Lung Cells From Embryonic Stem Cells
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Examples of continually improving control over stem cells have been rolling in of late; here is one from the University of Texas: "We have developed a reliable molecular procedure which facilitates, via genetic selection, the differentiation of human embryonic stem cells into an essentially pure population of lung epithelial cells ... the procedure also can be used to create other types of highly-specialized cells. ... The method involves the use of protein markers under the control of cell-specific promoters to convert undifferentiated human embryonic stem cells into highly-specialized cells. The human embryonic stem cells were cultured on specially coated dishes and transfected with a lung epithelial gene regulator of a drug selection gene. ... It is a general technology for developing select cells from human embryonic stem cells. The technology has allowed us to develop a platform that could potentially be useful in the development of spinal cord cells, heart cells, nerve cells and others. ... transplantable alveolar epithelial type II cells can be explored as treatments for pulmonary genetic diseases, acquired lung disease, as well as lung trauma caused by car accidents, gunshot wounds and sports injuries. ... These are the cells that can potentially be used for regenerative lung repair."

Link: http://publicaffairs.uth.tmc.edu/media/newsreleases/nr2007/EmbryonicStemCells.html

Continuing Explorations in Organ Regeneration
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Exploration of the biochemistry of regeneration in lower animals is turning up interesting new information. From Nature: "Researchers have known for decades that an electrical current is created at the site of regenerating limbs. Furthermore, applying an external current speeds up the regeneration process, and drugs that block the current prevent regeneration. The electrical signals help to tell cells what type to grow into, how fast to grow, and where to position themselves in the new limb. ... the complex networks needed to construct a complicated organ or appendage are already genetically encoded in all of our cells - we needed them to develop those organs in the first place. ... The question is: how do you turn them back on? When you know the language that these cells use to tell each other what to do, you're a short step away from getting them to do that after an injury. ... The simplicity of the regeneration start signal is promising ... it is just possible that a properly tuned electric signal is all humans need to jumpstart tissue regeneration."

Link: http://www.nature.com/news/2007/070226/full/070226-8.html

PLoS Genetics Kicks Off Review Series on Aging
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Via Ouroboros and a few other places, I note that the open-access journal PLoS Genetics has started off on a series of reviews and opinion pieces on aging science.

An Age-Old Problem

In keeping with the mission statement of our journal to present interdisciplinary research in the broadest possible context, we have commissioned a series of Review and Opinion articles bound thematically to a discrete set of topics of inherent complexity, as well as broad interest. Each component of the series will examine a facet of the chosen problem and we hope that the amalgam of each series, which will be available electronically as a unified entity, will both educate the non-specialist as well as provide a balanced view that will transmit to our readership an appreciation of the progress made and the future trends in each field.

Our inaugural series focuses on aging, a field under both rapid evolution and substantial controversy.

Yes indeed - though the focus here skirts around the most interesting controversy of all, that surrounding the moral imperative to apply scientific knowledge to treat, repair and otherwise cure aging as soon as possible. There is considerable controversy and ongoing change within and surrounding the gerontology community on topics such as the potential timescales of extending healthy longevity, and whether that goal should be the focus of research.

(My point of view: what is the point of researching a field of medicine that relates to great suffering, pain and death if not to as rapidly as possible use that knowledge to prevent that suffering, pain and death? Aging is no different from cancer or AIDS in that respect, and you don't hear many voices within the cancer research community advocating a "look but don't touch" philosophy of science).

The first review in the series is a topic long-time readers might be familiar with; an examination of the nuts and bolts of the mitochondrial free radical theory of aging, such as it is understood today.

The Role of Mitochondrial DNA Mutations in Mammalian Aging

The mitochondrial theory of aging is based on the premise that reactive oxygen species (ROS), generated throughout the lifespan of an organism, damage mitochondrial macromolecules, including proteins, lipids, and mtDNA. Although most molecular damage is reversible through repair or molecular turnover mechanisms, unrepaired DNA damage may lead to mutations that accumulate as a function of age. The accumulation of mutations ultimately leads to permanent age-related mitochondrial dysfunction, which contributes to the aging phenotype.

The precise nature of the details are still being debated; the plausible scenario put forward by biomedical gerontologist Aubrey de Grey a few years back (and explained for the layman in a past post here at Fight Aging!) is still not an open and shut case at this time. Bulletproof analysis of the evolution of very complex biochemical systems across years and decades of time is still a little beyond present day capabilities - but not for too much longer. If I had to throw a date into the ring, I'd suggest we should be looking for final settlement of the details of the mitochondrial free radical theory of aging no later than 2012.

That said, I suspect research teams will be entering clinical trials for therapies for the repair and replacement of damaged mitochondria en mass in the body somewhat in advance of that date. That feat has already been demonstrated in animals, and the pace of research is blistering these days.

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CIRM Legal Update
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For those following along at home, another milestone in the legal battles over state-funded embryonic stem cell research in California is reported at TechNewsWorld: "The 1st District Court of Appeal upheld a decision by a lower court judge who last year ruled in favor of the California Institute for Regenerative Medicine, which was created when Proposition 71 was passed by 59 percent of the electorate in 2004. Opponents of the stem cell agency said after Monday's ruling that they likely would appeal to the state Supreme Court. ... Once again, the judiciary has upheld the constitutionality of California's innovative stem cell research project in its entirety, without equivocation, and with absolutely no room for further argument." Given the baseline motivation for the legal challenges - absolute opposition to embryonic stem cell research, as opposed to any of the specific fig leaves given by the legal folk - it seems unlikely this will be the last word. So long as they can raise funds and have an obvious next step, the anti-research opponents will continue working through the legal system.

Link: http://www.technewsworld.com/story/55980.html

Regeneration With Embryonic Stem Cells
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Progress in using embryonic stem cells for regeneration is noted at EurekAlert!: "researchers have safely transplanted cardiac preprogrammed embryonic stem cells into diseased hearts of mice successfully regenerating infarcted heart muscle without precipitating the growth of a cancerous tumor - which, so far, has impeded successful translation into practice of embryonic stem cell research. ... Embryonic stem cells have the potential to become any cell type in the body. But directing the stem cells to regenerate targeted tissue is a process that hasn't yet been perfected. Scientists continue to closely scrutinize stem cell strategies to establish even safer and more effective treatments for disease. ... Embryonic stem cells are like a stealth fighter jet that flies virtually undetectable by radar. The host body doesn’t recognize embryonic stem cells, which it allows to multiply freely in an unimpeded fashion. ... The [study] is the first known report of a successful strategy for programming embryonic stem cells to suppress cancer genes, to mature into heart cells (also known as cardiomyocytes) and to successfully fix injured hearts without causing tumors to develop. The study removes a critical obstacle towards translation of regenerative technology into developing new therapies for people with heart disease."

Link: http://www.eurekalert.org/pub_releases/2007-02/mc-rsr022707.php

New at the Methuselah Foundation: Group Membership of The Three Hundred
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As noted over at the Methuselah Foundation blog, the Foundation technology volunteers have enabled group memberships in The Three Hundred:

For the price of a cup of coffee per day, would you like to join a select group of humanitarians who will be remembered for their vision and saving millions of lives?

Modern medical science continues to show us that the aging process may no longer be the intractable problem it has been perceived to be for every generation preceding ours. There is a present need to move faster towards a previously unattainable goal: the control of aging. This need for more rapid medical progess is only magnified by the current profound lack of funding for aging research. Funding springs, at root, from widespread public awareness of advances and possibilities in aging research. Educating the public is an essential step in moving philanthropists and governments to allocate more resources to the study of aging. The problems caused by aging leave us poor in body, spirit, and finances. We must step forward to tackle them!

...

What's it worth to you to live 150 healthy years? What's it worth to you to raise the average human lifespan to 150 years, just as a start? These are not idle questions! Membership of The Three Hundred is a meaningful but affordable commitment: $1,000 a year, by the end of each year, for 25 years. This amounts to $85 a month or $2.75 a day, the equivalent of a visit to Starbucks.

I and many others in the healthy life extension community have joined The Three Hundred in the fast few years order to meaningfully influence the future of longevity research - these funds go to the Mprize for anti-aging research, and the SENS research funded by the Methuselah Foundation. But if you don't want to take on a place in The Three Hundred by yourself, why not band together with your friends and share in the knowledge that you are helping to advance the healthy life extension cause?

For an examination of why everyone should step up and contribute to the growth of the Methuselah Foundation and success of its initiatives, I turn to an essay by Michael Rae:

While I am still relatively young and believe that I am indeed aging more slower than those around me, I have suffered the loss of my loved ones to the aging process already. It's bad enough to watch allegedly "independently-living" aged strangers out in public, idly shuffling their feet, pushing cleverly designed wheeled walkers or balancing on their canes, unable to open the doors for themselves, faces a mask of apathy. It's much worse to spend even a few minutes in a nursing home, walking out of a world of relative health of body and mind into an asylum of decay: men and women, once fit and optimistic about the future, now tied to oxygen tanks, raving mad or sunk into almost complete retreat from the outside world, sitting down hours in advance of their meals for lack of any better purpose to their lives, needing help to get out of bed or clean their own wastes.

...

We need an intervention that will fundamentally arrest, or reverse, the biological decay that creeps into our every cell with each passing year. Too few people are pushing this agenda. We - the healthy life extension community - must put our hands upon the wheel. If not us, who else, after all?

The first group membership has been opened by Parish Mozdzierz for the Betterhumans community; what will your group be?

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More On Early Artificial Eye Development
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Here is a general interest article from MSNBC on early work in the development of artifical eyes: researchers are "[researchers are] implanting special silicon chips in partially blind cats in a bid to help replace or possibly repair diseased retinas in humans. ... The chips, which provide their own energy, have shown encouraging results in clinical human trials, in some cases improving sight in people with retinitis pigmentosa or at least slowing the disease's development. ... Then there are the many attempts, like Optobionics, of creating artificial sight. Some efforts include miniature video cameras that pipe images straight to the brain, devices that send signals to a network of miniature electrodes attached to the retina or chips that eventually could graft themselves to retinal cells, creating a cyborglike system for producing images." The overlap between the development of prosthetics and regenerative medicine is particularly interesting: "A French company is conducting trials for an implant that would release proteins in the eyeball to offset the damage done to retinal cells, perhaps indefinitely."

Link: http://www.msnbc.msn.com/id/17248417/

Activism: Post Pro-Longevity Fliers Worldwide
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I'm very much in favor of folk who step up and inspire people to get things done: all sweeping changes start with a single act, and the world can be changed greatly if a million people each contribute one small but meaningful action to the whole. So I'm pleased to see people itching to get started and make a difference to the future of healthy life extension technology over at the Immortality Institute:

27 May - 2 June : The world will be introduced to the concept of longevity, and healthy lifespan extension.

It will be done by simply having every available member of ImmInst subscribing to this thread, following this thread, participating in this thread, and achieving the goals of this thread so that between those dates every single member who has participated will be mobilised to post between 10 and 20 flyers in very public places in their local area. Inexpensive, easy, effective.

It is late February. I am arbitrarily designating 1 month to discussion time, 1 month to flyer design, and 1 month to movement organisation. 3 months maximum. The date I am picking then is the week from 27 May 2007 - 2 June 2007. In that week I intend to have every single member of ImmInst who is functionally capable of doing so, to have printed themselves a number of "Awareness Raising Flyers" and to then post these flyers to strategic points in their local city, suburb, town, village, workplace, university, bus stop and any other place they can get to.

Simple and to the point - a clearly defined goal that everyone can help accomplish. Very good. The discussion thread and flier design thread are both active, so jump on in and show your support!

As I often repeat here, the future is a matter of what you make of it, and the greatest hurdle to the rapid development of medical technologies to greatly extend the healthy human life span is the absence of widespread support and understanding for such a goal. That is a problem everyone can help with - you don't have to be a scientist or wealthy to reach out and educate a couple of people on the real prospects for progress towards greater longevity. If our future is one of frailty, suffering and death, it will be because we have failed to convince our fellows of the plausibility and merits of working towards a cure for aging.

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Indefinite Life Extension Petition
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The fellow behind the Coalition to Extend Life is looking for signatories for his online petition: "Our Declaration of Independence declares that, 'Life, liberty, and the pursuit of happiness' are inalienable rights for all people. Heretofore, life was a fixed period of time, which has steadily risen over the years. Recently, medical science has made amazing discoveries about how humans age and why they die. Many diseases are being conquered and our lives are being prolonged. The possibility of Indefinite Life Extension is on the horizon. No longer is an unrestricted lifespan an impossible dream, but many hurdles still remain. It is our position that Indefinite Life Extension be considered a national priority. In order to give full meaning to the right to 'life' we need a 'war on aging.' We ask you to create the conditions that will make this possible. First, a National Institute for Life Extension be created with sufficient revenues to fund research in this area. Second, that the Food and Drug Administration classify aging as a disease. Third, a National Commission be organized to study the social and economic impacts of this new reality. Fourth, a 'Manhattan Project' to cure the terminal disease of aging." I'm no fan of the enforcement of positive rights by government, as I'm sure you know, but you should feel free to do as your conscience directs.

Link: http://www.petitiononline.com/CEL/petition.html

Inside Alcor
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A Channel 12 News feature looks in depth at the cryonics provider Alcor in a two part video that can be viewed online: "The non-profit organization, founded in 1972, relocated to Arizona in 1994, in response to concerns that its California facility was too small and vulnerable to earthquake risk. Cryonics is the process of using very cold temperatures to stop the dying process when ordinary medicine can no longer sustain life. The idea is to preserve patients until cures are found for their illnesses and the technology to revive them becomes available. Alcor says it uses an ice-free process, called vitrification, in which more than 60% of the water inside a patient's cells is replaced with protective chemicals, preventing freezing during deep cooling. ... Alcor has about 800 members and nearly 75 patients." You can learn more about the basics of cryonics, the science and personal financial details behind cryonics at the Alcor website. Alcor also maintains a newsletter and blog for those who like to keep up to date with research and organizational developments.

Link: http://www.azcentral.com/12news/news/articles/insidealcor02212007-CR.html

Immortality Institute Skypecast, March 1st
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A group of the regulars over at the Immortality Institute forums - a place where a number of advocates and activists for healthy life extension gather to swap notes and plan next steps - are planning a regular voice chat event. The first will be held on March 1st to establish the level of interest and iron out the bugs:

Ok, so at night during the week seems like the best time. I am going to go ahead and make it for Thursday, March 1st at 10 pm (22:00) EST (in the US: 9 Central, 8 Mountain, 7 Western). It should last about 30 minutes to an hour, give or take a little.

Here is the calculation for the time it will be in different parts of the world at 10pm (22:00) EST March 1st:
http://www.timeanddate.com/worldclock/fixedtime.html?month=3&day=1&year=2007&hour=22&min=0&sec=0&p1=25

...

It will be a Skypecast (info on Skypecasts below), and here is the page for it (I scheduled it):
https://skypecasts.skype.com/skypecasts/skypecast/detailed.html?id_talk=470647

Hopefully it is a success!

You might want to take a brief look at the way in which Skypecasts work before diving in:

You really have to try it to see, but basically there are 3 levels of people: 1) those with permission to speak, 2) those waiting to speak, and 3) those just listening.

When you first sign in, you are in the group that is just listening (generally the largest group), and you click the "request to talk" button at the top when you want to talk, which moves you into group 2. The moderator can allow anyone to talk, bump someone from speaking ability down to regular, or bump someone from the room completely if they are being bad.

It is really very easy, and once you are in there for about 15 seconds you will realize how it works.

Post to the discussion thread if you have suggestions on procedure, specific topics, timing going forward, or any other thoughts.

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Longevity and the Financiers
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The Financial Times takes a look at changes afoot in the financial industries most affected by growth in longevity - those who have in effect, inadvertently or otherwise, bet against such a thing coming to pass. "Some are cynical about whether the longevity market will ever come to life - or at least on a meaningful scale. ... some banks are already testing schemes: Deutsche Bank is considering creating bonds using the cash flows from life insurance portfolios. It believes that it will receive a credit rating for these instruments soon, which should allow trading to start this year. Several other banks are experimenting with bonds and derivatives linked to longevity risk. ... Sooner or later, the City of London will find a better way to count deaths: the financial incentives to get this right are huge. And once a timely death index emerges, the first fully-fledged longevity bond will appear, 'almost certainly over the next year.'" We shouldn't feel sorry for those investors about to lose money betting against longevity; they'll benefit themselves from additional years of life. What is money compared to being alive, healthy, and thus possessed the opportunity to recover from loss through hard work? Longer heathy lives are no disaster - it means more production, more savings, and a greater, more vibrant economy all round.

Link: http://www.ft.com/cms/s/f7a24c26-c3ac-11db-9047-000b5df10621.html

Cigarette Smoke As Aging Accelerator
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I have to say that I think this paper is reaching a little at the edges of the analogy, given some of the very specific and localized conditions associated with smoking, but it is promising to see more research implicitly understanding aging as a process of damage accumulation: "Cigarette smoking reduces life span by an average of 7 years, and tobacco consumption accounts for a shortening of disease free life by 14 years. The exact mechanisms by which smoking causes disease and death are generally not well understood, but evidence continues to mount that cigarette smoking exhausts cellular defense and repair functions, leading to an accumulation of damage e.g. mutations and malfunctioning proteins. In this review, we make an attempt to ascribe many of the deleterious effects of smoking on human health to a general principle, namely the acceleration of aging processes by cigarette smoke chemicals." Smoking is much like maintaining excess body fat - something to cut out of your life if you'd a better chance of living healthily for longer.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17084574

On Repairing Tendons
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From the Philadephia Enquirer, a look at one corner of the regenerative medicine research community: "when tendons are damaged in a fetal mouse, they grow back almost like new. In a recent breakthrough, researchers found that this occurs even when the fetal tissue is transplanted into an adult. Now they are starting to figure out why, in hopes of someday helping people heal better. At the University of Pennsylvania, two main avenues are being explored: Experiments with lab animals suggest that part of the answer lies with certain 'growth factors' secreted by fetal cells. And scientists are trying to give the healing process an artificial boost by implanting 'scaffolds' - pieces of stretchy fabric that guide the orderly growth of new, healthy cells. ... The work is part of a broader field, less than two decades old, called tissue engineering - coaxing the repair or regrowth of bodily tissues through a combination of artificial and natural means. Scientists in the booming field have made headway with heart valves, bladders, liver and skin cells. ... Fifteen years ago, tissue engineering was considered science fiction. Now it's reality."

Link: http://www.philly.com/mld/inquirer/living/health/16730481.htm

Fishing For Aging Science at PubMed
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I strongly encourage everyone interested in healthy life extension to put in at least a little time to become familiar with the underlying science and concepts - how else are you to distinguish the cranks from the forward-looking researchers and advocates, if not by educating yourself as a layman? It also pays to garner a better understanding of the way in which the scientific method - the foundation of science - works in practice; you'll be far better equipped to identify the strength of support for of a concept, as well as those trying to game the system by cherry-picking results. On this latter topic, you might want to read a couple of related posts from back in the archives:

After you have the basics down, it can't hurt to regularly stroll through the searchable archives at PubMed, or similar resource for scientific publications. It's easy enough to skip over the densely worded material that is presently beyond you (and there will always be material that is beyond you - science has grown to the point at which very technical discussions in any given field are beyond casual reading even for other scientists), and you'll usually find something interesting and new. Don't be intimidated by new words, long words and unfamiliar names; that's what Google and Wikipedia are for - make use of these resources, and benefit by them. You'll find that a good deal of scientific nomenclature is simply a matter of precision in naming, and mostly easy and helpful once you get into the swing of things. The process of learning about present research - the sort of thing you won't find in a textbook - is one of identifying common threads, and finding the links that transform what you read into a coherent whole.

Running a quick search in PubMed for "aging" today, and ordering by date, I fished out up the following items of interest from recent publications:

Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle

It is well established that neurogenesis in the dentate gyrus slows with aging, but it is unclear whether this change is due to slowing of the cell cycle, as occurs during development, or to loss of precursor cells. ... Taken together, these findings indicate that precursor cells [are] lost from throughout the dentate gyrus in old age with no concomitant change in the cell cycle time.

This first paper is interesting because it contributes to an ongoing debate I have had my eye on for some months: researchers know that stem cell activity and accompanying regenerative capabilities diminish with age. The logical explanation is that this is an evolutionary adaptation to reduce the risk of cancer due to the activity of age-damaged cells. But is there less activity due to a decline in the number of stem cells, or because the stem cells are performing less work due to environmental cues or changes in regulatory mechanisms? The strategies for restoring function - assuming you have a way to deal with the cancer risk to hand - would be different in either case, and the papers demonstrating evidence for both sides of the debate are piling up.

Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging

In response to progressive telomere shortening in successive cell divisions, normal somatic cells enter senescence, during which they cease to proliferate irreversibly and undergo dramatic changes in gene expression. Senescence can also be activated by various types of stressful stimuli, including aberrant oncogenic signaling, oxidative stress, and DNA damage. Because of the limited proliferative capacity imposed by senescence, as well as the ability of senescent cells to influence neighboring non-senescent cells, senescence has been proposed to play an important role in tumorigenesis and to contribute to aging.

WRN at telomeres: implications for aging and cancer

Werner Syndrome (WS) is a premature aging syndrome characterized by early onset of age-related pathologies and cancer. Since WS is due to a single gene defect, it has attracted much interest from researchers seeking to understand pathways that contribute to cancer and aging at cellular and molecular levels. The protein mutated in WS, WRN, appears to play a major role in genome stability, particularly during DNA replication and telomere metabolism. Much of the pathophysiology associated with WS, including the rapid onset of cellular senescence, early cancer onset and premature aging, can be attributed to a defect in telomere maintenance.

Telomeres - the protective ends of chromosomes that are worn away with progressive cell division - and cellular senescence play an important part in the developing picture of aging. Telomeres, and the various biochemical mechanisms for shortening and lengthening them, are the lynchpin connecting aging and cancer, part of an evolutionary balance between too little cellular regeneration and too great a risk of developing cancer. Werner syndrome is one window allowing scientists to learn more about this system as a whole - and how to manipulate it. A number of research groups are presently working on the control of telomeres with the goal of treating age-related disease or intervening in aging - it remains to be seen just where this path will go.

Microglia derived from aging mice exhibit an altered inflammatory profile

Microglia play a critical role in neurodegenerative diseases and in the brain aging process. Yet, little is known about the functional dynamics of microglia during aging. ... Aging microglia were characterized by the presence of lipofuscin granules, decreased processes complexity, altered granularity, and increased mRNA expression of both pro-inflammatory (TNFalpha, IL-1beta, IL-6) and anti-inflammatory (IL-10, TGFbeta1) cytokines. ... The low but sustained production of pro-inflammatory cytokines by aging microglia may have a profound impact in the brain aging process.

Two items here: the first is the presence of lipofuscin, one of the many "junk" chemicals that build up in the body with aging; lipofuscin is demonstrated to damage a number of important processes in the day to day operation of cells. Lipofuscin is a target for some research groups, including the LysoSENS bioremediation research funded by Methuselah Foundation donors. If you could remove this buildup of junk from cells, a number of processes would improve - this would in fact be the repair of some facets of aging in the treated tissues.

The second item is inflammation: we know that chronic inflammation over years and decades is a cause of accumulating damage in the body. This is why too much fat is a bad thing - it pumps out the cytokines too. You might find some of the information online on "inflammaging" interesting; the puzzle of the aging immune response is that it does too little and too much at the same time. It runs rampant with damaging inflammatory signaling, and yet accomplishes little of its job.

These last two papers relate to another topic of interest that I have been watching in recent months: the effect of antioxidants in cellular mitochondria on healthy life span. Antioxidants applied liberally to our biochemistry (such as those taken as supplements) appear to have little or no benefit. More advanced methologies of localizing antioxidants to the mitochondria have been shown to increase life span in mice by 20-30% or so - but this is a good deal more of an engineering proposition than a matter of ingesting the right chemicals.

Age-related changes in mitochondrial function and antioxidative enzyme activity in fischer 344 rats

The disintegration of mitochondrial membrane integrity was determined higher in the liver of old rats than that of young rats. This was well correlated with the decrease of total superoxide dismutase (SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase activities in most of the organs, except for the increase of catalase activity in heart of old rats. Similarly, the protein expressions of these enzymes were down regulated in the liver and kidney of old rats. Taken together, we suggest that the mitochondrial malfunction in old rats is associated with the decrease of antioxidative enzyme efficiency.

Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase

Mitochondrial superoxide dismutase (SOD-2 or Mn-SOD) is a key antioxidant enzyme that scavenges superoxide. Thus, SOD-2 may not only prevent aging-related oxidative stress, but may also regulate redox signaling in young animals. We used transgenic mice overexpressing SOD-2 to study the role of mitochondrial superoxide in aging, synaptic plasticity, and memory-associated behavior. We found that overexpression of SOD-2 had no obvious effect on synaptic plasticity and memory formation in young mice, and could not rescue the age-related impairments in either synaptic plasticity or memory in old mice. However, SOD-2 overexpression did decrease mitochondrial superoxide in hippocampal neurons, and extended the lifespan of the mice. These findings increase our knowledge of the role of mitochondrial superoxide in physiological and pathological processes in the brain.

Why the benefit from more antioxidants in the mitochondria? Well, mitochondria are damaged by free radicals such as superoxide, and this leads to a range of age-related damage and resulting degeneration throughout the body via an interesting process of many steps. But the normal operations of mitochondria (energy generation for the cell) are the source of the vast majority of these damaging free radicals - in other words, if you want to reduce the damage to mitochondria by soaking up those free radicals, you'd better put the antioxidants right at the source. Anywhere else just won't do the job.

I hope that this provides something of an illustration of the way in which you can look into aging research yourself, and learn something of what the research community is presently working on. Knowledge is power.

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Why Are Some Organs Better At Repair?
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Interesting research from the Harvard University Gazette: "The rules governing mammalian organ repair and regeneration are so widely varied as to suggest at first glance that there are no rules: Blood has such an enormous regenerative capacity that you can literally give it away by the pint and be none the worse for wear; rip a hole in your skin and new skin will cover it; donate a portion of your liver and it will regenerate; but lose a kidney or suffer damage to your pancreas, and what's lost is lost. ... a new study [helps] to explain the variation both in organ regenerative capacity and in organ size determination as well. The findings also underscore the value of embryonic stem cells as tools to study normal development. Comparing development of the liver, which can regenerate to compensate for damage, and the pancreas, which cannot, [researchers] found that the ultimate size and regenerative capacity of certain organs, e.g., the pancreas, is determined by the specific number of progenitor cells that are set aside during a very early time in development - about day 10 in the mouse." The more we learn, the closer we come to greatly improving regenerative capabilities.

Link: http://www.news.harvard.edu/gazette/2007/02.22/05-pancreas.html

Alcor Is Hiring
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Cryonics provider and research organization Alcor is looking for a research scientist: "We have an immediate job opening for a research scientist. The candidate will be working in Alcor's R&D lab, assisting in research on cerebral ischemia, cardiopulmonary bypass, hypothermia, and cryobiology. The candidate will also assist in human cryopreservations and related tasks. Requirements include a graduate degree and experience in biology, biochemistry, or other medical science. Candidates must have a publication history. Preference is given to candidates who demonstrate a familiarity with cryonics and human cryopreservation." By way of a reminder, Alcor recently celebrated its 35th anniversary, and is presently nearing completion of the 2006-2007 Matching Grant for Intermediate Temperature Storage Research - help out if you can. All too many people presently alive today will have no other option than cryonic suspension as a chance for healthy life in the future, as they will age to death faster than healthy life extension technologies can be developed and commercialized.

Link: http://www.alcornews.org/weblog/2007/02/job_opening_at_alcor.html

Alcor's Epilogue
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Way down at the bottom of the left navigation bar of the Alcor website stands a link entitled "Epilogue." I don't know whether you folk have ever wandered that way, but it's a potent thought for the day:

What kind of world will another century bring? History teaches that humans will become much better at meeting both their basic needs and higher aspirations. People may reach across frontiers of time and space more vast than their ancestors dared dream.

The first generation that will see the 22nd century is already here. They are our young children. Among them are individuals who may see the 23rd century and beyond; people who will one day walk under strange stars and skies; people whose lives and worlds will grow beyond the imagination of science fiction.

The last generation to fall short of future centuries might not have to. All revolutions begin with a small group and a new idea. At Alcor we have an idea that may be more revolutionary than any ever before it. That idea is:

If humanity can survive long-term, then so can we.

This is why we support healthy life extension and cryopreservation research and development - because a golden future of growth and exploration lies ahead, science fiction made science fact, and to miss out on a moment of it would be a tragedy.

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20% Of Actuarial Escape Velocity
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An interesting take on recent trends in life expectancy in the old can be found at the IEET blog: "US life expectancy at 65, up 1 year from 1999-2004 ... Meaning the U.S. is at 20% of escape velocity. ... During 1999-2004, life expectancy at age 65 years increased by 1.0 year for the overall U.S. population, 1.1 years for white men, 0.8 years for white women, 0.9 years for black men, and 1.3 years for black women." One year up, five years forward - a 20% incline. We would like to aim for a near future in which medical technology advances rapidly enough to add an additional year of healthy life expectancy for the old with each passing year of time. This goal is known as actuarial escape velocity, the point at which our life is moving faster than the approach of age-related degeneration and death. The plausibility of this goal is not in doubt, from any consideration of our understanding of physics and biochemistry, but the timing of future developments and funding is always in question. It is encouraging that the indirect effects of modern medicine on later life have brought us a modest fraction of the way towards escape velocity - but much more deliberate, directed work is needed!

Link: http://ieet.org/index.php/IEET/more/9904usle/

The Utility of Life Extension
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From Agoraphilia: "What if you could costlessly extend your life by one year? Suppose that the additional year would be a decent one - not a fantastic year, but definitely worth living. By 'costlessly,' I mean that you could achieve this life extension with no sacrifice of utility in previous years, so you really would just be tacking one more decent year onto the end of your life. Would you do it? I sure would. Now, suppose you've tacked this additional year onto your life. You now have the option of improving the quality of that added year by slightly reducing the quality of previous years - perhaps by saving more money or improving your nutrition. ... Moreover, the resulting increase in utility in the last year will outweigh the reduction in utility in the earlier years. Would you do it?" The author goes on to illustrate a paradox in utilitarian considerations - but consider for a moment that the above material perfectly describes saving and investing for future years, or investing in healthy life extension research. It all boils down to this: if you're enjoying life, why leave? Why let yourself be forced out by degenerative aging if there is some way to act in advance to prevent that from happening?

Link: http://agoraphilia.blogspot.com/2007/02/utility-of-life-extension.html

Working to Bend Stem Cells to Our Will
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Scientists the world over are working hard to control stem cells - because if you can control stem cells, if you understand the biochemical cues and pathways in charge of their biomolecular machinery, you can regrow and regenerate pretty much any portion of the body you care to, as well as potentially turn off all cancers ... and those are just two of many uses for such a capability. Here are a couple of recent items from the popular science press illustrative of present work:

Liposuctioned fat stem cells to repair bodies:

Expanding waistlines, unsightly bulges: people will gladly remove excess body fat to improve their looks. But unwanted fat also contains stem cells with the potential to repair defects and heal injuries in the body. A team led by Philippe Collas at the University of Oslo in Norway has identified certain chemical marks that allow him to predict which, among the hundreds of millions of stem cells in liposuctioned fat, are best at regenerating tissue.

...

That fat-based methods work is not surprising, perhaps, because adipose tissue is closely related to bone, cartilage, muscle and other connective tissue. But some say it is impossible to re-programme adult cells to become nerve or liver cells, for example, without using embryos. Adult stem cells, such as those from fat, are thought to have more limited potential.

Collas insists that the transformation is possible. The hurdle lies not with the genes but with a cell’s epigenetic status, the subtle chemical modifications of DNA and its surrounding histone proteins. Epigenetic marks contribute to switching genes on and off, and stem cells rely on them heavily as they divide and mature. The Oslo team has found that low rates of DNA methylation, for instance, boost the chances of transforming fat stem cells from one cell type into another. "Look at a cell’s epigenetic profile," says Collas, "and you may be able to predict what that cell is likely to turn into."

How stem cells are regulated:

Director of BRIC, Professor Kristian Helin led the research team consisting of Jesper Christensen, Karl Agger and Paul Cloos. Last year, the same research group published an article in Nature on how a group of Jumonji proteins regulate the growth of cancer cells and are involved in the development of specific cancer types.

BRIC’s new results show that a different subgroup of Jumonji proteins is essential for cellular differentiation. The Jumonji enzymes can turn off, or inactivate, particular genes that play an important part in embryogenesis. The conclusions are based on studies of the nematode (roundworm) C. elegans and studies of mouse embryonic stem cells. The C. elegans studies were carried out in collaboration with another of BRIC’s research groups, led by Associate Professor Lisa Salcini.

The BRIC researchers are currently developing inhibitors to the Jumonji proteins. Their aim is to use these inhibitors to treat cancer patients with increased levels of the Jumonji proteins.

Scientists produce neurons from human skin:

Tests conducted by the researchers demonstrated that stem cells from the skin can proliferate and differentiate in vitro when placed in the appropriate environment. They progressively took on the oblong shape typical of neurons. At the biochemical level, researchers discovered that in the days following the start of the experiment, the cells began producing markers and molecules associated with the transmission of nerve impulse between neurons. "This suggests the beginning of synapse formation between neurons," points out Professor Berthod.

In the short term, this breakthrough might have an impact in the field of neuroscience research. "Producing neurons from skin cells could solve the problem of human neural cell availability for research," explains Berthod. "Since neurons do not multiply, researchers now have to rely on laboratory animal neurons to perform their experiments."

In the longer term, the ability to produce neurons from skin cells opens the door to revolutionary therapeutic applications. "We could take a patient’s skin cells and use them to produce perfectly compatible neurons, thus eliminating the risk of rejection. We could then transplant these nerve cells in the diseased areas of the brain," explains Berthod. "This type of procedure seems particularly interesting for diseases such as Parkinson’s, but it’s all theoretical for now. Before we can think of doing such things, we’ll have to improve nerve cell differentiation and prove that they can transmit nerve impulses," concludes the researcher.

Take a few minutes one of these days to stroll back a few years in the archives of one of the popular science websites - you'll be impressed at how fast the basic science is moving in this field.

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The Advance of Practical Tissue Engineering
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A good demonstration of the state of practical tissue engineering for muscles and connective tissue can be found at ABC Online: "The researchers used a synthetic scaffold seeded with ligament cells to regenerate the new tissue in the damaged anterior cruciate ligament (ACL) of rabbits. The bunnies were able to begin bearing weight on their knees 24 hours after surgery, and by the end of the 12-week experiment, the animals had fresh collagen and blood vessels growing in the damaged area. ... The ACL is the stabilising ligament that connects the thighbone to the leg bone. It unravels like a plait when ruptured, making healing difficult. In humans, the standard treatment for this is reconstructive surgery. Surgeons remove healthy tissue from tendons around the knee and graft it onto the damaged ligament to regenerate it. But it can take five to six months for a full recovery, and surgeons would prefer not to harvest healthy tissue if possible. Researchers have tried to craft ligament-like scaffolds to help the healing process before, but success has been limited. This is the first time that researchers have combined synthetic materials with ACL cells and been able to substantially engineer new ligament tissue."

Link: http://www.abc.net.au/science/news/stories/2007/1852113.htm?health

Update on Inkjet Tissue Printing Technology
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The use of inkjet printing in tissue engineering research continues to expand, as reported at ScienceDaily: scientists have shown "that producing cardiac tissue with off-the-shelf inkjet technology can be improved significantly with precise cell placement. ... Since Boland's discovery in 2004, 'printing' tissue using 3-D printers has focused on printing materials for hard tissue applications, such as in the jawbone. The [study] focused on precise placement of cells, which is essential to achieving function in soft tissue, such as the heart. In this study, live, beating heart cells were achieved more efficiently. The breakthrough with this technology is that cells now can be precision-placed virtually instantaneously with the materials that make up a scaffold to hold the cells in place ... Precision placement of the cells is achieved by filling an empty inkjet cartridge with a hydrogel solution (a material that has properties similar to tissue) and another inkjet cartridge with cells. The printing is accomplished much in the way that color photographs are made, activating alternatively the hydrogel and cell nozzles."

Link: http://www.sciencedaily.com/releases/2007/02/070221093208.htm

A Sadly Common Viewpoint
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Buried in the midst of a collections of guesses on the defining dualities of the century ahead, we have this:

Life extension for all vs for some

There will be an increasingly agonised division between those who feel that new life-extension technologies should be either available to those who can afford them or available to everyone. Life itself will be the resource over which wars will be fought: the “have nots” will feel that there is a fundamental injustice in the possibility for some people to enjoy conspicuously longer and healthier lives because they happen to be richer.

This is a sadly common viewpoint, driven by a worldview that precludes opportunity and change - not a world in which the "have nots" are beset with opportunity to become wealthier with hard work and savings, as is still the case out here in most parts of reality, despite great efforts on the part of politicians and government employees to cut the lowest rungs from the ladder.

But economic understanding aside, just how sensible is it to predict war over early healthy life extension - even when the technologies are still expensive and poorly available, before the engines of commerce and competition take over and do what they do for every new technology; bring down the price, make the goods better, and increase the level of safety? Even in this over-regulated medical socialism in the Western democracies, was there a war over heart surgery? Only the rich could get their hands on that back in the day, and that made a big difference. Is there a war right now over the rationing of Alzheimer's treatments in the UK, treatments that any wealthy individual can obtain on their own dime? Is there a war brewing over stem cell therapies for heart disease, again something unavailable as yet to those of us who have not saved up enough for a down-payment on a nice house?

At least in the case of these two technologies for the heart, competition and research is steadily driving down costs and improving quality, despite the choking regulatory burden that makes research and development far more costly and slow than it might be. But in the case of the UK rationing, the heavy hand of government is the problem, and things are unlikely to become better until that changes.

The world is unfair to those who choose to be poor, and far more unfair to those whose escape from poverty is closed off by corrupt and malign governance. This is a simple truth: if you have less, you can buy less, and that includes the use of medical technology to improve health and lengthen healthy life. Yet most people have the opportunity to escape from poverty on timescales far shorter than their life span. A world of both dramatic inequality and opportunity for all is a far better world than one of utter equality and absent opportunity - because you cannot build the latter world without tearing down every engine of progress and reducing society and its works to a wasteland. It is the opportunity to climb that ladder - and the freedom to undertake that work - that drives human ingenuity, competition and the provision of ever better goods and services at all levels.

There will be no war so long as there is freedom, opportunity and the prospect for ongoing improvement at every level. It is where these opportunities and avenues of progress are blocked that conflict occurs.

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Searching For the Keys to Cancer
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Following up on my last post on cancer research, I thought I'd point out a release illustrative of the search for keys to cancer - and the ongoing process of evaluating whether it is even sensible to be searching for such keys. By "keys" I again mean some sort of common mechanism, or small number of common mechanisms, by which all (or even almost all) cancer could be prevented or successfully treated with the technology of the next decade - if only we knew these keys existed.

Most types of cancer are believed to begin with a random genetic mutation that makes a normal cell go horribly awry. This is followed by mutations, which endow the cancer cells with properties allowing them to grow without normal controls to become a tumor. These mutated genes would be targets for chemotherapy.

But Loeb had another idea that he originally hatched many years ago – what if the cancer cells changed somehow, and became much more likely to mutate? These "mutator" cells would develop dangerous genetic mutations at a much faster rate than normal cells, which might account for the high number of mutations seen in tumor cells.

Since the technology of cancer genetics has dramatically improved, Loeb and his colleagues have only recently been able to test this hypothesis. They found that tumor tissue had random mutation rates up to 100 times higher than normal tissue from the same patient. The "mutator" hypothesis seems to be correct.

Now for the bad news: if cancer cells do indeed become "mutator" cells, traditional chemotherapy and other drugs may never be very effective against advanced tumors.

...

Loeb’s work may also lead to a discovery of why cancer cells are becoming mutator cells. If scientists understand what happens in a cancer cell that makes it become a mutator, they might be able to prevent that from happening in other cells, or slow down the mutation rate.

"The idea is that if you might normally get exposed to something in the environment at 20 years old that would give you cancer by age 55, then if we cut the mutation rate in half, you might not get cancer until age 90, and you may even die of something else before that," Loeb explained.

You might recall a similar look at a potential root cause leading to greatly increased rates of mutation was mentioned a little while back at the Longevity Meme:

When the teams compared patterns of gene activity in stem cells from healthy and cancerous tissue they found that those from cancers were often locked in a state in which they carry on multiplying as primitive stem cells, instead of maturing into specific tissues. ... When they're in this state they divide more, and in the process may accumulate additional mutations which ultimately turn them cancerous.

What are the real roots of cancer? Do the keys to cancer exist in a form that we can find and take advantage of within the next decade or two? Can researchers produce global anti-cancer technologies dramatically better than the development of an effective therapy, one type of cancer at a time? Stay tuned.

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What Calorie Restriction Does For You
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No new news here from phillyBurbs.com for those already familiar with the human calorie restriction studies of the past couple of years, but still worth showing to your friends: "The 48 participants, all slightly overweight, were randomly assigned to one of four groups: calorie restriction, which cut usual daily calories by 25%; calorie restriction plus exercise, which cut daily calories by 12.5% and increased physical activity by 12.5% five days a week; very low calories, with an 890-calorie liquid diet for up to about three months followed by a weight-maintenance diet; and a control group that aimed to keep weight steady. ... Their insulin levels fell and metabolisms slowed - changes that are thought to increase longevity. ... Blood tests showed substantial decreases in the amount of age-related DNA damage in each of the three dieting groups, compared with their initial levels. That kind of microscopic damage is linked to cancer and other age-related ailments, but it's unknown whether the small changes seen in the study would affect the study volunteers' disease risks. No changes were seen in the control group. Insulin levels also decreased after six months in all three reduced calorie groups. Core body temperature also dipped slightly in two low-calorie groups but not in the liquid-diet or control group. The results show that the diets are safe, and not impossible to follow."

Link: http://www.phillyburbs.com/pb-dyn/news/276-02192007-1301557.html

The State of Bone Tissue Engineering
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A PLoS Medicine review looks at the present state of regenerative medicine for bones: "To overcome the drawbacks of the current bone graft materials, bone tissue engineering (BTE) using bone marrow stem cells has been suggested as a promising technique for reconstructing bone defects. Indeed, various animal studies have shown the capacity of BTE to produce bone, both in a non-bone environment (ectopic bone formation) and in a bone environment (orthotopic bone formation) ... Surprisingly however, until recently, no convincing successes have been achieved in humans. In this article, we review the available clinical data in the area of bone tissue engineering together with our own clinical experience. We discuss possible new directions that need to be exploited to make bone tissue engineering a clinical success. ... Cell survival is the most important requirement for achieving clinical success in cell-based bone tissue engineering. ... What is indisputable is that [mesenchymal stem cells] are crucial for the healing of bone defects."

Link: http://dx.doi.org/10.1371/journal.pmed.0040009

Where Science Knocks Heads With the "Anti-Aging" Marketplace
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Biochemists and a range of other scientists devote a great deal of time and resources to understanding and manipulating the processes of oxidation in the body - free radical generation, discovery, design and manufacture of antioxidants, oxidative stress, impact of reactive oxygen species on age-related conditions and physiological changes, and so on. This is to good ultimate end; a couple of new animal studies in recent years have demonstrated extended healthy life spans as a result of careful direction of antioxidants, for example. All too often, however, the scientific story is "works in the test tube, no effect in living animals." No shame in this - any story of progress is that of a series of inventive failures preceding ultimate success.

Since the early 1990s scientists have been putting these compounds through their paces, using double-blind randomised controlled trials - the gold standard for medical intervention studies. Time and again, however, the supplements failed to pass the test. True, they knock the wind out of free radicals in a test tube. But once inside the human body, they seem strangely powerless. Not only are they bad at preventing oxidative damage, they can even make things worse. Many scientists are now concluding that, at best, they are a waste of time and money. At worst they could be harmful.

There are good reasons for this general failure of antioxidants applied as supplements after promising test results on cells; the full complexities of a living being are a far cry from a modest selection of cells in a petri dish. The recent antioxidant research initiatives that do extend life in animals are an entirely more ambitious endeavor than the work of past generations - clever biochemistry, gene therapy, mitochondrial targeting, and a far greater knowledge of the internal workings of the cell.

None of this stops folk within "anti-aging" marketplace making money on antioxidant supplements shown to have no effect in animal studies; nor should it, for that matter. Caveat emptor is a good rule, alongside a free market in reviewing organizations - a much better rule than centralized regulation. Do the small amount of research yourself to find out who is talking nonsense; it's not hard. You do it when you buy a new car, or a new computer, so why not with something you plan on ingesting for the next few decades or so? All industries are just as packed with people who can pass for legitimate, talking the talk, but who are in actual fact full of it and on the take. Learning to tell who is who is part and parcel of living a good life, and is a responsibility you should take especially seriously when it comes to your health.

You'll see a certain dynamic tension at the intersection of the scientific and "anti-aging" communities around antioxidant research - the scientific rejects, those shown to have no effect in animal studies, still make people money on the back of promising, selectively presented early test tube results. It makes it very clear that the "anti-aging" marketplace is a mature delivery system that came into being prior to any actual, real anti-aging medical technology. Lack of a real product has never been any barrier to misapplied human ingenuity and the burning need for answers now, this very instant, however.

A representative article showed up in an Australian daily recently:

The product, gamma glutamyl cysteine (GGC), is a precursor of a so-called master anti-oxidant naturally produced by our bodies.

That compound, glutathione, helps protect us against the damaging effects of free radicals ... As people age, their cells' components become oxidised, and this leads to age-related diseases. What we're hoping to do is re-build glutathione in the cells to a normal, healthy level,

...

Dr Bridge and his colleague Dr Martin Zarka have invented what they say is a low-cost process for producing this natural compound so it can eventually be added to foods, vitamin pills, toothpaste or cosmetics.

One of the first practical applications, currently being developed, is a skin-repair cream.

Dr Bridge says the next phase of experimentation is to confirm whether GGC can increase the glutathione content of cells grown in laboratory conditions.

...

As we grow older, our glutathione levels drop, and our ability to detoxify free radicals decreases.

Unfortunately, increasing glutathione in our diet won't solve the problem. Many foods, such as yeast extracts, are rich in glutathione but the glutathione can't directly enter the body's cells where it's needed.

So, yes, same old, same old. On the one hand, the ultimate goal of the science is sensible: identify a way in which our biochemistry changes with age and look for a way to fix it. Not to mention that any future use for glutathione will benefit from the better manufacturing process devised by these researchers. On the other hand ... skin cream based upon tests on cells in the lab - it's not as though we haven't seen that a hundred times before to no good end; tests worth making even with low expectations in the best case, modern magical thinking in the worse cases.

We're a smart species. We can do better than this.

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Aging and the Mechanisms of Forgetting
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Scientists continue to investigate the mechanisms underlying changes in memory with age - with an eye to preventing those changes: "rats become forgetful because a routine part of the memory process falls out of kilter, no matter their ages. This change seems to be related to the chemicals necessary for brain cells to communicate with each other. ... Aging is associated with an increased rate of forgetting. My work indicates that the problem may be a slight shift in a normal forgetting mechanism. ... This same mechanism probably is used to clear the brain circuits and make them ready to be used the next day. However, this mechanism in excess may lead to rapid forgetting as seen during brain aging ... as we begin to understand the mechanisms of memory, it becomes possible to predict promising targets for therapeutic strategies aimed at postponing or alleviating age-related memory impairment ... The basic gist is that information storage requires a balance between mechanisms that make synapses stronger and weaker. In aging and disease, if that balance is [disrupted], the unchecked synaptic weakening leads to memory loss. The good news is we are developing a good understanding of these mechanisms, and that will help us find ways to protect memory."

Link: http://news.ufl.edu/2007/02/19/memory-path/

Tissue Engineered Teeth Demonstrated in Mice
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The New Scientist reports on an advance in dental regenerative medicine: "a Japanese team has successfully grown replacement teeth and implanted them into the mouths of adult mice, suggesting that a similar technique could replace missing teeth in humans. [The researchers] took single-tooth mesenchymal and epithelial cells - the two cell types that develop into a tooth - from mouse embryos. They stimulated these cells to multiply before injecting them into a drop of collagen gel. Within days, the cells formed tooth buds - the early stage of normal tooth formation. The team then transplanted these tooth buds into cavities left after they had extracted teeth from adult mice. There, they developed into teeth with a normal structure and composition. The engineered teeth also developed a healthy blood supply, and nerve connections. ... Since mesenchymal and epithelial cells have the potential to develop into other organs and hair follicles, Tsuji hopes his method could eventually be applied more widely." The past few years have seen rapid progress in the tissue engineering of replacement teeth; we should expect to see the same for other simple organs in the years ahead.

Link: http://www.newscientist.com/article/dn11204-labgrown-replacement-teeth-fill-the-gap.html

Is Successfully Managing Cancer a Hard Hard or Easy Hard Goal?
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The cancer research establishment seeks - as a near-term goal - to develop the means to turn almost all cancers into managed conditions. Possibly costly and inconvenient, but not fatal, just as researchers have accomplished for class after class of medical conditions over the past century - and they were hard tasks all. As suggested by a recent Technology Review piece, however, we might ask ourselves what sort of hard task this is in the case of cancer - easy hard or hard hard:

The largest study yet of genetic changes across a broad range of cancers has turned up some unexpected results. Mutations thought to cause one kind of cancer also seem to be important in others, suggesting that the same drugs might be useful for patients with very different kinds of cancer. But all the mutations in the study--even those shared among cancers--occurred at low frequencies, suggesting that the search for cancer genes may be more difficult than researchers had hoped.

...

But Chanock says the study also provides "a good reality check." Thirty percent of the tumors in the study had none of the mutations Garraway's group looked for. Chanock says this study forces researchers to address the question, "What's it going to take to make sense of [the genetic changes behind cancer]?" The answer, he says, is even larger genotyping studies, on the order of 10,000 tumors. And, as those tumors with no known mutations in this study suggest, many of the genetic changes that drive cancer remain to be discovered.

Genes are keys to cancer, because they are a starting point from which to decode biochemical mechanisms, and thus move onto the development of ways to intervene. There are other possible forms of key too, buried in process, and more subtle than single gene mutations:

When the teams compared patterns of gene activity in stem cells from healthy and cancerous tissue they found that those from cancers were often locked in a state in which they carry on multiplying as primitive stem cells, instead of maturing into specific tissues. ... When they're in this state they divide more, and in the process may accumulate additional mutations which ultimately turn them cancerous ... supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.

Easy hard means that there is a key within reach - or at least only a few keys - for almost all cancers; some small group of unifying or common mechanisms that could be addressed with the biotechnology we have today, or will have in the 2010s. The easy hard problem is finding the keys - or perhaps the real easy hard problem is determining that the keys are likely to exist, and thus devoting effort to finding them.

Hard hard means that we'll have to undertake 300, 3000 or some other unfeasibly large number of different projects in biochemistry, with little common ground between them, to tame cancer with the tools we have now or will develop over the next decade or so. The bottom line in that case is that we'll need much better tools, which means more time to slip the leash upon cancer.

If we ignore the limitations of today and look at the blue sky future of biotechnology, it seems that we may be able to engineer out cancer by modifying our biochemistry in some fundamental way - a better type of key impossible to verify or make use of now, but quite possibly an easy hard task for the medical science of 2040. Aubrey de Grey includes one suggested methodology as a present component of SENS, the Strategies for Engineered Negligible Senescence, a proposed plan for repairing the damage caused by aging - though I can imagine there will be others:

we don't actually need to fix chromosomal mutations at all in order to stop them from killing us: all we need to do is develop a really really good cure for cancer. The one that I favour (which was the topic of the third SENS roundtable, a roundtable meeting I convened in Cambridge in 2002) is called WILT, for Whole-body Interdiction of Lengthening of Telomeres.

You can download a PDF explaining WILT from the SENS website; it makes for interesting reading against the backdrop of present day cutting edge cancer research.

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Early Days of Artificial Eyes
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In the years ahead, fully functional artificial eyes will be an option for the blind. Science Daily notes that the path to that end is just getting underway today - a little healthy competition for the methods of regenerative medicine: "The first phase of our implant work began in 2002. We have successfully implanted six patients in the trial, and we have found that the devices are indeed electrically conducting and can be used by patients to detect light or even to distinguish between objects such as a cup or plate. ... While the first generation of implants contained 16 electrodes laid out on an array, the Argus II is designed with 60 electrodes, which is intended to allow for higher-resolution images. The new device is also approximately one quarter the size of the original, reducing surgery and recovery times. The array is attached to the retina and used in conjunction with an external camera and video processing system to provide a rudimentary form of sight to implanted subjects." The capabilities of exactly these sorts of technologies have improved by something like a factor of 1000 in the past 15 years - the field of endeavor concerned with integrating devices into the human body will catch up with that trend.

Link: http://www.sciencedaily.com/releases/2007/02/070216221522.htm

More On Artificial Cells as Medical Tools
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From earlier this month, a Nanowerk article goes into more detail on the proposed use of artificial cells and cell-like structures as medical devices: "Some fundamental problems like the targeting of nanoparticles in vivo, the transport of unstable drugs, and the dosage control of drug-carrying nanoparticles lead some scientists to think even one step further. Rather than delivering external drugs into the body, they conceptualize 'pseudo-cell' nanofactories that work with raw ingredients already in the body to manufacture the proper amount of drug in-situ under the control of a molecular biosensor. ... This approach draws its inspiration from the ability of the human body to self-medicate by actively adapting molecular production in response to its intrinsic biochemistry. This new approach proposes that molecular machinery could, in principle, be introduced into the body to convert pre-existing materials into therapeutic compounds, or to change molecules that a patient is unable to process, owing to some medical condition, into other compounds that the body can process. ... rather than reverse engineering an extremely complex system, generating an artificial cell provides a robust platform where researchers can add functionality in a component-by-component process. Furthermore, artificial approaches may be more controllable as living cells can respond in unanticipated ways."

Link: http://www.nanowerk.com/spotlight/spotid=1418.php

"Every Story is the Story of the Fall"
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"Every story is the story of the Fall" - except the one that matters, the one we're all writing together with quills of science, will and toil in the real world. That story is a grand arc of irresistible rise, of the defeat of obstacles and surpassing of limitations to our true potential. But you wouldn't know it from the myths that we find most comforting, as illustrated by their widespread nature.

I forget where I first heard the quote above: "story" in that context means "myth." Myths are not a remote line item from our history; they are the resonances in the conversation of ten thousand winding threads that takes place across a culture; common, retold and reinvented stories we tell ourselves to describe who we are, where we've come from, where we are going and what it is we want. Modern myth directly impacts any sort of large-scale activities, any project that requires the support and understanding of millions. Go against a mythic viewpoint and you'll have a tougher time of it.

So it is that advocating and working towards healthy life extension is greatly affected by the stories we tell to one another about aging and its place in the world. I have briefly discussed this in the past:

Given a technology that allows us to do something new, we will turn that capacity to build our world a little closer to the world of myth that makes us comfortable. In the process, some feedback or change to the human condition slowly - very slowly - introduces changes into our mythic structure.

Myth drives the application of technological capabilities, which then in turn change the myth - but in the short term, myth is in the driving seat, all other things being equal. For our near-term future, the myths of longevity and immortality - and the myths used to make us feel better about lacking both - are important considerations when it comes to raising support for research to greatly extend the healthy human life span.

...

The common thread running through our earliest mythological tales of immortality is that death, while not necessarily desirable, is unavoidable and a fundamental part of being human. In spite of his best efforts, Gilgamesh could not achieve immortality. Given a choice, Tithonus likely would have chosen death over eternal decrepitude. While there is no suggestion in these stories that death gives value to life, they both certainly leave the impression that we should grow accustomed to the idea of dying, because there can be no desirable alternatives to it.

The story of the Fall is an old and simple one; the world is one of shortages, pain, suffering and death, yet we humans can conceive of a world absent these troubles. Nostalgia is a part of the human condition also - we see earlier times in our own lives as better than they were, and it's a short leap from there to draw a line of decay from an imagined golden age to the imperfect present. The Fall is an alignment of the mythic world - a better, imaginary world - with the arrow of time; for a variety of reasons, we have come to put that mythic world in the past rather than the future.

A great deal of modern myth extends this imaginary Fall to continue into our own future. This is odd, since the golden age of our imagination might actually come to exist in the future - see the above quoted text on what we tend to do with our increasing technological prowess.

If you look for the Fall in subtexts far and wide, you'll see it everywhere. Malthusians, luddites and many environmentalists immediately spring to mind as those who most obviously buy into and support the myths of the Fall in the most modern way. To their view, the world is going to hell in a handbasket, and the myths of that Fall - for whatever reason - resonate most in their currents of the cultural river. But for every outright Malthusian you'll find a hundred young people who will claim they'd rather age and die than live to see the hand-me-down, grey future they imagine for themselves. They're not up for helping meaningful progress: why should they? That isn't the place for themselves they have defined, nor even meaningful in their view of the world. Such is the power of myth.

Sadly, one result of the comparative wealth and prosperity brought by modern technology is that ever more people are insulated from the consequences of being absolutely wrong about the way in which the world works for long enough for great damage to be done. Myths that, if followed, will lead to proverty and suffering can thrive for long enough to do just that.

We need better myths if we are to gather support for a major effort to extend healthy life span, analagous to the quest to cure cancer - these myths do in fact exist, but, unfortunately, are not widespread to the degree required. Speaking from my experience, we most definitely need better myths when it comes to aging, longevity, health, the economic organization of medicine and our ability to enact change in these areas. So long as the vast mass of people are entirely comfortable to describe a world in which aging is inevitable - and the role of the elderly is to suffer, become frail and die on schedule - then progress towards healthy life extension will remain frustratingly slow.

If people choose to reject healthy life extension, then so be it: but you have to first hear the myth in order to turn your back on it. Insofar as advocacy goes, we're still at the point today of telling our stories more loudly, and broadening the audience. Strive to live healthily and live long - we think you'll find it's a better class of myth for the real world than those in which the hero dies young.

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T Cell Biochemistry and Immune System Aging
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From Ouroboros, a look at research into internal changes in T cells with aging, some the mechanisms driving the ongoing depletion of the naive T cell population, some not: "The adaptive immune response requires waves of T-cell clonal expansion on contact with altered self and contraction after elimination of antigen. In the case of persisting antigen, as occurs for example in cytomegalovirus or Epstein-Barr virus infection, this critical process can become dysregulated and responding T-cells enter into a dysfunctional senescent state. Longitudinal studies suggest that the presence of increased numbers of such T-cells is a poor prognostic factor for survival in the very elderly. ... These pathways and affected genes may play a significant role in driving the cellular senescent phenotype and warrant further investigation as potential biomarkers of aging and senescence. These genes may additionally provide targets for intervention. ... A possible mechanism for some age-related transcriptional changes is provided by Das et al., who describe the negative effect of oxidation (both experimental and age-related) on the proteasome. ... These results suggest that the decrease in proteasomal activities observed during aging may be secondary to oxidative stress and underlie immune senescence."

Link: http://ouroboros.wordpress.com/2007/02/16/2-on-t-age-related-changes-in-immune-cell-gene-expression-and-a-role-for-protein-oxidation/

There Are No Deaf Chickens: How Does This Help?
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EurekAlert! takes a look at one group working towards regenerative cures for deafness: "Heller's vision is to develop a variety of possible cures for deafness. For the past year and a half [he's] been focused on two paths: drug therapy - which could be as simple as an application of ear drops - and stem cell transplantation into the inner ear to remedy hearing loss. Currently he's working on perfecting the steps toward eventual stem cell transplantation into humans, with the goal of first curing deafness in mice within the next five years. His lab is also busy studying the ability of birds to regenerate the tiny hair cells in the cochlea. It's these cells that convert the mechanical energy of sound into electrical impulses that are sent to the brain so that a chicken, a mouse or a human can hear. Chickens, like all birds, have the ability to spontaneously regenerate these hair cells, which explains why there are no deaf birds. This is promising because it means the genetic program for regeneration exists somewhere in the vertebrate family. We know there is an unknown signal to regenerate that we could use, but we first have to find it."

Link: http://www.eurekalert.org/pub_releases/2007-02/sumc-sct021407.php

Testing the Bounds of Regeneration
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(From Delaware Online). Researchers continue to explore the boundaries of regeneration: how much or how little will we have to do to convince human biochemistry to regrow digits and limbs? "It sliced off his fingertip, leaving just a bit of the nail bed. The missing piece, three-eighths of an inch long, was never found. ... Spievack, however, did have a major advantage - a brother, Alan, a former Harvard surgeon who'd founded a company called ACell Inc., that makes an extract of pig bladder for promoting healing and tissue regeneration. ... Within four weeks his finger had regained its original length, he says, and in four months 'it looked like my normal finger.' ... it's not completely clear what happened inside Lee Spievack's finger. The broad outline is pretty straightforward. The powder is mostly collagen and a variety of substances, without any pig cells ... It forms microscopic scaffolding for incoming human cells to occupy, and it emits chemical signals to encourage those cells to regenerate tissue ... we are very uninformed about how all of this works. There's a lot more that we don't know than we do know." This is one end of a broad spectrum of work presently taking place - interesting results will come in the years ahead.

Link: http://www.delawareonline.com/apps/pbcs.dll/article?AID=/20070216/NEWS/70216007

CIRM Awards $45M in Grants
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For those keeping track of such things, SFGate.com notes that first major set of grants have been rolled out by the California Institute for Regenerative Medicine (CIRM): "Officials for [CIRM] authorized a modest package of 72 grants totaling $45 million over the next two years. Researchers at 20 institutions, most of them affiliated with the University of California, will carry out the research in labs throughout the state. ... Most of the first research projects announced today involve discovering the fundamental properties of stem cells derived from early-stage human embryos. ... Scientists want to find better ways to isolate the flexible stem cells from the embryos so they can be turned into any of the myriad cell types that comprise the human body, particularly those that fall prey to disease such as diabetes and neurodegenerative disorders." The press release at the CIRM website lists the specific projects funded in this set of grants; quite a few attempts to better control cellular differentiation are amongst their number.

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2007/02/16/BAGDNO6EC94.DTL

Regeneration Is Not Rejuvenation
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Attila Chordash of Pimm thinks we can get further along in the healthy life extension path using just stem-cell based regenerative medicine than I do.

Systemic regenerative medicine is a coherent and inclusive engineering approach to eliminate all aging related problems indefinitely. Systemic regenerative medicine theoretically means the continuous, gradual and consecutive regeneration of every tissue and organ of the human body n times by combined regenerative medicine approaches, i.e. tissue engineering (in vitro grown organs and tissues implants or parts of them), systemic (via circulation) and locally targeted stem and progenitor cell transplantation, and endogenous stem cell niche activation with proper growth factor delivery aiming to maintain the physiological turnover and condition of the human body.

Which may be the case, and you never know for sure until the job is either done or failed. It seems to me I have the more defensible position, if somewhat less clearly articulated - but I'd be happy to proven wrong on this topic, given that the field of regenerative medicine is well on the way to become a behemoth to dwarf the cancer research community. No need for the years-long process of building up understanding, support, funding, institutes and enthusiasm - all those early days are behind us for regenerative medicine, tissue engineering and similar areas of research. Great and rapid progress lies ahead.

But, inconveniently, regeneration is not rejuvenation. Salamanders still grow old and die, as do the impressive mice of Ellen Heber-Katz. What Chordash is discussing is much more than assisted healing processes culled from the natural world, of course - it's more like the replacement scenario I touched upon a few days ago. Chordash sees this arriving sooner than I would predict:

Hypothetically, yes, pretty much everything except your brain is open to replacement just as soon as scientists can figure out how to build and install those replacements in a useful manner. That's a high bar, however. Your body isn't easily divided into piecemeal components; it's an overlapping bundle of interlinked, complex components - age-related damage to one system may make many related replacements useless or even counterproductive. Developing the technology base for safe replacement of the entire aging body is a long term project - not impossible, but certainly not something that you'll be seeing any time soon.

In order to make yourself physically younger, you must remove the molecular damage of aging within cells - either by replacing cells (such as entire stem cell populations) with less damaged cells, or by repairing that damage. Those are much the same thing if you want to replace cells with more of your own cells grown to order; you have to find a way to repair the damage of aging inside cells one way or another. You can't just regenerate - you must also rejuvenate by repairing this damage to cellular mechanisms.

Which is not to say that regeneration is worthless. The control of stem cells will drive an amazing series of advances in medicine, and quite possible provide the decade or two of additional healthy life that the system biologists think they can manage. There's great value and additional years in repairing broken hearts, blocking the source of cancer and doing everything else you can do at the level of cells.

But I don't see us progressing to a sufficient level of prowess in terms of replacing all systems in the body - and developing a strategy for the brain based upon cellular replacement and regeneration - to greatly extend the healthy human life span more rapidly than we can by following a path more like the Strategies for Engineered Negligible Senescence. The overwhelming question is not "is radical life extension possible?" Of course it is; the laws of physics and our understanding of biology are quite clear on that count. The question is whether we will live to see it - and I doubt that a technology base built only upon regenerative medicine and replacement can possibly advance fast enough and far enough for that.

Which means we have a lot of work to do. But we knew that - and how much better that position is than the experience of those who lived and died before us! We have a chance, and should seize it.

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Li-Fraumeni Syndrome: p53, Telomeres and Cancer
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Medical researchers are learning a great deal about the age-related degeneration of human biochemistry by looking at the extreme edge cases and malfunctions - such as Li-Fraumeni syndrome in the case of increased cancer risk with advancing age: "Li-Fraumeni was associated with inheritance of a mutated form of the p53 tumor suppressor gene, but we also noticed each generation developed cancer earlier than the preceding generation ... we have discovered that telomeres become shorter in each generation of disease carriers, leading to a genetic instability that primes them for progressively earlier cancers ... Telomeres are repeated sequences of DNA at the tips of every chromosome that function as a sort of genetic slack. As cells grow and divide throughout life, the chromosomes, which contain all of an individual's genetic information, replicate as well. The enzymes that create copies of chromosomes cannot, however, physically reach the very end of the chromosome, so they leave a minute bit of this telomere slack behind each time. This is known to researchers as the 'end replication problem' and has made telomeres an important subject of research in the science of aging and cancer." What then is the mechanism linking p53 and telomere length?

Link: http://www.eurekalert.org/pub_releases/2007-02/aafc-scc021507.php

Ingenuity in Bioengineering
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Via EurekAlert! a good example of the sort of combinatorial ingenuity - so common in the cancer research community these days - enabled by modern biotechnology: "HIV knows how to insert itself into many different types of cells. A portion of the HIV protein called TAT can transport biologically active compounds into cells. TAT is small, but it can move massive molecules. You could almost hook TAT up to a train, and TAT would drag it inside a cell. So we've taken advantage of this ability ... the researchers describe using TAT to pull a protein called Bim into cancer cells. TAT alone cannot cause AIDS and has no adverse health effects. Bim acts as a tumor suppressor and causes cancer cells to die through apoptosis ... Now that we've proven we can do this, we've started creating a battery of proteins that can push cancer cells to die. ... clinical trials of these compounds could be just a few years away." The components of cures and transformative biotechnologies already exist, scattered a piece here and a piece there, waiting for clever humans to learn how to use them to create more healthy life for the ill and aging.

Link: http://www.eurekalert.org/pub_releases/2007-02/wuso-hpe021507.php

Noteworthy Stem Cell Research
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So how do those first generation stem cell therapies work? Stem cells, often from the patient, are delivered to a damaged heart and seem to be making a measurable difference - but it has taken a few years to understand just how this process works:

In 2003, the researchers demonstrated that adult stem cells circulating in blood can be used to repair hearts, and that it is not necessary to take the stem cells from bone marrow. In 2004, they found stem cells use different methods to morph into the two kinds of cells needed to restore heart function. In animal studies, they showed that to make new heart muscle cells, the human stem cells fuse onto cardiac cells to produce new muscle (myocyte) cells. But to form new blood vessel cells, the stem cells "differentiate" or mature by themselves to provide new endothelial cells that patch vessel damage.

In this study, they looked into the mechanism by which stem cells fuse to cardiac myocytes.

...

Heart muscle cells do not divide, so the researchers did not know whether the new fused cells were an endpoint in themselves, designed to replace dying cardiac muscle, or whether they could give rise to other new cells. They discovered that fused cells took on some "stemness" - they divided, and continued to do so as long as new tissue is needed, but not long enough to produce a tumor.

...

The accepted dogma is that heart cells cannot divide, but we show that fusing stem cells onto muscle cells bestows these cells with a new and wonderful ability to divide again to repair the heart.

Meanwhile, scientists continue to document the ever more evident complexity of human tissue: the closer you look, the more there is to see, and biochemistry is always more complex than you'd like to think it is. Stem cells, for example, do much more than just act as a source of new cells:

"We found that stem cells can participate actively in determining what type of cell their daughters will become right at the moment of stem cell division," said Embryology director and study co-author Allan Spradling. "This suggests that tissue stem cells might not just be a source of new cells, but could actually be the ‘brains' of the tissue - the cells that figure out what type of new cell is needed at any given moment."

...

"Each individual stem cell seems to have a great degree of independence from the rest of the animal's body," Spradling explained. "On one hand, the [intestinal stem cells] can respond quickly to the needs of the gut lining as it loses cells. On the other hand, they seem rather vulnerable to losing control of cell division."

Deconstructing these mechanisms will lead to better control over cells - if scientists can accurately reproduce the natural environment of biochemical signals, they can start to control the growth of cell populations to therapeutic ends. The body builds and repairs organs; so will we, in due course - but better, deliberately, and to save and extend lives.

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Ouroboros on Reversing AGE Accumulation
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You'll find more commentary on recent research into advanced glycation endproducts (AGEs) and alagebrium over at Ouroboros: "A drug was designed against a specific form of age-related damage, demonstrated to attack this damage in vitro, and then shown to be efficacious in a clinical setting. In addition to providing good news for sufferers of hypertension, the study takes an important step toward verifying the model that AGE in fact do play a causative role in the onset of age-related disease. Most enticing is the idea that AGE reversal (in this case via treatment with alagebrium) appears not to delay the onset of of damage but to actually reverse it - even in elderly patients, even after that damage has contributed to a potentially life-threatening clinical condition. Slowing the accumulation of damage will be an important part of the anti-aging pharmacopoeia of the future - an ounce of prevention being worth a pound of cure - but unless the rate of damage accumulation can be slowed to zero, methods of reversing existing damage will also be required."

Link: http://ouroboros.wordpress.com/2007/02/14/reversing-age-in-the-cardiovascular-system/

On the Importance of Framing
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Anne C. looks at how to frame persuasive advocacy for healthy life extension research: "Matt thinks that maybe we ought to start simple -- e.g., unless specifically grilled on the end-goals of longevity research, we should simply attempt to frame it as a natural extension of medical care. The purpose of medicine, after all, is to save lives, so longevity medicine really ought to be a no-brainer. The only reason it isn't for a lot of people might be due to the way it can sometimes end up being framed, so framing it properly is undeniably important. This is a subtle point, but possibly one worth mulling over. I have become reasonably convinced that focusing too heavily on specific diseases in terms of research could be harmful -- that is, it might encourage progress in a direction that results in treatments that really only apply to people who are already experiencing dangerous or even deadly symptoms." I'm in favor of advocacy to push out the bounds of the debate, and against any sort of retreat to moderation for the sake of short term advantage - but others are trying the moderate path (or at least what is now the new moderate path, given that the limits of the discussion have been extended). May the best efforts win.

Link: http://rationallongevity.blogspot.com/2007/02/notes-from-fringes-of-longevity.html

You Can't Row the Whole Distance With Oars Made of Stem Cells
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Many people new to healthy life extension look at the projected future of regenerative medicine, stem cell research and tissue engineering and say "hey - why do we need all the rest of this science and hard work yet to be done? Why can't we just get all the way to rejuvenation with ever-improving stem cell medicine and parts replacement as needed?" An example of this sort of thought process showed up as a reprint at the LEF News recently:

The search for the fountain of youth is an old one, but it looks like scientists may just have found the real deal, at the tip of a syringe.

No, we don't mean plastic surgery - that's just looking like you'll live forever. What we're talking about is space-age regeneration, and they do it with stem cells.

Unless you live under a rock, you already know that scientists think stem-cell research will provide treatments for cancer, Parkinson's disease and spinal-cord injuries. But here's where you really start to care: It also has the potential to reverse the aging process.

Hypothetically, yes, pretty much everything except your brain is open to replacement just as soon as scientists can figure out how to build and install those replacements in a useful manner. That's a high bar, however. Your body isn't easily divided into piecemeal components; it's an overlapping bundle of interlinked, complex components - age-related damage to one system may make many related replacements useless or even counterproductive. Developing the technology base for safe replacement of the entire aging body is a long term project - not impossible, but certainly not something that you'll be seeing any time soon.

What will come in the next two decades are commonplace, affordable (for suitable definitions of "affordable") replacements for commonly failing organs and tissue types - new heart muscle, new liver cells, new dopamine neurons, and so forth. Many people will benefit and live modestly longer as a result, but while this first step into the world of replacement parts is underway, your biological systems will still be aging. Your immune system will still be becoming ever more frail, your telomeres shortening, free radicals spreading their damage, chemical junk building up within and between your cells, risk of cancer increasing - and most importantly, wear and tear growing in your brain.

What, then, will be the causes of age-related death 30 years from now? The body is an exceedingly complex machine; blocking off one failure mode, or preventing a single mode of death that results from a class of accumulated damage will leave many other possibilities. Behind the neurodegenerative diseases we know lie a hundred, a thousand ever more subtle and devilish ways in which age-related cellular damage can kill us. You can plug as many holes as you like, but eventually you're going to run out of fingers.

We can plausibly look forward to sidestepping this problem of ongoing damage by replacing an old heart with a young, tissue engineered heart lacking age-related damage. We are within a decade or two of being able to do the same for any other organ or system within the body ... but not the brain.

This prospect of unending discovery of new failure modes - and the long development of a cure, all too late to save those unlucky enough to be at the head of the queue - is one of the reasons that an engineering approach to fixing age-related disease is so attractive. Rather than play catch-up and research with ever more complex consequences of age-related cellular damage, let's identify, repair and prevent that damage. Strike at the root, in other words, by taking the path of greater effectiveness and least complexity. If we can do that, there would be no need to determine and decipher the fatal neurodegenerative conditions that follow Alzheimer's - no-one will ever accumulate the damage required to suffer from these presently unknown killers.

Your great-grandchildren may well live in a world in which bodies are like cars: built well, and discarded with regret when they have passed their prime, exchanged for new models. If we are to live to see that world, however, we have to take smaller first steps in the fight to defeat aging. The stem cell technologies of the next few decades are but one part of the technology base needed to repair the aging human body and brain.

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Cloning From Adult Stem Cells
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Via ScienceDaily, a research group is claiming greater success than in past years in cloning efforts using adult stem cells: "A main hurdle in nuclear transfer with adult cells has been its efficiency - out of a hundred attempts, only a handful may succeed - with reported success rates never reaching into double digits. ... Using purified adult skin stem cells as our source of nuclei, we have found that higher nuclear transfer efficiencies can be achieved. ... Nuclear transfer can also be used to make embryonic stem cell lines, a process which can be done in a tissue culture dish and which is simpler and more efficient than generating a cloned mouse. Although this procedure has not yet successfully generated human embryonic stem cell lines, once technological hurdles are overcome, it may be possible in the future to use a patient's skin stem cells to tailor make embryonic stem cell lines, circumventing the problem of immune rejection." An early step in the path to growing replacement tissue (and eventually organs) to order from your own cells, in other words. It's a way to go yet to supercharge regenerative medicine with this line of work - and if you work from adult cells, you transfer some of the damage that comes with being older - but this is a positive step forward.

Link: http://www.sciencedaily.com/releases/2007/02/070212173432.htm

Results From the LysoSENS Soil Contest
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From the Methuselah Foundation: researcher John Schloendorn "requested soil donations throughout 2006, in order to discover microbes that degrade 'junk' molecules inside our bodies - the LysoSENS project, aimed at repairing one type of age-related damage via bioremediation. Further encouragement for the donors was provided by a soil contest - $100 for what the investigators deem the "best" submitted samples, i.e. the ones that contained the most biodiversity, and were the most difficult to collect. We were amazed at the level of creativity and organizational talent that our soil donors threw at this problem. We are proud to announce the winners of the contest and their stories. ... Michael obtained the cooperation of several Kentucky funeral directors. This resulted in a large selection of deep grave samples from different graveyards. We used these to construct our first large (>3 Gbp) metagenomic clone library, which has not yet undergone selection. This experiment will hopefully provide an answer to the question of whether graveyard soil is the preferred sample source, as a microbial habitat where our target compounds naturally get degraded. Mike would like to acknowledge the funeral directors Mr. Bernard, Mr. Wilson, and Mr. Hamm."

Link: http://blog.methuselahfoundation.org/2007/02/results_from_the_lysosens_soil_1.html

The Damage Done by the FDA, Symptom of the Deeper Problems
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It's not hard to point out the damage done by the US Food and Drug Administration (FDA) - as for any regulation, you just have to follow the incentives and the results. The shackles cast on progress by the FDA are an entirely expected end result in any system where power is disconnected from accountability for results; it achieves exactly the opposite result to that intended by those foolish idealists who set it in motion.

For various political reasons, also unconnected to the production of meaningful results in medical research and development, it is the season for savaging the FDA at the moment. Which means, for a change, various political talking heads - selectively - speaking a little truth about the effect of regulation, centralized power and large, unaccountable government. We'll see how long that lasts:

Free the Elderly

Consider a 90-year-old man suffering from severe kidney disease. He would like to take an experimental drug, but his doctor can't get him in on the clinical trials. As a result, the man must wait nine more years until the drug is approved by the FDA. Unfortunately, this man's advanced age means he has only a slight chance of living another nine years.

Heart Stents and FDA Blockage

FDA is a scientific bureaucracy with police powers. Patients and physicians are free to choose only those drugs and medical devices that it has approved. When FDA approves a therapy that later turns out to be unexpectedly risky, the agency is the subject of front-page headlines and congressional hearings. On the other hand, when FDA delays a badly needed new therapy, patients will suffer but hardly anyone will blame FDA. We'll just think that medical science can't help these patients.


Consider, for example, FDA's 10-year delay, in 1967-76, in approving beta-blockers to prevent death following heart attacks, because of the agency's fear that the drugs might be carcinogenic. During those years, the drugs saved lives in Europe and elsewhere, while an estimated 10,000 heart attack victims unnecessarily died in this country each year. When beta blockers were finally approved in the US, to wide acclaim, hardly anyone raised the lethal effects of FDA's slowness.

A Better Way to Increase Access to Prescription Drugs

If the agency approves a drug or device that later is found to be unsafe in any way, the public and politicians blame FDA for the error. But, if the agency delays when reviewing applications, the patients who need experimental new treatments are worse off, and some may even die waiting for FDA to act. In both cases, real people are hurt. But FDA is only criticized for approving risky medicines - never for keeping beneficial ones off the market. As the Vioxx episode shows so clearly, FDA faces huge incentives to slow the pace of its reviews.

As it turns out, however, that extra agency caution doesn't actually improve drug safety. Studies conducted by FDA itself show that the rate of drug withdrawals has remained essentially unchanged over the last 25 years, despite rising and falling approval times during that period. On the other hand, the health benefits of faster approval decisions far outweigh the risks associated with the small number of unsafe drugs that occasionally do make it to market.

The Harmful Side Effect We Never Hear About

The FDA's "cover" for these ill-advised innovations is that they are a response to a report on "drug safety" published last Fall by the quasi-governmental Institute of Medicine. However, the IOM's deeply flawed, one-sided analysis will remedy few, if any, of the FDA's shortcomings. In fact, many of their recommendations would make the agency even more risk-averse, reduce the number of drugs emerging from the R&D pipeline, and compromise public health.

Neither the Congress nor FDA (nor the IOM) is willing to admit that the agency's most significant problems are mismanagement and excessive risk-aversion. It's much easier to conclude that there is insufficient regulation and to throw more resources at the problem. (And recall economist Milton's Friedman's wry observation that only government responds to a failed program or project by expanding it.) Meanwhile, regulators keep raising the bar for approval, especially for innovative, high-tech products. The FDA is requiring ever larger numbers of patients in clinical trials, its demands for post-marketing clinical trials have proliferated wildly, and "risk management" plans for newly approved drugs have been inconsistently applied, punitive and often more appropriate for weapons-grade plutonium than prescription drugs.

Congressional Cures?

These proposed legislative remedies for the FDA's problems, with more planned for later in the year in both the House and Senate, are analogous to the discredited medical practice of bleeding the patient with leeches. By intensifying the FDA's notorious risk aversion, the new measures will inflate even further the costs, difficulty and uncertainty of drug development and reduce the number of drug candidates that begin and complete clinical testing. They will drain the life's blood from innovation and inflict harm on patients. If these pieces of legislation are enacted, they will validate yet again Will Rogers's observation about Congress: "Every time they make a joke, it's a law. And every time they make a law, it's a joke." And as usual, the joke will be on us.

The Bipartisan War on Medical Liberty

There are a million reasons we should have medical freedom, and they must be articulated if we are to avoid a disaster in the next several years. Libertarians must go beyond what we often hear from free-market wonks: the usual denial that there’s anything wrong at all with the system, as if it’s already a free market, and the usual defenses of the largest pharmaceutical companies as the most persecuted minority, what with its inflated, FDA-protected, federal-patent-ensured mega-profits under attack. We must mount a principled, radical and informed intellectual assault on the fascist and socialist threats to medical liberty if we are to restore it or even defend what’s left of it.

The economics should speak for itself, but the right to control one’s own life and body is the core, moral argument for medical freedom. Life and death are intimately involved with the healthcare issue as with few others. Unfortunately, for the time being, it appears that creeping healthcare totalitarianism is on the agenda of both parties. They only disagree on how fast to run us off the cliff, and who should navigate us there.

Though I suppose I should mention that the originating site for that last article rolls out the attacks on big government and an unaccountable FDA on a regular basis, regardless of the season - they could do with upping the quality, however. As that author points out, the FDA is just one component of a dynamic establishment built upon, interacting with and changing the direction and application of government power - a bunch of pigs squirming around at the trough, and fighting just as rough as they can without upsetting the slop.

Access to centralized power (and money, and control) is something of a cancer, spreading throughout a society, destroying potential and progress - the lure of short-term gain at someone else's expense is irresistible to many. The culture of large business and venture capital embraces the use of government to suppress competition - through control by force, such as through patent law and intellectual property, or by raising the cost of doing business through regulation to lock out innovative and disruptive young companies. In the process, progress - which absolutely requires competition - is stifled, and these corporate cultures become corrupt, moribund and dependant on government. This process described well in a article at Mises.org

The Chicago School of economics favored and still favors the theory of "regulatory capture." Under this theory, an industry or some portions of an industry cultivate government to obtain laws and rules that favor the industry.

The government trades favors for what it wants. Politicians gain political contributions, side payments, and votes for being seen to control the industry. The industry captures the regulators. End of story.

North went much further. He called the first step of obtaining favors "baiting the trap." But matters do not stop there, he pointed out. The trap is set when the industry becomes comfortable with its subsidy, tax break, tariff, exclusive position, license, or whatever. It then begins to extract monopoly rents and to lower product quality.

This then leads to further steps such as public outcry and a government demand for the industry to police itself. Then come crisis, further regulatory intervention, and eventually a government stranglehold over the entire industry via a panoply of boards and price controls. This is when the trap is sprung. The market is replaced by government power and bureaucrats. Government, its aim being control, traps and captures the industry.

In the shorter term, the interest groups use the state against the public. In the longer term, the state and its bureaucrats rule the roost. In the end, the government bureaucracies expand. Paperwork and soft jobs rule the industry, innovation and competition are eclipsed, and the public suffers from poor product quality and high prices.

The motivation for most of these recent attacks on the FDA? That would be coming from the other squirming pigs wrestling in the pen, such as the large pharmaceutical and medical development companies, trying to make the most money they can from the suppression of competition and progress. They might be working on progress, but they're working just as hard at pushing new and better ideas below the waterline - so long as there's the threat that someone else will make money or threaten the bottom line for an aspect of their business model.

The greatest risk to any progress is the elimination of open competition within a framework of the rule of law. We have neither open competition nor a rule of law for medical research and development in the "representative" democracies of this modern world - which means each year that passes adds more to the opportunity cost of where we could have been. We live in a world in which the enormous photographic industry went from film to stored bits in something like a decade, with tremendous long-term benefit to all - and in which hospitals are crammed with paper records and give terrible service because they and the innovators who would help them are not permitted to do better. That is the cost of the regulatory burden, and it is being exacted in the future years of your life, the years you might have lived in good health - but will not because research and development is not progressing as fast as it could in a free society. Politicians and government employees are not enablers of progress - they are millstones; the glue in the works; the boot on the neck:

This state of affairs, in which politicians and special interest groups willfully hold back and destroy the engines of progress, is not peculiar to healthy life extension. All medical research in the US and Europe is subject to ignorant, pandering regulation: price controls, shortages, enormous tax burdens, and so forth. In the worst cases, such as Germany and France, you see entire countries that contribute next to nothing to the advance of medical science. This is not for lack of will or desire, but their research and medical industries are hamstrung by decades of destructive government intervention.

In the US, the grand debate over medical regulation is currently best represented by price controls, drug reimportation, "free riding" and the effects of the FDA on the cost of new medical science. This debate is not academic for those of us who focus on healthy life extension - all the medical research that interests us must go through this same broken system. If the system creates too much of a burden on research or commercialization, then new medicine will never see the light of day, no matter how useful or compelling it is.

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The Anti-Aging Cargo Cult
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As you're reading this Guardian piece, remember that for every huckster so obvious that you'd never fall for their nonsense, there are a dozen who are much better at their nefarious trade - it pays to take a closer look at everyone who is trying to sell you something. "She says DNA is an anti-ageing constituent: if you 'do not have enough RNA/DNA', in fact, you 'may ultimately age prematurely'. Stress can deplete your DNA, but algae will increase it: and she reckons it's only present in growing cells ... the scholarliness of her work is a thing to behold: she produces lengthy documents that have an air of 'referenciness', with nice little superscript numbers, which talk about trials, and studies, and research, and papers ... but when you follow the numbers, and check the references, it's shocking how often they aren't what she claimed them to be in the main body of the text. McKeith's pseudo-academic work is like the rituals of the cargo cult: the form is superficially right, the superscript numbers are there, the technical words are scattered about, she talks about research and trials and findings, but the substance is lacking. I actually don't find this bit very funny. It makes me quite depressed to think about her, sitting up, perhaps alone, studiously and earnestly typing this stuff out."

Link: http://www.guardian.co.uk/food/Story/0,,2011095,00.html

On p66Shc and Poking Around in Mitochondrial Biochemistry
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Mitochondrial processes - especially those involving free radical production, damage and propagation - are deeply implicated in the advance of aging. Aging is damage at the cellular and molecular level throughout your body, and one form of that damage is caused by the normal operation of your mitochondria, the cell's power plants.

So it is with interest that we watch the efforts of scientists to pick apart the complex web of biochemicals and regulatory pathways relating to mitochondria and shed light on how one might go about building a better mammal - one more resistant to aging:

The 66-kilodalton isoform of the growth factor adapter Shc (p66Shc) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66Shc was not known. We demonstrate that protein kinase C beta, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66Shc causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.

That might be a little dense for some of you; decompacting it, we have that free radicals (a category that includes reactive oxygen species) lead to oxidative stress, a term for damage caused to cellular mechanisms by these chemicals. Cells destroy themselves via apoptosis in response to excess oxidative stress, a process initiated in the mitochondria, so as to prevent their own failing mechanisms causing further damage to the body - but the processes of identifying just when is most advantageous to do so are quite varied and complex.

The protein p66Shc is very involved in apoptosis, as noted in the paper above. It is an important part of one scheme by which a cell starts in on destroying itself. This paper suggests putting off apoptosis is a way to extend healthy life span - but lengthing the life of cells is not necessarily a good thing, especially if those cells are being damaged; it might just be the case that you're better off with dead cells than with live cells running ragged. But as it turns out, removing p66Shc from the equation does seem to extend healthy life in mice:

Additionally, p66Shc is phosphorylated on Ser36 within its unique amino-terminal region in response to oxidative stress, an event that markedly sensitizes cells to apoptosis. One way p66Shc seems to enhance oxidative stress-induced apoptosis is by participating in the phosphorylation-induced repression of Forkhead transcription factors, which regulate expression of several antioxidant enzymes. Consistent with this, p66Shc knockout mice exhibit higher catalase activity. Another way is likely mediated by a mitochondrial pool of p66Shc because evidence suggests that activation of this pool leads to further ROS generation by inducing mPTP opening and cytochrome C release.

Remarkably, p66Shc knockout mice not only show increased resistance to oxidative stress, but a 30% increase in life span.

So removing p66Shc extends life - but is this because of a lowered rate of apoptosis with oxidative stress, or is it in fact the higher levels of catalase, an antioxidant that helps soak up the free radicals before they break things? As I'm sure regular readers recall, engineering mice to have more catalase in their mitochondria is good for a 20-30% boost in life span:

The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this [DNA] leads to an unfortunate chain of events that causes entire cells to rabidly produce damaging free radicals and export them throughout the body. But stop a fraction of the original mitochondrial free radicals from attacking their birthplace, and you have slowed the rate at which one cause of aging happens - you have slowed down aging, and extended healthy life.

If you look back in the literature available online, you'll see going on for ten years of work on the topic of p66Shc; scientists picking away at the knot, inch by inch. It's a complex subject. But the discussions are not that much further along now - the general outline is much the same - and I don't hold out a great deal of hope that they'll be significantly and materially advanced in 2017 either. There are only so many scientists, and a great deal of biochemistry to cover. In many ways, the tools of modern biotechnology have already greatly exceeded the management capacity of the scientific community - we can collect far more data per unit time than can be usefully turned into knowledge at this time.

The better mammal - the better human, the version 2.0 that ages a good deal more slowly due to improvements in the fundamentals of metabolism and biochemistry - lies somewhere in the future, but there is a daunting amount of work between here and there. If the scientific community can't fully categorize and understand all the biochemistry surrounding a small, simple chunk of complexity like p66Shc in ten years, one amongst thousands or tens of thousands of equal importance, what makes us think we can roll out safe, significant upgrades to human metabolism in time to help those reading this now?

Changing metabolism, building better, more age-resistant humans, is a very long term exercise. We should be looking at other avenues of development and more promising strategies for rapid progress if we want to see meaningful healthy life extension - of decades or more - within our lifetime.

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"Win Longevity For All"
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From the Institute for Ethics and Emerging Technologies: "When seniors stay healthy and vigorous they can continue contributing their lifetime of accumulated skill and experience to society, without driving up nursing or healthcare costs, or becoming dependent on loved ones. If medical therapies could be developed which slowed the rate of aging, and the development of disease and disability, we may be able to slip past the demographic transition in economic strength, and greater health and longevity for everyone. This is the promise and challenge of the 'Longevity Dividend.' Join us in Chicago on July 23rd for a day long seminar with leading experts on the politics, science and political economy of longevity - including Jay Olshansky and Aubrey de Grey - to help build the campaign for an intensive international research program on anti-aging medicine. ... The seminar will take place the day before the three-day gala Transvision 2007, with keynoter Ray Kurzweil. ... The targets for this event are: scholars and journalists interested in the future of aging and healthcare; legislative aides and policy makers considering the Longevity Dividend as a policy program; pro-longevity, health care and senior activists interested in building the Longevity Dividend campaign."

Link: http://ieet.org/index.php/IEET/more/1255/

Grailsearch and the Myth of Death by Old Age
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Pimm should be in your reading lists already, by virtue being a pro-healthy life extension blog written by a molecular biologist - someone actually working away on the core biotechnologies of tomorrow. I'm all for more visible evidence of the support within the life science and biotechnology communities for plausible, rapid progress towards far longer, healthier lives. A growing community of scientists discussing healthy life extension for a broader audience will make the job of raising public awareness and support for specific longevity research far less troublesome.

A couple of the recent posts over at Pimm are worth a second look:

Grailsearch.org: aging information from a systems biology perspective

Grailsearch is a “community web portal intended for use by biogerontologists, students of biogerontology, software engineers, biochemists or anyone else interested in working towards the search for systems solutions to the diseases of aging.”

[Grailsearch developer] Jim was interviewed at Pimm in November, 2006, and said that: “I have adopted life extension as a hobby. I now study microbiology, proteomics and molecular design about 20 hours per week and plan to guide the next 20-40 years of my career through bioinformatics and eventually into de novo drug design with an emphasis on aging solutions.”

The initial set of blog posts on the site seems really exciting for the multi-disciplined systems biologists of the future. As my point of view on indefinite life extension technology is systemic regenerative medicine, I am strongly committed to all the computational based large scale model approaches and quantitative aspects of the human body

Dying of old age: an unfounded myth?

“There is no compelling explanation for the cause of death in old but otherwise healthy humans, mice, worms or flies, or any other organism for that matter. The colloquial expression ‘dying of old age’ belies our knowledge of the biological basis of this event. ... Yet no hypothesis has emerged that yields a useful definition of dying of old age in terms of cell and tissue biology.

Everyone who grows physically old dies from some specific combination of events - but "old age" is a catch-all for our ignorance in the face of complexity and the unknown. Ideally, that situation would persist, as we have far better things to do with resources devoted to research than to understand the details of the final stages of life for the sake of accurate postmortem notation. Instead, we should be aiming to develop the medical technology to make becoming physically old, suffering and aging to death a choice rather than a fate set in stone.

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Linking Calorie Restriction and Neuroprotection
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This paper examines a mechanism to link the practice of calorie restriction to greater resistance to age-related neurodegeneration via slowing the rate of cellular damage caused by your own mitochondria: "Dietary protocols that increase serum levels of ketones, such as
calorie restriction and the ketogenic diet, offer robust protection
against a multitude of acute and chronic neurological diseases. The
underlying mechanisms, however, remain unclear. Previous studies have
suggested that the ketogenic diet may reduce free radical levels in
the brain. Thus, one possibility is that ketones may mediate
neuroprotection through antioxidant activity. ... Ketones also significantly decreased mitochondrial production of
reactive oxygen species." This is a similar mechanism to that associated with melatonin - reduce the ongoing rate of damage through oxidative stress due to free radicals, such as reactive oxygen species. Like melatonin, however, calorie restriction is a crude tool indeed for impacting health and life span - we move the whole interconnected, poorly-understood system towards a change for the better, so far as we can tell. But the prospect of doing far better for our future longevity is right in front of our noses - all we have to do is to support and fund the research.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17240074

AMPK, Aging and Exercise
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From the BBC: researcher "compared the skeletal muscle of three-month-old rats and two-year-olds. They found that a process called AMP-activated protein kinase (AMPK) slowed down in the older animals. AMPK's role in skeletal muscle is to stimulate the body to burn off fat and to fuel cells, via the production of mitochondria - cells' power sources. ... a person would have to work harder when trying to maintain the same benefits from exercise as they did when they were young. AMPK activity in our skeletal muscle is probably a good thing because it activation stimulates glucose uptake, increases fat oxidation [fat burning], and promotes mitochondrial biogenesis [production]." As Randall Parker points out, this looks a lot like an evolutionary adaptation to minimize damage caused by increasing numbers of cells taken over by age-damaged mitochondria - which has the effect instead of making insulin resistance, type 2 diabetes and age-related muscle loss (sarcopenia) the order of the day. Expect to hear more on this in the next few years as scientists determine where AMPK fits within the hierarchy of cause and effect in aging.

Link: http://news.bbc.co.uk/2/hi/health/6334899.stm

Betting on Medical Progress
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A perspective on some areas of modern medical research and development from Anders Sandberg: Branson's venture into stem cell banking "may turn out more useful than we could possibly think today because of advances in regenerative medicine that enable new uses of stem cells. It could also become totally obsolete if the advances go so far that normal cells can be turned into stem cells. ... This raises the interesting issue of gambling on future medical advances. Cryonics already does this in a spectacular and controversial fashion. Storing stem cells is a less radical gamble (we already know they can be useful for some things, but we don't know if they will ever prove useful for our particular maladies). ... Might we use known areas of medical progress to bank on things that are currently not useful but will be useful in the future? ... Maybe we should start documenting our healthy metabolome, kineome and proteome when we are young, somehow. Having a backup never hurt." If investment, competition and a lack of oppressive regulation can drive the cost low enough, all these things would be a bet worth taking.

Link: http://www.aleph.se/andart/archives/2007/02/banking_and_insuring_stem_cells.html

Crude Tools
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A post on the applications of melatonin from Ouroboros is a good illustration of just how crude are the tools available to us today. It's like having a complex machine and trying to keep it running for longer by hitting it with a hammer at various points to jog the components. Entire branches of the scientific community are devoted to figuring out where best and how hard to hit the machine; it used to be a matter of trial and error, but now is moving towards better understanding how the components fit together. "Animal and cell culture models of several [neurodegenerative] disorders have benefited from the application of melatonin. The mechanisms underlying the neuroprotective properties of melatonin are likely to involve activation of specific melatonin receptors. This can lead to modulation of transcription factors and consequent altered gene expression, resulting in enhancement of antioxidant enzymes and downregulation of basal levels of inflammation. Melatonin has potential utility both in slowing normal brain aging and in treatment of neurodegenerative conditions." The greatest advance that stems from modern biotechnology will be the ability to move beyond the hammer approach - and melatonin is very much a hammer approach - to precisely interact with the components of the machinery rather than reaching into the rack of blunt implements.

Link: http://ouroboros.wordpress.com/2007/02/09/melatonin-as-an-anti-aging-therapeutic-for-the-brain/

On Leucine, Metabolism and Aging
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Researchers continue to pull new knowledge from their ongoing investigations into metabolism and diet; matters are moving faster now that calorie restriction mimetic science is drawing much more funding into this field.

Leucine Deficiency Emulates Calorie Restriction

Organisms adapt metabolically to episodes of malnutrition and starvation by shutting down the synthesis of new proteins and fats and by using stores of these nutrients from muscle, fat, and the liver in order to continue vital functions. Cavener and Guo found that the removal of a single amino acid, leucine, from the diet is sufficient to provoke a starvation response that affects fat metabolism. "These findings are important for treating two major problems in the world," Cavener says. "The starvation response we discovered can repress fat synthesis and induce the body to consume virtually all of its stored fat within a few weeks of leucine deprivation. Because this response causes a striking loss of fatty tissue, we may be able to formulate a powerful new treatment for obesity."

"Emulates calorie restriction" is somewhat unwarranted, I think - it would be more accurate to say that this emulates some aspects of dietary restriction in general as applied to fat metabolism. It is interesting to see that, as scientists continue to deconstruct the workings of metabolism, ever more parts of the metabolic control system are found to be keyed to surprisingly specific components of diet.

Another item on leucine: it seems that we become less able to utilize this amino acid as we age, which leads to sarcopenia, or progressive age-related muscle loss. There is a modest weight of evidence for enhancing leucine intake with age on those grounds.

Muscle in adults is constantly being built and broken down. As young adults we keep the two processes in balance, but when we age breakdown starts to win. However, adding the amino acid leucine to the diet of old individuals can set things straight again. ... After the age of 40, humans start loosing muscle at around 0.5-2% per year. ... The team of researchers believe that the age-related problem results from defective inhibition of ubiquitin-proteasome dependent proteoloysis, a complex degradative machinery that breaks down contractile muscle protein, and that leucine supplementation can fully restore correct function.

These two views (of many) of the role of leucine form a good illustration of the complexity of metabolism - it's all so interconnected that any attempt to manipulate it safely and usefully requires an enormous amount of knowledge, or acceptance of a lot of risk. This insight is one basis for the engineering approach to tackling age-related degeneration, or other progressive conditions. Don't try to manipulate metabolism to slow things down - it's a hard job with limited rewards. For the much the same amount of expenditure, you could instead learn to repair progressive changes (damage, in other words) caused by metabolism to cellular and biochemical structure. This would be a matter of understanding how to fix up the damage to the existing engine, rather than the far greater understanding needed to build a better engine.

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Recent Alagebrium Research
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Alagebrium, or ALT-711, is an AGE-breaker - a class of compound designed to break up the advanced glycation endproducts (AGEs) that contribute to some types of age-related degeneration. "Arterial stiffening and endothelial dysfunction are hallmarks of aging, and advanced glycation endproducts (AGE) may contribute to these changes. We tested the hypothesis that AGE crosslink breakers enhance endothelial flow-mediated dilation (FMD) in humans and examined the potential mechanisms for this effect. ... Alagebrium enhances peripheral artery endothelial function and improves overall impedance matching. Improved endothelial function correlates better with reduced vascular fibrosis and inflammation markers than with vessel distensibility. AGE-crosslink breakers may reduce cardiovascular risk in older adults by reduced central arterial stiffness and vascular remodeling." Unfortunately, despite promising animal studies, results in people have not been unambiguously positive: it is probably the case that alagebrium targets a type of AGE that is common in old animals, but not in old people. AGE-breakers are a serious branch of research, but we need to move past alagebrium as anything other than an illustrative example, and on to the fruits of more advanced biotechnology.

Link: http://www.ncbi.nlm.nih.gov/pubmed/17278974

On "Human Dignity"
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(From Reason Online). Those who would work to ensure we all age, suffer and die wave the banner of "human dignity" - a twisted construct of tortured meaning in their hands, as any rhetorical tool must become in the service of herding millions to their graves: "That deeply felt lack and limitation, of which Kass speaks, is what motivates scientists to develop new treatments not only to rescue people from the ordinary degradations of disease and the slow loss of vitality that comes with aging, but it is what also inspires them to conjure the new technologies that will enable people to flourish. Transhumanists argue for allowing people to choose the good of augmented capacities such as stronger immune systems, more agile bodies, sharper minds, greater powers of self-control, and radically longer lives. Instead of being degraded, people will be liberated to perfect as never before arts and crafts, song and story, noble deeds and customs, fine character, the search for wisdom, and yes, even a reaching for the eternal and the divine. The pursuit of mastery over pitiless nature will not only expand and enlarge human capabilities, but it will also expand and enlarge true human dignity. ... Surely the salient lesson we learn from Brave New World is that we must guard against tyranny, not against technological progress."

Link: http://www.reason.com/news/show/118608.html

A Brace of Items of Interest
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Some days there are more items of interest than I care to choose between; here are some that caught my eye today:

Does a component of niacin point the way to anti-aging drugs?

Using the techniques of structural biology, the Wistar team demonstrated that a component of the common vitamin B3, also known as niacin, binds to a specific site on the sirtuin molecule to inhibit its activity. This observation suggests that drugs designed to prevent the vitamin B3 component, nicotinamide, from binding at this site could have the effect of activating sirtuins. Any such drug would, in essence, inhibit the inhibitory effect of nicotinamide. As in mathematics, the two negatives would create a positive result – activation of sirtuins.

"Our findings suggest a new avenue for designing sirtuin-activating drugs," says Marmorstein. "The jury is still out as to whether a drug of this kind might result in longer life in humans, but I'm equally excited by the possibility that such interventions might help counteract age-related health problems like obesity and type II diabetes."

This is an insight into the way in which modern biotechnology can aid the search for more mechanisms of interest associated with any new discovery; it also illustrates the way in which any line item that is heavily funded (e.g. sirtuin research) will attract ever more funding around the peripheries. People flock to funded areas, as more conservative funding organizations tend to grant more readily to well-known, low-risk explorations. I leave it up the reader to decide whether this is a good thing or not; we're stuck with it either way, at least until human nature undergoes some radical change.

As I'm sure many of you know by now, I think this business of manipulating metabolism into a better mode of running is a poor path - the slow, expensive, low-yield way - to achieve meaningful results in enhanced longevity. Leave metabolism the way it is, and learn how to repair the accumulating damage that causes aging - that'll cost just as much time and money, and the results will be far more effective in terms of extending our healthy life spans.

Meanwhile, cancer and stem cell researchers continue to forge ahead with the tools of modern biotechnology - learn, and then turn that learning into a tool to strike at the problem. It's rare for a week to pass these days without the news of a new mechanism documented and understood:

Cold Spring Harbor Laboratory scientists discover new gene that prevents multiple types of cancer

Specifically, Mills' discovery identifies CHD5, a protein that prevents cancer, as a novel tumor suppressor, mapping to a specific portion of chromosome 1 known as 1p36. When CHD5 is not doing its job, the machinery within our cells that normally prevents cancer is switched off. The ability of CHD5 to function as a master switch for a tumor suppressive network suggests that this gene is responsible for a large number of diverse forms of human cancers. "CHD5 functions like a circuit breaker that regulates the tumor-preventing power in our cells - when it blows, cancer occurs," explains Mills. Modulation of CHD5 activity may provide novel strategies for better design of more effective cancer therapies.

...

The findings of Mills' study will influence the future of cancer research. It shows that deletion of a part of 1p36 causes cancer and increased "dosage" of CHD5 triggers extra tumor suppression. One extra dose, or copy, caused cells to either stop dividing or to undergo cell suicide by switching on a battery of potent tumor protective machinery. This work indicates that pharmaceuticals that switch on CHD5 may provide a way to treat many types of human cancer.

New protein inhibitor impedes growth of cancerous cells

Because cancer cells are typically fast growing and can mutate to adapt to new growth conditions, effective drug-based therapies will likely succeed in part by impeding multiple functions required for cell division and survival. One particular class of proteins, known as kinases, is known to play especially critical roles in the division of healthy cells, and appears to also be important for cell division in cancer cells, even though these cells are diseased and have lost some of the restraints on division that normal cells impose on themselves. Because central aspects of cell division are under the control of just a few key kinases, these proteins represent potentially important targets for new cancer therapeutics, but few if any effective inhibitors have been identified as acting specifically and effectively against one particular cell-division kinase, known as Plk1.

In the new work, Steegmaier et al. isolated a chemical compound, which they term BI 2536, that they demonstrate to be a potent inhibitor of Plk1, and show that BI 2536 can indeed effectively halt the growth of cancerous cells, both in cell culture and in an animal model for human tumor growth. BI 2536 caused growth arrest and cell death in cell lines derived from a variety of human cancers, and it inhibited the growth of human tumor grafts in mice, resulting in the death of tumor cells and regression of large tumors. The authors report that BI 2536 has now been brought into use in clinical studies of patients with locally advanced or metastatic cancers in order to address the therapeutic potential of the compound.

Master switches found for adult blood stem cells

Johns Hopkins Kimmel Cancer Center scientists have found a set of "master switches" that keep adult blood-forming stem cells in their primitive state. Unlocking the switches' code may one day enable scientists to grow new blood cells for transplant into patients with cancer and other bone marrow disorders.

The scientists located the control switches not at the gene level, but farther down the protein production line in more recently discovered forms of ribonucleic acid, or RNA. MicroRNA molecules, once thought to be cellular junk, are now known to switch off activity of the larger RNA strands which allow assembly of the proteins that let cells grow and function.

"Stem cells are poised to make proteins essential for maturing into blood cells, but microRNAs keep them locked in their place"

It's a revolution out there, as you may have noticed; the next few decades will see an explosion of knowledge and technology to better the human condition. But that won't be enough to greatly extend our healthy life spans - as opposed to a slow, incidental lengthening through advances across the board in medical technology - without far more interest and investment in the most efficient, direct paths to making rejuvenation a reality. It would be a real shame if we missed this golden opportunity to see a great deal more of the future in good health and vigor.

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More on Mitochondria, Gender and Aging
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Via PhysOrg.com, more on possible biomechanisms for gender differences in longevity: "While both parents contribute to their offspring's cellular genetic inheritance, only the female passes on the mitochondrial genome to the next generation. Why, and how, this asymmetrical inheritance happens is not clear, but Tower thinks understanding it may be key to understanding sex differences in aging. ... Mitochondria play a key role in regulating the programmed cell death pathway, or apoptosis. In flies and humans, apoptosis works during normal embryonic development and sexual differentiation, sculpting the body by killing unwanted cells. But the cell death pathway, in which the p53 gene is a central player, also appears to malfunction more frequently over an organism's lifetime, thereby contributing to aging and aging-related diseases like Parkinson's. This might happen more often or differently in males, Tower speculates, leading to a shorter life span. Tower's far-reaching model leads to 'a list of predictions,' which his lab has already started testing in experiments with Drosophila. One that he's particularly interested in following up on is the idea that the human Xist gene may control sex determination and be very much involved in regulating human life span."

Link: http://www.physorg.com/news90156140.html

On the Culture of Instant Gratification
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I think the recent article on calorie restriction with optimal nutrition (CRON) in Slate gives more insight into the damaging culture of instant gratification - and instant results, or else - than anything else. "[Mary] Robinson told me how she came to adopt the CRON life six years ago. ... She joined the Calorie Restriction Society and wrote a computer program to track everything she ate and its nutritional value. It has vastly improved her health. Robinson was in a study of CRON followers done by Dr. Luigi Fontana at Washington University School of Medicine. Fontana found that the CRON adherents - many of whom, like Robinson, had been formerly pudgy - now had arteries as efficient as fire hoses and blood pressure readings like those of 10-year-olds. ... Is CRON crazier than having a doctor suck out your fat, or staple your stomach? Is it crazier than a world in which a drug company is looking to market a product to temporarily eliminate people's sense of taste and smell so they will lose weight? ... But can someone without any notable will power - me - stay on a CRON diet? I decided to try CRON for two months, but it's past that now and I'm still avoiding seconds and skipping my late-night snack. CRON was supposed to do much for me that it hasn't." All worthwhile results require a little effort and persistence.

Link: http://www.slate.com/id/2158975/pagenum/all/

Overthinking and the Utter Absence of a Need For Justification
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Some folk like this sort of stuff, but I can't help but feel that a certain degree of overthinking of healthy life extension takes place in some parts of the community.

Walker offers an interesting analysis, in which he defends longevity research against Singer's attack, even on the assumption that it would lead to an additional 70 or 80 years lived in less-than-optimal health. He points out that the available empirical studies do not support the idea that people are less happy in old age than at earlier times, despite inferior health. In fact, the happiness curve seems to be U-shaped: actually at its lowest point when we are in our late 30s or early 40s. (This may seem surprising, since that is exactly when we are at our peak in many ways, but perhaps that itself creates pressures which are not yet experienced when we are younger, and which start to recede as we move deeper into middle age. I'll avoid any further speculation about such issues.)

People should be free to cast their dispositions as they will, but really, aren't there better things to be doing in connection to lengthening the healthy human life span? Such as helping to make it happen in the first place? If that's not your priority, so be it, but I can't be the only one who thinks this world is possessed of a good deal too much talking and a good deal too little accomplishment. I'd be happier to see overthinking only in the ranks of opponents of healthy life extension - as that would be a good indicator that they aren't actually doing anything more than rearranging their tidy formations of words and concepts.

Yes, I am aware of the irony inherent in devoting a blog post to this topic.

From my perspective, there is a certain liberation in a simple view of healthy life extension that stems from libertarian principles. Your body is your own, and people should be free to associate in order to improve and lengthen their lives. Since no-one has any claim over your body and life, there is no need to justify yourself, your existence, and your choices with regard to longevity any more than you have to justify paying for rice versus potatoes for dinner. Hence utilitiarian pontifications for and against developing the technologies necessary to live longer are no more than light reading pieces for those who like that sort of material - not to be mistaken for anything of substance. Persuasion is rife in such a worldview, force absent. Those who wish to work on longevity, get on and do it. Those who don't, don't.

Now, if only we didn't live in a world in which government employees have the power to rip you from your life, suppress medical research on a whim, and otherwise make every private choice and collaboration a matter open to inference for anyone who can hold a purse to a politician's ear.

Think about that the next time you read one of these pieces on the justification for or against longevity research - that you live in a world in which you have to convince all other people that you be permitted to work towards living longer, because any one objector can efficiently shut down your efforts through the agency of government; an effort most would never undertake had they to fund it all themselves. This is a world in which every matter of progress and endeavor becomes a battle of snarling, ignorant, uninvolved crowds at the chokepoint of regulation and government power - in which truth is sacrificed for emotive argument, and resources squandered on fighting for the ability to progress.

This is a world in which progress towards advanced medicine and greater longevity is far slower than it might be, sadly.

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Linking Tau and Amyloid Beta in Alzheimer's
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Tau and amyloid beta are implicated in the mechanisms of Alzheimer's disease; here researchers look into why we see both: "two kinds of abnormal structures accumulate in the brain: amyloid plaques and neurofibrillary tangles. The plaques contain fibrils that are made from protein fragments called 'beta-amyloid peptides.' The tangles also are fibrous, but they are made from a different substance, a protein called 'tau.' ... researchers found a deadly connection between beta-amyloid and tau, one that occurs before they form plaques and tangle ... We think we've found one of the seminal cell biological events in the pathogenesis of Alzheimer's and if we can figure out all of the steps in the process and understand each player at every step, it will represent many potential new drug targets for Alzheimer's therapy. Our paper defines one of the earliest events that causes neurons to die in both early-onset familial Alzheimer's and late-onset Alzheimer's disease. We believe this is the first evidence for the long elusive 'missing link' between amyloid and tau in Alzheimer’s disease."

Link: http://www.virginia.edu/uvatoday/newsRelease.php?id=1435

What Early Medical Nanorobots Will Look Like
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Scientists will be designing and mass-producing medical nanorobots from carbon feedstock some decades from now, so as to directly manipulate biochemistry to cure and prevent disease, wear and tear, and ultimately aging itself - but we'll have to get the whole molecular manufacturing technology base sorted out for that. Earlier than this, it seems likely that the first medical nanorobots (well, microrobots in this case) will be highly modified or even completely artificial cells. Why ignore the working blueprint that's right in front of you, after all? Via EurekAlert!: "Our proposal is to use naturally available molecules to create pseudo-cell factories where we create a super artificial cell capable of targeting and treating whatever is ailing the body. The human cell is like a bustling metropolis, and we aim to tap the energy and diversity of the processes in a human cell to help the body essentially heal itself. ... Understanding both the nature of a cell as an independent unit and its role in the life processes of larger organisms is crucial in our quest to duplicate the molecular units which form the building blocks of the cell and its parts. We see this development of artificial cells as a building block for a variety of new and exciting therapeutic approaches."

Link: http://www.eurekalert.org/pub_releases/2007-02/cmu-cmr020707.php

On the Flip Side, There Is Much Yet To Be Done
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Yesterday, I pointed out that advocates for healthy life extension research have made great progress in the past few years, both within and beyond the scientific community. This is undoubtably a good thing - we'll be seeing more discussion, more scientific work on repairing the damage of aging, and more funding for more ambitious research in the years ahead.

This is a huge improvement over the state of affairs even as recently as ten years ago. Those in the audience who were involved in past efforts in longevity research and advocacy in the 1980s and 1990s will recognize just how amazing it is that today we can see a well-known and vocal organization aiming squarely for the defeat of aging through advanced biotechnology attract more than $8.5 million from supporters. More to the point, just how much ten years of progress in biotechnology has increased supports the plausibility of rapid progress towards longer healthy lives!

But let's pull back to the big picture, since successful, rewarding work always looks like a great deal of progress when you're up close to the pedals and machinery. At the grand scale, serious efforts to greatly extend the healthy human life span are just getting geared up to begin to start. Similary, the efforts to raise sufficient awareness, understanding and support in the public at large - to change the culture of aging, educate away the present poor understanding of prospects for rejuvenation through future biotechnology, and challenge the acceptance of death and suffering that result from aging - are nascent at best.

The past few years of success and progress - raising some millions of dollars, changing the balance of viewpoints and support within gerontology, plugging away at broadening the conversation and growing the interconnected base of active supporters of healthy life extension - are "just" a ticket to the next level. At this next level, the real work has yet to begin in earnest.

In the world at large, most people still think of living longer through medicine as being older for longer, not being younger for longer - and they knee jerk in rejection. Most people believe that "anti-aging science" is supplements, hucksters and flashy nonsense from cosmetics companies, and that real rejuvenation is impossible - or so far away as to be unworthy of consideration. Many people believe that overpopulation is a serious threat, that pollution will outrun technology, that the future is one of rust and poverty, rather than a golden age of technology; they see not worth in living into such a future. Many people believe that cannot affect or change the way the future unfolds. Many people have so armored themselves with a mindset of acceptance against the ugly realities of age-related suffering that they are unwilling to even talk about the subject, or consider any form of change, even for the better.

This is essentially no different today than it was ten years ago. The changes for the better made in a few years of work are small compared to the whole; a stream feeding into a sea. But it's a start, and it's growing.

For all intents and purposes, the same can be said for funding for research into slowing, reversing or meaningfully understanding aging. It has gone nowhere in the past ten years, when seen from the highest level and largest scale of funding, and certainly nowhere near the many billions of dollars and directed, crystal-clear target of the defeat of aging that would be required for results within a few decades of work. Those advances that have been made are small - but significant and growing.

There is much work to be done in the years ahead to reach the goals of rapid progress and large-scale funding in the repair and prevention of aging, but it is eminently achievable - which is more than can be said of the promises of those who offer silver bullets that work today.

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Evolutionary Tradeoffs: Stem Cells and Cancer
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From Ouroboros, a look at where evolution has left us in the aging and longevity stakes: "An emerging theme in biogerontology is the idea that lifespan may be determined by the balance between regeneration and tumor suppression. Long-term tissue health demands that damaged and dead cells be replaced, but unlimited replicative potential poses the risk of cancer. Therefore, to prevent tumors, organisms must accept a decrease in regenerative capacity. ... How direct is this connection? In an indirect model, differentiated cells are the initiatiors of tumor growth. p53 limits stem cell proliferation, which in turn decreases the rate of production of new differentiated cells. Fewer cells available to undergo neoplastic transformation means fewer cells available to initiate tumors, with the unfortunate consequence that tissues requiring new cells to maintain homeostasis must go begging. In a direct model, tumor suppressor activity decreases the number of stem cells that might become dysregulated and transformed into cancer stem cells, a relatively new concept in cancer biology." Evolution got us this far, and now its up to us to carry the ball forward to greater longevity through advanced biotechnology.

Link: http://ouroboros.wordpress.com/2007/02/06/devils-bargain-tradeoffs-between-stem-cell-maintenance-and-tumor-suppression/

Sign Up For SENS3
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From the desk of biomedical gerontologist Aubrey de Grey: "registration and abstract submission are now open for the third Strategies for Engineered Negligible Senescence (SENS) conference, to be held at Queens' College, Cambridge, England on September 6th-10th 2007. The early registration and abstract submission deadlines are both June 15th. ... The preliminary program already has 48 confirmed speakers, all of them world leaders in their field. As for previous SENS conferences, the emphasis of this meeting is on "applied gerontology" - the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to a youthful degree of physiological robustness ... In addition, there will be at least a dozen short talks selected from submitted abstracts, as well as poster sessions each evening. Authors of short talks and posters will, like the invited speakers, be invited to submit a paper summarising their presentation for the proceedings volume, which will be published in the high-impact journal Rejuvenation Research early in 2008."

Link: http://blog.methuselahfoundation.org/2007/02/registration_and_abstract_subm.html

Three Years of Fight Aging!
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I failed to note the actual anniversary at the tail end of January, but Fight Aging! has now marked three years of a daily post on (or close to) the topic of healthy life extension. In that time, I have sought to bring those who stop by, or who otherwise stumble upon my writings, around to a more productive way of looking at aging, longevity, science and human action:

This is a game in which all who choose to win will win big, should enough of us choose to win - but otherwise we all lose, suffer and die far sooner than we might. Significant progress in healthy life extension science requires the widespread support and understanding necessary for large-scale funding, just as it requires the early advances in science and advocacy that encourage that support.

Fight Aging! commenced around the time I first started volunteering with the Methuselah Foundation - back when the pledge fund stood at $10,000, and folk were drumming up support and donations from the healthy life extension advocates of the transhumanist community. Pledges today have topped $8.5 million dollars, and that seems like a big deal in terms of progresss. The environment for debate on healthy life extension has changed greatly for the better in the past few years, and I don't think it's just the incremental advance of science, nor the many new faces who swell the ongoing conversation. This is the start of a thaw, a sea change in attitudes that will continue and reinforce itself.

Life is good, and the future is golden - you stand a good chance of living to see far more of it if you step up to the plate and help support the scientists who will make it happen.

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Learning From Werner Syndrome
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The rare accelerated aging (or progeroid) conditions have a lot to teach us about "normal" aging, as illustrated by this EurekAlert! piece: "Patients with Werner Syndrome manifest signs of aging, such as skin wrinkling, baldness, or hair graying, in their teens. Most die in their 40's or 50's due to a predisposition to diseases like cancer. ... Cancer is almost always related to chromosomal instability. If telomeres are lost on individual chromosomes, then chromosomes are not protected and can fuse with other nonprotected chromosomes. Then when cells divide, chromosomes randomly break, leading to genome instability ... The lack of a single protein (WRN) [mutant or nonfunctional in Werner Syndrome] induced loss of some telomeres, leading to a premature cellular growth arrest ... When we put telomerase into cells [it] fixed the defect by elongating short telomeres seen in Werner Syndrome cells ... We study this disease because it is an excellent model for aging, and we show here a direct relation between aging, telomere loss, and cancer occurrence. I predict that cancer in older people has precisely the same basis as that seen in Werner Syndrome patients. That is why this was such a satisfying study."

Link: http://www.eurekalert.org/pub_releases/2007-02/si-ffl020107.php

The Myth of Antioxidants
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The New Scientist looks at the myth of antioxidants: that piling them into your system is necessarily a good thing. "Since the early 1990s scientists have been putting these compounds through their paces, using double-blind randomised controlled trials - the gold standard for medical intervention studies. Time and again, however, the supplements failed to pass the test. True, they knock the wind out of free radicals in a test tube. But once inside the human body, they seem strangely powerless. Not only are they bad at preventing oxidative damage, they can even make things worse. Many scientists are now concluding that, at best, they are a waste of time and money. At worst they could be harmful." Mouse studies have shown that carefully directing antioxidants to the cellular mitochondria extends healthy life span on the order of 20-30% - a fairly complex feat of biochemical engineering that no presently available pill can match. Those studies further showed no benefit from the same antioxidants sent elsewhere in mouse biochemistry. Haphazardly throwing chemicals at a very complex problem and hoping for the best does not have the best record of success - when that's all you can do, you do it, but we can do better now.

Link: http://www.newscientist.com/article/mg19125631.500

Aubrey de Grey on the Science Weekly Podcast
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You can listen to biomedical gerontologist Aubrey de Grey talk about the science behind the Strategies for Engineered Negligible Senescence (SENS) in a the first segment of a podcast from the UK Science Weekly show:

What would you do if you could live forever? The question may not be as far fetched as it sounds, according to Cambridge University biologist Aubrey de Grey. He believes that people alive today will live beyond 1000 thanks to medical advances to prevent ageing.

Here is a direct link to the mp3 (a weighty 25MB or so).

If you'd like to read more about SENS - in its capacity as a plausible best foot forward for more rapid progress on the road to defeat age-related frailty, disease and suffering - then you should head on over to the SENS website. Highlights include:

  • an overview of the molecular and cellular damage that causes aging, and possible research strategies to produce repair technologies
  • a prospective timeline for progress and the funding required to make it happen
  • presentations from the scientists attending the SENS2 conference

You also might take a look at a gentle introduction to SENS at the Longevity Meme, and should certainly pass by the Methuselah Foundation, a volunteer organization funding SENS research from the generous donations of hundreds of supporters. You might recall that Peter Thiel recently pledged $3.5 million to this cause - you should give some thought to helping out as well.

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On the Roots of Parkinson's Disease
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Medical News Today looks at present understanding of the biochemical mechanisms that lead to Parkinson's disease, "in which nerve cells in part of the brain called the substantia nigra die, resulting in the loss of dopamine, a nerve-signaling molecule that helps control muscle movement. The absence of dopamine from these cells, called dopaminergic neurons, causes a loss of muscle control, trembling and lack of coordination. ... The molecule that prevents damage to the substantia nigra is an enzyme called GST pi ... This molecule stands like a sentry at the crossroads of several biochemical pathways, any one of which can lead to Parkinson's disease ... The study sheds light on the cause of most cases of Parkinson's disease, which currently are unexplained. ... The majority of these cases of Parkinson's disease appear to arise because individuals who have a genetic susceptibility to the disease are exposed to environmental toxins such as pesticides and herbicides, which trigger the formation of free radicals that kill dopaminergic neurons in the substantia nigra. We also know that GST pi blocks the process of cell suicide triggered by stresses that the cell can't overcome, such as an increase in the presence of free radicals or a loss of the cell's ability to produce energy."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=62197

From the Buck Institute President
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Via SFGate.com: "Kovach, who is both a physician and lawyer, is president and CEO of the Buck Institute for Age Research ... The Buck Institute is the only independent research institute in the country dedicated exclusively to age research and age-associated disease. I came here about a year and a half ago. ... I view it as just entering the second half of my 100-year life. ... We do work in yeast and flies and worms to look at how we can provide chemicals, for example, to double, triple, quadruple life-span. We'll overlap that with researchers in a specific disease area like Alzheimer's or Parkinson's, and determine the signals that are being activated in these model organisms and how they correspond to human pathways. ... With 11,000 Baby Boomers a day turning 60, the goal is to have therapies in place that stabilize them. ... By delaying the process of aging you'll delay the onset of every chronic disease. So it's the longevity dividend that by investing in age research we can help delay Alzheimer's, delay Parkinson's, delay diabetes, delay cardiovascular disease."

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2007/02/04/CMGRJN7QBP1.DTL

Interesting Posts At Longevity Science
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Two recent posts over at Longevity Science, Leonid Gavrilov's blog, are worthy of attention. Gavrilov is one of the scientists in the husband and wife team behind the very useful reliability theory of aging and longevity, you might recall, and maintains a website on his work in addition to the blog. In any case, a little background first: an at times acrimonious discussion on Aubrey de Grey's Strategies for Engineered Negligible Senescence (SENS) - and issues relating to radical life extension - has been taking place on the Gerontology Research Group mailing list over the past week or so, spurred by publicity for a recent book that included discussion of SENS. The practicing life scientists on the list span the gamut from support to guarded interest to outright rejection of SENS as a strategy to move forward towards healthy life extension, so it sometimes makes for fireworks.

Gavrilov posted his opinion - which many of you will know already from his previous public comments - at Longevity Science, but I think the post is made much more interesting for the comments from researchers Stephen Spindler and Ruth Itzhaki:

My personal attitude to the SENS scientific initiative could be best characterized with a quote by George Bernard Shaw (1856-1950):

"The reasonable man adapts himself to the world; the unreasonable one persists in trying to adapt the world to himself."

"Therefore, all progress depends on the unreasonable man."

...

There is quite a lot of superheated rhetoric being posted about SENS. SENS is undeniably highly optimistic and may or may not be realistic. Many think it too optimistic, and worry that it will hurt the science of gerontology.

But, Aubrey has already raised more than one million dollars for gerontological research with his optimism. This money might never have been available if he had not started SENS. He has captured the imagination of some people. Pessimism and criticism (even if you think it is realism) rarely raises money, captures the imagination of successful people, or accomplishes much which is positive.

...

Heresies should be encouraged, even if they merely make those doing more conventional work – the vast majority in most fields - think more broadly. It’s astonishing how reluctant many researchers are even to contemplate innovative ideas, especially if the person is an outsider from a different field, unless the ideas directly bolster their own work. Have they forgotten how often such creative people are proved correct, years after their ideas have been derided or ignored, and have they forgotten Crick, and Perutz – two amongst the many outsiders - physicists - who trod indelicately, but oh so fruitfully, in the field that subsequently developed as molecular biology? Aubrey might not be proved right or wrong until well after we’re all dead, but it’s excellent that he has brought a breath of fresh air (as well as funding), into ageing research.

The second of Gavrilov's posts is an educational look at the mindset of public with regard to healthy life extension through the filter of the books they buy. If you want to see what someone really things - as opposed to what they say - watch where they direct their money. As he notes, this is a somewhat disturbing list of best-selling books on aging and longevity:

Looking on this list you may find some common features of these books:

1. Promise for human dreams to become "younger next year" or even "ageless."

2. These dreams are achievable for a low price, sometimes as low as just $2.94

3. From a scientific point of view the concepts of becoming "younger next year" or even "ageless" represent propagation of a sheer nonsense, unless you take them metaphorically.

4. Where are the great minds making the cutting-edge research on anti-aging & longevity studies? Why are they not in this list of authors?

This leads to a suggestion:

If we wish to prevent propagation of nonsense in public minds, we should encourage good scientists who are involved in legitimate anti-aging & longevity studies to write popular books for a general public.

People are interesting creatures. Most will loudly declaim against any desire to live indefinitely in good health, with any number of common "justifications," but if you ask them at any point whether they want to die now or live longer in good health, they'll always choose to live longer. Then we have this matter of the books, and the huge "anti-aging" industry - people voting their hopes for longer healthy lifes, more youth, with their wallets, no matter what they might say about accepting aging and death. But at the same time as blinding themselves to common sense and science, at the same time as chasing any old nonsense that falsely promises an immediate result, the majority of people reject out of hand serious scientific attempts to achieve far better results.

It's a real Gordian knot, the present bundle of attitudes to aging, youth, longevity and death that twists its way through our culture. No-one has brought a suitable sword to the party yet, but we can hope that the first radical life extension in animals like mice will cut through the nonsense and help people to see where their support should be placed.

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Mining the Biochemistry of Hibernation
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CBC News looks at the search for new tools for medicine in the biochemistry of hibernators. Researchers have been looking at bear biochemistry for some time now, but many other species are worthy of investigation: "hibernators' amazing ability to manipulate their own metabolisms could lead to breakthroughs in improving organ transplant and in fighting such illnesses as obesity, diabetes, heart disease and even Alzheimer's, research shows. ... Remember, our physiology, and even our genetic makeup, isn't that different, in terms of basic bodily functions, from these hibernating mammals ... The blueprint, the genes to do these things are there - we're just not activating the same physiological pathways. ... As the time mammals spend in torpor increases, vital cell connections begin to weaken within their brains. However, most hibernating mammals actually rouse themselves in their burrows every so often, and this appears to help these neural connections reestablish themselves ... In essence, hibernating mammals experience real brain damage, 'but then they reverse themselves.'"

Link: http://www.cbc.ca/cp/HealthScout/070202/6020219AU.html

Thoughts on Longevity Mutations
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Michael Rae has posted some thoughts on known longevity mutations to the Immortality Institute forums. Cleaning it up a little, we have:

While laypeople and non-biogerontologist biologists often subscribe to the idea that we are 'programmed to age and die' (usually as a means to clear out the old to free up resources for the young, and/or to facilitate evolution by increasing the turnover of the generations), almost no gerontologists do: the idea is actually logically incoherent granted the basic logic of natural selection.

Instead, almost all biogerontologists subscribe to some version of the idea that aging is the result of stochastic molecular damage that is only partially prevented or repaired because to invest the resources into creating maintenance mechanisms powerful enough to obliterate such effects would be a waste - natural selection selects organisms that leave behind the most viable progeny, not those that win the longevity medal. Thus, evolution tends to select for maintenance systems that retard aging ENOUGH to let individuals live out a relatively long life - relative to what can be expected if they aren't killed by starvation, predation, exposure, etc - but not DRAMATICALLY more. The resources that would have been invested in repair are instead directed to either reproduction matters (fertility, attractiveness, etc) or line items related to surviving those other, grossly environmental threats (warmer fur, sharper claws, etc). Such ideas can be grouped under the "disposable soma theory," and mechanisms include the lack of selective pressure against mutations whose ill effects are felt only late in life -- most dramatically, in the case of "antagonistic pleiotropy," where a trait is selected because it has effects that are beneficial for fitness, but that cause negative consequences that are not normally felt in the wild. These negative consequences are only seen when the organism is sufficiently shielded from the natural environment to age significantly past its prime (e.g. growth hormone, sex steroids and reproductive and other cancers).

An apparent challenge to this has been raised by studies in C elegans (tiny roundworms) and other model organisms that have mutations that dramatically slow the rate of their aging, seemingly at no cost to fitness. However, studies have shown that this is often the result of the animals not being subjected to the rigors of a natural environment, and that when they have to compete under more natural conditions, they rapidly lose out to their wild-type cousins.

Which is why you don't see these sorts of mutations in the wild. Rae goes on to give examples - you should read the whole thing - and concludes:

This should give pause to those looking to intervene in aging by pharmaceutically exploiting these pathways (a standard strategy of the "gerontologist's school" of anti-aging biomedicine), and again reinforce the benefits of allowing metabolism to remain in its normal state, but cleaning up the ensuing damage directly, at the molecular level, iteratively pushing the level of damage beneath the threshold of pathology (the "engineer's school" of anti-aging biomedicine).

I'm not sure I agree with that conclusion as a blanket over the subject; after all, we're already very reliant upon technology to shield us from the consequences of not having technology - i.e. to have to endure the rigors of the environment and extremely poor control over basic needs for life. I'm sure we'd jump into the pool of being less generally resilient and more reliant on technology to live significantly longer in good health, given that we're pretty much already in that pool today. But that isn't the only option on the table, fortunately.

My arguments for the same conclusion as Rae above - let us primarily aim to repair damage rather than manipulate the rate at which damage happens - are primarily utilitarian. One path looks to be much easier than the other, and plausible arguments exist for it to produce more rapid gains per dollar invested in research. Furthermore, the resulting technology will likely be far more useful for those who are already old. Slowing the rate of further damage doesn't do much for those already greatly damaged.

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The Merits of the Basics
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From the Australian, a reminder of the basics: firstly, good general health practices; secondly, a sober appreciation of the realities of scientific progress - don't blind yourself by chasing illusionary immediate and easy answers when you could be helping to bring the real future of better, more effective medicine closer. "It's the unproven remedy or the individual 'wonder food' that dominates cancer headlines, rather than genuinely exciting treatment breakthroughs in evidence-based medicine - which must first be rigorously tested before being trumpeted to a public that faces a 30 per cent increase in cancer incidence over the next five to 10 years. Even less prominent in the news is the evidence that more than a third of Australia's cancer deaths can be attributed to lifestyle. So, while an ageing Australia looks to the horizon for a cancer cure, we need to be reminded that technology for significantly reducing our cancer burden is already here - we're just not using it effectively. It would appear that our understanding of the lifetime risk of getting cancer is far stronger than our knowledge of what we can do to prevent it."

Link: http://www.theaustralian.news.com.au/story/0,20867,21159559-23289,00.html

The Folk Who Want You Dead On Schedule
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Anne C. comments further on a petition for all our deaths to be scheduled at 70 - the petition is the opinion of one individual, but sadly redolent of the opinions of many others: "So, that's it, senior citizens. Never mind that novel you were writing, that dollhouse you were building for the grandkids, or that new computer you were in the process of putting together. Your existence is threatening the "wonders of the next generation", so it's high time the world stopped wasting resources trying to keep you alive and healthy. I'm hoping that the writer of this petition wasn't actually serious, but I'm guessing he probably was. And sadly, his attitude is only the tip of a very large iceberg. As far as we've come in our ethical evolution, even over the past few decades, there are still plenty of unfortunate memes making the rounds. It has always amazed me how close the ties are between resource-based arguments and discrimination. Feel free to call Godwin's Law on me here, but I think most semi-educated people in the world probably know what happened last time the idea that some people were 'unworthy of life' due to the supposed 'drain' they were on society took hold."

Link: http://rationallongevity.blogspot.com/2007/01/if-you-are-over-70-these-folks-want-you.html

Reminder: SENS Documentary, February 3rd
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By way of a reminder, the Christopher Sykes documentary "Do You Want to Live Forever?" will be shown in the UK on Saturday February 3rd. The focus is on biomedical gerontologist Aubrey de Grey, the Strategies for Engineered Negligible Senescence (SENS) and the scientific goal of radical life extension. "Computer scientist turned biologist Dr Aubrey de Grey is on a mission to end 'the scandal of death.' Award-winning filmmaker Christopher Sykes goes on the road with de Grey to find out whether old age and death could soon be a thing of the past." Hopefully this will all continue to raise the profile of real, serious longevity and rejuvenation research in the public eye. The more people who know about the real prospects for the future, the greater the support for research, and the faster science can move forward. We all have skin in the very personal race of medical technology versus aging, but the ongoing, staggering death toll caused by aging should be motivation enough for any humanitarian to join the fight to defeat age-related degeneration, frailty and death.

Link: https://www.fightaging.org/archives/001106.php

A Little Friday Aging Science
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Here are a couple of interesting items in aging science for this fine Friday. The first is something of a puzzle in terms of its significance:

The smell of food can affect the lifespan of flies and even partially reverse the life-prolonging effects of dietary restriction, scientists report this week in Science. These findings suggest the beneficial effects of caloric cutbacks on lifespan may not only depend on the decreased presence of food, but also on the decreased perception of it.

...

To see if losing the sense of smell could increase lifespan, the researchers used Or83b knockout flies from the lab of Leslie Vosshall at Rockefeller University in New York. (Or83b, unlike the other 62 putative Drosophila odorant receptors, is broadly expressed throughout olfactory tissues.)

Relative to wild-type flies, fully-fed female Or83b-null fruit flies showed a 56 percent increase in median lifespan. In fully-fed males, the effect was smaller than in females, but males without Or83b showed an up to 42 percent increase in lifespan. Flies that were heterozygous for the mutation exhibited intermediate longevity, and expressing a Or83b transgene in mutant flies restored normal lifespan.

Lifespan further increased in Or83b-null flies after dietary restriction, suggesting that odors affect longevity largely, but not exclusively, through a pathway independent of diet.

It's hard to say where this will go; metabolism and its regulation is eternally more complex than anyone would like it to be, even in lower animals. The many years of work ahead to decipher the underlying mechanisms, working up to mice, primates and then people, in ever more costly and long-term studies remind us that it would be nice to be able to produce benefits in healthy life span without having to fully understand the way in which the entire convoluted system hangs together and reacts. In the meanwhile, the results above do not mean you should drop the practice of calorie restriction for your health and longevity just because you are constantly surrounded by the scent of junk food - some things are similar in flies and people, some are not.

In that vein, Chris Patil of Ouroboros points out research that demonstrates the raw power of modern biotechnology in terms of producing metabolic and biochemical data for interpretation:

Li et al. perform a comprehensive analysis of the colon epithelial proteome over the course of aging. The approach is intellectually straightforward with few surprises, but it’s technically sound, and I think it’s important for biogerontologists to appreciate how far proteomic technology has come - the approach used by these authors could be applied to any system of interest, comparing the old and young states and allowing us to learn about the mechanisms of age-related change in our favorite tissues

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In order to understand the peculiarities of aging cells’ behavior, we must learn not only about their gene expression and proteome but also the condition in which the macromolecules find themselves at any given point in time.

Cellular biochemistry and its changes across a lifetime are fantastically complex - but it is plausible that we can act to identify significant changes (those which cause the most age-related degeneration) and develop the technology to repair or mitigate the effects of those changes without a full understanding of the entire system. You can repair an engine without having to understand how to build each component part - and a setting up a repair shop requires a fraction of the cost of a manufacturing plant.

To look for viable shortcuts in the face of overwhelming complexity is the path of engineering: scientists seek to understand the entire system, while engineers make the best of each new piece of information. For example, the Strategies for Engineered Negligible Senescence (SENS) form a sober look at the state of knowledge today, concluding that we are far enough ahead in the game to strike out and produce viable rejuvenation biotechnologies within the next few decades. More knowledge of biochemistry and aging will make the task easier, and the final results better, but there is nothing (save a lack of funding and will) stopping the research and development community from working towards significant healthy life extension today.

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A Look at Tau, Tangles and Alzheimer's
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This piece from PENN Medicine News is illustrative of the class of research into the mechanisms of Alzheimer's presently taking place. More researchers focus on the role of amyloid than on tau proteins, but progress in understanding is still being made: "In Alzheimer's and other neurodegenerative diseases, misfolded tau and other proteins accumulate inside neurons. Proteins used to make healthy synapses are moved via microtubules to the synapse along the nerve axon. However, accumulation of tau in clumps inside nerve cells (that is, the tangles described 100 years ago by Alzheimer in the first reported AD patient) impairs the function of nerve cells and causes them to degenerate. This is because tau is needed to stabilize microtubules like cross-ties stabilize train tracks. But if tau clumps, the microtubules break up, thereby disrupting the transportation network in normal nerve cells. This has lethal consequences because nerve-cell axons and dendrites are critically dependent on this normal transportation network." But understanding how this comes about and what to do about it - the process of the root cause, in other words - is a good deal more complex than just this.

Link: http://www.uphs.upenn.edu/news/News_Releases/jan07/microglia-activation-alzheimers.htm

Yet More Cancer Stem Cells Identified
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EurekAlert! brings news of more cancer stem cells: "The cells we isolated are quite different from 99 percent of the millions of other cells in a human pancreatic tumor, and we think that, based on some preliminary research, standard treatments like chemotherapy and radiation may not be touching these cells. If that is why pancreatic cancer is so hard to treat, a new approach might be to design a drug that specifically targets pancreatic cancer stem cells without interfering with normal stem cell function ... theory suggests that only cells that have the properties of 'stemness' - that is, cells that can self-renew and differentiate into other types of cells - are the only ones capable of producing tumors. These 'cancer stem cells,' could derive from normal adult stem cells in organs that have mutated, or from a differentiated cell that has devolved to take on the qualities of stem cells. They are resistant to traditional therapy designed for cells that rapidly turn over because stem cells don't, according to some researchers. Thus, they remain after tumors shrink and may be responsible for cancer recurrence and metastasis."

Link: http://www.eurekalert.org/pub_releases/2007-02/aafc-sip013007.php

The State of First Generation Stem Cell Therapies
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Work on developing first generation autologous stem cell therapies is starting to look a lot like work on old school drug trials; this is to be expected under the present regulatory regime, and by the general way in which new technologies mature. Here's an example:

The Autologous Cellular Therapy CD34-Chronic Myocardial Ischemia (ACT34-CMI) Trial is the first human, Phase II adult stem cell therapy study in the U.S. designed to investigate the efficacy, tolerability, and safety of blood-derived selected CD34+ stem cells to improve symptoms and clinical outcomes in subjects with chronic myocardial ischemia (CMI), a severe form of coronary artery disease.

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The baseline frequency and severity of anginal episodes are established as a first step for all study subjects. Next, all subjects receive a series of subcutaneous injections (needle shots, typically delivered under the skin in the arm, thigh or abdomen) of a commercially produced protein (granulocyte colony stimulating factor). The protein helps to release CD34+ stem cells (also known as endothelial progenitor cells) from a subject’s bone marrow into the bloodstream.

Then, investigators use a cell separation system, similar to the automated systems that are used with people who donate specific blood components such as platelets or red blood cells, to collect from the subject’s bloodstream, an enriched preparation of cells that contain CD34+ stem cells.

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The researchers then use a special investigational catheter that functions like a "global positioning system" to precisely deliver CD34+ cells, or placebo, into the areas of the heart that have been identified as having poor blood flow.

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Researchers are encouraged by reports that the therapy appeared to be well-tolerated and no serious adverse events directly related to the stem cell therapy in an earlier study. According to preliminary, anecdotal patient reports, 16 of the 24 total Phase I study subjects reported feeling better with reductions in chest pain and improved exercise capacity during the early stage of the trial.

The first phase of development in any new technology is a struggle to best the performance of old, mature technologies - here we have an early stem cell trial looking well placed (like others) to do at least as well as the best drugs and other well-developed medical technologies can do. The difference here is that stem cell researchers are just getting started; this is a matter of doing a little with the first steps into the pool. If we can gain benefits at this level through utilizing only the first laboratory steps of being able to identify, separate and culture stem cells, then just imagine what is to come soon, armed with the knowledge and techniques of controlling stem cell behavior.

Stem cell therapies and related areas such as tissue engineering will make up one pillar of the fight to eliminate age-related frailty and degeneration in the years ahead, replacing tissue and specialized cell populations that have been lost, diminished and damaged. What we see now are the early days, the first steps. Stem cell medicine will become much more impressive in just a few short years from now.

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