the 1970's. What possible use could it have?

[10:28] Anders Nadir: Ageing is natural, and it was said that we needed to treat the many diseases of old age, not aging itself. The field was associated with generations of quacks, alchemists and other suspect characters seeking the elixir of youth. Even today when the field is mature and produces a steady stream of scientific discoveries most researchers are unwilling to speculate on where our knowledge may lead us. They often point out that we do not know any scientifically proven ways of even slowing ageing in humans. But that is just part of the story.

...

[10:30] Anders Nadir: Experts have time and again estimated limits to this trend: the curve has to stop somewhere. So far they have been wrong. On average their predictions are proven too pessimistic just five years after being made. This is unsettling, since it suggests that the models used to plan our pension systems and health care likely underestimate how long the people of the future will live. If the current trend continues for 60 more years the average lifespan in 2066 will be around a hundred years. But there are reasons to think this is an underestimate, because ageing itself is now under attack.

...

[10:33] Anders Nadir: The new consensus in biogerontology is that ageing is not inevitable.

[10:33] Anders Nadir: That bears noting, because it goes again so much established wisdom. Even if one does not expect radical life extension it suggests that the length and possibly shape of life can be changed deliberately. And given human motivation, it is likely that it will.

...

[10:42] Anders Nadir: In the past there was little chance of actually doing much about ageing, so it would actually have been rational to accept limited lifespan as any other inevitability. But given the current technological state it seems that the opposite is true: it would be irrational to not want to at least fix the negative aspects of ageing.

As I may have remarked upon before, the core concepts of transhumanism - of which healthy life extension is one of the foremost - are spreading, mixing, changing and diluting as the rest of the world catches up to an acceptance of what was once fringe and radical. Such is the way ideas and their cultural packaging evolve. What is self-evident to a few futurists - and no-one else - in one decade is greeted with a shrug and "of course" by the man in the street three decades later, long after the first, small groups of evangelists completed their work, and generations of subcultures have arrived, grown, whithered and died.

We are somewhere between those two extremes today, insofar as healthy life extension goes, and working hard to bring the concept to a wider audience. When most people see extending their healthy life span as feasible, the pool of those willing to step forward and help out grows large indeed - and then progress begins in earnest. Many hands make light work.

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The Costs and Consequences of Medical Socialism
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I should point out an excellent essay at LewRockwell.com on the present level of Western government interference in medicine, and the costs and consequences that result. You should most certainly read the whole thing; it's one of the better introductions to the subject I've seen in recent years. A few excepts:

There are two popular images of socialized medicine. I don't think either captures what the reality is in our prosperous and largely capitalistic country.

...

I find it striking that after the collapse of socialism in Eastern Europe and the Soviet Union, virtually no effort was made to privatize health services. To be sure, there are now private health services in these countries, but the official systems of socialized medicine still exist. This fact is a testament to the reigning orthodoxy. The world seems to understand that it is a mistake to nationalize agriculture and factory production. No one advocates a Department of Software Development, even if there are far more interventions in this sector than there should be. And yet health care, all over the world, is assumed to be a normal function of government.

...

This is despite the vast number of stories we hear about English and Canadian health care socialism, mostly having to do with a lack of innovation and a grim shortage of medical, surgical, and emergency services. In these countries, there is much that mirrors the former Soviet experience, except in one area: their governments are not as poor. This changes the incentive structure. The government has incentives to spend money. Indeed, governments win from passing money around, and that can mean making more money available rather than less, unlike in the Soviet system.

To understand this point is to add an additional factor to the way we understand socialist medical care. It's time that we change our expectations concerning what socialism will look like in our future, though we have it partially now. The key problem with socialism is that it misallocates resources, and when applied to the U.S. medical sector, this means a vast overconsumption of medical services as well as artificially high prices. The system is carefully structured in a mercantilist way to socialize losses and privatize profits. In this way, the largest players in the market benefit and a small group of semi-private cartels are insured against financial failure.

...

First, there are severe limits on the number of service providers, as there have been for a century. We brag about the specialization we have among doctors, but what we do not have is a range of choices among levels of training. When we want our car fixed, we can go to the dealer or we can go to another 40 places with a range of mechanics, some of whom have had extensive training and some of whom have not - a fact which may or may not reflect on the quality of their work.

In medical economics, however, we are supposed to believe that physicians are a class set apart like ordained priests with special powers. You are either ordained to practice medicine or you are not. The limits on the numbers - which are built into the cartel of medical schools as well as the licensure system - are nothing but a mercantilist effort to increase prices and incomes. Of course every profession has its licensure system, but the medical one has been uniquely successful in making the barriers to practice incredibly high.

...

Everyone has horror stories to tell of how aging people are treated by our medical system. What strikes me as strange is how the financial incentives of hospitals and insurers are rarely considered to be a factor in the medical decisions made on their behalf. We are all supposed to believe that our medical establishment is purely interested in human welfare. But if we understand the financial incentives at work, we have a new window into why it is that so vast a percentage of medical resources are used to treat people in the last months of their lives.

The level of freedom in research and medical commercialization matters greatly. It is a very large determinant of the speed with which future medicine arrives - and especially medical technologies capable of reversing age-related cellular damage that lies at the root of frailty, degeneration and death. At the moment, right this instant, the system is broken. The very fact that we have "a system" is a breakage; that entrepreneurs are held back from investment by rules and political whims that are now held to be of greater importance than any number of lives. That decisions about your health and ability to obtain medicine are made in a centralized manner, by people with neither the incentives nor the ability to do well.

As is always the case, the greatest cost of socialism in medicine lies in what we do not see. It lies in the many billions of dollars presently not invested in medical research and development, or invested wastefully, because regulations - and the people behind them, supporting and manipulating a political system for their own short term gain - make it unprofitable to invest well. Investment is the fuel of progress, and it is driven away by self-interested political cartels.

The situation is grim; the greatest engines of progress in medicine - the research communities of the US and other Western-style countries - are moving forward very much despite the ball and chain of regulation that drags them down. In the fight against age-related disease, and aging itself, how much further ahead would we be if we cut those chains and restored freedom to research, manufacture, review and quality assurance of medicine?

Sadly, I do not see this happening in the near future; a long, hard battle lies ahead for advocates of freedom and faster progress in any field. We live in an era of creeping socialism, economic ignorance, and blind acceptance thereof. It's almost as though no lesson was learned from the megadeaths, poverty and suffering of the Soviet experience, as we step a little at a time in that direction once more.

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Alzheimer's and the Eyes
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InfoAging reports on one of the possible paths to early detection of Alzheimer's disease: "I noticed that my mice were developing dense bilateral cataracts in their eyes - at an age when mice simply don't get cataracts ... So I took a look at a few more of the Alzheimer's mice, and they all had the same cataract ... the cataracts were composed of the same protein, beta-amyloid, that forms sticky, tangled plaques in the brains of Alzheimer's patients. ... This was the first time the beta-amyloid protein had been seen outside of the brain, suggesting that the disease results from a problem affecting the body's entire system. ... [researchers have] also created new non-invasive laser technology that can detect beta-amyloid in the eye even before the cataracts become visible. ... Intriguingly, they have also found that amyloid buildup appears earlier in the lens than the brain." Some evidence suggests that Alzheimer's is similar to diabetes; more a consequence of lifestyle and metabolism than inevitable. If true, detecting the disease early means the ability to avoid or mitigate it through lifestyle changes.

Link: http://websites.afar.org/site/PageServer?pagename=IA_feat47

Bruce Ames on Micronutrients
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SFGate.com looks at the work of Bruce Ames on the biochemistry of mild micronutrient deficiencies, long term health and longevity: "For years, Ames kept his microscope focused narrowly on cancer and aging. Today, he's increasingly concerned with the cellular consequences of a diet short on vitamins and minerals. ... The relationship between diet and cancer has, historically, been thought of in terms of exposure to potential carcinogens, such as alcohol. Dietary deficiencies, however, might be a much more important factor in cancer risk. ... We know a lot about severe deficiency, we know some about moderate deficiency, we know little about mild deficiency. ... We still have to prove it in people and at what level, but so far for every vitamin and mineral deficiency we've looked at [cells] senesce early and we see a lot of DNA damage ... Inadequate micronutrient intake, Ames believes, affects the mitochondria in much the same way as aging."

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2006/12/17/CMGDVMHITE1.DTL

"Won't Work" and the Entrepreneurial Mindset
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Kevin Dewalt has some nice things to say about Dave Gobel, co-founder of the Methuselah Foundation (and the Mprize for anti-aging research). Stroll over to his blog and take a look:

As we chatted over lunch, David talked about his many past experiences as an entrepreneur and the challenges he faced in starting the Methuselah foundation. How his idea has evolved…how he connected with Aubrey de Grey…the challenges in getting credibility and the victory of Peter Thiel's donation.

At some point he began talking about his other endeavors and projects to help make our country safer. At one point in the conversation I found myself slipping into the “why it won’t work” mindset during the discussion. Then I caught myself and laughed internally.

Here I was in the company of someone who was pursuing perhaps the greatest human endeavor in history. Against all odds and critics, David Gobel was trying to defeat age-related diseases and turn back the aging clock for all of us in our lifetime.

I mean no disrespect to the other great human accomplishments, but does anyone know of another pursuit which measures up to this level of challenge and importance? Wallking on the moon? Discovery of DNA? Theory of Evolution?

I can’t think of one. Maybe the guy who discovered fire might argue with me.

In any case, can you imagine how many people have told David Gobel that his outlandish idea “won’t work”?

No-one commits absolutely to the fulfillment of a vision if there is any significant doubt of success in their mind. Entrepreneurs of all stripes are people deaf and blind to the cries of "won't work!" in their particular space of endeavor - and we all profit greatly from this mindset, where it is directed towards enabling a better future. Progress is only possible when at least some people are willing to risk financial security to attain a vision, and are willing to work themselves to the bone to see that vision accomplished. This is the mindset necessary to sow and nurture the seeds of new organizations, new technologies and new popular movements.

The Methuselah Foundation is on the way to a future of grand success; raising more than $8 million in cash and pledges in a few years is ticket enough to move from five and six figure donations to seven-figure fundraising and more. It is enough to influence the direction of longevity science, and start to wake the scientific community to action. It is enough to attract worldwide attention from the philanthropic and medical advocacy community. The challenges of growth faced by the Foundation volunteers today are just as tough as those of two years ago, but the potential rewards and results are far greater now. Success attracts further success, provided you keep putting the work in.

If you do one thing this year to help make the future a better place, make it a donation of time or money to the Methuselah Foundation. Reward the success to date by helping the Foundation achieve even more in the future; your contribution accelerates progress towards reducing the suffering of hundreds of millions, and eliminating the dreadful toll of more than 100,000 lives lost to aging each and every day. Little else any of us can do will have as much impact on the future well-being of humanity.

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Towards Medical Nanoscopy
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While we're on the subject of the nanotechnologies required for the development of real anti-aging medicine, here is an interesting piece from Nanowerk: "Based on the premises that diseases manifest themselves as defects of cellular proteins, these proteins have been recently shown to form specific complexes exerting their functions as if they were nanoscopic machines. Nanoscopic medicine refers to the direct visualization, analysis (diagnosis) and modification (therapy) of nanoscopic protein machines in life cells and tissues with the aim to improve human health. ... In two recent papers, the researchers introduce their concept. 'Checking and fixing the cellular nanomachinery: towards medical nanoscopy' [and] 'Nanoscopic Medicine: The Next Frontier' ... While nanoscopy refers to the visualization of structures on the nanometer scale, 'medical nanoscopy' goes beyond diagnostics by including therapeutic applications as well." The root of aging is change in proteins and other biomolecules - we need the technologies that will enable us to reliably repair our cells (and thus our bodies) at this level.

Link: http://www.nanowerk.com/spotlight/spotid=1154.php

Nanomedicine, Most Desired
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From Nanodot: "As a veteran nanowatcher, I can testify that what most people want most from nanotechnology is dramatic medical advances, such as the cancer treatments now showing so much promise. ... Instead of focusing on what is or is not part of nanobiotechnology, scientists wonder more what is going on in this broad area. First, this field brings researchers together from many areas: cellular and molecular biology, chemistry, engineering, physics, and more. In addition, nanobiotechnology aims at improving automated laboratory procedures, imaging, diagnostic assays, and more. In the near term [the] most exciting developments will probably be in cancer treatments. Some wonderful results are already coming from that area.'" Over the next two decades, the maturing of this technology base will enable development of much of the necessary toolkit for real anti-aging medicine - techniques based on the repair of damage at the molecular level, such as those proposed in the Strategies for Engineered Negligible Senescence.

Link: http://www.foresight.org/nanodot/?p=2384

The Edmonton Aging Symposium
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From the folk at the Methuselah Foundation: "we are always looking for ways to raise awareness of the near-term potential for the development of promsing intervention-oriented aging therapies and one of the opportunities we are helping to organize and support is the Edmonton Aging Symposium. The Symposium is a unique blend of economics, ethics and the social and biomedical sciences dealing with aging. It is the first serious attempt to bring together individuals from normally disparate communities under one roof to hear the same message of the potential of these new technologies to repair the damage of age-related dysfunction. ... The Symposium program includes such speakers as Aubrey de Grey, Judith Campisi, Michael West, Ellen Heber-Katz, Ronald Bailey and a host of others presenting on the state of knowledge of what you can do now to stay healthy while presenting evidence of the future technologies that will be able to take us beyond mere lifestyle choices."

Link: http://blog.methuselahfoundation.org/2006/12/the_edmonton_aging_symposium_r_1.html

NJ Stem Cell Research Funding Update
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Via the Washington Post, a brief update on the process of state funding for stem cell research in New Jersey: "the state Legislature on Thursday agreed to borrow $270 million to build labs and pay for related programs. Gov. Jon S. Corzine said he looked forward to signing the bill ... The legislation provides $150 million for a stem cell research institute at Rutgers University in New Brunswick, $50 million for a biomedical research center at Rutgers-Camden, $50 million for an adult stem cell research facility at the New Jersey Institute of Technology in Newark, $10 million for the Garden State Cancer Center in Belleville, and $10 million for the Elie Katz Umbilical Cord Blood Program in Allendale."

Link: http://www.washingtonpost.com/wp-dyn/content/article/2006/12/14/AR2006121401817_pf.html

End of Year Matching Grant For Alcor Donations
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All too many of the people alive today are not going to survive to see a future of advanced biotechnology and anti-aging science capable of greatly extending the healthy human life span. This is an unpleasant truth, but one we should not hide from. The only reasonable option for these folk rests in advancing the technology, industry and provision of cryonics, the technologies used to place the recently deceased into low-temperature storage, called cryonic suspension.

Such suspension can be essentially indefinite, for so long as some agency acts to maintain the storage facility. This allows for the possibility of future repair and resuscitation, perhaps via the agency of a mature molecular manufacturing technology base or other advanced nanotechnology, combined with a greater knowledge of cellular structure in the brain, and enough computing power to manage the complexity of the task. The passage of time is less of a barrier for the vitrified; waiting out the future is more a matter of long-term planning and organizational longevity for the cryonics provider.

There is no known barrier in physics to rescuing someone whose fine brain structure remains intact; our present inabilities are entirely a matter of lacking knowledge and technology. Undergoing cryonic suspension is an educated gamble on the future - just like most aspects of life - but the technology and progress side of that gamble looks to be a sure thing in the long term. The more interesting question is when and how the provision of cryonics will grow into a large, mainstream industry, more likely to sustain itself for another fifty or a hundred years; a lot of work remains to be done there.

With all that in mind, I should mention that a matching grant is in place for charitable donations made to Alcor's cryonics research program prior to February 28th, 2007. Do you have a particular view of the future of cryonics that you would like to see come about? It is far more likely to come to pass if you step forward and help:

This year, a member who prefers to remain anonymous has put up $25,000 for another matching grant, this one focused on his own personal interest: fracture free storage. When a patient is cooled below the glass transition temperature (about -120°C), mechanical stresses form that can lead to fracturing of tissue, significantly increasing the level of technology needed for revival. Contrary to previous belief, we have found that simply maintaining a patient at higher temperatures may not be enough to prevent this damaging fracturing, since we have indications that fractures occur at temperatures too warm to be safe in the long-term.

To understand and seek ways to prevent these damaging fractures in our patients, Alcor has an ongoing project to analyze the biophysics of fracturing using newly developed technologies and methods. Your donation to this matching grant will support progress already underway, including ongoing testing and development of intermediate temperature storage and transportation systems. This research is separate from the whole body vitrification research, which is continuing into 2007.

From now until February 28, 2007, contributions up to a total of $25,000 will be matched by our anonymous donor. As usual, donations are fully tax deductible. This is your opportunity to further Alcor’s goals, double your contribution, and enjoy a tax deduction.

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Deciphering Regeneration
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It's only a matter of time until scientists decipher the biochemistry of regeneration in lower animals - and then develop the technology to bring the same to humans. Another step forward in the process is noted by EurekAlert!: "apoptosis has [a] critical role in regeneration. ... Simply put, some cells have to die for regeneration to happen. ... We were surprised to see that some cells need to be removed for regeneration to proceed. It is exciting to think that someday this process could be managed to allow medically therapeutic regeneration. ... when apoptosis is inhibited during the first 24 hours, regeneration cannot proceed ... Later inhibition of apoptosis has no effect, suggesting that the programmed death of a specific cellular component is a very early step in the regeneration program. One possible model is that tissues normally contain a population of cells whose purpose is to prevent massive growth in the region surrounding them."

Link: http://www.eurekalert.org/pub_releases/2006-12/fi-fsd121206.php

Methuselah Foundation Forums
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The Methuselah Foundation is nearing $8 million in total backing for the Mprize for anti-aging science and SENS research - and well past that if you want to include expense donations and airmiles from the small army of donors. Thank you all! The Foundation technical volunteers have recently put up an online forum for both public and internal discussion. If you'd like to meet the volunteers, administrators and researchers, talk about the mission - to engineer the defeat of aging! - or just hang out, feel free to drop by. There can never be too much discussion about the modern scientific approach to extending the healthy human life span; the more we talk, the more we educate and raise awareness for the cause.

Link: http://www.methuselahfoundation.org/forums/

Mix Exercise In With That Calorie Restriction
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Not that I imagine there are many people out there under the impression that calorie restriction (CR) replaces the need to exercise to maintain good health ... but it never hurts to keep hammering nails into these coffins as they drift back into immediate reach.

Those who dieted lost muscle mass while those who exercised did not. This is because exercisers routinely challenged their muscles, which prevented muscle tissue from degrading. Dieters didn't work their muscles as vigorously as those who exercised. ... It's important that dieting not be seen as a bad thing because it provides enormous benefits with respect to reducing the risk of disease and is effective for weight loss. Furthermore, based on studies in rodents, there is a real possibility that calorie restriction provides benefits that cannot be achieved through exercise-induced weight loss." So then, as before, and as CR practitioners do, the best way forward would seem to be some combination of CR and exercise, not one or the other.

The topic of exercise, bone loss (rather than the muscle loss above) and calorie restriction has been in the popular science press of late. A recent study on the subject is referenced over at Ouroboros:

A recent study addresses the effect of CR on bone loss, and finds that limiting caloric intake can result in decreased bone mineral density (BMD) at clinically relevant sites in the body, i.e., places where fractures often occur in the elderly. ... These data suggest that [exercise] should be an important component of a weight loss program to offset adverse effects of CR on bone.

It really isn't hard to come to an 80/20 benefit situation in personal health - and thereby increase your chances to living into the coming era of working anti-aging medicine and the end of age-related frailty. The basics of good health and maintenance are not rocket science; eat less, eat the right levels of nutrition, modest supplementation and exercise. If, like many people, you treat your body worse than your car, you might stop for a moment and ask yourself just what the cost of that course might be - is it worth it?

In the Epicurian world of the past, in which there was no possibility of extending the maximum human life span through science, there was little to said in criticism of those who chose to burn their candle faster. But we don't live in that world anymore; science is advancing so rapidly that modest differences in your expected healthy life span today could lead to enormous consequences for your future. Will you miss the advent of the first therapies capable of repairing age-related damage and restoring a degree of youth? Or will you make it with a few years to spare? We are fortunate to be in the midst of the early stages of a transformative revolution in science and medicine; to those cutting their lives short, I feel we have some obligation to ask "are you sure you know what you are doing?"

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Improving On Resveratrol In Yeast
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Through an understanding of the way in which known calorie restriction mimetics work - those acting via sirtuins, in any case - scientists are working on producing compounds that should do a better job. "This past decade has seen the identification of numerous conserved genes that extend lifespan in diverse species, yet the number of compounds that extend lifespan is relatively small. A class of compounds called STACs, which were identified as activators of Sir2/SIRT1 NAD+-dependent deacetylases, extend the lifespans of multiple species in a Sir2-dependent manner and can delay the onset of age-related diseases such as cancer, diabetes and neurodegeneration in model organisms. Plant-derived STACs such as fisetin and resveratrol have several liabilities ... Here, we describe synthetic STACs with lower toxicity toward human cells, and higher potency with respect to SIRT1 activation and lifespan extension in Saccharomyces cerevisiae. These studies show that it is possible to improve upon naturally occurring STACs based on a number of criteria including lifespan extension."

Link: http://dx.doi.org/10.1111/j.1474-9726.2006.00259.x

Longevity Research As An Industry
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Longevity research, and future commercialization of the first real, working anti-aging medicine, is an industry as any other. It should be no surprise that those who think in terms of building industries look at healthy life extension in that way. From the Edmonton Journal: "A 78-year-old man grows back a finger he lost in an accident. A man near death is able to walk away from the operating table after his failing heart is injected with bone-marrow stem cells. A monkey controls its robotic arm using only its thoughts. It's not science fiction. It's happening right now in medical research ... An aging population has created a chance to generate jobs, make money and improve our quality of life ... Top gerontologists in the U.S. have asked for $3 billion for research to slow the aging process. We have a huge opportunity in Alberta to accelerate this research ... the Edmonton Aging Symposium on March 30 and 31 will raise awareness of the rapid development of age-related therapies. The line-up includes renowned researchers on aging from Canada, U.S. and Europe."

Link: http://www.canada.com/edmontonjournal/news/business/story.html?id=f79ca0cc-1e30-4716-97ab-30276f5ee115

Accept the Risk, But Do Not Embrace the Risk
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A thoughtful post on the simple realities of life and death in this age of rapidly advancing biotechnology and nascent healthy life extension medicine can be found over at Existence is Wonderful:

Do we really need to "come to terms" with death in order to be psychologically healthy? Many would assume that the answer to this question is "yes", but where does that leave the rational life-extensionist?

Some of us today might very well reach some degree of escape velocity, through a combination of healthy living, luck, and simply being in the right place at the right time -- but no one person can afford any degree of complacency. And while the laboratory work and technological development continues, those directly or indirectly involved with such efforts will continue to struggle with developing what we feel is the most rational outlook with regard to the future, and our prospects of living to see more of it than a traditional human life expectancy would allow.

The risk of death - by accident or aging - prior to the advent of truly effective rejuvenation medicine is an unpleasant reality that we all face. Ignoring this reality, as folk are wont to do, is not going to lead you to the most effective strategy for lengthening your healthy, active, enjoyable life span. If you want to walk into the future with your eyes open, and benefit from having the best of plans in front of you, you should understand the risks you face - living as a vulnerable, aging human in a world of inadequate (but improving and improvable) medical technology.

But accepting a risk, understanding a risk, does not mean that you have to embrace that risk. The risk of death in future decades as seen today is no more than the risk as projected now, prior to the new information, medical technology and breakthroughs that tomorrow could bring. You don't have to reconcile yourself to living with a risk that you can change! This is what makes our modern era so very different from all that has come before - the advance of technology means that for the first time, we can all work together to greatly extend the healthy human life span.

Don't look about you at the future of medical technology and accept what you find as set in stone. That is not the path taken by the founders and volunteers of the Methuselah Foundation, presently nearing $8 million in cash and pledges for research and research prizes for longevity science. That is not the path taken by any of the scientists, patient advocates or others presently working to extend life and health.

You can help to make a difference! You can change the future, your risk of death and aging, and everyone's risk of death and aging. All it takes is making the decision to do something, to take an action - with small individual effort, many people can change the world by acting together. Don't let the chances pass you by.

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More On ReNeuron Phase I Trial
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As a follow up to a recent Fight Aging! post on the regenerative medicine industry, here is another piece on the work of ReNeuron from DrugResearcher.com: "It is unknown as to whether stem cell therapies can repair the whole region of stroke damage in the brain or, as is more likely, just the periphery. ... We will be looking at people who have had a stroke within the last 3 to 12 months and who have a stable level of disability that isn't going to improve spontaneously. We're hoping to regenerate the area of damage through the injection of stem cells. Ultimately, it is our goal to develop a therapy that can assist in repairing the whole area of damage." It may be infrastructure technologies that come out of this and similar first generation efforts that provide the greatest value in the long term: "We can take any tissue derived stem cell and expand it up to a clonal line. There are a million possible doses [of ReN001] already made up."

Link: http://www.drugresearcher.com/news/ng.asp?n=72688-reneuron-nih-stem-cells-stroke-disability

Education Is Still Needed
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An article from the Prospect looks at aging and longevity as a program - which is, most likely, the wrong perspective for human biochemistry. "Ageing in humans, as in other mammals, appears to be a co-ordinated process orchestrated by a relatively small number of genes. If this is the case, then it makes sense to tackle many age-related diseases through this genetic core rather than treating each one as a separate case - with the possible exception of some brain conditions." So near and yet so far; aging appears to be an uncoordinated stochastic process stemming from a relatively small range of different types of molecular damage. There are a range of other errors and old, abandoned views in the article; I leave their discovery as an exercise for the reader. It is articles of this sort that show we must continue to work hard to make the case supported by the most recent science - that human longevity is plastic, and can be greatly extended via future biotechnology.

Link: http://www.prospect-magazine.co.uk/article_details.php?id=8152

A Leon Kass Retrospective
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A reminder from Michael Anissimov that some people are not just opposed to healthy life extension, but also quite willing to steer government power to block research and the development of working anti-aging therapies. So much for live and let live.

“Could the beauty of flowers depend on the fact that they will soon wither? . . . How deeply could one deathless ‘human’ being love another?”

“Biotechnologies may undermine the likelihood that I will find my path to a full and rich life.”

“Fancy medical technology wasn’t going to benefit a lot of people. It would lead to a trade in human spare parts.”

...

"Withering is nature’s preparation for death, for the one who dies and for the ones who look upon him.”

...

“One could look over the past century and ask oneself, has the increased longevity been good, bad or indifferent?”

Leon Kass may not presently possess the high profile of past years, and these views are not expressed in the mainstream media in quite such volume these days, but the President's Council on Bioethics that was his podium is just as bad now as then - stacked with folk who believe it best to force you to age and die on schedule. Bah. I've nothing against people who want to age, suffer and die, but there's a strong, ugly word for someone who forces death on others.

These sorts of pro-death viewpoint are rightfully brought out in the sunlight, ridiculed, and squashed. You cannot rationally debate people who are on the side of legislative murder.

When debating the views and opinions of Leon Kass, chair of the President's Council of Bioethics, it's rather hard to get past the point at which he says he wants to use government power to ensure medical technology for healthy life extension is never developed or used. While there may or may not be wonderous subtleties and interesting points being made, they're being made in the service of arguing for legislated murder. We can debate differences all we like, but using state power to enforce bans on the use of healthy life extension technologies is a form of murder, condemning millions to slow, painful death by age-related degeneration that they could otherwise have avoided. So you can see that after a man says "I would like to ensure that you die" it is somewhat hard to continue to treat anything he says with dignity and gravitas.

Really, you are left with pointing out the obvious, and working to see that rational thought prevails.

If you want to take the interview at face value, Leon Kass is a mystic. He is a modern alchemist. The alchemists of old stood atop what little knowledge of chemistry they had and built a speculative religion of hermetic magic, transient wishes, celestial signs and hidden gold. Leon Kass stands atop what little biotechnology we have today (and seems to have a good grasp thereof), building his own structures of fanciful thought, equally disconnected from the real world.

To repeat myself: the Kasses of this world are more quiet of late, but they haven't gone away. A part of the work needed to bring about great change in medicine and longevity is the defeat of those who would try to sabotage progress and ensure the deaths of billions. We should endeavor to remember that.

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The Right Mindset
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Comments from researcher David Sinclair in this Boston Globe article: "Aging is the worst thing that has ever been put upon humanity. When I was 3 years old, I was horrified by the idea that my grandparents would die, and then my parents would die. And then one day I would die. ... I've been working without break for 11 years on this because I realize that it has the potential to revolutionize medicine. ... Cancer, heart disease, diabetes, cataracts, Alzheimer's. We aim to treat diseases of aging with a single pill. I want to see 90-year-olds play squash with their grandchildren. ... We've come farther than I ever thought we would in my lifetime." More scientists like this, please; I can't say I think the path of metabolic manipulation stands as the best foot forward towards greatly extended healthy life spans - but there can never be too many people thinking the way Sinclair does about aging and the need for action.

Link: http://www.boston.com/news/globe/health_science/articles/2006/12/11/his_research_targets_the_aging_process/

Mprize Fund Passes $4 Million
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The Mprize fund of cash and pledges, purse for a research prize to invigorate and transform longevity research, has passed $4 million thanks to the latest member of The Three Hundred: "With her generous ongoing commitment, Shannon Vyff joins 'The 300', the Methuselah Foundation's select group of supporters, who have pledged to fund the Methuselah Mouse Prize - the Mprize. ... I want my kids to know that I'm also trying to help them and their children and grandchildren live longer and healthier lives. This is about families - we're pulling together as a family to support the Mprize because the suffering and death from aging affects all of us - children, grandchildren. There's a myth that somehow it's OK for old people to get sick and die because they're 'tired of living'. ... I hope more people will donate to the Mprize, because we need to end aging now for real people and real families - not just in science fiction stories."

Link: http://www.mprize.org/index.php?pagename=newsdetaildisplay&ID=113

Ageless Animals, the Turtle Edition
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Within the vast range of the animal kingdom, there are many examples of metabolic processes more resilient and long-lasting than even exceptional mammals such as we humans. Whales, for example, appear to be capable of a century or two. Large tortoises are good for that sort of run as well.

On that note, the New York Times mentioned turtle longevity in passing today:

Dr. Christopher J. Raxworthy, the associate curator of herpetology at the American Museum of Natural History, says the liver, lungs and kidneys of a centenarian turtle are virtually indistinguishable from those of its teenage counterpart, a Ponce de Leonic quality that has inspired investigators to begin examining the turtle genome for novel longevity genes.

“Turtles don’t really die of old age,” Dr. Raxworthy said. In fact, if turtles didn’t get eaten, crushed by an automobile or fall prey to a disease, he said, they might just live indefinitely.

While I'm not sure that manipulating our human metabolisms for greater longevity is the best path forward at this time, I point this out as a reminder that the realm of the possible is much larger than most people credit - in the long term, armed with future biotechnology, at least. Scientists have learned a great deal about the biochemistry and genetics of longevity from yeast, flies and mice in past decades; there is no reason we can't also learn from far older animals.

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Can Damaged Mitochondria Repair Their DNA?
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The fellow of average scientific literacy, passing by this entry, might wonder "do I care whether or not my damaged mitochondrial DNA is being repaired?" A valid question; I would direct your attention to a previous post that explains what mitochondria are and why damage to their DNA appears to be an important root contribution to the degenerations and frailties of aging - and quite likely to your eventual death:

How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You

Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration - but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your own metabolism as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the basic mechanisms of your of metabolism are themselves damaged by the free radicals they created.

Take a look; a chain of dominos exists in your cellular biochemistry. It starts with the accumulation of damaged mitochondrial DNA and ends with a good 1% of your cells turned into bloated generators of damaging chemicals. These chemicals spread throughout your body, degrading important systems, causing pain, illness and suffering - until eventually something fails explosively enough to kill you.

So it is probably of interest to most of us just how and when mitochondrial DNA might be repaired. As it turns out, there has been some debate in past years as to whether or not the body does perform these repairs, or is capable of doing so, and what sort of repairs are possible - certainly our biochemistry doesn't appear to be repairing mitochondrial DNA to a level that would prevent the very visible suffering of the elderly. Here are a couple of recent papers that perhaps illustrate where scientists are on this topic at the present time:

Mitochondrial DNA repair: a critical player in the response of cells of the CNS to genotoxic insults

Cells of the [central nervous system] CNS are constantly exposed to agents which damage DNA. Although much attention has been paid to the effects of this damage on nuclear DNA, the nucleus is not the only organelle containing DNA. Within each cell, there are hundreds to thousands of mitochondria. Within each mitochondrion are multiple copies of the mitochondrial genome. These genomes are extremely vulnerable to insult and mutations in mitochondrial DNA (mtDNA) have been linked to several neurodegenerative diseases, as well as the normal process of aging. The principal mechanism utilized by cells to avoid DNA mutations is DNA repair. Multiple pathways of DNA repair have been elucidated for nuclear DNA. However, it appears that only base excision repair is functioning in mitochondria.

'To repair or not to repair – no longer a question': repair of mitochondrial DNA shielding against age and cancer

The role of mitochondria in energy production and apoptosis is well known. The role of mitochondria and particularly the role of the mitochondria's own genome, mitochondrial (mt) DNA, in the process of ageing were postulated decades ago. However, this was discussed, debated and more or less disposed of. Recent data from elegant mouse models now confirm that mutations of mtDNA do indeed play a central and pivotal role in the ageing process. Newer reports also indicate a possible role of mtDNA mutations in the carcinogenesis of several organs. But is damaged mtDNA repaired, or is it simply degraded and discarded? This question appears to be answered now. According to recent data, mitochondria possess functional repair mechanisms such as base excision repair, double-strand break repair and mismatch repair, yet nucleotide excision repair has so far not been detected.

"Some repair" it is then. Why my interest in this in a world in which protofection will be a viable technology in a few short years?

Today our team confirmed our previous preliminary data showing that we can achieve robust mitochondrial transfection and protein expression in mitochondria of live rats, after an injection of genetically engineered mitochondrial DNA complexed with our protofection transfection agent. A significant fraction of cells in the brain is transfected with this single injection even though we so far did not optimize the dose.

This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.

In other words, if we could just up and replace all our damaged mitochondria at once with a single therapy, why worry about the investigation of repair mechanisms? Well, a wide range of approaches is better than a single approach for starters. Secondly, it's often easier to manipulate an existing biochemical process than to generate an entirely new one. Thirdly, as that first paper notes, scientists have some experience and idea on where to start with improving the performance of existing DNA repair mechanisms.

it appears that only base excision repair is functioning in mitochondria. This repair pathway is responsible for the removal of most endogenous damage including alkylation damage, depurination reactions and oxidative damage. Within the rat CNS, there are cell-specific differences mtDNA repair. Astrocytes exhibit efficient repair, whereas, other glial cell types and neuronal cells exhibit a reduced ability to remove lesions from mtDNA. Additionally, a correlation was observed between those cells with reduced mtDNA repair and an increase in the induction of apoptosis. To demonstrate a causative relationship, a strategy of targeting DNA repair proteins to mitochondria to enhance mtDNA repair capacity was employed. Enhancement of mtDNA repair in oligodendrocytes provided protection from reactive oxygen species and cytokine-induced apoptosis.

Could this sort of repair enhancement be effective enough for this component of the aging process to merit funding on a par with full-on replacement strategies like protofection? Could it do more than just gently slow the accumulation of damage? An interesting question; maybe, maybe not - though I'm leaning towards the latter answer.

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The Growing Role of Ink-Jets
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Ink-jet printing is well on the way to becoming a foundation stone for the next generation of tissue engineering technology. From EurekAlert!: "The custom-built ink-jet printer [can] deposit and immobilize growth factors in virtually any design, pattern or concentration, laying down patterns on native extracellular matrix-coated slides (such as fibrin). These slides are then placed in culture dishes and topped with muscle-derived stem cells (MDSCs). Based on pattern, dose or factor printed by the ink-jet, the MDSCs can be directed to differentiate down various cell-fate differentiation pathways ... Because the ink-jet system employs such precision, it could be used one day to co-culture multiple MDSC lineages - including bone, muscle and other cell types - in complex, patterned configurations that could be incorporated directly into specific areas of the body in need of repair of multiple tissue types ... such as joints where bone, tendon, cartilage and muscle interface."

Link: http://www.eurekalert.org/pub_releases/2006-12/cmu-pte120506.php

More On IGF-1 and Calorie Restriction
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Calorie restriction (or rather protein restriction in this case - there is a difference) is linked with reduced levels of insulin-like growth factor-1 (IGF-1): "people on a low-protein, low-calorie diet had considerably lower levels of a particular plasma growth factor called IGF-1 than equally lean endurance runners ... That suggests to us that a diet lower in protein may have a greater protective effect against cancer than endurance exercise, independently of body fat mass. ... Past research has linked pre-menopausal breast cancer, prostate cancer and certain types of colon cancer to high levels of IGF-1, a powerful growth factor that promotes cell proliferation. Data from animal studies also suggest that lower IGF-1 levels are associated with maximal lifespan." Some commenters feel that the study didn't control enough of the other variables to make any strong suggestion, but the evidence is piling up.

Link: http://mednews.wustl.edu/news/page/normal/8388.html

When and How Does the Decay of Your Immune System Start?
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Evolution is a harsh but efficient mistress; you can consider yourself surprisingly well optimised as a piece of machinery, but your warranty only goes so far as the number of years in which your recent ancestors contributed to the success of their offspring. After that, you're on your own - biochemical processes unwind and break down free from any past selective pressure to do better.

Take the immune system, for example, one of many absolutely vital components in the very complex system that supports your life. It is remarkably well optimized for reliable and effective use of resources in early and mid-life, but the rules that govern that optimization lead to a system that breaks down badly after extended usage. A crude illustration of the problem in the adaptive component of the immune system is much as follows:

  • Your immune system is capped in its use of resources; it can only have a set number of T cells in operation at one time.

  • A reserve of naive T cells is needed to effectively respond to new threats. These are untrained cells that will be educated and drafted to combat new intrusions.

  • A small reserve of memory cells is needed to respond effectively to previously encountered threats - one reserve per threat.

  • The more threats you have encountered, the more cells become devoted to memory; eventually you don't have enough naive T cells left to mount any sort of effective defense.

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

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

Why Our Immune System Degenerates:

Throughout our lives, we have a very diverse population of T cells in our bodies. However, late in life this T cell population becomes less diverse ... [one type of cell] can grow to become more than 80 percent of the total [T-cell] population. The accumulation of this one type of cell takes away valuable space from other cells, resulting in an immune system that is less diverse and thus less capable in effectively locating and eliminating pathogens.

Decline of the Aging Immune System:

Longitudinal studies are defining progressive alterations to the immune system associated with increased mortality in the very elderly. Many of these changes are exacerbated by or even caused by chronic T cell stimulation by persistent antigen ... Lifelong exposure to chronic antigenic load is the major driving force of immunosenescence, impacting on human lifespan by reducing the number of naive antigen-non-experienced T cells, and, simultaneously, filling the immunological space [with] antigen-experienced T cells. Gradually, the T-cell population shifts to a lower ratio of [non-experienced] cells ... the repertoire of cells available to respond to antigenic challenge from previously unencountered pathogens is shrinking.

Inflammaging:

Our immune system has evolved to very efficiently get rid of acute infections in young bodies but it has not been selected to get rid of subclinical viral infections in old age. ... The constant attempt to suppress slow-acting viruses such as cytomegalovirus (CMV) could eventually throw the immune system out of balance ... CMV is a passive infection in many old people - and more and more of the immune system is devoted to fighting it.

Destroying Chronic Infection:

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

CMV doesn't really hurt you at all in the short term; most people don't even show symptoms. But because you cannot clear it from your system, its presence chews up more and more of your limited immune resources with time. When does this process get underway, and when does it cross the line? A recent paper from the open access journal Immunity & Aging looks at setting some boundaries to that question:

We observed consistently high frequency and phenotypically mature (CD27 low, CD28 low, CD45RA+) CMV-specific CD8+ T cell responses in children, including those studied in the first year of life. These CD8+ T cells retained functionality across all age groups, and showed evidence of memory inflation only in later adult life.

...

CMV consistently elicits a very strong CD8+ T cell response in infants and large pools of CMV specific CD8+ T cells are maintained throughout childhood. The presence of CMV may considerably mould the CD8+ T cell compartment over time, but the relative frequencies of CMV-specific cells do not show the evidence of a population-level increase during childhood and adulthood. This contrast with the marked expansion (inflation) of such CD8+ T cells in older adults.

These results suggest that the accumulation of CMV-specific T cells is not a gradual process throughout life, but rather a more exponential process, or a transition from slow to fast accumulation later in life. There may be a therapy lurking in a greater understanding of how that transition comes to pass.

I should not close thoughts on the matter of age-related decay of the immune system without looking at a SENS-like approach to the problem: something direct and from the engineering school, based upon what we already know and using the tools available to us now or in the near future. The problem is that we have too many of a certain type of cell; the tool would be one of the new technologies enabling precision targeting of cells by their unique surface biochemistry - perhaps a dendrimer therapy with the right attachments. What we'd want to do is eliminate all those memory T-cells specific to CMV that are clogging up the system. This is very similar to the problem faced by cancer researchers; you need to nail all the bad cells, but you can't risk harming other cells or putting undo undue stress on the patient's system. Large amounts of time and money are going into solving this problem today, so we can expect to see a brace of suitable technologies to be adapted to this sort of use in the years ahead.

Will this sort of approach work? There is precedent for attacking, suppressing, manipulating or destroying components of the immune system when they malfunction or otherwise get in the way; destroying CMV-specific memory cells is somewhat less drastic than some immune therapies attempted in the past or under development today. After all, you would be removing cells that appear to be largely useless. I think it's well worth exploring.

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Cholesterol and Alzheimer's
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The New York Academy of Sciences on cholesterol and Alzheimer's disease (AD): "Over the past decade, as cell biologists and biochemists have investigated the complex pathogenesis of AD with new tools in neurochemistry, the metabolic pathways of cholesterol in the brain have generated fruitful and promising research, produced new ideas, and helped to advance old hypotheses. Epidemiologic observations support a relationship between lipid metabolism in the brain and AD, but much work remains to elucidate it and harvest any clinical yield. ... Importantly, the AD-cholesterol link is consonant with the amyloid cascade hypothesis. Although not the only proposed explanation, it is by far the best supported and has generated a preponderance of research. It proposes that AD arises through a chronic and deleterious imbalance between ß-amyloid (Aß) formation and clearance, leading to the accumulation of insoluble plaques and tangles."

Link: http://www.nyas.org/ebriefreps/main.asp?intEBriefID=579

An Interview With John Schloendorn
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Over at Pimm, you'll find an interview on healthy life extension with LysoSENS researcher John Schloendorn: "LysoSENS by itself is meant to address only parts of the age-related damage we accumulate. Magically achieving all LysoSENS goals would not extend life greatly, because other exponentially rising causes of death should rapidly take over, most importantly cancer. Thus, LysoSENS by itself would presumably count as moderate life extension. However, the major part of the reason I am doing LysoSENS is to support the Methuselah Foundation and all of its efforts. The goal of the Methuselah Foundation is to 'declare the arrival of the real war on aging and use our new tools to attack aging at its root, the fundamental biological processes which drive it.' A proof of concept for LysoSENS would presumably greatly increase the resource influx for the Methuselah Foundation, and so all things considered this would probably make me committed to 'maximum' life extension."

Link: http://pimm.wordpress.com/2006/12/08/john-schloendorn-the-lysosens-connection-chat-on-life-extension/

Tackling Osteoporosis
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One potential approach to halt osteoporosis is to reprogram the underlying processes of bone growth and destruction. From EurekAlert!: "Bone health is maintained by the balanced activities of osteoblasts and osteoclasts. The study shows that the inactivation of gene Atp6v0d2 in mice results in dramatically increased bone mass due to defective osteoclasts as well as enhanced bone formation. These findings may provide some clarity into the regulation of bone metabolism and show that targeting the function of a single gene could possibly inhibit bone decay while stimulating bone formation. ... Now that we have demonstrated a new approach that is theoretically attainable, one that combines the best of both worlds, we can go to work on the genes up and down stream from our target gene. If we can find a way to get to our target gene with a drug we may be able to help the millions of seniors with osteoporosis."

Link: http://www.eurekalert.org/pub_releases/2006-12/uops-ob120806.php

Stepping Towards Replacement Hearts
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(From EurekAlert!). Scientists are rapidly working their way up the tissue engineering ladder, from small and simple to large and complex. Replacement organs for the old or damaged are in our future, and a good thing too. "It looks, contracts and responds almost like natural heart muscle - even though it was grown in the lab. And it brings scientists another step closer to the goal of creating replacement parts for damaged human hearts, or eventually growing an entirely new heart from just a spoonful of loose heart cells. ... researchers are reporting significant progress in growing bioengineered heart muscle, or BEHM, with organized cells, capable of generating pulsating forces and reacting to stimulation more like real muscle than ever before. The three-dimensional tissue was grown using an innovative technique that is faster than others that have been tried in recent years, but still yields tissue with significantly better properties."

Link: http://www.eurekalert.org/pub_releases/2006-12/uomh-ana120706.php

Further Explorations in Calorie Restriction
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Once money starts flowing into a field, as it has been for the study of the longevity and health benefits of calorie restriction in the past couple of years, you'll find a contingent working on advancing knowledge by mapping those parts of the problem space not yet paved and built up. I thought I'd point out a couple of recent papers that take a short term study approach by examining the effects of calorie restriction of different dietary components on mitochondrial metabolism. Given the link between mitochondrial free radical generation, cellular damage and degenerative aging, this might be a helpful proxy for effects on long term health and longevity.

Carbohydrate restriction does not change mitochondrial free radical generation and oxidative DNA damage:

Many previous investigations have consistently reported that caloric restriction (40%), which increases maximum longevity, decreases mitochondrial reactive species (ROS) generation and oxidative damage to mitochondrial DNA (mtDNA) in laboratory rodents. These decreases take place in rat liver after only seven weeks of caloric restriction. Moreover, it has been found that seven weeks of 40% protein restriction, independently of caloric restriction, also decrease these two parameters, whereas they are not changed after seven weeks of 40% lipid restriction. This is interesting since it is known that protein restriction can extend longevity in rodents, whereas lipid restriction does not have such effect. However, before concluding that the ameliorating effects of caloric restriction on mitochondrial oxidative stress are due to restriction in protein intake, studies on the third energetic component of the diet, carbohydrates, are needed.

Not all dietary components are equal - some are a good deal more equal than others, it seems. Research into protein restriction has been going on for a while, but there's no such thing as too much supporting evidence. This next study heads off in the other direction, however, in search of benefits obtained without restricting protein:

Synergistic effects of caloric restriction with maintained protein intake on skeletal muscle performance in 21-month-old rats: a mitochondria-mediated pathway:

Caloric restriction (CR) delays the onset of age-related mitochondrial abnormalities but does not prevent the decline in ATP production needed to sustain muscle protein fractional synthesis rate (FSR) and contractile activity. We hypothesized that improving mitochondrial activity and FSR using a CR diet with maintained protein intakes could enhance myofibrillar protein FSR and consequently improve muscle strength in aging rats. Wistar rats (21 months old) were fed either an ad libitum (AL), 40% protein-energy restricted (PER) or 40% AL-isonitrogenous energy restricted (ER) diet for 5 months.

...

the synergistic effects of CR with maintained protein intake may help to limit the progression of sarcopenia by optimizing the turnover rates and functions of major proteins in skeletal muscle.

People like optimizing complex things - such as metabolic processes that contribute to longevity and health. Enjoyment of this sort of activity is hardwired into us; a very necessary part of our success story as individuals and as a species. Long after aging has been defeated through the application of advanced technology, there will be communities that optimize baseline human metabolism for fun.

But today, it's something of a distraction - there are better initiatives we could be advancing with these resources, so as to more rapidly and effectively defeat aging. You can't get to the finish line by manipulating metabolism; all you can do is buy a little more time. But if you spent all your efforts on that, what time is left to really work on the defeat of aging?

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Attacking Cancer Stem Cells
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Now that scientists are getting a handle on cancer stem cells, it comes time to develop the means to precisely attack these cells, and thereby strike at the root of cancer. EurekAlert! outlines one of many early attempts: "The most common type of brain cancer - glioblastoma - is marked by the presence of these stem-cell-like brain cells, which, instead of triggering the replacement of damaged cells, form cancer tissue. Stem cells, unlike all other cells in the body, are capable of forming almost any kind of cell when the right 'signals' trigger their development. For their treatment experiment, the researchers relied on a class of proteins, bone morphogenic proteins, that cause neural stem-cell-like clusters to lose their stem cell properties, which in turn stops their ability to divide." The first step to working the machine is understanding what the levers do; our understanding at this level is still very crude, but even this is sometimes enough to get the job done.

Link: http://www.eurekalert.org/pub_releases/2006-12/jhmi-nps120706.php

Stem Cell Transplants For Parkinson's
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A number of research groups are working on different approaches to regenerating the neurons that fail and die in Parkinson's disease. From ScienceDaily: "a human neural stem cell transplant essentially enables an animal model for Parkinson's to continue functioning normally ... researchers compared animals that received placebo treatment with those that received only protective neurotrophic factors secreted by stem cells and those that had a transplant. Animals that received transplants essentially regained control of their movement, placebo-treated animals did not recover and those that received neurotrophic factors, called stem cell factors, recovered partially. ...transplanted neural cells had formed synapses to communicate with each other and ultimately the striatum, the portion of the brain dopaminergic cells act on to control movement."

Link: http://www.sciencedaily.com/releases/2006/12/061204123212.htm

The Business of Regenerative Medicine in Growth Mode
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The business side of research and development in regenerative medicine is in growth mode these days, with young companies starting up and expanding even in more highly regulated areas of the world - which should tell you just how great the potential benefits (and therefore financial rewards) are. A couple of articles on British companies caught my eye today:

Stem cell firm on growth fast-track:

Stem cell specialist NovaThera is pursuing a strategy of ‘organic growth,’ with plans to double its Cambridge workforce, build a new manufacturing plant and raise a sizable venture capital round

...

The field of tissue engineering brings together the scientific disciplines of biology, materials science and biomedical engineering directed towards the long term repair and replacement of failing human tissues and organs.

Most obviously the ability to repair or replace tissue that has degenerated addresses directly a wide range of ailments and diseases associated with the aging process from hair loss to renewed joint replacements and even damage to the lungs, an area in which NovThera specialises.

ReNeuron seeks to begin stem cell stroke trials:

ReNeuron Group PLC unveiled narrower interim losses and confirmed it has asked for permission to begin clinical trials of its experimental treatment for chronic disability caused by stroke, the first time the therapy will be studied in humans.

The filing, with US regulators the Food and Drug Administration, is a key step for the AIM-listed company, and will be the first therapy developed by ReNeuron to reach the clinic.

The British company believes the trials will be the world's first application of a neural stem cell treatment for a major neurological disorder.

This is just the tip of the iceberg, and what fell out of the search engines today. Tens of thousands of scientists and medical engineers are working away at the medicine of the 2010s as you are reading this, developing ways to manipulate your body into replacing tissues damaged by aging, disease and accident.

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Video From the 2006 Calorie Restriction Society Conference
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Via CRON Diary, I notice that a number of videos from the 4th annual Calorie Restriction Society conference have made their way to Google Video. For those who have a little spare time in what remains of the day, and want a taste of calorie restriction science in 2006, I might suggest the following:

I've focused on the scientific presentations, but you'll find a range of other multimedia has been uploaded to Google Video, including interviews with calorie restriction practitioners and other conference footage.

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And What About the Whales?
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The expression of telomerase, and therefore risk of cancer, has apparently been tailored by evolution to scale by body mass (meaning total number of cells): "Until now, scientists believed that our relatively long lifespans controlled the expression of telomerase - an enzyme that can lengthen the lives of cells, but can also increase the rate of cancer. ... Mice express telomerase in all their cells, which helps them heal dramatically fast ... but the flip side of it is runaway cell reproduction - cancer ... evolution has found that the length of time an organism is alive has little effect on how likely some of its cells might mutate into cancer. Instead, simply having more cells in your body does raise the specter of cancer - and does so enough that the benefits of telomerase expression, such as fast healing, weren't worth the cancer risk. ... What, then, does this mean for animals that are far larger than humans? If a 160-pound human must give up telomerase to thwart cancer, then what does a 250,000-pound whale have to do to keep its risk of cancer at bay? ... It may be that whales have a cancer suppressant that we've never considered."

Link: http://www.rochester.edu/news/show.php?id=2698

Australians End Research Ban
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The Washington Post notes that Australian politicians have ended their ban on therapeutic cloning - a vital technology for the advance of stem cell medicine. Australia is a representative democracy of an authoritarian bent; this sort of thing should be a clear warning for those who call for more power in the hands of government. When that happens, it will be people who don't know you and don't care what happens to you who will control your access to medicine and longevity technologies, both directly and by suppressing research. Is that really what you want? "The law passed Wednesday allows therapeutic cloning, the splicing of skin cells with eggs to produce stem cells, also known as master cells, which are capable of forming all the tissues of the human body. Scientists hope stem cell research will eventually lead to treatments for conditions including Parkinson's and Alzheimer's, as well as spinal cord injuries, diabetes and arthritis."

Link: http://www.washingtonpost.com/wp-dyn/content/article/2006/12/06/AR2006120600215.html

Sinclair on Metabolism and Aging
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Scientist David Sinclair holds forth on metabolism, aging, calorie restriction and his research at Newsweek: "About 70 years ago, scientists discovered that when animals are forced to live on 30 to 40 percent fewer calories than they would normally eat, something unusual happens: they become resistant to most age-related diseases - cancer, heart disease, diabetes, Alzheimer's - and live 30 to 50 percent longer. Restricting calories slows aging. But how? What are the underlying genes that preserve vitality and stave off disease? ... Many scientists are encouraging Congress to increase funding for aging research, to launch the equivalent of the Apollo program. Only a few humans made it to the moon. In the future, millions may live a century or more, and remain vital and productive during those added years." But there are better ways forward than tinkering with metabolism (or than involving government in anything, for that matter).

Link: http://www.msnbc.msn.com/id/15994157/site/newsweek/

CR Slows Immune System Aging
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More good news for calorie restriction (CR) practitioners via The Scientist: "The link between caloric restriction and longevity may be mediated by reduced susceptibility to disease ... scientists found that calorie-restricted older adult rhesus monkeys have at least 30% more naive T cells than controls. ... Some people said there's something special about short-lived animals and that this wouldn't work in humans. This is one of the very best pieces of evidence that show those doubters may be wrong. If it works in something as long-lived as a rhesus monkey, then there's reason to hope that caloric restriction principles can work in people as well." Recall that you need naive T cells to mount a response to new invasions, and that the number of these cells declines with age - a significant part of age-related frailty is the inability to deal with infections and other microscopic threats.

Link: http://www.the-scientist.com/news/home/37246/

Peering at Newt Regeneration
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If the accidentally regenerative MRL mice are anything to go by, there is the strong possibility that salamander-style regeneration of limbs and organs could be brought to mammals - and humans in particular. The biochemistry might just be there, latent and unused ... after all, we all grew the limbs and organs we have once already.

Since this field has some overlap with more mainstream regenerative medicine via the study of stem cells and their role in regrowth in lower animals, money is beginning to move into limb and organ regeneration. Here's news of an interesting study in newts:

When a newt loses a limb, the limb regrows. What is more, a newt can also completely repair damage to its heart. Scientists at the Max Planck Institute for Heart and Lung Research in Bad Nauheim have now started to decode the cellular mechanisms in this impressive ability to regenerate and have discovered the remarkable plasticity of newt heart cells.

...

whereas humans cannot regenerate damaged heart muscle adequately after a heart attack and the destroyed muscle tissue scars over instead, following damage, a newt’s heart can be completely repaired and the organ’s function can be completely restored.

The key to this ability to regenerate are the heart muscle cells themselves. When a newt’s heart sustains damage, its cells can lose their characteristic properties; they can dedifferentiate. The researchers were able to show that proteins typical of heart muscle cells - the heavy myosin chain and various troponins - were dramatically down-regulated in this process. At the same time, the cells embark on massive cell division to build up new heart muscle. It takes around two weeks for the heart function to be restored in the newt. The data shows that at this point the expression of the muscle-specific proteins is again normal, i.e. the cells have differentiated again, and have regained their characteristic properties.

The researchers isolated the heart muscle cells and cultured them. In most of the cells, Braun and his colleagues were able to demonstrate the existence of a protein called Phospho-H3. This protein is a marker for the G2 phase of the cell cycle and indicates that the newt heart regenerates without the involvement of stem cells. It also seems that the heart regeneration does not create typical wound healing tissue, called a blastema. Braun explains this finding: "The heart only has a relatively small number of different cell types. This could be a reason why the regeneration of heart tissue does not require a blastema." The researchers in Bad Nauheim found no indication that stem cells were involved in repairing newt hearts.

No stem cells - just heart cells getting up, changing, doing the work of stem cells, and changing back again. What might that mean for the future of regenerative medicine? There is a gleeful sort of "who knows?" with upthrown arms to be given in response to this sort of question at this sort of time - it's a revolution out there. Answers will come soon, and the medicine of the next decade will look very different as a result.

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All About Identification
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(From Newswise). This is an interesting juncture in the advance of biotechnology: scientists can accomplish a great deal with the latest tools, but learning to identify specific cells is still somewhat harder than taking action with the cells in hand. We should therefore be following the advance of identification strategies with some interest: "A sugar molecule present on embryonic stem cells also has been found on the surface of a type of adult stem cell, a discovery that may help researchers isolate and purify adult stem cells for use in therapies aimed at bone healing, tendon repair and cartilage regeneration ... With a purer cell population, you should have a more effective therapy ... Is the expression of this marker elevated in a tumor? If so, perhaps it might be useful to identify cancer stem cells."

Link: http://www.newswise.com/articles/view/525619/

Regenerating Intervertebral Discs
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Another nice application of early regenerative medicine via Medical News Today: "Lower back pain (LBP) affects a large proportion of the adult population at some point in their lives and in many of these cases it is persistent, eventually leading to debilitating pain. The majority of the cases of LBP are due to degeneration of the intervertebral disc (IVD), the soft tissue which separates the vertebrae in the spine and protects them from damage ... The treatment Dr Richardson is developing uses a cell-based tissue engineering approach to regenerate the IVD at the affected level. This is achieved through the combination of the patients' own mesenchymal stem cells (MSCs) and a naturally occurring collagen gel that can be implanted through a minimally-invasive surgical technique." So far as timing goes, the researcher is "hoping to enter pre-clinical trials next year."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=57953

The First and Last Generation of Calorie Restriction Practitioners
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April Smith makes a good point:

I honestly hope that mine is the last generation that would consider doing [calorie restriction (CR)] for life-extension purposes. That's because I hope that biotech will be developed that will actually reverse aging, not just slow it down a little. Even if CR were to get us to 120 (which I think is overly optimistic, btw), I would rather see therapies developed that will get us more than that, and will be available to people outside of that small subset of people willing to make the sacrifices that hardcore CR entails.

If medical science is pushed forward as fast as we'd like, the folk that presently gather to encourage calorie restriction research and practice calorie restriction for its health and longevity benefits will likely form the first and last generation of that community.

There will still be forward-looking people eager to seize better health and a longer, healthier life in the future - but they will have far better tools at their disposal. I imagine that the mindset informing calorie restriction practitioners today is the very same that will generate eager open source biotechnologists tomorrow, earnest folk who will collaborate to build better, cheaper and more effective healthy life extension technologies.

Food for thought; all things change, and change means progress.

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Stem Cell Therapies, Underway
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From Newsweek, a short but illustrative look at the present breadth of stem cell work, a great deal of it focused on the repair of aging bodies and age-related conditions: "There are now more than 1,000 stem-cell therapies in early human trials around the world. The vast majority use cells from patients' own bone marrow, but doctors are also using cells from healthy adults, and last month saw the first patient treated with embryonic cells ... Burt alone has now treated patients with lupus, rheumatoid arthritis and a host of other immune disorders. ... [researchers] also plans trials for two diseases in which 'nothing else really seems to work': Lou Gehrig's disease and a rare type of autism involving the immune system. ... Next year may also bring hope for patients with cancer and heart disease. The FDA has fast-tracked a stem-cell therapy for leukemia patients; it could reach the market in late 2007. And an approach that has helped many congestive heart failure patients abroad is also making inroads in America."

Link: http://www.msnbc.msn.com/id/16011377/site/newsweek/

The Nature of Aging
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One of the recent "Ask the Expert" pieces at InfoAging features Steven Austad: "The one thing that seems to hold across species is that animals that are long-lived are better at repairing their DNA. That seems to be something that's pretty general because we find it across a whole range of species. One generality - that animals with high metabolic rates live shorter lives - has actually turned out to be untrue. It was a reasonable assumption because the very processes that make energy in an organism's cells produce free radicals that can cause damage. If those internal processes occur at a faster rate, it seemed logical to assume that they caused more damage. It was really quite a surprise - and exciting - to find animals with high metabolic rates that are such dramatic exceptions."

Link: http://websites.afar.org/site/PageServer?pagename=IA_expert_Austad

The Past Year of Progress in Calorie Restriction Science
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I had noticed a recent review paper on progress in calorie restriction (CR) research over the past year or so; unfortunately it has no freely available abstract, which makes referencing fairly pointless for the majority of readers here and at the Longevity Meme. However, the folk of the Calorie Restriction Society mailing lists have more information:

Selected quotes from CR research progress report over the past year. The PDF article is quite technical. I may have missed numerous significant points. I cherry-picked those of interest to me (that I could understand!).

1. CR Lifespan increase appears to be very robust and plastic

The fact that alternate pathways promoting longevity are induced in [yeast] strains lacking respiratory capacity [no mitochondrial retardation of aging] does not negate a role for mitochondrial metabolism where the organelles are functional. The important finding from these studies on strain dependent differences is that CR may extend lifespan by impacting multiple pathways and that there may be a certain amount of mechanistic plasticity.

2. TOR pathway affects nutrition, metabolism and longevity

The influence of TOR on mitochondrial function is of particular interest in the context of CR, because mammalian studies have demonstrated that mitochondrial metabolism and [free radical] generation are altered in tissues from restricted animals compared to controls.

3. CR does not work in some genetically altered species

In rodents, CR extends the lifespan of the Ames dwarf but does not further extend the lifespan of the growth hormone receptor knockout (GHRKO) mouse (Bonkowski et al., 2006).

So in short, as I mentioned the other day, it seems likely that sirtuins are not the end of the calorie restriction story insofar as genes and biochemistry goes. In addition, it is clear that scientists are making real progress in narrowing and clarifying the focus on the core biochemistry of CR-induced longevity and health benefits - what is essential, and what is not. It would not surprise me to see mitochondrial function amongst the important changes brought about by the practice of calorie restriction, given the prominent role most likely played by mitochondria in causing aging.

A fair amount of money is presently going towards calorie restriction studies - certainly much more than in past years, even if modest in comparison to many other fields of medical research. Expect to see much more progress in the next couple of years, especially as some calorie restriction mimetic drugs start to move ahead in the pipeline.

Now if we could just raise more effective longevity and anti-aging research - based on repair rather than metabolic manipulation - up to even this level of funding...

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Beyond the Choir
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On the matter of healthy life extension science, the choir - which is to say gerontologists, bioscientists and those advocates closest to the research - has more or less finished up the infighting of the past decade. There are degrees to which healthy life extension is supported, but the choir now largely faces in the same direction - forward, to longer, healthier lives.

A glance around the community sees a younger generation of scientists who take the goal of healthy life extension through science in their stride, as a given:

it is good to be alive today, so why not tomorrow? I could write a book on all the things I'd like to do that one lifetime isn't enough for. I can understand how it is culturally advantageous (or at least inevitable) to come up with justifications for aging being ok when there is no prospect of intervention. But to maintain those beliefs when intervention is foreseeable is irrational. Any pro-death argument is vastly out of proportion with the horrible reality of aging: the gradual decay of your body that culminates in the ceasing of your existence.

That was from a pro-life extension blog written by a young molecular biologist, in an interview with another pro-life-extension young molecular biologist. Further afield, researchers only a few years more advanced in their careers bemoan the conservative culture that prevents them speaking openly about the defeat of aging:

"The cure for aging" is the instant-death third rail of grantsmanship and we stay away from it.

That culture won't be around for much longer. There's only so long that folk with another decade or two in the field can sit around harrumping in the face of advancing science and public support. Indeed, this year the dam started to break - and the choir are aligning.

Dear Fellow Scientists and Public-Health Advocates:

In March of this year we published an article in The Scientist entitled "In Pursuit of the Longevity Dividend" in which we contend that the time has arrived for governments and national health care organizations to invest in the extension of healthy life by recognizing that one of the most efficient ways to do so would be to aggressively pursue the means to slow aging in humans.

There is a school of thought that suggests putting the choir in order is sufficient to expand the congregation and move forward. Another school of thought suggests that without first building the congregation, you'll never have the right level of support to create a meaningful choir for a new purpose in research. I suspect that both have an element of truth, and that you have to move forward with both initiatives at once for the best possible rate of progress.

If the choir is shaking itself out, where then should the preaching be directed?

Not so long ago, my attention was directed to a rather slick stem cell presentation website from MIT and Harvard aimed putting forward the most elementary factual information into the mass market. I don't see this as a better path forward than the wordier approach, but I point it out to illustrate that even in a field that has undergone a saturation of attention for years, there is still tremendous value in education and broadening the understanding of the simple concepts.

In the case of health life extension and support for research aimed at reversing or slowing aging, for all the fact that a fair number of people have been out there stumping on the topic for years, we still live in a world dominated by the Tithonus Error and myriad other forms of hostility to extending the healthy human life span. Much of it is of the knee-jerk variety, dispelled by education and changing viewpoints - but there's a great deal more to be done in this space if we are to engineer the broad support needed to build an engine of progress to match the cancer research community.

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An Interview With Mark Hamalainen
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Mark Hamalainen is funded by the Methuselah Foundation under the MitoSENS banner, a project to replicate fragile mitochondrial DNA in the cellular nucleus and thus prevent its contribution to aging. Like many of the younger generation of bioscientists, he's open about the desired goal of healthy life extension: "it is good to be alive today, so why not tomorrow? I could write a book on all the things I'd like to do that one lifetime isn't enough for. I can understand how it is culturally advantageous (or at least inevitable) to come up with justifications for aging being ok when there is no prospect of intervention. But to maintain those beliefs when intervention is foreseeable is irrational. Any pro-death argument is vastly out of proportion with the horrible reality of aging: the gradual decay of your body that culminates in the ceasing of your existence."

Link: http://pimm.wordpress.com/2006/12/01/mark-hamalainen-the-mitosens-fellow-blogterview-on-life-extension/

Update On CIRM Funding
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MSNBC looks at the funding situation for the California Insitute for Regenerative Medicine: "Voters passed Proposition 71 in 2004 to create the institute and give it authority to borrow and spend $3 billion over 10 years. Lawsuits, however, have prevented it from going to the Wall Street bond market for its money. So the institute will fund the next rounds of grant-giving with a $150 million loan from the state and another $31 million in loans from philanthropic organizations ... A grant-review committee led by 15 scientists from outside of California last week sifted through 232 applications from state researchers vying for 30 grants worth a combined $24 million. Many of the grants will go to scientists getting into stem cell research for the first time and will be formally awarded in February. In March, another round of 25 grants worth about $80 million will go to established stem cell scientists."

Link: http://www.msnbc.msn.com/id/15992709/

Beyond the Hurdle: Another Hurdle
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As a general rule, hurdling a hurdle presents you with another, different hurdle. Such is progress - but the space between two hurdles is better than the one you just came from. Knowing that the space beyond is better yet, off you go again, at a run and aimed at the next challenge that has presented itself. In that spirit, here is a slice of the way in which science is just this - or, in the words of a cynic, "something like knocking down an infinite series of unevenly spaced brick walls with your head."

Parkinson's approach with stem cells a promising first step

Brain cells derived from human embryonic stem cells improved the condition of rats with Parkinson's-like symptoms dramatically, but the treatment caused a significant problem - the appearance of brain tumors - that scientists are now working to solve.

...

"The results are a real cause for optimism," said Goldman. "These animals with severe Parkinson's symptoms had a dramatically improved outcome after treatment. Now we have a new problem to work on, how to achieve the same benefit without creating tumors. But we expect to be able to solve this problem within the next year or two, using new approaches to cell sorting that we've been developing."

Scientists are attempting to produced controlled growth - which is what embryonic stem cells do in nature. Cancer is nothing more than uncontrolled growth; a sign that the work to be done here is (much as expected in the scientific community, if not in the popular press) much more than simply dropping cells into place and standing back to watch. Regenerating the neurons that die in Parkinson's disease is more than anyone could do just a few short years ago - and a solution to the problem of cancerous growth in the controlled use of embryonic stem cells will come in the years ahead. Hurdles after hurdles, and each leap to a place better than the last.

Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast.

Two models have been proposed for how calorie restriction (CR) enhances replicative longevity in yeast: (i) suppression of rDNA recombination through activation of the sirtuin protein deacetylase Sir2 or (ii) decreased activity of the nutrient-responsive kinases Sch9 and TOR. We report here that CR increases lifespan independently of all Sir2-family proteins in yeast. Furthermore, we demonstrate that nicotinamide, an inhibitor of Sir2-mediated deacetylation, interferes with lifespan extension from CR, but does so independent of Sir2, Hst1, Hst2, and Hst4. We also find that 5 mm nicotinamide, a concentration sufficient to inhibit other sirtuins, does not phenocopy deletion of HST3. Thus, we propose that lifespan extension by CR is independent of sirtuins and that nicotinamide has sirtuin-independent effects on lifespan extension by CR.

It was coming time for another round of stirring the calorie restriction research pot, and thereby complicating the picture. Here we have a claim that sirtuins really aren't the root mechanism for life extension via CR in yeast. All sorts of interesting and complicating findings are being made in yeast - not to mention human genetic studies - with regard to the mechanisms of calorie restriction; it is by no means certain that sirtuins are the end of the story in mammals, for all that Sirtris and others are achieving good results. The pool of knowledge is growing rapidly, however, and answers will be found.

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Progress in the Longevity Community
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Those folk engaged in making a difference to the future of longevity science continue to move forward; here, Anne C. looks back at some recent advances: "It can sometimes be difficult to detect change and progress as it is occurring -- when following and studying a given subject or scientific endeavor, it is not always immediately apparent which data points and events are significant amidst the noise and buzz of journalism, discussion, and argument. But it seems quite certain that things are indeed happening in the realm of longevity science and related research. For starters, the SENS challenge has been addressed, the MPrize has received generous support this year, and the Longevity Dividend represents, perhaps, one of the first vestiges of mainstream attention to the criticality of addressing the health needs of members of the present and future elderly population (who, of course, have as much a right to stay alive and well anyone else)."

Link: http://rationallongevity.blogspot.com/2006/11/longevity-science-brief-snapshot-of.html

Generating the Longevity Dividend
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TechNewsWorld eyes the Longevity Dividend initiative, the most moderate degree to which one might still be called a supporter of healthy life extension: "A group of scientists including S. Jay Olshansky, who is known for skepticism about aging cures, published a paper calling for a goal of decelerating human aging by seven years. Aging is directly linked to cancer, Alzheimer's disease, and heart disease. The scientists argue that a seven-year aging delay 'would yield health and longevity benefits greater than what would be achieved with the elimination of cancer or heart disease.' Many benefits would accrue if anti-aging technologies slowed the deterioration of the unprecedented numbers of humans around the world who are now approaching old age. If people stayed younger longer -- and, therefore, healthier -- they would stay in the workforce longer, need less medical and other care, and spark economic booms in 'mature markets' such as travel and intergenerational transfers."

Link: http://www.technewsworld.com/story/54503.html