It seems Second Life is even more popular post-grey goo; no such thing as bad publicity. Mark your calendars: Anders Sandberg will be giving a presentation on healthy life extension in the virtual space:

It is not a coincidence that the oldest remaining literary epic is the one about king Gilgamesh’s search for the herb of immortality: the dream of eternal youth is as old as mankind. But what has so far mainly been wishful dreaming is increasingly becoming medical and demographic reality. Today life is routinely extended and ageing slowed in lab animals. We live in a rapidly greying society where the average lifespan, health and vigor would have seemed nearly divine to king Gilgamesh, whose subjects had a life expectancy at birth around 25 years. As researchers increasingly see ageing as something mutable - and hence potentially treatable - we have to start considering how to deal with the changes it will cause in society and our lives.

Extending lifespans is something many do not take seriously. It is in the realm of wishful thinking, science fiction and health gurus. But if one is concerned about the current demographic trends and the somewhat long-term future, then one ought to at least consider progress in extending lifespans as one possibility to take into account. In his report “Keep on raging against ageing” Anders Sandberg, research director Eudoxa and transhumanist par excellence, will make a moral and scientific case for life extension.

As for a number of other transhumanists of a more philosophical bent, Sandberg has come to be a part of the new Future of Humanity Institute. The transhumanist community builds as it goes, a sort of diffusive expansion into the broader world, and one that produces interesting secondary reactions, vortices and calcifications. Such is the evolution of most movements from a small core community with an intense, pinpoint vision, out to dilution, evolution, change and a widespread acceptance of ideas once too radical for adoption.

Twenty years from now, it will be hard to explain to the young folk just how ridiculed and shunned was the concept of scientific research to extend healthy longevity - and it will be our shame that we and those who came before advanced this cause too slowly to benefit the billion who will die between now and then.

Technorati tags: advocacy, life extension, presentation

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An aging body has changed in many ways, and not just in those obvious to visual inspection. The typical old body is identifiably different from the typical middle-aged body at the level of cells, genes and biochemistry: biochemical processes, gene expression, levels of molecular damage, cellular behaviors, cellular populations, and so on.

Some of these differences are clearly causally linked - a wide range of age-related changes can often be shown to be caused by a lesser number of underlying changes. For example, damage to mitochondria leads to oxidization of low-density lipoproteins (LDL), which in turn leads to detrimental changes involved in atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. Most modes of biochemical wear and tear contribute to a wide range of recognized age-related conditions and frailty.

One role of aging research should be to explore these linkages, so as to better characterize the core of aging; what, really, are the essential changes of aging when all the chains of failure have been cut back to their root causes?

The other role of aging research - a role that continues to be woefully underserved - is to develop the means to prevent and repair changes associated with aging. This is where the engineering and scientific viewpoints tend to diverge. Scientific culture aims for full understanding prior to action; engineering culture aims for enough information to enable working, reliable tools and outcomes. Strong, long-lasting bridges and large buildings existed long before the tools and knowledge to completely understand strategies for architecture and construction. Similarly, an engineering approach to aging could make meaningful inroads in extending our healthy life span prior to a complete scientific understanding of all the complex change that comes with the passing of years and the workings of our bodies.

At root, what the engineer proposes is to fix all observed change. Science is essential to this goal - it reduces the problem space down to one that can be tackled in a short enough timeframe by identifying root causes. Science then provides the knowledge needed to build the tools - modern biotechnology in this case - to do the job. But you have to recognize the point at which there is enough information to set forth and engineer results; this point is usually far in advance of complete understanding.

Don't know whether a characteristic change between an aged body and a youthful body is harmful? Work to fix it anyway. The worst that can happen at the end of the day is you'll make an aged body even more like the youthful body next door, but gain little in the doing of it.

As it turns out, the list of root causes (changes that occur with aging) looks to be small, especially when considering the fact that gerontologists have divided the world of the failing human body into thousands of named medical conditions. I'm sure most of you are familar with the list from the Strategies for Engineered Negligible Senescence, an engineering-oriented proposal and young research program to extend the healthy human life span by reversing changes that occur with aging:

Some tissues lose cells with advancing age, like the heart and areas of the brain. Stem cell research and regenerative medicine are already providing very promising answers to degeneration through cell loss.

We must eliminate the telomere-related mechanisms that lead to cancer. de Grey suggests selectively modifying our telomere elongation genes by tissue type using targeted gene therapies.

Mitochondrial DNA is outside the cellular nucleus and accumulates damage with age that impairs its critical functions. de Grey suggests using gene therapy to copy mitochondrial DNA into the cellular nucleus. Other strategies for manipulating and repairing damaged mitochondrial DNA in situ were demonstrated for the first time in 2005.

Some of the proteins outside our cells, such as those vital to artery walls and skin elasticity, are created early in our life and never recycled or recycled very slowly. These long-lived proteins are susceptible to chemical reactions that degrade their effectiveness. Scientists can search for suitable enzymes or compounds to break down problem proteins that the body cannot handle.

Certain classes of senescent cell accumulate where they are not wanted, such as in the joints. We could in principle use immune therapies to tailor our immune systems to destroy cells as they become senescent and thus prevent any related problems.

As we age, junk material known as amyloid accumulates outside cells. Immune therapies (vaccines) are currently under development for Alzheimer's, a condition featuring prominent amyloid plaques, and similar efforts could be applied to other classes of extracellular junk material.

Junk material builds up within non-dividing, long-life span cells, impairing functions and causing damage. The biochemistry of this junk is fairly well understood; the problem lies in developing a therapy to break down the unwanted material. de Grey suggests searching for suitable non-toxic microbial enzymes in soil bacteria that could be safely introduced into human cells.

You'll find one of these classes of change mentioned today at Ouroboros:

I currently work on a phenomenon known as cellular senescence, which is a permanent growth arrest caused by telomere dysfunction (e.g., the critically shortened telomeres that arise after many cell divisions) and also by other kinds of stress (particularly genotoxic damage).

One of the active controversies in this sub-field of biogerontology is, somewhat paradoxically, whether it’s part of biogerontology at all: While senescence certainly arises as cells get older in culture, and while there’s a good story to be told about how senescent cells could contribute to age related decline in tissue function, it’s not yet fully clear to what extent the phenomenon actually plays a role in physiological aging of intact animals.

Research scientists will keep investigating. In the meanwhile, given that the buildup of senescent cells accounts for a significant fraction of some tissues in later life, the engineers should already be looking at potential fixes. It's not hard to think of approaches to reversing the acculumation of senescent cells in this day and age of targeted therapies for discriminating cell destruction and other advanced biotechnology under development:

Getting rid of cells is a much simpler job than most of the other things we have to do as part of SENS. In the case of fat, it's possible to use simple surgery, but that's unnecessarily invasive. There are two main other ways: we can inject something that makes the unwanted cells commit suicide but doesn't touch other cells, or we can stimulate the immune system to kill the target cells. Both approaches involve making use of distinctive molecules on the surface of the target cells: luckily, different cell types tend to have different things on their surface, so this shouldn't be too hard. But it hasn't been done yet, and not enough people are working on it -- it needs much more attention.

Sadly, comparatively little funding is directed towards any of this, and the engineering side garners far less than the better established investigative community. That will have to change, and the way it changes is the same way it changed for other growth fields in science: the bootstrapping of advocacy and progress side by side, within and without the scientific community.

Technorati tags: advocacy, life extension, medical research

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Having completed phase I trials of calorie restriction in humans, the CALERIE research program is moving on into phase II:

Dr. William Wong, professor of pediatrics at Baylor College of Medicine's USDA Children's Nutrition Research Center in Houston, was awarded a $2.2 million grant from the National Institute of Aging to help determine if a reduction of calories can increase longevity and decrease the risk of chronic disease. Previous animal studies suggest this is the case.

Wong's lab will serve as the central doubly labeled water lab to support the NIA's Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy, or CALERIE, study.

...

The phase 2 CALERIE clinical trial will study the effects of cutting calorie consumption by one-fourth. Wong's lab will use the doubly labeled water method to establish the participant's caloric need, which will then be decreased by 25 percent in participants assigned to the treatment group.

The study will follow two groups for two years with participants coming in periodically for follow-up doubly labeled water studies.

As is often left out in articles on the subject, the practice of calorie restriction is a matter of engineering your diet to lose the empty calories - those that were not contributing essential nutrients. In other words, eat less of a better diet. Expect to see more news articles of the following variety in early 2008 as the results start to firm up for publication.

It's very clear that calorie restriction has a powerful, protective effect against diseases associated with aging ... We don't know how long each individual actually will end up living, but they certainly have a much longer life expectancy than average because they're most likely not going to die from a heart attack, stroke or diabetes.

The real benefit from this sort of broader study - and that sought by the present fundraising efforts of the Calorie Restriction Society - is to better characterize the differing responses to this sort of dietary choice in different people. Given that people show a range of responses to more or less everything else the world can throw at them, I would expect response to calorie restriction will vary as well. How wide is this range? Is there even a small number people in the world who might react poorly to calorie restriction by way of their genes, rather than due to illness or other medical conditions? Only broader usage and measurement will tell.

I'm sure this will also further boost interest in potential calorie restriction mimetic drugs presently under investigation; the actual practice of calorie restriction seems unpopular in certain quarters. Oh well - their loss.

Technorati tags: calorie restriction

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Into every well-organized life a little entropy must fall, and hence here a post with little direct relevance to science and healthy life extension.

A note to those who are wondering why the latest Longevity Meme Newsletter is not in their in-box - well, I'm wondering much the same thing myself. It seems the mailserver ate it, and then the secondary mailserver ate the backup mail batch that was to replace it. Puzzlement all around, and I'm working it through with the ISP.

UPDATE: Seems that a few people did get it, multiple times even. A very strange situation, and apologies to those folk.

Meanwhile, comments here at Fight Aging! are suspended until I can work up a better protection against denial of service style runs of comment spam - such as the one that took down the entire server earlier today. This "mandatory upgrade" version 3.33 of Movable Type has some serious flaws that were not present in the 2.* versions, one of which is acute vulnerability to these sorts of attacks.

Work, work, work.

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If you want a taste of present opinions and debates within the scientific community on any given topic, run a search of the past couple of months of publications at PubMed. It helps to have general background knowledge of the field in question, not to mention an appreciation for the nature of science and research at the leading edge, but there's always something new to learn. Here are some of the results obtained by searching on "aging longevity" and "molecular damage aging":

Theories of biological aging: Genes, proteins, and free radicals.

Traditional categorization of theories of aging into programmed and stochastic ones is outdated and obsolete. Biological aging is considered to occur mainly during the period of survival beyond the natural or essential lifespan (ELS) in Darwinian terms. Organisms survive to achieve ELS by virtue of genetically determined longevity assuring maintenance and repair systems (MRS). Aging at the molecular level is characterized by the progressive accumulation of molecular damage caused by environmental and metabolically generated free radicals, by spontaneous errors in biochemical reactions, and by nutritional components. Damages in the MRS and other pathways lead to age-related failure of MRS, molecular heterogeneity, cellular dysfunctioning, reduced stress tolerance, diseases and ultimate death. A unified theory of biological aging in terms of failure of homeodynamics comprising of MRS, and involving genes, milieu and chance, is acquiring a definitive shape and wider acceptance. Such a theory also establishes the basis for testing and developing effective means of intervention, prevention and modulation of aging.

A very dry way of jumping right on in to say that a SENS-like approach is a sensible next step if you buy in to a reliability theory view of aging - i.e. that aging is no more nor less than an accumulation of varied forms of molecular and cellular damage in a complex biological machine, and that we can work to understand and find ways to repair that damage. By repairing the damage, we prevent and reverse aging.

Speaking of SENS, it's not surprising that Aubrey de Grey shows up in any such search of PubMed:

Foreseeable pharmaceutical repair of age-related extracellular damage.

Various molecular and cellular alterations to our tissues accumulate throughout life as intrinsic side-effects of metabolism. These alterations are initially harmless, but some, which we may term "damage", are pathogenic when sufficiently abundant. The slowness of their accumulation explains why decline of tissue and organismal function generally does not appear until the age of 40 or older. Aging is thus best viewed as a two-part process in which metabolism causes accumulating damage and sufficiently abundant damage causes pathology. Hence, a promising approach to avoiding age-related pathology is periodically to repair the various types of damage and so maintain them at a sub-pathogenic level. Some examples of such types of damage are intracellular and others extracellular. Several types of intracellular damage are highly challenging--sophisticated cellular and genetic therapies will be needed to combat them, which are surely at least 20 years away and maybe much more. Extracellular damage, by contrast, generally appears more amenable to pharmaceutical repair which may be feasible in a shorter timeframe. In this article, the major types of age-related extracellular damage and promising avenues for their repair are reviewed.

One form of extracellular damage is the accumulation of advanced glycation endproducts, or AGEs. This is the sort of purely chemical problem that could be addressed by the existing pharmaceutical research and development infrastructure, within the present very limiting regulatory straitjacket, and more rapidly than many other aspects of aging that will require new technologies or research communities to be developed.

Moving on, we find another confirmation of one of the steps in the present form of the mitochondrial free radical theory of aging, which describes how mutated mitochondria take over cells and turn them into exporters of damaging free radicals - and how those free radicals lead to age-related disease and damage to other systems in the body.

Mitochondrial DNA damage and the aging process-facts and imaginations.

the accumulation of acquired mutations to functionally relevant levels in aged tissues seems to be a consequence of clonal expansions of single founder molecules and not of ongoing mutational events.

The clonal expansions of damaged mitochondria occur because some types of damage prevent the cell from flagging that particular mitochondrion for destruction in the lysosome. When it comes time to repopulate after a cycle of tearing down old mitochondria, the new ones are cloned from the old - after a few cycles of this, the bad non-recycleable mitochondria take over the cell ... and then matters go south from there. Hence "clonal expansion" - the population of bad mitochondria in a cell expands through cloning.

If you're up for something a little more dense, here is more on naked mole rat biochemistry; in essence it recapitulates what has been said in the popular science press - naked mole rats produce lots of free radicals, but don't appear to be suffering anywhere near the same level of consequences to cellular components, health and life span that other rodents do.

Comparison of endothelial function, O2-{middle dot} and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice.

Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assesment of vascular function among rodents with disparate longevity may offer insight into the mechanisms determining successful vascular aging. ... Interspecies comparison showed there is a negative correlation between H(2)O(2)-induced apoptotic cell death and [maximum life span]. Thus endothelial vasodilator function and vascular production of reactive oxygen species do not correlate with maximal lifespan, whereas increased lifespan potential is associated with an increased vascular resistance to proapoptotic stimuli.

One theory advanced is that it has to do with the proportionality of various species of lipid, the biochemicals in which such damage is most consequential to your heath. It seems that naked mole rats have more of the resistant lipids and less of the easily damaged lipids.

Lastly, a reminder that senescent cells are most likely not good for you:

The second type of supernumerary cells, senescent cells, accumulate in quite large numbers in one tissue, the cartilage in our joints. They also accumulate elsewhere, but in much smaller numbers; however, these may still be important by being actively toxic. They aren't able to divide when they should, and they also secrete abnormally large amounts of some proteins.

Accumulation of senescent cells in mitotic tissue of aging primates.

Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over 40 years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA.

If a function or population within the body differs between youth and age, then that is something researchers need to look at: is a root cause or consequence of aging? If the former, then we should aim to do something about it.

Technorati tags: aging, biotechnology, medical research, science

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Quiet if you're avoiding the rush, that is. A couple of items caught my eye, or otherwise came to my attention - such as by being the one to post it. That first then; a group photo from the Methuselah Foundation core volunteers meeting in Boston earlier this month. If you'd like to put faces to the names, go and take a look.

If all the folk who have helped and donated over the past few years were at the meeting, there wouldn't have been room on the pier - a great many people indeed have helped to make the Methuselah Foundation grow and succeed. Thank you all!

If you would like to see the Methuselah Foundation's initiatives - aimed at turning ever more of the scientific community to the defeat of aging - continue to grow, then the best ways to help are to offer your time and talents, and contribute to meeting Peter Thiel's $3 million matching grant for SENS research.

Moving on, I'm sure you've noticed that the work of Leonid Gavrilov and Natalia Gavrilova on the relationship of maternal age (and thus also birth order) to longevity is back in the press:

It turned out that first-born children were 1.7 times as likely as their siblings to live to be 100. An even stronger predictor of longevity was how young their mother was when they were born. Those whose mothers were less than 25 years old were twice as likely to survive beyond a century.

While the researchers aren't certain why this should be, they suspect younger mothers are less likely to have acquired latent infections during their life that could damage the health of the fetus. Younger mothers may also have better-quality eggs. "If the best, most vigorous maternal ova cells are used first - very early in life - this could explain why particularly young mothers produce particularly long-lived children," Gavrilov says.

As I pointed out earlier this year, this raises a great many questions:

This can be tied in with the researchers' reliability theory of aging - younger mothers are producing children with a lower initial load of cellular or genetic damage. This is a conceptual framework for thinking about the processes and advance of degenerative aging; it poses many more questions than it answers, says nothing about the underlying biochemistry, and exists to guide future research.

It will be interesting to see what the underlying mechanisms turn out to be - but I doubt they will be anything other than yet another advertisement for the merits of working rejuvenation technologies. We really need to get moving on the development of ways to effectively turn back and repair the accumulation of cellular damage that causes aging.

Next, a couple of good posts from Randall Parker on reasons for - and examples of - the accelerating trend of cost-effectiveness and capabilities in biotechnology:

Stem Cell Regulatory Circuitry Mapped

While I sometimes write posts about promising individual stem cell treatments no one announcement of a promising treatment or even a dozen such announcements will amount to much of a breakthrough given our current deficient state of knowledge on how cells work. The real breakthroughs that will provide us with the most power to produce treatments are going to come from the development of knowledge on how cells control their differentiation (i.e. how cells specialize to become heart muscle cells or liver cells or other specialized types). So this announcement is much more important than the average report about stem cell advances.

Once scientists understand the complex circuitry governing cell differentiation the next set of real important breakthroughs (though mostly invisible to the general public) will come. Scientists will seek to intervene in those cellular circuits and to do so they will develop techniques to tweak those circuits in highly precise and controlled ways.

Cells in the embryonic state are several state changes away from any other state such as muscle cell or artery lining cell or liver cell. Once we have detailed knowledge of the circuits that control cell state the need for embryonic stem cells will go way down. It will become possible to start with a cell in any state and tweak it to shift into any other state.

One Third Of MIT Engineers Work On Biology Problems

Biology used to advance at a snail's pace because its tools were so primitive. The influx of talent from semiconductor engineering and other engineering disciplines has greatly sped up the rate of progress in the field and promises to speed it up by orders of magnitude in the future. The field of microfluidics chases the idea of highly automated and cheap labs on a chip.

Imagine a chip made using semiconductor processes that has lots of reaction vessels and miniature tubes and valves, all digitally controllable. No more pipettes. No petri dishes. No lab techs making mistakes from the tedium. Software will be able to carry out long experimental sequences. Computer programs with limited domain-specific artificial intelligence will even be able to generate hypotheses and carry out experiments. That's where the world of biology is going.

Lastly, Phil Bowermaster discusses the intersection of popular culture, attraction to mortality, and the mindset that welcomes it; something that seems very embedded in the story forms and myths our culture is built upon and propagates anew.

The Hard Stuff

Or let's put it another way. If we can all agree that an average lifespan of 70 years possesses a poignancy and urgency that a 500-year lifespan might not, shouldn't we also agree that an average lifespan of 30 years would be even more beautiful and meaningful? Isn't it time we started rolling back the clock on sanitation, nutrition, medicine, and public safety so that people can lead more beautiful / meaningful lives?

No. I didn't think so.

...

Our ancestors of a couple centuries ago who had those poignant and urgent 30-year lifespans also struggled with figuring out the meaning of life. As do we. As will our offspring.

But the nice part is, they’ll get more time to work on it.

If we (personally, as younger individuals) don't make it into an era of radically extended life spans and advanced medicine, it'll be in no small part because we did ourselves in by failing to work and produce results when we could have succeeded.

Technorati tags: activism, biotechnology, life extension

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Attila Csordás has hit on a good meme with this short interview question and answer format on aims and means for healthy life extension. A couple more can be found over at the Pimm blog, such as with David Kekich, one of the first donors to the MPrize for anti-aging research, and brain behind the Maximum Life Foundation - an ongoing search for a self-sustaining healthy life extension research funding engine.

Maximum Life CEO David Kekich: the investment strategy of life extension

I have basically committed all my professional efforts to help reverse aging within the next 25 years. My commitment was a by product of watching my parents relatives slowly deteriorate and die off due to aging related conditions. Life extension was also a strong interest of mine since my late 20’s, about 35 years ago. My total commitment happened as a result of a productivity and goal reaching exercise designed to show how much productive time I had left to accomplish my goals. My conclusion was, I needed to live longer.

Maximum Life’s James Clement: what can a lawyer do for life extension?

The vast majority of the public still thinks that extreme life extension is science fiction. Blogs and websites can help educate them as to how close we really are to ending the suffering of disease and aging. Every day, 100,000 individuals die from aging related disease. If we are to put an end to this travesty as soon as possible, we need to motivate the public to make this a priority of our society.

Life extension interviews: Nick Bostrom and the philosopher’s point of view

I’m in favor of research into anti-aging medicine for precisely the same reasons that I’m in favor of cancer research, heart disease research, and diabetes research: because it might prevent or cure disease and save lives.

...

If you put your effort into building awareness and support, try not to talk exclusively to other life extension supporters, but also reach out to other audiences. Speak up; don’t let negative attitudes to healthy longevity go unchallenged.

You might know Nick Bostrom as the author of the truly excellent Fable of the Dragon-Tyrant - if you haven't yet read it, shame on you. Get thee hence and do so this very instant.

Technorati tags: interview, life extension

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The latest issue of the rather glossy McGill University magazine Headway contains a couple of popular science articles on Alzheimer's research and the advance of technology for the repair of neurons.

The Mind Thief :

"We believe that we've identified one of the very early markers of Alzheimer's disease," she says.

The missing piece in the puzzle might be an elusive enzyme produced in aging human brains that, in its active form, systematically kills neurons. Known as Caspase-6, this protein destroys other proteins that are known to be involved in learning and memory. "If those proteins are being chopped up by our enzyme, it may be that this is what leads to the very first signs of cognitive impairment," LeBlanc says. After a dozen years of studying samples of donated brains and tissue cultures in the lab, LeBlanc hopes next to search for elevated levels of Caspase-6 in the cerebrospinal fluid of Alzheimer's patients - and then identify specific inhibitors of the enzyme that could stop the disease.

A range of new and interesting lines of research are presently underway in the Alzheimer's research community. Along the way, they are building a foundation of technology and knowledge for the next generation of brain medicine. This is a very good thing; assuming that tissue engineering and cancer research proceed much as we expect over the next few decades - and assuming similar levels of progress in dealing with damaged mitochondria and the aging immune system - then the brain begins to look like the complex sticking point for healthy life extension.

We're going to have to become very good at maintaining and repairing the brain at the cellular and sub-cellular levels; fortunately, the first steps towards the technologies required are already underway.

Bridge Over Troubled Neurons:

The orb is a latex bead, micrometres in diameter, coated with the organic compound polylysine; the organic blob is a neuron. Lucido and Colman, a Canada Research Chair, believe the image captured on that slide was the cell attempting to form a synapse - an active communication - with the bead.

Get that cell communicating with some man-made electronics, and it could be possible to create a bridge between severed nerves and muscles up to a metre away - light years in neuronal terms. The possibilities are breathtaking - malfunctioning glands linked to artificial regulators, severed spinal cords repaired, stroke victims rehabilitated.

Technorati tags: biotechnology, medical research, neuroscience

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It's pleasant to see that the fine art of the snooty anti-science piece is being kept alive even in this age of research breakthroughs and new knowledge every other week. No sense in moving forward - or advancing your own personal store of knowledge on a topic - when you can pad out a few thousand words with cheap shots and an exhortation upon the limits of what you know. On this theme, I thought I'd point out a couple of articles.

This first one is a determined defense of avoiding the opportunity to extend an enjoyable, healthy life via calorie restriction (CR). I'll say this for the somewhat snarky NYM piece last month - at least the author got out there, did the research, and tried the practice of CR. You'll have a watch a brief advertisement to read this Salon piece:

A distorted sense of self-satisfaction, while on the whole a cheerier disorder than outsized self-loathing, can still be troubling, especially when it is the result of having forsaken eating habits that many people would love to be able to enjoy. When Matt Lauer introduced "Today's" CR segment by dramatically asking, "Could food itself be the problem?" it was hard not to wonder how insane we've become to devote airtime (larded with food commercials, no less) to demonizing something that people all over the world do not have enough of. Is it so that people who can afford organic scallops can live to be 150 while everybody else dies their regularly scheduled death?

As I said, cheap shots, either calculated or ignorant; some people seem to make a fair living by turning out that sort of thing, however. It takes a certain distasteful point of view to stand behind the idea that only the rich are capable of putting in a little effort to plan their diet, and that CR is therefore some hitherto unseen form of class warfare. Equally distasteful: that simple reporting from the world of science has context based on your preferences for socioeconomic organization. But enough of that.

On the plus side, there are plenty of resources online that people can use to learn about calorie restriction and the research backing it. There really is no such thing as bad publicity in an era of search engines, and the calorie restriction community is a gateway to other communities and initiatives aimed at the development of more effective means to extend healthy life span. If you're interesting in calorie restriction, you should also be interested in the Longevity Dividend project, SENS, the Methuselah Foundation, and so forth.

The more the merrier, and even dumb articles mean that more folk will come to realize that aging is not set in stone. From that realization will come the support and understanding needed to grow the healthy life extension community and build a larger funding base for serious research aimed at putting a halt to aging.

The second article I wanted to link to today concerns the state and future of stem cell science, and is a touch more subtle in its attack. You'll always see articles of this nature as the first wave of research and commercialization in a new field fades into the second wave. Most of the early companies fail or dramatically reduce their stated goals - this is very much par for the course in biotechnology and medical research, or indeed any other field. The early investors take a high risk, but the potential rewards are great indeed, so in they dive. Equally par for the course are the solomn analysts come to pronounce on the corpse; most such dirges look pretty silly a decade later.

In short, yes, stem cells do have the potential to turn into more specialized cells (that is what we mean by a stem cell). But after eight years of trial and error, scientists have not yet shown that they know how to nudge or coax or direct any given cell in a desired direction -- for example, into the dopamine producing cells that are needed to combat Parkinson's disease.

"It looks hard to me, so we'll never make the progress we'd like!" If I had a dime for every time I've seen some variety of that sentiment ... well, I'd have a fair-sized pile of dimes. Meanwhile, progress continues: tools become cheaper, capability per dollar increases.

Tune up your nonsense filters; these sorts of things come in cycles, and it looks like it's that time again.

Technorati tags: calorie restriction, stem cell research

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The thing about trends is that they exist right up until the point at which they don't; they are best used as tools to corral the boundaries of uncertainty, and never as the basis for firm predictions. In the case of healthy life extension - and the medical research trends driving it - the worst thing that could happen would be for everyone to look at the trends, think "great, job well done, we're on course!" and then fail to contribute to further progress.

A trend is not a beast with a life unto itself. A continuing trend only continues because research is funded, people are hard at work, results are achieved, and support for progress is growing.

A reminder on the trends that make us feel better about the prospects for later - and longer, healthier - life can be found over at the Longevity Meme. Hopefully they don't make us feel as though we can coast by without helping make these trends a continuing reality. In light of that post, I thought it worth pointing out a Scientific American piece from last week entitled "Trends in Research, Business and Policy":

[Alzheimer's] treatments might one day be based on a synthetic protein fragment Robert P. Hammer of Louisiana State University has developed to disrupt formation of the plaques believed to provoke massive brain cell death in Alzheimer's patients. The plaques are aggregations of fibers that form when individual amyloid-beta peptides begin abnormally sticking together. Hammer also tweaked building blocks of amyloid-beta, synthesizing a non-sticky version of the amino acids that permit amyloid-beta proteins to bind to each other. Adding the engineered fragments to a test tube of normal amyloid-beta blocked the proteins' ability to form fibers, even after four months' exposure. If it does the same in human brains, tens of millions of Alzheimer's sufferers might finally be liberated from a deadly burden of poisonous plaque.

...

The promise of stem cells was again reaffirmed by an experimental therapy to treat patients with lupus - a disease in which the patient's immune system targets the body's own tissue. A group led by Richard K. Burt of the Northwestern University, Feinberg School of Medicine, removed stem cells from the patient's bone marrow. Drugs then wiped out the population of white blood cells before the stem cells were returned to the body, where they formed new white blood cells that were less likely to make damaging antibodies. In a study of 48 patients, half did not have the disease after a period of five years.

...

Although we may not be able to re-grow limbs as salamanders do, the human body does have intrinsic regenerative power, and the discipline of tissue engineering has discovered ways to exploit it. Biodegradable scaffolds made of both natural and synthetic fibers can be seeded with cells that come together to form sheets that mimic the body's natural matrix of soft tissue.

...

The exorbitant cost of deciphering a person's genome dropped sharply in 2005, from $20 million to roughly a tenth of that amount. DNA sequencing technology using off-the-shelf equipment devised by George M. Church at Harvard Medical School and collaborators at Harvard and Washington University in St. Louis may help realize the federal goal of reducing that price to $1,000 by 2015, which experts say would make it practical to decode an individual's genes for routine medical purposes.

...

Conventional wisdom specifies that the central nervous system--the brain, spinal cord and eye--cannot heal in adults. Once injured a patient remains impaired for life. Experiments with animals have demonstrated regrowth of injured nerve fibers. But these techniques often need to be applied at or before injury. The standard thinking no longer holds. Larry I. Benowitz at Children's Hospital Boston and his colleagues found a molecule that triggers better nerve regeneration than any other studied-and one that that proves effective when applied days after injury. The scientists discovered that a protein, oncomodulin, is secreted in damaged eyes by immune cells known as macrophages. They found that oncomodulin, when given with compounds that enhance its activity, can increase nerve regeneration fivefold to sevenfold in rats with injured optic nerves.

The trend in biotechnology and medicine is onward and upward, at an accelerating pace. The burning question is whether this trend can be sustained and harnessed in the direction of enabling healthy longevity by repairing the root causes of aging, and not just patching up diseases one by one.

Technorati tags: life extension, medical research

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To follow up on comments on the culture of Alzheimer's research linked over at the Longevity Meme, I thought I'd point out some of the folk working hard to inject new ideas and theories into the field. You don't have to look far; quite a few interesting lines of research have reached the popular science websites in just the past few days:

Alzheimer's heart link explained:

Scientists have discovered how heart disease or a stroke may trigger Alzheimer's disease. Both conditions lead to a reduction of oxygen flow to the brain. A University of British Columbia team, studying mice, found this stimulates increased development of the protein clumps thought to cause Alzheimer's.

...

Scientists have known for some time that people with certain diseases that restrict their supply of oxygen, such as stroke or lung disorders, are more prone to Alzheimer's and also that people who live at high altitudes are also at greater risk of developing the disease. This research provides a molecular explanation for that anecdotal finding and shows that cues from cells, genes and a person's environment all play a role in causing this dreadful disease.

Nerve Fibers Need Specific Growth Factor Chemical To Form Connections Within The Brain:

The study uncovers how cholinergic neuronal circuits, which help the cerebral cortex process information more efficiently, rely on neurotrophin-3, a chemical that stimulates nerve growth. The scientists have determined the circuits need this chemical in order to recognize and reach their target nerve cells in the brain.

...

This finding, according to Robertson, has significant implications for neurodegenerative diseases like Alzheimer’s. Cholinergic neuronal circuits play a key role in the proper information processing by the cerebral cortex and other areas of the brain. The cerebral cortex is the part of the brain that determines intelligence, personality, and planning and organization, and these actions are compromised by neurodegenerative diseases.

“Studies on the brains of Alzheimer’s patients have shown a marked decline in these cholinergic circuits. Our work demonstrates that neurotrophin-3 is essential to maintain the connections to cerebral cortex neurons,” Robertson said. “This study shows that a neurotrophin-3 therapy may be able to induce nerve fibers to regrow in the cerebral cortex, which would be beneficial to people with Alzheimer’s.”

More insight into Alzheimer's disease with Stanford discovery of possible cause:

A peacekeeper in the body's defenses against infection may hold the key to understanding - and eventually treating - Alzheimer's disease. Researchers at the Stanford University School of Medicine discovered that when a molecule responsible for dialing down the immune system malfunctions in the brain cells of mice, the rodents develop symptoms of the degenerative brain disease.

...

Wyss-Coray and Ina Tesseur, PhD, an instructor in the Department of Neurology, examined thin slices of the brains of Alzheimer's patients who had died, and discovered abnormally low levels of a molecule involved in controlling the body's response to infection. That molecule allows the brain to detect and respond to TGF-beta, or transforming growth factor, a protein teeming through our bodies, involved in fighting infection, stopping cancer and perhaps keeping brain cells alive.

No other researchers had seen this change before, so Tesseur and Wyss-Coray set out to investigate whether it had some connection to Alzheimer's disease. They hypothesized that by protecting neurons, TGF-beta may help prevent Alzheimer's disease. If the TGF-beta pathway is turned off, the brain becomes more susceptible to a toxic buildup of proteins.

The problem with Alzheimer's - and most other complex biochemistry - is the matter of identifying what is the cause and what is the effect. It is to be expected that much of what has been discovered by researchers will fall to the wayside as a side-effect of the progression of Alzheimer's rather than an actual root cause. Equally, most of the therapies currently under development will turn out to be largely ineffective patching up of consequences rather than cures. Such is the way we forge into the unknown; understanding will come, as the scientific method is a powerful filter for effective solutions to any problem.

Is Alzheimer's actually a form of diabetes at root? Is it a failure of amyloid clearing mechanisms? Is amyloid even a cause, or is it a giant red herring and consequence of the real underlying biochemistry of the condition? It's a complex business - new ideas and broader exploration are certainly needed while the establishment forges ahead with consensus work on understanding and defeating the buildup of amyloid.

Technorati tags: Alzheimer's, neurodegeneration, medical research

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Some reading matter, light and not so light, for you folk today - while the interest bubble blooms for the calorie restriction mimetic compound resveratrol. First some comments from an Immortality Institute thread:

We do not know how it will perform in humans, but when was the last time we saw another "Resveratrol" in the past? Has there been other substances which have received as much attention in research for anti-aging application such as resveratrol?

...

The only one that comes close is HRT (hormone replacement therapy). It was widely accepted until the long term studies came out. I hope and believe that reveratrol will have a happier ending. Time will tell.

A good reminder that patience hurts little, given the present breakneck pace at which research is moving forward. Jumping into the fast boat carries certain risks; if you're really interested in obtaining these sorts of health benefits in the near future, it seems to me you should first look into the practice of calorie restriction rather than the drug pipeline.

On to the scientific papers; via the GRG list, Robert Bradbury notes:

Apparently Cell isn't clever enough to do direct upload abstracts into PubMed (unlike perhaps Nature & Science???) so the abstract isn't in PubMed yet. But in a rare(?) display of public seduction by a closed source journal they have made the full article PDF generally available [1]. The URL for the most recent Sinclair reference is [2]. It unfortunately does not appear to be available to the public.

As a side note, PubMed reports that there are now 1646 references now for resveratrol -- so going through the literature is not exactly a walk in the park. Though the papers involving resveratrol and Sirtuins and related genes ( i.e. the regulatory pathways) are only currently ~30-40 so at least that aspect can be managed.

1. http://images.cell.com/images/EdImages/cell/lagouge.pdf
(This really works, I'm looking at the PDF in Adobe Reader right now on my screen and I'm quite positively shocked.)

2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17086191

Worth reading if you are familiar with the present state of thought with regard to metabolism and longevity; the interesting question to me is to what degree all of this genetic and biochemical process manipulation via diet, drugs and other methodologies will be found to boil down to effects on a few core processes. Such as, say, the effects of fat and inflammation, or the insulin pathways. To put it another way, how much of the benefit of calorie restriction stems from lacking fat, how much from low levels of inflammation, and so forth?

I don't think we'll be left hanging for too many more years insofar as answers to these sorts of questions go. Metabolic manipulation may not be the most efficient path forward for healthy life extension, but it's most interesting to see answers, understanding and further questions in equal measure starting to flow thick and fast.

Moving on, Randall Parker put up some thoughts and links on all this resveratrol work:

It would be hard to get regulatory approval for a drug that increased life expectancy because it is a claim that is hard to prove in a clinical trial. But Sitris is chasing a more provable claim: That their modified resveratrol molecule, SRT501, will reduce the symptoms of old age and obesity such as high unhealthy blood lipids and insulin resistance in the form of type II diabetes.

...

Back in March 2005 Sirtris co-founder David Sinclair of Harvard said that most commercial resveratrol preparations have no active resveratrol in them - with activity measured by the ability to activate the SIR2 enzymes.

...

Bulk sources of resveratrol from knotweed can be found on the internet. But which of those sources is selling real active resveratrol? Your guess is as good as mine.

Then there's the question of whether this stuff is safe. We do not know. Okay? Really, we do not know. We need a big study of large numbers of people taking a gram of resveratrol a day with all sorts of checks done on them to look for bad signs. My guess is we are not going to see such a study on resveratrol because the money is in making a patentable commercial variation of resveratrol into a marketable drug. That'll take 6, 7, 8 years more and hundreds of millions of dollars.

He goes on to make much the same point as I have been making - that slowing aging by manipulating metabolism is a comparative waste of resources if we don't also devote serious effort to reversing aging through repair of age-related cellular damage, such as is proposed in the Strategies for Engineered Negligible Senescence.

The resources exist to do both - but I can tell you that from the high level view, in comparison to, say, the cancer or AIDS research establishment, even metabolic manipulation is barely funded. From the high level point of view, work to repair and reverse aging isn't even on the radar. This must all change - we must make this all change - over the next decade if we are to have a shot at far longer, healthier lives. Unless we act soon to build infrastructure and a research community, we will not live to see significant progress in human longevity.

Technorati tags: biotechnology, calorie restriction, life extension, resveratrol

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The latest issue of Rejuvenation Research is available online. Attila Csordás of Pimm - who happens to be a molecular biologist in addition to a pro-life-extension blogger - is published therein; folks who recently picked up on the (probably quite important) factoid that our cells may transfer mitochondria or mitochondrial DNA back and forth will find his commentary interesting:

Experiments recently reported by the Prockop laboratory show that some form of mitochondrial transfer can occur among cells in vitro and can have a physiologic role by rescuing the respiration of respiration-deficient cells. However, these results do not establish whether it was only [mitochondrial DNA] or whole functional mitochondria that were transferred, or if the latter, whether the mitochondria were transferred through direct cytoplasmic transport or as discrete vesicles. Two hypotheses are discussed here concerning the physiologic role of mitotransfer (the first is preferred): (a) respiration-competent mitochondria transfer from respiration-competent cells to respiration-deficient cells with damaged mitochondria (the "entropy" scenario); and (b) respiration-competent mitochondria transfer from predominantly respiration-deficient cells to respiration-competent cells, which provide a more favorable host environment (the "selfish" scenario).

As you all no doubt know, molecular damage to the functionality of mitochondria features prominently in the mitochondrial free radical theory of aging - it's the starting point of a cascade of events that wind up causing a fraction of age-related damage, disease and frailty.

The theory as it stands rather assumes that mitochondria and their fragile DNA do not shuttle around from cell to cell in any significant numbers, however; this new research provides an interesting twist that people will no doubt be exploring and integrating in years ahead. From a practical standpoint, might this explain the rapid success of scientists who introduced fresh, undamaged mitochondrial DNA into mice via the protofection technique? Or perhaps it is a separate mechanism that could be utilitized in the same way - to mass-replace damaged mitochondria and therefore remove their contribution to the aging process.

What interesting times we live in, that we are so tantalizingly close to repairing the accumulating root cause of an entire class of age-related disease and cellular damage.

Technorati tags: biotechnology, life extension, SENS

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It has to be said, the dusty articles arriving at this end of the virtual silk road of journalism that links the laboratories of Russia with the English-speaking internet are a strange looking bunch. Odd customs, an impenetrable accent, an oftimes ferocious disregard for the need to fit into a particular clade (such as, say, journalism versus outright fiction), and delicate technical matters mangled and spiced three and a half times in as many languages by non-technical editors - all this is par for the course.

The enthusiasm for life extension shines on through wherever it is mentioned, however, and there's a certain charm to that. Just as for the Life Extension Foundation and A4M closer to home, it's hard to savage their activities quite as much as they deserve, given the degree to which the hearts and intentions of the founders are in the right place. Savage we must, however. The future of science belongs to those who avoid the backwaters and seductive, flashy sideroads of little progress - those who understand the likely value of their work and its place in the infrastructure. Grandiose exaggeration and focus to the point of self-defeat need not apply.

A good rule of thumb is to leave an article well alone if it was published in the English language edition of a Russian outlet. There might indeed be some science of note at the far end of the silk road, somewhere, but like as not you'll never know for sure.

By way of contrast, here's an example from the English language section of a German publication (and so perhaps only translated twice over from the Russian ... ) in which it is possible to pick out the science and its relevance to progress in healthy life extension research. All the rest of the warning signs are there in force, however, so sit back and enjoy the ambiance:

It seems that if researchers strive to cancel the ageing program, they should start acting at the genome level. Such experiments are already being carried out: researchers have found the gene, switching off of which prolongs the life of the nematode worm and the laboratory mouse. But “we do not want to interfere in the human genome, because this can cause unexpected consequences”, says V.P. Skulachev. The researchers decided to interfere not in the program itself, but in its execution at the very early stage. At this stage, aging is connected with accumulation of free radicals in the organism, this taking place initially in the mitochondrion - a power substation of a cell. The SkQ substance synthesized in the course of the research, acts as a very efficient antioxidant, which is fighting against free radical oxygen at the mitochondria level.

Hundreds of antioxidants are already being applied in the world, but not all of them are efficient as they get quickly destroyed. The peculiarity of a new substance is that the so-called “Skulachev’s ion” (the name was given by foreign colleagues) is part of it, the ion penetrating through the cell’s membrane and accumulating inside mitochondria thanks to its positive charge (the charge inside the mitochondrion is negative). This ion “drags” behind itself the proper antioxidant part. The result is that the substance saves mitochondria’s lipids from oxidation.

The SkQ influence on the life span was studied in experiments on mice. Laboratory mice were given to drink “life-giving water” with SkQ, the substance being contained in this water in nanodoses (5 nanomoles). The life time of such mice increased by one third on average as compared to that of the reference group mice. Even more demonstrative are experiments with mutant rats, where accelerated ageing - progeria - was observed. SkQ prolonged their life span by three times, besides, it cured them from a large number of senile diseases. They include infarctions, strokes, osteoporosis, hemogram abnomality, reproductive system disorders, behavior change, visual impairment.

...

It remains only to wish the researchers good luck in continuation of their effort, and the entire humanity - to obtain in the future if not immortality but the extension of active life.

Those of you following along at home will hopefully recognize this as a parallel path to research reported a year ago in the US in which production of the antioxidant catalase was enhanced in mice via gene therapy; it was shown that only when applied to mitochondria did it extend healthy 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.

Instead of gene therapy, Skulachev's group has found a viable biochemical strategy for effectively localizing ingested antioxidants in the mitochondria; clever. Of course, the proof is in scientific publication, peer review, and so forth. Unless I am much mistaken, here is the item in question at PubMed:

Lipophilic monocations can pass through phospholipid bilayers and accumulate in negatively-charged compartments such as the mitochondrial matrix, driven by the membrane potential. This property is used to visualize mitochondria, to deliver therapeutic molecules to mitochondria and to measure the membrane potential.

I'll leave the non-technical readers to mull over which report they prefer.

Technorati tags: biotechnology, life extension

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Since I posted on the topic way back when (and again the next year, even), I should probably note that the legal exchange between the folk running the American Academy of Anti-Aging Medicine (A4M) and researcher S. Jay Olshansky - backed to the hilt by the University of Illinois - is at an end. Both sides settled, the suits are dismissed, and the net result appears to be a modest flow of capital in the general direction of lawyers. No victory for freedom of speech if you had to pull out a bigger club and wallet in order to obtain it.

No link either, I'm afraid; this comes via folk of the Gerontology Research Group mailing list. If you're interested in watching scientists and healthy life extension advocates discussing the latest happenings, or threads on the plasticity of human longevity (and the plasticity of our expectations thereof), then you should be signed up.

Insofar as this legal affair goes, the end result is pretty typical of the genre; courts move glacially, and the world of business and research - the world of people in general, really - moves rapidly. The changing activities and public positions of both sides made the original point of the exercise - such as it had one - somewhat irrelevant. Once it became framed as a slugging match, there was little to gain and much to risk in continuing.

I will say this; if a scientist claims - with backing - that your products don't work, or that you are cherry picking studies to make a bad point, lawsuits are a poor response. In fact, they bolster the accusation being made. If you have something that works, you can demonstrate that fact via the scientific method. If you don't, you can't. If you're in that grey zone of uncertainty that exists in complex, poorly understood fields, then that's where you are - but you can't fight reality with the legal system. Instead, get out there and find or develop something better to sell.

The A4Ms and Life Extension Foundations of this world are afterthoughts and sideshows to the real action in the healthy life extension sphere. They are a form of brand pasted onto the normal, everyday businesses of general health and wellbeing. They are aspects of a commercial development and delivery mechanism for healthy life extension science that, as of yet, has nothing meaningful to deliver. This is the failure of the last generation of advocates - the cart placed well and truly before the horse. They could be doing a great deal of good ... but for every person woken to the potential that life span can be extended, there is a person trained to think that it's all about vitamins and what you eat.

The healthy life extension of the future will have nothing to do with the often earnest folk who peddle supplements, exercise and good advice for general health. Take a trip to the Strategies for Engineered Negligible Senesence website, or look back in the archives here and at the Longevity Meme. The future is nanotechnology to cure cancer, gene therapies to repair specific molecular age-related damage in nerve cells, the replacement of faulty mitochondria via protofection, replacement of worn, failing stem cells and immune cells with undamaged clones, the building of new organs to order, and a hundred other soon to be realized results of the biotechnology revolution. Advanced medicine - that is what will meaningfully extend your life. Recognize this fact and you're doing better than a great many people who see no further than the materials put out by the "anti-aging" marketplace.

Technorati tags: anti-aging, legal

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Buried amidst stock silliness in a standard mainstream media look-ahead piece, we have this brief quote from Ellen Heber-Katz, of organ-regenerating mice fame.

Life on Earth will also be transformed, scientists predict, with farms designated to grow human organs. By 2056, even the most sophisticated medicine of the 20th century will begin to look barbaric.

There will be no need to take transplant organs from dead people, according to Bruce Lahn, a human geneticist at the University of Chicago. Instead, human organs will be grown in animals such as pigs. "When a patient needs a new organ - a kidney, say - the surgeon will contact a commercial organ producer and supply them with the patient's immunological profile ... One organ that is probably off limits though is the brain."

Another way forward is drugs to regrow lost limbs and organs. "Advances in heart regeneration are around the corner, digits will be regrown within five to 10 years, and limb regeneration will occur a few years later," Ellen Heber-Katz at the Wistar Institute in Philadelphia told the magazine. "Within 50 years whole-body replacement will be routine."

You might recall that Heber-Katz was one of the presenters at the SENS2 conference - there's even an mp3 recording of her presentation on the MRL mice amidst the conference records, if you are interested.

Interestingly, we find out a little more about Richard Miller's thoughts on the future of healthy life extension from the same piece:

It might not lead to an elixir for life, but by 2056, scientists anticipate unravelling the crucial complex molecular mechanisms that govern wear and tear in our cells, causing damage that manifests as ageing. Richard Miller, professor of pathology at the University of Michigan, envisages "the first class of centenarians who are as vigorous and productive as today's run-of-the-mill sexagenarians".

Miller famously holds the opinion that SENS - the Strategies for Engineered Negligible Senescence, a repair-based approach to research into extending healthy life - is so much nonsense. Miller is one of the backers of the Longevity Dividend initiative - a metabolic manipulation approach to research aimed at slowing aging - that is gathering steam.

As I've noted all too many times in the past weeks, repairing damage to reverse aging and reducing the rate of damage to slow aging are two very, very different approaches to the same problem; one is very much better than the other, in my opinion.

On that note: it has to be said, if all we manage after 50 more years of the biotechnology revolution (and the advanced nanotechnology that will follow) is a mere 40 years of healthy life extension ... well, we must have all been sleeping on the job. Take a look at the computers of 1956 and the computers of 2006 and draw your own conclusions as to what can be done in 50 years if the will is there.

Technorati tags: aging, biotechnology, gerontology, life extension

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The lifestyle choices most likely to dimish your health, shorten your life and leave you more frail and suffering in old age - not to mention poor, broken by the cost of therapies - are no big secret.

High grip strength and avoidance of overweight, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with both overall and exceptional survival. In addition, high education and avoidance of hypertriglyceridemia were associated with exceptional survival, and lack of a marital partner was associated with mortality before age 85 years. ... probability of survival to oldest age is as high as 69% with no risk factors and as low as 22% with 6 or more risk factors. The probability of exceptional survival to age 85 years was 55% with no risk factors but decreased to 9% with 6 or more risk factors. ... avoidance of certain risk factors in midlife is associated with the probability of a long and healthy life among men.

Yet still, the majority of the population in more comfortable, wealthy locations in the world persists in indulging. Such is the power of choice, and the consequence of that primate-scale level of time preference we humans have inherited. We've all stolen quality and years of life from the person we will be in future decades - and some of us just keep on doing it right up until we're living (and dying) in the pocket we once picked.

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

Basic good health is not rocket science; talk to your physician if you're unsure about any of it. Most people are well aware of the trade-offs they make in terms of present bad habits versus future health consequences - but too few realize that what looks like a 10 year reduction in life span under the healthcare available today might mean they'll miss the boat on the introduction of working anti-aging medicine. Missing the boat means possibly missing out on centuries or more of healthy life if medical science moves forward at a fast enough pace.

Hurdles and caltrops strewn in the path ahead; this we do on a personal level, as well as in society at large and its institutions.

Technorati tags: health, longevity

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The physical, biological infrastructure that supports our minds is hamped by any number of shortcomings beyond the simple fact of aging - but you have to accept that any system will age and wear. The trick will be repair that wear and damage sufficiently well, economically and often to ensure prevention of problems and infrastructural failure. Such failures are neither pleasant, nor pretty - we'd all like to avoid that fate if at all possible.

In effect, we're all riding around in cars, but without the services of car mechanics. The first wave of technologies to meaningfully impact the great limitation of aging will center around dramatic improvements in our ability to repair biochemical wear and tear - it will be the advent of mechanics in a world filled with failing automobiles. In comparison, attempts today to rework our mechanisms - our metabolism - to lead to a tougher, more efficient biological engine with a longer mean time to failure are unlikely to have anywhere near as much impact on the same timescale. It's a great deal easier to build a garage and staff to service automobiles than it is to build a shop of specialists capable of machining up new cars from near-scratch.

But in the longer term, with more decades of biotechnology under our belts, reworking our bodies right down to the genetic level becomes a very viable possibility. Early explorations are already underway:

The public and even many scientists are unaware of how close science is to making germ line engineering a reality, said Dr. Michael Rose, who studies the genetics of ageing at the University of California at Irvine and who was a speaker at the meeting. He said the meeting would bring public attention to "one of the most important questions for the human species: the extent to which it will direct its own evolution."

...

Today, obstacles to germ line engineering are practical, not theoretical. Scientists have the ability to add desired genes - snapping gene cassettes onto artificial chromosomes and injecting the chromosomes into newly fertilised eggs. Because every cell in the body is a descendant of that first fertilised egg, every cell would have a copy of the artificial chromosome once inserted.

Artificial chromosomes, even human artificial chromosomes, have already been created and patented, the scientists reported, and companies have sprung up to exploit the technology. Dr. Leroy Hood, chairman of the department of molecular biotechnology at the University of Washington in Seattle, said he has now developed a way to create an entire custom chromosome on a computer chip containing DNA.

If we have developed SENS or similar repair-based medical technologies to hold aging at bay, and we have a low-cost biotechnology base to work with, all sorts of limitations are open to removal. Vulnerability to viruses, genetic disease, the quirky, evolved weaknesses and imperfections of biology; with sufficient understanding, it's all open to modification and improvement. The focus on the germ line is something of a red herring, however: mature, future gene therapy will mean an ever-expanding array of upgrades, fixes, cures and modifications that you can choose for yourself as an adult.

But it would be a shame if we all missed out on that, aged to death because we didn't focus on accomplishing the defeat of age-related degeneration that is presently just arriving in the realm of the possible:

My point here is that widespread complacency will be an undoing for us all - it's a common failure mode for those who look towards a better future, but never manage to engineer it. Massive assignment of time and resources is required for the goal of healthy life extension in our lifetimes. Engineering this use of resources is a huge task in and of itself. But supporters become enthusiastic, overestimate the degree of progress and the number of people helping make a better future, and stop making their own contributions. That scenario repeated en mass would mean that no progress is made - that healthy life extension technologies will not become effective enough to reach actuarial escape velocity within our lifetimes. Thus, game over; oblivion or taking your chances with cryonics.

We have a chance, a shot at radical life extension. We have to contribute, all of us, or it will slip from between our fingers.

Technorati tags: biotechnology, life extension

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Progress in medical science - and that most interesting portion of medical science that relates to extending the healthy human lifespan - is not an easy matter. But it would be a good deal easier and more rapid than it is at the present time if we could just cut down on the level of self-inflicted hurdles and caltrops. As in every area of human endeavor, it seems that people with the best of intentions and the worst of intentions inadvertantly conspire to drag us all down.

We'll start with a straightforward one: patents, those pieces of paper by which you use government force to obtain money from other people who are doing far more than you to advance a particular field. Though in fact, as with all forms of taxation, it usually works far better at suppressing the field as a whole than at lining your pockets - if you want to predict the results of any policy, you have to follow the flow of incentives. Why do something expensive when you can do something cheap? And thus, the exodus begins.

So can someone own the cells that make up what is important about a human embryo? And if so, do we have to pay them every time we make our own embryonic cells, every time we make a medicine or other innovation from embryonic cells, and even when we use the cells to teach?

At least at the blastocyst stage, the answer is essentially yes.

...

Basically, if it looks like an embryonic cell, you'd better pay up. And if you try to make something out of your own embryo - yes, the one you made with your own body, from your own body - well, hope you have good lawyers.

...

The protection of patents is supposed to extend to "things under the sun made by man." There has yet to be a serious challenge to the absurdity of patents on disease genes, and the even more absurd notion that the ability to find, to discover, constitutive parts of an embryo means that you own them.

The belief that the system of patents in its platonic, intended form (for whatever definition of that term you happen to support) is fine and dandy - i.e. that it isn't still a form of taxation or theft by government, enriching the few at the cost of the many, and suppressing progress by incentivizing people to work elsewhere - is another form of hurdle we throw in front of ourselves.

But onwards. You might have heard the recent news that scientists are seeking permission to use cow eggs and human DNA to advance our understanding of stem cell science. The normal suspects are making the normal song and dance about "hybrids." All nonsense. The real crime is that a scientist has to ask permission before setting out to help people through bettering biotechnology; progress is not encouraged by the boot of bureaucracy and regulation upon its neck.

Take an egg (a cow’s in this case), remove all the DNA, so you effectively have an empty shell. Put the DNA you want to clone (a human’s) into the egg. This then grows into an embryo. However, as the DNA of this embryo is almost entirely human now, the embryo would be a human embryo, not a mixed cow-human creation.

This research may also have important implications for organ repair. Cloned stem cells could replace the damaged cells. In a study announced this week on heart attack patients, the stem cells will be extracted from the patients’ bone marrow and injected straight into the heart, where it is hoped that they will then help to repair the organ.

My group at King’s College London is interested in creating cloned human embryonic stem cell lines from individuals with genetic forms of diseases, such as Alzheimer’s and spinal muscular atrophy.

Although to some the thought of using an animal egg may seem gruesome and unnecessary, it is the best solution that we can come up with for the egg shortage in cloning research. The Human Fertility and Embryology Authority (HFEA) does not permit egg donation for research purposes. At the moment, our only source are eggs that fail to fertilise in fertility treatment, and such eggs are hard to use.

The whole egg donation regulatory mess is fit for a post unto itself; it's a wonderful example of Medieval attitudes towards women and commerce transposed into our era. Scientists are, often as not, just as bad as the regulators when it comes to this sort of thinking. More caltrops strewn in their own path:

I am opposed to young women donating eggs for money. I do not feel it is appropriate to encourage women to undergo a risky and invasive procedure for which they receive no direct medical benefit and where most of the donated eggs are wasted.

Everyone has an opinion, it seems, but no-one wants to offer the potential donors a chance to express theirs in the free market. What a mess people make when given the opportunity to write rules backed by government force, rather than peacefully try to persuade others to see things their way. The one thing that ends up rather stomped beneath all this is, of course, the best and most effective way forward - the very thing that would leap to the top if unrestrained by regulation.

Technorati tags: biotechnology, libertarian, medical research, patents, politics, regulation

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S. Jay Olshansky recently posted an update on the Longevity Dividend initiative to the Immortality Institute forum thread on the topic. Links for reference (except for the last to the Alliance for Aging Research (AFAR) website) are added in by my hand, as is usually the case - next to no-one makes as much use of hypertext as they should:

The event in D.C. on the 12th of September went extremely well. Senator Craig kicked off the meeting using the language of the Longevity Dividend to suggest that health care spending will swamp the budget unless we pursue this initiative. Several of us met with Senator Harkin personally after the meeting to discuss the idea. He subsequently asked us for language to place in the appropriations bill, which we did. We're now drafting a follow-up to the Longevity Dividend calling for a paradigm shift in the way at which we look at aging and disease. It's important that we begin using the language of the Longevity Dividend to keep up the momentum.

...

Here is a link containing copies of the slides used by everyone during the event in D.C., and the video of the event.

http://www.agingresearch.org/longevitydividend/overview.cfm

Not just slides, but video also. There's quite a bit of material to look through there at the AFAR site. The people and organizations backing the Longevity Dividend approach are clearly gearing up their efforts; the end goal is a redirection of gerontology towards slowing aging via metabolic manipulation - and thus pushing back the onset of age-related disease, disability and frailty - rather than the present strategy of tackling the diseases, pathology by pathology, after the fact. We all know that prevention is better than cure; it's certainly more cost effective.

I'll (mostly) spare you folks a retreading of my opinions on this path - largely centered around the inherent limitations and undesirability of big tents, politics, government, redirection of taxed funds, trying to slow aging versus trying to repair the cellular damage that causes aging, etc - except to point back at this post, which more or less summarizes the salient points as I see them.

As many of you know, I am equal parts enthused by and critical of the Longevity Dividend. It is a big step forward for the conservative position in gerontology; an admission that the debate over healthy life extension is now "how much and how soon is possible." This is wonderful progress when compared with the state of the field even just five or ten years ago. A rising tide raises all boats: the Longevity Dividend approach makes Strategies for Engineered Senescence (SENS) research and the MPrize for anti-aging research more likely to grow and prosper.

...

At the same time, there is much to be critical of. The scope of the Longevity Dividend is unambitious in comparison to what is possible. It is also primarily geared towards government, public funding and political positioning - not my favorite ways of getting things done.

But you should make your own mind up; Olshansky, Perry, Miller, and Butler are demonstrably influential and talented folk. I predict they will attain a good fraction of their goals, having now set their minds to it.

And of course this recent post, which looks at why it's better to aim resources towards reversing aging via damage repair rather than slowing aging by reducing the effective rate at which damage accumulates.

I'll pick out two early stage technologies that are starting to show promise for a game of compare and contrast. Both involve the age-related damage wrought by free radicals that occurs in - and is caused by - mitochondria, vital cellular components that convert food into more convenient forms of energy to power your cells.

...

It should be quite clear that protofection is a far superior and more efficient answer to free radical damage of mitochondria than any form of antioxidant therapy. Now consider this: in the present day of highly regulated medicine and expensive development, both these technologies would likely cost much the same in money and time to move from where they are now to widespread, safe use in humans. Where would you invest the time and money?

Technorati tags: aging, politics, life extension

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One of the recent New York Academy of Sciences web features is a nice focus on mitochondria and neurodegeneration. As I'm sure you know, mitochondria are complex little cellular components responsible for turning food into a more convenient, standardized source of energy for cells; they also produce "chemical waste" in the form of damaging free radicals. Beyond that, there are any number of external influences that can change the way in which mitochondria behave. More effort in recent years has been going towards determining the mechanisms by which mitochondrial changes and damage are linked to age-related disease.

David Nicholls of the Buck Institute for Age Research in Novato, California, has studied mitochondria for 40 years. In his talk at the Academy, he began by discussing recent advances in techniques with which to study mitochondrial bioenergetics in intact neurons. His experimental setup allows one to measure oxygen respiration while also monitoring a variety of other dynamic cell processes, such as mitochondrial membrane potential, plasma membrane potential, cytoplasmic calcium concentration, and the presence of reactive oxygen species [ROS]. Nicholls described dynamic interactions between mitochondria and the rest of the cell, interactions that were previously unknown but are now being revealed with his techniques.

Nicholls found that in many instances of cell failure, ROS are a red herring - a symptom rather than a cause. One example that stands out is that of glutamate excitotoxicity, in part because it has been studied so much. When neurons are continuously exposed to glutamate, calcium rushes in. Cells can maintain a holding pattern for a short period of time, but then succumb. Nicholls showed that ROS were present, but they did not interrupt the holding pattern. Instead, changes in the respiratory capacity of mitochondria were linked with triggering neurons' demise.

As we know, mitochondrial-generated ROS contribute to cellular changes that lead to age-related degeneration; the link is most clear for atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease - but there are many other potential problems that can result. For specific conditions, it is not always the case that this background age-related trend towards more damaged mitochondria and more ROS is at the root of the problem, however.

More information is more information, and it will all be useful at some point. An increase in resources dedicated to the study of mitochondria - prompted by advances in understanding in other fields - can only help in the long term. The results build a foundation for increased capabilities and funding to develop ways to repair age-related mitochondrial damage.

Technorati tags: biotechnology

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As you might recall, Attila Csordás of Partial Immortalization put out a set of questions on healthy life extension - primarily aimed at bloggers - and set out to get folk to answer them.

1. What is the story of your life extension commitment?

2. Is it a commitment for moderate or maximum life extension?

3. What is your favourite argument supporting human life extension?

4. What is the most probable technological draft of human life extension, which technology or discipline has the biggest chance to reach it earliest? (regenerative medicine, nanotechnology, gene therapy, caloric restriction, bionics, hormones, antioxidants, …)

5. When?

6. What can blogs do for LE?

Here is a selection of responses to date:

Chris Patil of Ouroboros (and part 2 and part 3)

I want to encourage the readership of aging-related blogs to take advantage of the interactivity of the web, and to get involved with their favorite sites, as commenters and missionaries and contributors. Building an online community devoted to the biology of aging can only help the cause of lifespan extension.

Jim Craig

I think all of the present “big potentials” like stem cells, gene therapy, etc will contribute to modest extensions to average and maximum life expectancy but I believe that the most significant gains will fall out of accurate and large scale computer models that can simulate the emergent properties of protein-protein and protein-enzyme interactions. These will be the tools of the multi-disciplined systems biologists of the future. I see advancements in life extension tightly bound in a triple helix with proteomic knowledge and computing power.

Phil Bowermaster of the Speculist

Those who claim to have no fear of death, whether they be an Objectivist or the Dalai Lama or some Palestinian strapping dynamite to his chest, have lost touch with a primary truth of human existence: a truth which has lead us both to science and to faith. Those who seek to prolong human life - whether via antioxidants or cryonics or standard medical procedures - have tapped into that same fundamental truth: Death sucks.

Aubrey de Grey

I can’t trace when I realised that aging was a bad thing - I must have been so young that I can’t remember. But I was nearly 30 before I found out that most other people don’t think the same, or at least don’t think that it’s important enough to work on. I was in a very lucky situation to be able to make a contribution - I had training in research in a very different field, and I also had quite broad knowledge of biology - so I decide to have a go. My first publication was very well-received, so I kept going!

I encourage the rest of you to jump on in; let's see what people think.

Technorati tags: blogging, life extension

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A number of items caught my eye today. Stem cell politics first, since it seems to be that time of year:

Australian Senate votes to overturn stem cell ban:

Australia's Senate voted on Tuesday to allow cloned stem cells to be used for medical research after an emotional and divisive debate on relaxing restrictions on research.

The bill passed by two votes in the 76-seat Senate and will now go to the lower house of parliament in late November, where supporters believe they can muster the numbers to overturn existing bans on research on cloned stem cells.

Stem cell measure narrowly wins:

ST. LOUIS Missouri voters have narrowly approved a state constitutional amendment that protects stem cell research, even involving the use of human embryos.

...

The amendment guarantees that any federally-allowed stem cell research and treatments can be carried out in Missouri. That includes research involving the use of human embryos.

Would that we lived in a world in which government employees and politicians had no power beyond persuasion, just like the rest of us. Perhaps then, there would be less waste and battle - certainly less folk willing to abolish freedom of research, if it meant they actually had to work just as hard as those pushing science forward.

But on to matters of more substance; actual research, and people actually working to make progress, rather than fighting over control of one another. This first research isn't quite stem cell science, but it's both worthy of attention and something we're probably going to see much more of as scientists get better at this - the use of somewhat differentiated precursor cells.

Blind mice see again after retina cell transplants :

Previous studies that had used stem cells, master cells in the body that have the potential to become any type of cell in the body, had failed because the cells did not form into photoreceptors.

...

Researchers had thought that the mature retina, the part of the eye that senses light and forms images, did not have the capacity for repair.

MacLaren and his collaborators showed using precursor cells that are already programmed to become photoreceptors but are not quite there yet was the key to successful transplantation.

Osteoarthritis patients need not to come to a grinding halt:

Stem cell therapy - a technique that relies on the idea that stem cells can be prompted to turn into cartilage cells that will grow and repair damage - is another possible avenue for future treatment. Johns Hopkins researcher Jennifer Elisseeff has used the method in rats, finding that stem cells can fill in holes in the cartilage.

"These cells have the amazing ability to repair parts of the body," says Thomas Vangsness, an orthopedic surgeon at the University of Southern California in Los Angeles.

Vangsness and his colleagues are testing a stem cell therapy developed by Osiris Therapeutics. The Baltimore company has developed a solution of stem cells taken from a single adult donor. Vangsness and his colleagues injected the stem cell solution into the knees of 55 patients with a torn meniscus, cartilage-like tissue in the knee. They're hoping the stem cells will turn into cartilage cells and repair the injury, but the data are just now being analyzed, Vangsness says.

He hopes to have some answers in the fall. "If it does work - that would be a huge deal," Vangsness says. But can stem cells go beyond treating simple injuries and stop an ongoing disease process - one that constantly grinds up cartilage?

Fleischmann calls that concept "pie in the sky" but says that years from now doctors might have injectable stem cell therapy or some other technique that could hold the line on osteoporosis. "If we could regrow cartilage," Fleischmann says, "that would be the holy grail."

This next one is most interesting. Mice are little cancer factories in comparison to much more cancer resistant humans, so it isn't the case that everything that happens in mouse models of cancer is at all applicable to medicine - but still.

Vaccination With Embryonic Stem Cells Prevents Lung Cancer In Mice:

Researchers in America have discovered that vaccinating mice with embryonic stem cells prevented lung cancer in those animals that had had cancer cells transplanted into them after the vaccination or that had been exposed to cancer-causing chemicals.

...

Prof Eaton is the James Graham Brown Professor of Cancer Biology and Deputy Director of the James Graham Brown Cancer Center, University of Louisville, USA. He and his colleague, Dr Robert Mitchell, tested two different vaccines in the mice. One consisted of embryonic stem cells (ESC) only, obtained from mouse blastocysts (very early, pre-implantation embryos). The other vaccine consisted of the ESCs combined with cultured fibroblast cells producing GM-CSF, a growth factor usually made by white blood cells and blood vessel-lining endothelial cells, which "supercharges" the immune response and appears to enhance the vaccine-induced immunity to cancer.

...

He and his team injected mice with ESCs alone or ESCs + STO/GM-CSF. In mice that had Lewis lung carcinoma transplanted into them afterwards, ESCs were 80% effective in preventing tumour growth and ESCs + STO/GM-CSF were 100% effective. In mice subsequently exposed to a carcinogen that causes lung cancer (3-methylcholanthrene followed by repetitive dosing with butylated hydroxytoluene), ESCs resulted in 60% of mice remaining tumour free after 27 weeks and ESC + STO/GM-CSF resulted in 90% remaining tumour free. Importantly, tumours arising in vaccinated mice were, on average, about 80-90% smaller than tumours in unvaccinated mice. All the unvaccinated mice developed tumours. None of the vaccinated mice developed autoimmune disease or a showed a significant decline in adult pluripotent bone marrow stem cells -- both potential adverse responses to the vaccinations.

So much interesting research is going out there these days that it's hard to see more than a swathe of it. This is as to be expected: advances in biotechnology translate into cost reductions - more science per dollar.

Technorati tags: politics, stem cell research

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George Dvorsky notes that the planning for TransVision 2007 is rolling ahead:

The World Transhumanist Association's annual TransVision conference will be held in Chicago next summer. The dates have been announced as July 26 to July 28. Ray Kurzweil and Aubrey de Grey will be the keynote speakers. I will be there and I hope you will be too.

You can find the material for past TransVision conferences at the WTA website. For a short introduction to transhumanism and its relationship with advocacy for healthy life extension, you might try a short visit to the Longevity Meme.

Technorati tags: conference, transhumanism

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As indicated by some of the comments to a recent post about resveratrol - and why I'm not hot on research to slow aging in comparison to research aimed at repairing aging - I'm failing to clearly make what I consider to be the most important point. I made another go at it as a sequence of ideas in the most recent Longevity Meme Newsletter:

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

4) It does you no good in the long term to buy an extra decade of healthy life if that's all you get; it was only useful if researchers spent that decade working hard on repairing aging, rather than further metabolic science. There's only so much you can do with slowing aging through metabolic manipulation - the elderly wouldn't benefit, for example - but a working repair mechanism for the cellular damage associated with aging could be used to restore the aged and hold off aging over and over again. It's more efficient and effective.

5) There is more than enough money in the world to have your cake and eat it - to fund both lines of research, metabolic tinkering and repair of damage. But this is not happening now. Successful fields have gravity - they attract new researchers and shape the course of science on a timescale measured in decades; without a great deal of work, the fight against aging will be metabolic manipulation and little else for the foreseeable future. That would leave us rather stranded twenty years from now.

Which earned me some rather sarky comments in private email from one of those fellows who sells resveratrol. So, let's try again, by means of example this time; I'll pick out two early stage technologies that are starting to show promise for a game of compare and contrast. Both involve the age-related damage wrought by free radicals that occurs in - and is caused by - mitochondria, vital cellular components that convert food into more convenient forms of energy to power your cells. You might first want to take a look at a post from last month that summarizes the latest view of the mitochondrial free radical theory of aging, and explains how the accumulation of damage to mitochondria is a root form of aging damage.

First up is the enhancement of the anti-oxidant catalase:

"Rabinovitch's group genetically engineered mice to produce a natural antioxidant enzyme called catalase. The mice lived 20 percent longer than normal mice - on average they lived five and a half months longer than the control animals, whose average life span was about two years

...

We had differing hypotheses about where putting catalase might do the best in terms of the advantage to life and health of the mice," Rabinovitch explains. So they targeted the gene in three different places in the mouse cells - the cytoplasm, the nucleus - where they thought it might protect the all-important DNA of the cell - and the powerhouses of the cells, the mitochondria - where cells "burn" glucose for energy and churn out high levels of these oxidizing free-radicals. The mice that lived longest had the gene in their mitochondria.

"What we learned was that increasing the levels of catalase specifically in mitochondria was the way in which we could most effectively increase the 'healthspan,' as we call it, the increased time of healthy life for the mice," Rabinovitch says. Mice with high catalase levels in the other cell structures showed only modest life extension.

The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this DNA, as explained in that post I referenced above, 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.

Great, right? Well, yes, considered in isolation - and if you are young. If you are old and already damaged, you're pretty much out of luck. Gene therapy to boost your levels of catalase isn't going to do much for you, no matter how many hundreds of millions of dollars were spent getting it from the laboratory and into clinics. It can't repair what has already happened. It's also not so great if you were young at the outset, and after twenty years of research focus and construction of a multibillion dollar industry and scientific infrastructure, there has been little progression beyond ever more sophisticated manipulation of metabolism in this sort of way - you're still aging, and you will still suffer and die as a result.

Let's look at the second technology: protofection. This is a methodology demonstrated to be a means by which scientists will be able to completely replace the mitochondrial DNA in your cells:

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

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

Replacing damaged mitochondrial DNA means completely shutting down the consequences of free radical damage. You're not slowing this aspect of aging, you're stopping it - and for the already aged, you would be reversing this form of aging damage. With a mature protofection technology, people could repair mitochondria every time it was needed - and consider that most folk make it through their first 30 years just fine at the present rate of damage.

It should be quite clear that protofection is a far superior and more efficient answer to free radical damage of mitochondria than any form of antioxidant therapy. Now consider this: in the present day of highly regulated medicine and expensive development, both these technologies would likely cost much the same in money and time to move from where they are now to widespread, safe use in humans. Where would you invest the time and money?

That, then, is the point - the practical difference between slowing aging and reversing (or repairing) aging. Presently, that portion of the scientific community invested in longevity and aging research is heavily - almost completely - weighted towards slowing aging and manipulating metabolism, such as in the case of the catalase work above. If work in repairing aging had as much interest, backing and support, then we could have our cake and eat it - use techniques that slow aging as stepping stones to live in good health to take advantage of techniques that reverse aging. But that is not the case today, and without a great deal of hard work (by organizations like the Methuselah Foundation, amongst others) it will not be the case tomorrow either.

The bottom line is this: we can miss the boat or not - it's up to us.

Technorati tags: aging, anti-aging, biotechnology, life extension, medical research

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I thought I'd point out a couple of links of interest to those following the recent burst of news on resveratrol and the efforts of Sirtris Pharmaceuticals. First out of the gate, an interview with David Sinclair (co-founder of Sirtris) by Charlie Rose can be found at Google Video. From Sinclair's Harvard faculty page:

Our goal is to devise ways to prevent and treat the major diseases of society by manipulating genes that control how fast we age. ... These genes underlie the remarkable effects of the diet known as calorie restriction (CR), which delays aging in every species tested, from yeast to primates. CR is currently the only treatment that can prevent all diseases of aging including cancer, heart disease, osteoporosis, diabetes and neurodegeneration. Recent studies in our lab and others demonstrate that the ability of CR to extend lifespan in models organisms is governed by the Sirtuins. Animals lacking Sirtuin genes do not respond to CR and additional gene copies extend lifespan. Based on these findings, we have engineered small molecules that can activate mammalian Sirtuins in vivo, with a view to developing drugs that can (i) treat the diseases of aging and (ii) promote cell survival and recovery following an injury.

This is one of the most representative and advanced efforts of that segment of the research community presently attempting to safely change metabolism to slow aging. Unfortunately, given that the FDA will not approve any treatment for aging itself, these sorts of efforts are channeled into developing treatments for specific age-related conditions - the short-termist and ultimately ineffective process of patching up the consequences of aging, with no impetus to commercialize preventative methodologies. This is not good: you get things done by getting things done. If you're not working on A, you're not working on A, even if you're working on B that is related to A. Regulation in the US steers research investment and infrastructure away from making any serious effort to repair or prevent aging. This must change.

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

We can do better than this. Not right now, but soon.

But back to Sirtris and their present work:

Elixir and Sirtris:

So researchers are developing drugs to treat or prevent aging-related diseases like diabetes or obesity. The current explosion of anti-aging research dates to the 1930s when scientists discovered that dramatically reducing an animal's caloric intake will pile on extra years. ... Sirtris researchers have developed small molecules aimed at triggering the health-promoting effects from caloric restriction found in sirtuins, a class of enzymes. Elixir is also researching sirtuins, but it's seeking ways to treat diabetes and obesity by targeting ghrelin, a protein released in the stomach that regulates hunger and metabolic functions."

Press Release on Sitris' SRT501:

Sirtris Pharmaceuticals, the leading sirtuin therapeutics company, announced today that SRT501, its initial clinical candidate which is a proprietary formulation of resveratrol with improved bioavailability, has been administered to patients with Type 2 diabetes in a human Phase 1b clinical study. Sirtris is studying SRT501 as a drug candidate for Type 2 diabetes, based in part on the scientific evidence that sirtuin activation, by means of compounds like resveratrol, has been shown to have a positive effect on key clinical measures for diabetes.

Lastly, a teaser via Pimm and Chris Patil suggests there are more interesting attempts at metabolic manipulation to come:

I think the first really useful technological life extension will have a very familiar form, e.g., “take this pill and call me in fifty years when you’re still alive.” Drugs that activate sirtuins and related pathways are very promising (I can’t spill the beans but I saw some amazing data at Cold Spring Harbor suggesting that there are already several working drugs). Once we’re better able to get our brains around calorie restriction, I think that CR mimetics will be right behind the sirtuin-based drugs. To the extent that these sorts of drugs will help prevent acknowledged illnesses like Type II diabetes, there’s already a clinical indication for them, so they should sail through approval on that basis.

Like it or not, the main thrust of the research community interesting in healthy longevity is presently towards metabolic manipulation and slowing aging. If we want better ways forward - fixing age-related damage, rejuvenation and reversing aging - to gain greater funding and come to dominate, we're going to have to prove our case.

Technorati tags: biotechnology, calorie restriction, medical research, resveratrol, video

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This is rather too close to the wire, but hopefully there are still some folk in the community with time to spend tomorrow. I've been up at strange hours and editing over the past month - and this weekend.

As some of you know, and as mentioned a little while ago Aubrey and I have been working for some time on a popular book on SENS science. We are coming up on a publisher deadline this Sunday night (tomorrow), or early Monday at the absolute latest, and while our last request "grossed" a lot of volunteers, the "net" (in terms of folks actually in a position to help in the required time frame) was lower, and we now really need a few more hands on board urgently.

We really need some folks with the ability to put in some time on at least 1 (and of course preferably more) illustrations for the book in the next 36 hours. Projects range from line drawings and graphs to actual illustrations.

Please email main@mprize.org if you can make such a volunteer contribution; it would be greatly appreciated, and acknowledged in the book.

Thanks!

Nothing quite like that exponential increase in work as the deadline moves ever closer; enough to make one feel like time spent at university all over again.

Technorati tags: books, activism, SENS, volunteering, writing

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Attila Csordás of Partial Immortalization is running a series of interviews with folk in the healthy life extension community, starting with the bloggers. The interview questions are open to anyone to take a stab at:

1. What is the story of your life extension commitment?

2. Is it a commitment for moderate or maximum life extension?

3. What is your favourite argument supporting human life extension?

4. What is the most probable technological draft of human life extension, which technology or discipline has the biggest chance to reach it earliest? (regenerative medicine, nanotechnology, gene therapy, caloric restriction, bionics, hormones, antioxidants, …)

5. When?

6. What can blogs do for LE?

My responses were posted a few days ago, should you be interested, but I think that those of Chris Patil of Ouroboros - an actual life scientist, researching the biology of aging, rather than one of us cheerleaders - are far more worthy of your attention.

On the ideological side, I just think it’s a waste to have to die. It takes us a long time to figure this “life” thing out, and I find the moving-goalposts aspect of aging and decrepitude very frustrating. Additionally, there are so many things that I’d like to see with my own eyes, not just my imagination, things that require what we now think of as generations of time: planetary exploration, for one. Fixing the planet we’ve got, for another.

On the practical side, aging doesn’t seem necessary. The machine of our bodies is great at renewing itself early in our lives, and we know of lots of ways to keep it in good shape for a long time (exercise being my favorite example; and while I’m less convinced than some, I think calorie restriction is very promising). It’s not that much of a stretch to imagine prolonging the process of renewal substantially, if not indefinitely.

For all the advocacy and fundraising we might achieve in the next few years, someone has to perform the research that moves medicine and longevity ahead. You can't change the world with just good will and a fistful of dollars, however hard it was to get both of those line items in hand - you need infrastructure and a research community that can be purposed to the task at hand.

Technorati tags: advocacy, interview, life extension

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A small community of folk gently prod me with each new resveratrol study making its way through the research pipeline. Some of them sell the stuff, some are being helpful news scouts, but the general tenor is often "hey, check this out, best thing since sliced bread." This same behavior applies, with different small communities of folk, to most other better known (or better hyped) products of a similar class in recent years. I believe this all to be more than a touch overenthusiastic.

It has to be said that I'm a curmudgeon and rational, all round late adopter when it comes to applying biochemistry to my body. I'm not fundamentally opposed to the use of found or screened chemicals by any means, but metabolic science is hard. Very hard. Scientists don't yet have a good handle on the complexities involved; frankly, they don't even have a good handle on the complexities of using the mountains of information they are generating. As has usually been the case in human history, in the biotechnologies of metabolism, our ability to take action outstrips our ability to predict and control consequences.

With that in mind, let me say this: our metabolic biochemistry looks like a big wall full of levers. Some of them are painted red, and we think we understand what the instructions beneath these red levers say. Maybe. How much information do you feel you would like before you pull the big red levers in your own personal metabolism? What level of risk due to disease would you presently need to be suffering in order to take the risk represented by a new compound? How do you evaluate these levels of risk?

These are good questions; you'll find yourself in a position to be asking it often in the years ahead, as scientists become a good deal better at finding or generating new compounds for ever more narrow applications. There are no right answers; it's up to each of us to decide how we'd like to manipulate our own bodies. The sellers of resveratrol will rightfully argue that they are helping those who want to set forth on the basis of the information to date. From my point of view, however, resveratrol is a fair way from meeting the standard for something I'd choose to use.

However you think about this, I encourage you to do more reading than you were intending to do; there's a great deal of information out there on resveratrol.

The gold standard for science to back a form of metabolic manipulation is the research supporting the practice of calorie restriction. It is an open question to whether some shared mechanisms mean that calorie restriction mimetics like resveratrol can piggy-back on this wealth of data to a lower risk. But why take that risk? If you're healthy and young, why risk the use of a compound with comparatively little data behind it versus a lifestyle practice with a great deal of data behind it? Equally, why dive in now versus waiting for more information?

The scientific world is littered with biochemicals that performed wonderfully in mice and then fell by the wayside in humans. The medical and supplement world is littered with poor or varied formulations of chemicals that have little to do with the forms used to obtain well-known laboratory results. There are many slips between the lab and your body; many are very hard or even impossible for folk like you or I to detect ourselves, but each passing year will reduce their number in any given case.

As a final note, this is all a sideshow. It has no more application to the long-term future of medicine and enhanced longevity than whether or not you exercise regularly. It doesn't matter how much resveratrol you take. It wouldn't matter if the folks at Sitris Pharmaceuticals developed a miracle calorie restriction mimetic next year that gives 200% of the health and longevity benefits of actual calorie restriction with no downside. These line items would become a part of good health practices - but you will still age, and you will still weaken, suffer and die.

The point which often goes undiscussed by the CR folks, most biogerontologists, longevity gene fans (including people such as Sinclair and Guarente who are really studying the mechanisms by which CR works), centenarian researchers, most "anti-aging" physicians, etc. is that with these approaches the animals (and people) WILL STILL AGE and WILL STILL DIE! This approach does nothing but slow down the rate of aging -- it does not stop it or reverse it.

Metabolic manipulation is hard to perform safely; it's an enormously complex system, and dire consequences can be waiting to leap out decades down the line. Researchers are spending hundreds of millions of dollars on the problem, with the goal of perhaps a decade or two of healthy life extension as the end result, a decade or two from now. Not to be sniffed at - but you will still age, suffer and die.

There is a better way forward, however, a way in which hundreds of millions of dollars could be used to eliminate an entire contributing class of the molecular damage that causes aging - and in that same 10 to 20 year timeframe. Our metabolism produces an aggregate rate of unrepaired cellular damage; calorie restriction and compounds like resveratrol appear to alter the functioning of metabolism to lower this rate of damage. A form of engine optimization, if you like. There are paths of scientific endeavor that aim at the easier task of repairing - or rendering irrelevant - this damage, however, rather than slowing down its accumulation. Why pay hundreds of dollars for super-expensive, super-effective oil when you can take your car to a mechanic and gain ten times the benefit, in other words.

The Strategies for Engineered Negligible Senescence (SENS) is one such view of repair-based longevity medicine, setting out to show that we understand far more of the damage that causes aging than we do about the metabolism that generates this damage. The point of easiest and most effective action is made quite clear: it is to reverse aging, not slow it.

Think of it this way: an expensively developed slowing of one cause of aging is a one-shot deal that does not help those already physically old. But the expensively developed method of repairing one cause of aging can be applied again and again, and it does help those who are already loaded down with age-related damage. What's more important: rushing after the expensive development of drugs that give short term gains, or laying down the foundations for science that will actually repair aging? Where would you apply the dollars?

Technorati tags: calorie restriction, life extension, resveratrol

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As the year winds to a close, folk start to think about where to direct year-end charitable donations. Just prior to embarking upon this post, I finished sealing up a check to the Methuselah Foundation, my favored 501(c)(3) all-volunteer nonprofit dedicated to advancing real, meaningful anti-aging research.

By "real, meaningful anti-aging research" I mean the science of identifying and repairing the classes of molecular damage that accumulate with age, distorting and destroying the finely balanced workings of our body. I do not mean slowing aging through tinkering with the workings of our metabolism, and nor do I mean the futile and expensive effort of patching up the end results as best we can. It is an accumulation of damage - detrimental changes at the cellular and biochemical level - which lies at the root of age-related conditions; our body is a complex machine, and like other machines it fails when it becomes worn and clogged. Learning how to repair that damage will mean halting and reversing aging - scientific rejuvenation, in other words. Striking at the root is the best way to obtain results in any field, and here it offers the chance of results within our lifetime.

Given that the vast majority of all medical research goes towards ineffectively patching up the final failure of age-damaged bodies, and almost all longevity research is focused upon slowing aging through metabolic manipulation, there is a great need for organizations like the Methuselah Foundation. More effective roads forward must be encouraged and championed if we are to live the much longer, healthier lives promised by medical science.

You may have read about the work of the Foundation in the media in the past few years, including:

• The MPrize for anti-aging research
• LysoSENS and MitoSENS research projects

All of this has been funded by the generosity of donors, largely folk just like you and I, who have stepped forward to help make a future they would like to live in. Go ahead and read the statements of the donors.

How much more could we all achieve if we weren't slowly cut down and killed by our increasingly damaged, malfunctioning biochemistry? I hope you'll give some thought to supporting work in improving healthy human longevity, helping to bring about a world in which the 100,000 people who will die today from the results of aging can instead live on in health and vigor.

Technorati tags: activism, advocacy, life extension

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