Fight Aging!

Calorie restriction with optimal nutrition is known to extend healthy life span in mammals - this from the wait and see method of study, meaning that all we can say for sure today for humans is that it does great things for your long-term health. Researchers have been digging into the mechanisms of calorie restriction more energetically in recent years, hoping to find the keys that change metabolism to slow aging.

The other side of the metabolic approach to intervening in the aging process is the search for longevity genes - mutations or changes in gene expression that change the processes of metabolism to slow down the accumulation of age-related damage. Scientists have been turning up a handful of new longevity genes every year in the recent past, many connected to the mechanisms of calorie restriction, many not.

After studies demonstrating extended life span through single gene mutations, and studies demonstrating extended life span through calorie restriction, why not studies of both at once? There's a lot of that going on at the moment, as researchers attempt to understand just how many distinct ways exist to improve metabolism and slow aging.

How diet interacts with longevity genes:

In laboratory mice, suppression of growth hormone (GH) signaling by spontaneous mutations or targeted disruption of GH- or IGF1-related genes can lead to an impressive increase of longevity. Hypopituitary Ames dwarf (Prop1 df) and GH receptor knockout (GHRKO) mice live 35-70% longer than their normal littermates.

Many phenotypic characteristics of these long-lived mutants resemble findings in genetically normal animals subjected to calorie restriction (CR). Microarray and RT-PCR studies of gene expression suggest that effects of the "longevity assurance genes " (Prop1 df or Ghr-/-) and CR are overlapping but not identical.

Subjecting Ames dwarf mice to 30% CR starting at 2 months of age leads to a further significant extension of their average and maximal lifespans. In contrast, identical CR regimen has either no or very little effect (depending on gender) on longevity of GHRKO mice. We suspect that this difference in response is related to the fact that CR improves insulin sensitivity in Ames dwarfs but does not further increase the extreme insulin sensitivity of GHRKO mice.

To search for effects of CR associated with extension of longevity, we are studying expression of insulin and IGF1-related genes in the liver, skeletal muscle and heart of normal and GHRKO mice.

Researchers will be working on the mechanisms of metabolic longevity for many years to come - it's a rich vein. It does seem plausible, however, that the biomechanisms of calorie restriction could be completely uncovered and understood within the next five years. The present pace is fast, and a great deal of funding is available in that part of the field.

For all that, if you're one of those folk holding out for a good calorie restriction mimetic (a drug to trigger all the same controlling gene expression changes without the need to diet), it's worth bearing in mind that a fair chunk of the benefits of calorie restriction seems to stem from cutting down visceral fat mass and not triggering an insulin resistance feedback loop through chronic overeating.

Meanwhile, we should all recall that slowing aging buys us little in comparison to methods to repair aging, and that those repair methods will likely be easier to develop in any case. It's a big leap to build a better metabolism when we're so far from fully describing the one we have. A far smaller leap to undo the known changes that turn a young metabolism into an aged, damaged metabolism.

EurekAlert! reports on another of the many teams working to create a cost-effective source of dopamine-producing neurons to replace those lost in Parkinson's disease: "Previously, we were able to coax these multipotent [uterine] stem cells to differentiate into cartilage cells. Now we have found that we can turn uterine stem cells into neurons that can boost dopamine levels and partially correct the problem of Parkinson’s disease ... The stem cells in this study were derived from human endometrial stromal cells that were cultured under conditions that induce the creation of neurons. These cells then developed axon-like projections and cell bodies with a pyramid shape typical of neurons. ... The dopamine levels in the mice increased once we transferred the stem cells into their brains. The implications of our findings are that women have a ready supply of stem cells that are easily obtained, are differentiable into other cell types, and have great potential use for other purposes."

Link: http://www.eurekalert.org/pub_releases/2008-03/yu-usc032808.php

Over at Philosophy Now, an example of moderate, sensible support for the engineering of greater human longevity, and rejection of a variety of foolish arguments against that goal: "despite large increases in life span, the length of the period of illness before death is remaining steady, and the proportion of life spent ill is declining. ... Even this welcome prospect does not satisfy some miserabilists: 'We cannot afford all these old people' is the cry. Hidden in that statement is the assumption that old people, even in good health (as most are), are not going to contribute to the wealth of the nation. There is, of course, no reason why they too should not be producers - so long as they are not prevented from doing so by negative expectations and ageist attitudes, and policies ensuring that those negative expectations are fulfilled. ... We may anticipate therefore that for many, perhaps most people in developed countries, average healthy, productive life expectancy will increase indefinitely."

Link: http://www.philosophynow.org/issue66/66tallis.htm

Here's a third transcript from last year's Securing the Longevity Dividend event. The speaker is S. Jay Olshansky, representative of those who believe the best path forward is to slow aging via metabolic manipulation. "Now, let me just give you the bottom line, and then I will give you the rationale behind it. The main argument in this manuscript was fairly straightforward, and that is, the time has arrived for us to make an investment that we have never made before, and that is an effort to slow the biological process of aging in people. We are making this argument now for a number of reasons, one of the most important of which is - and you are speaking to a very conservative individual here - I am willing to say something now that I was not willing to say just five to ten years ago. That is that I believe the technology and the field of aging has advanced sufficiently that many of us now believe that it is not just a plausible goal to slow aging in people, but a necessary goal - something that we must pursue in the coming decades, for reasons that I am going to demonstrate shortly."

Link: http://www.acceleratingfuture.com/people-blog/?p=1744

Tissue engineers at work: "Engineering blood vessels for bypass surgery, promoting the formation of new blood vessels or regenerating new skin tissue using stem cells obtained from the most accessible source - hair follicles - is a real possibility ... We have demonstrated that engineered blood vessels prepared with smooth muscle progenitor cells from hair follicles are capable of dilating and constricting, critical properties that make them ideal for engineering cardiovascular tissue regeneration ... Since smooth muscle cells comprise the muscle of numerous tissues and organs, including the bladder, abdominal cavity and gastrointestinal and respiratory tracts, this new, accessible source of cells may make possible future treatments that allow for the regeneration of these damaged organs as well. ... The best case scenario is that from this one very accessible and highly proliferative source of stem cells, we will be able to obtain multiple different cell types that can be used for a broad range of applications in regenerative medicine."

Link: http://www.buffalo.edu/news/9287

Carrying more visceral fat in your body than you need to get by - the standard result of a life involving too many calories and too little exercise - reduces your longevity. It also greatly increases the chances of your later years being unhealthy, painful and expensive. I've looked at a range of mechanisms by which this happens:

• A Gentle Reminder That Fat Will Eat Your Mind
• Fat and Inflammation
• How Excess Fat Tissue Slowly Destroys You
• Fat, Inflammation and Atherosclerosis

Knowing is half the battle, but putting the work in to shed that fat will pay great dividends over the years. Who wants to be frail and incapacited by diabetes and Alzheimer's at 70, versus fit enough to get out and play a game of tennis whenever you feel like it?

Continuing this examination of reasons not to be overweight, I noticed an interesting paper that demonstrates quite directly the cost of visceral fat (visceral adipose tissue in science-speak) on life span.

Visceral Adipose Tissue Modulates Mammalian Longevity

Caloric restriction (CR) can delay many age-related diseases and extend lifespan, while an increase in adiposity is associated with enhanced disease risk and accelerated aging. Among the various fat depots, the accrual of visceral fat (VF) is a common feature of aging, and has been shown to be the most detrimental on metabolic syndrome of aging in humans.

We have previously demonstrated that surgical removal of visceral fat (VF) in rats improves insulin action, thus, we set out to determine if VF removal affects longevity.

We prospectively studied lifespan in 3 groups of rats: ad libitum fed (AL), 40% caloric restriction (CR) and a group of ad libitum fed rats with selective removal of VF at 5 months of age (VF-). We demonstrate that compared to AL, VF- rats had a significant increase in mean and maximum lifespan and significant reduction in the incidence of severe renal disease.

CR animals demonstrated the greatest mean and maximum lifespan the lowest hazard rate of death as compared to AL rats. Taken together, these observations provide the most direct evidence to date that a reduction in fat mass, and specifically VF, may be one of the possible underlying mechanisms of the anti-aging effect of CR.

This conclusion seems likely - but note that sensibly practicing calorie restriction does much more under the hood than just lower the level of fat in your body. Also note that you don't need to be full-on calorie restricted to lose enough visceral fat to greatly benefit from its absence. The difference between an average, healthy body weight and what passes for the norm in much of the developed world today is large enough to make a big difference to health and longevity in later life.

The body is a complex machine, and like all machines, it ages more slowly if you take better care of it. That much should be common sense.

Generally speaking, I'm not a big fan of the sort of hyperaggressive tinkering with supplements that passes for action amongst a large portion of the healthy life extension community. It's highly unlikely to improve significantly on simple exercise, calorie restriction and a sane multivitamin. You have no reliable tool to measure how effective your vitamin regimen is in any case, short of waiting for the necessary decades to see how your long term health goes. Furthermore, solid scientific support is sorely lacking for most of the recommendations you'll see out there - a situation far removed from the vast array of detailed support for exercise and calorie restriction. The waters are muddied by less than ethical marketeers with supplements to sell and money to make; it's very hard for the average fellow to figure out what's what.

Quite aside from all that, how exactly is that tinkering with supplements helping to advance the science of repairing age-related damage? Answer: it isn't. Perhaps your energies are better directed elsewhere...

There are, of course, exceptions to all rules. Leucine supplementation for older folk might just be one of those - although there's a little more work to be done to make an airtight case. Take a look back at the Longevity Meme archives:

Preventing Age-Related Muscle Loss:

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

Sarcopenia As Dietary Issue

Sarcopenia, age-related muscle loss, is well known as a common result of aging - and the resulting lack of exercise hastens age-related decline in other ways. ... Since nutritional studies show that many elderly individuals eat less protein than the average person, researchers have reasoned that if the elderly simply increased their protein intake, they might slow down muscle loss -- as long as old age doesn't inherently interfere significantly with the ability to make muscles out of the protein in food. ... We wanted to know if there is some reason your grandmother's body, for example, can't stimulate muscle growth in response to eating the same protein-rich meal that you eat, which might over time contribute to muscle loss ... [however] older bodies are just as good as young ones at turning protein-rich food into muscle.

So, maybe leucine, maybe just protein deficiency. A more recent study caught my eye today; it manages to add support to both sides without actually resolving the question either way:

Supplementation with Dietary Leucine to a Protein-Deficient Diet Suppresses Myofibrillar Protein Degradation in Rats

Muscle mass is regulated by the synthesis and degradation of muscle protein, which in turn are affected by aging, several catabolic diseases, and malnutrition. Amino acids, particularly leucine, are known to stimulate muscle protein synthesis and suppress muscle protein degradation, although their long-term effects are unclear. The objective of our research was to elucidate whether long-term feeding of a protein-free or low-protein diet supplemented with leucine suppresses myofibrillar protein degradation.

...

These results suggest that long-term feeding of leucine suppresses the rate of myofibrillar protein degradation and muscle weight loss in rats fed a protein-deficient diet.

Which supports the use of leucine supplementation in a low-protein diet to slow the rate of muscle loss over time, but doesn't tell us whether simply increasing the amount of dietary protein is a better solution. This is probably of interest to folk practicing calorie restriction, given that their intake of protein is reduced (indeed, reduced protein intake may be the driving mechanism for the beneficial metabolic changes brought on by calorie restriction). As I said above, however, this all needs more weight of research.

A long audio interview with biomedical gerontologist and healthy life extension advocate Aubrey de Grey can be found at Futures in Biotech: "Benjamin Franklin said: 'In this world nothing is certain but death and taxes'. But in these times of technological revolution, does this statement still hold true? And if so, for how long? Genes have been identified that upon activation can extend lifespan in most organisms. The great labs of Leonard Guarente at MIT (featured in FiB episode 2), Cynthia Kenyon at UCSF, as well [as] Linda Buck, Nobel Laureate in 2004, are all working arduously to elucidate the molecular details to both slow down the aging process and extend lifespan. Well, Aubrey de Grey is a fairly controversial figure because he proposes doing away with death all together - leaving us with only taxes, I guess?" Find out more about how the repair of aging can be achieved - as well as ongoing research to make this a reality - at the Methuselah Foundation.

Link: http://thisweekintech.com/fib30

Biomedical gerontologist Aubrey de Grey will be one of the scientists featured in a Barbara Walters special to be aired on April 1st. I can't imagine that this will be at all rigorous in its examination of longevity science, but the more who hear the message, the better: "From a potential breakthrough pill to controversial rejuvenation technologies, Walters reports on what the future may hold, as well as what one expert says is the only proven way to extend life. ... 'I think that within the next few decades, we have a pretty good chance of effectively defeating aging as a cause of death,' says [Dr. Aubrey de Grey], a respected and controversial expert on the biology of aging. But if the keys to living a long, healthy life are not found soon, some people will rely on [cryonics] - chemically preserving one's body at very low temperatures in hope of one day being brought back to life. ... Also, how close are we to using rejuvenation technology to regenerate body parts? ... 'someday, if you get into an auto accident, we'll just take a skin cell and grow you up a new kidney... cells could, in the future, replace almost any part of the body.'"

Link: http://www.allamericanpatriots.com/48744649_barbara-walters-reports-live-be-150-can-you-do-it-

That excess visceral fat you're carrying causes chronic low-level inflammation, which damages you in all sorts of ways. One of those ways is atherosclerosis, which tends to up and kill you without warning. In fact, eating all the food required to gain a large amount of visceral fat causes a feedback loop in your metabolism that spirals down into insulin resistance and diabetes - both of which make the effects of having a lot of visceral fat that much worse and that much more rapid.

But that extra fat won't just make you much more prone to be frail, and it won't just try to kill you - it'll also eat your mind. Researchers are coming to view Alzheimer's disease as analogous to diabetes, a result of lifestyle choices for most, touching on many of the same metabolic processes as diabetes, and the risk factors seem to be much the same.

Big Bellies Linked to Alzheimer's Disease:

The study of more than 6,000 people found the more fat they had in their guts in their early to mid-40s the greater their chances of becoming forgetful or confused or showing other signs of senility as they aged. Those who had the most impressive midsections faced more than twice the risk of the leanest.

Surprisingly, a sizable stomach seems to increase the risk even among those who are not obese, or even overweight

...

The research is the latest evidence that fat in the abdomen is the most dangerous kind. Previous studies have linked the apple-shaped physique to a greater risk of diabetes, heart disease and even cancer. Researchers suspect that those fat cells are the worst because of their proximity to major organs. They ooze noxious chemicals, stoking inflammation, constricting blood vessels and triggering other processes that might also damage brain cells.

"There is a lot of work out there that suggests that the fat wrapped around your inner organs is much more metabolically active than other types of fat right under the skin," Whitmer said. "It's pumping out toxic substances. It's very potent toxic fat."

Another excellent reason to take care of the health basics - a responsible level of diet and exercise - before your body sabotages your mind. The longer you leave it, the more damage you're creating, and the more you're cutting from your likely healthspan.

Ouroboros looks at advanced glycation endproducts (AGEs) and age-related damage in the extracellular matrix: "The authors exposed fibroblasts to two types of [AGE-modified proteins], which had overlapping but non-identical effects on gene expression. The common features of the response to the two proteins are most intriguing, however: increased transcription of matrix metalloproteases (MMPs), which break down the extracellular matrix (ECM), and decreased transcription of ECM components like collagen and fibronectin. Taken together, these effects would result in a net weakening of the ECM, which in turn would have profoundly negative effects on organ function, ranging from skin wrinkling to cardiomyopathy. ... increased MMPs and ECM breakdown are hallmarks of fibroblast senescence, which is usually associated with DNA damage or telomere shortening - could AGEs be stimulating premature senescence, either by damaging DNA or via some other pathway?"

Link: http://ouroboros.wordpress.com/2008/03/26/ages-and-the-ecm/

What makes a stem cell pluripotent, or an embyronic stem cell totipotent, able to form all other cell types? It has to be down to the mechanisms of genes and proteins, and researchers are working to understand those mechanisms: scientists have "identified a network of hundreds of genes that keep embryonic stem cells in their characteristic malleable state, able to develop into any cell type when the time comes. The finding, based on studies of mouse cells, provides valuable insight into the way stem cells function, and could help researchers find ways to reprogram adult cells for therapeutic use. ... there has been a recent explosion of interest in reprogramming skin or other developed cells to act like stem cells, with the ultimate goal of treating disease. But currently, he said, the process is still essentially a "black box." ... You add genes, and the cells reprogram. What happens in between? ... This kind of work provides the materials to get a better understanding of that process. The goal is to be able to manipulate cells in a very directed way."

Link: http://www.hhmi.org/news/orkin20080325.html

The March progress report and newsletter from the Methuselah Foundation is up: "A new donation program was recently launched at the Foundation. A brainchild of Dave Gobel, the 1% For Life program is a committed giving program where individuals or corporations commit 1% of their selected assets to the Foundation. ... A paperback edition of Ending Aging, including a new afterword bringing the scientific content right back up to the leading edge of current research, will be published in September this year. ... Our MitoSENS team is moving during this quarter to the laboratory of Dr. Marisol Corral-Debrinski in Paris. Corral-Debrinski's group is unique in the world in focusing specifically on allotopic expression, the technology that will eventually allow us to protect our life-sustaining mitochondrial genes from the mutations resulting from aging. Meanwhile, LysoSENS has continued to generate a stream of exciting results, including the publication of a peer-reviewed paper in the international journal Biodegradation. ... As well as strengthening our existing research teams, we are now ready to initiate work in at least two more strands of the SENS program during the coming year; all thanks to the generosity of our supporters."

Link: http://blog.methuselahfoundation.org/2008/03/methuselah_foundation_newslett.html

Researchers are working their way closer to a grail of tissue engineering: a fabricator that can print out living organs in three dimensions just like the rapid prototyping devices used today in a variety of industries. Plastics and inks become cells and biomaterials, and the whole works much the same way. Organs are many magnitudes more complex in structure than the plastic prototypes turned out by fabricators in the design industry, but the cells used to build those organs can - in theory - be induced to do most of the small-scale organization for you. Roland Piquepaille notes one of the latest technology demonstrations:

"We will never be able to print a liver with all of its many details," says Forgacs. "But it is not necessary. If you initiate the process, nature will do it for you."

According to MU, "the team used bio-ink particles, or spheres containing 10,000 to 40,000 cells, and assembled, or 'printed,' them on to sheets of organic, cell friendly 'bio-paper.' Once printed, the spheres began to fuse in the bio-paper into one structure." Nature adds that "when they printed out cardiac and endothelial cells, the cells fused into a tissue after 70 hours, and began beating in time like regular heart tissue after 90 hours."

Nature also explains why this project is different from previous ones. "What makes this work different from that done in most other tissue-engineering labs is that Forgacs's team does everything without a scaffold - they don’t start with an object shaped like the tissue or organ they are aiming to create, but instead plan to print the whole thing from scratch, from the vasculature up. This should make it easier to print any type of organ, they say, as they don’t have to develop different scaffolds for each tissue type. 'Often when you implant a scaffold you get inflammation,’ says Forgacs.'"

Researchers are still building the components of organs in the technology demonstrations - we're a few years away from fabrication of even "simple" organs, such as the heart or liver. As I've noted previously, the big hurdle of the moment is getting the blood vessels - the vasculature - right. Blood transport is vital to building living tissue of any meaningful size, and it's a hard problem if all the blood vessels, from microscopic capillary networks on up, have to be designed by hand into the tissue you're printing.

I'm pleased to note that the Immortality Institute folk will be offering incentive prizes to participants in the Longevity Meme Folding@Home team on a quarterly basis going forward: "The Longevity Meme team has grown and performed very well in the years since its formation. It takes organization and active recruitment to break into the top 200 ranked teams; many of the Immortality Institute regulars have stepped up to provide that organization. Thank you all for helping to make the team a continuing success. ... Winners will be determined by how many points are accumulated over the course of three months as reported at the Stanford Folding@home statistics site. The first quarter of competition begins at 12:00 a.m. Eastern daylight time (U.S.) April 2nd and ends at 12:00 midnight, Eastern daylight time, on June 30th." Newcomers are welcome, so jump on in and help the team climb the ranks.

Link: https://www.fightaging.org/archives/001441.php

Some interesting material from a scientific study of attitudes to healthy life extension and enhanced longevity is posted to Cryonet:

The age of the respondent was related to life-extension attitudes [with] the older respondents tilting in the pro-longevity direction.

Pro-longevity attitudes were strongest in the separated-divorced group and weakest in the single group.

From a utilitarian, economic action viewpoint, that is much as I would expect. I think there's ample circumstantial evidence to suspect that those who claim to be fine with aging and dying will mostly change their minds when they get there. The unpleasant future is all too easily hand-waved away for another day - until that day finally comes home to roost.

The study presented subjects with a range of positive and negative viewpoints on healthy life extension. The viewpoints vary widely in validity, with those on the economic side of the house being particularly bad, but I don't think that's too important when it comes to drawing conclusions from the reactions of study participants:

I. Personal Emotional Rejection (PER) reflects a harsh rejection of life extension with endorsement of items focused on pointlessness and waste, and contrary-to-nature aspects of extending life span. Other items reflect the personal cost of life extension (e.g., delaying commitments or prolonging goals, inducing boredom).

II. Utopian Vision (UV) points to the many advantages of life extension for older people and for society at large.

III. Social Economic Burden (SEB) highlights the economic burdens on the individual and the health-care system flowing from life extension. The highest loading items stress preference for health over longer life and a fear of financial dependency for the individual, and exhaustion of resources for the society.

Age was significant for each of the factors. ... The older the adult, the more likely is he or she to reject the harsh negativity toward life extension reflected by the items loading on factor I. Correspondingly, chronological age is positively associated with endorsement of items that promise a Utopian future with life extension (Factor II). Finally, the outcome for Factor III is somewhat counterintuitive as we observe that older adults are significantly more disposed to endorse anti-longevity items. These items concern the added costs of health-care and social welfare and hence raise the possibility of exhaustion of financial resources.

That last point only reinforces my conviction that economic ignorance is one of the greatest threats to the future of healthy life extension (and indeed to all meaningful advancements in technology). It is a strange world when so many believe that more healthy people working away to produce value and trade with one another will somehow make us all poorer:

• Jealousy, Fear, Envy and Economic Ignorance - Powerful Poisons
• If We Fail, It Will Be From Ignorance
• Death (For Everyone) Before Inequality (For Anyone)

The points that found the most favor in the study might lead us to a little more optimism, however:

Of the positive survey items, these were the most stable across the studies:

Longevity improving life more time for goals
Extending life giving respect to old age
Longevity research as duty to future generations
Long Term Relationship (LTR) quality will increase with longevity
Society will benefit from greater wisdom
Increase budget for this research

Other positive items from the LEQ:

Favor longevity research even if product unaffordable
Extend life to have more leisure time
Estimate satisfaction greater at age 110 than 75
Families benefit from cross-generation interaction

I'm sure you'll recognize a number of these in past material produced by longevity advocates, myself included. Biomedical gerontologist Aubrey de Grey in particular has argued for duty to those yet to live - in his view, who are we to decide that our grandchildren's lives must be as short as our own? By failing to heed the moral imperative to longevity research, we condemn future generations to have no choice in their own longevity.

The New Scientist reports on the use of therapeutic cloning in development of a cell therapy for Parkinson's disease: "An international team has restored mice with a condition similar to Parkinson's disease back to health, using neurons grown in the lab that were made from their own cloned skin cells. ... All six mice that had been given grafts of neurons derived from their own skin cells got significantly better, scoring well on tests of movement. ... It was a very challenging project. You need a special set of expertise that is typically not available in an individual lab. ... If the process cannot be made less technically demanding, any treatment for human patients is likely to be extremely costly. This is why many researchers are excited about the possibility of using a simpler genetic reprogramming technique [that can] can turn skin cells into cells that have similar properties to [embryonic stem] cells."

Link: http://www.newscientist.com/article/dn13523.html

Scientific American looks at work on bringing organ regeneration from lower animals to mammals like us: "Our research group has already described a natural blastema in a mouse amputation injury, and our goal within the next year is to induce a blastema where it would not normally occur. ... We hope that this line of investigation will also reveal whether, as we suspect, the blastema itself provides critical signaling that prevents fibrosis in the wound site. If we succeed in generating a blastema in a mammal, the next big hurdle for us would be coaxing the site of a digit amputation to regenerate the entire digit ... Developmental biologists are still trying to understand how joints are made naturally, so building a regenerated mouse digit, joints and all, would be a major milestone in the regeneration field. We hope to reach it in the next few years, and after that, the prospect of regenerating an entire mouse paw, and then an arm, will not seem so remote. Indeed, when we consider all that we have learned about wound healing and regeneration from studies in various animal models, the surprising conclusion is that we may be only a decade or two away from a day when we can regenerate human body parts."

Link: http://www.sciam.com/article.cfm?id=regrowing-human-limbs&print=true

Far too much energy is spent on looking at what presently exists, our present state of being in ever greater detail and fine degree of measurement, when rampant change is the nature of the day. Why are people willing to spend inordinate amounts of time and energy examining and debating which narrowly separated socio-economic groupings of humanity live a year more in health here or year less in health there? This is an age of foaming scientific revolution and rapid progress in biotechnology and medical science, in which all these factors are changing very rapidly. Time spent carefully drawing lines between groups of people - that will be erased almost immediately with the speed of change these days - is time not spent helping to make lives better.

It seems evident to me that I should spend far more effort in relation to progress in the fields that will add decades to healthy life spans in due course, swamping all minor variables of the human condition. Those small differences are insignificant in that context - and will become increasingly so as success in medical research continues.

So why is it that most people care so much more about the shiny, distracting trinkets of the now, a few years more or a few years less than someone else, in comparison to the far more important issue of the desired future and how to get there? I wonder. I seem to recall saying much the same thing in connection with research into telomere length and socio-economic status back in 2006:

[We should] recognize that time is far better spent acknowledging that we're all suffering from a condition that will deliver suffering, pain and death - and then doing something about it rather than simply observing it.

We are all doomed unless we dig ourselves out of the hole of aging via the future of medical technology. What does it matter that some of us are a handful of percentage points more or less doomed than others, largely through our own actions in exercise, diet and other controllable factors? It's still doom, and we'll all be just as rescued by technologies capable of repairing the damage that is aging.

My thinking was steered this way once more by a brace of recent articles on education level and longevity - which is just another correlation in the general pattern of wealth, use of medical resources, good health practices, and all that other fun stuff that fits in with "socio-economic status." I don't see more in the way of separating causation from correlation this time around - and the press is generally much more interested in playing the game called "who has more" in any case. Not a forward-looking group, mainstream journalists, nor much acquainted with context in terms of past and future. They are the voice of the shiny trinkets of the now. See what you think:

Harvard Researcher: Education Key to Longevity

"We looked at life expectancy at age 25," Meara says.

"How many additional years can you expect to live if you arrive at age 25 and your education has stopped at high school, or sooner? Versus how many years, can you expect to live if you've reached aged 25 and you've gone on to at least some college…"

Meara says they found that in 1990, a 25-year-old who only had some secondary school could expect to live for a total of 75 years. In 2000, a 25 year old with some secondary education could also expect to live to the age of 75.

In contrast, for a better educated 25-year-old, they could expect to live to the age of 80 in 1990. Someone with a similar education level in the year 2000, could expect to live to be more than 81 years, 81.6 years to be exact.

Longevity rising for educated:

"If you look in recent decades, you will find that life expectancy has been increasing, which is good, but when you split this out by better-educated groups, the life expectancy gained is really occurring much more so in the better-educated groups," said lead researcher Ellen Meara, an assistant professor of health-care policy at Harvard Medical School.

The answer may lie with tobacco. About one-fifth of the difference in mortality between the groups can be accounted for by smoking-related diseases such as lung cancer and emphysema, Meara said.

A large chunk of the rest of the difference is likely related to exercise habits and excess body fat - obesity is at least as damaging to healthy longevity as smoking, and possibly more so when combined with lack of exercise. We can also throw in psychological stress for consideration; plausible evidence suggests that chronic stress damages biochemistry into more rapid aging over the years.

I could go on - there are all sorts of ways in which we can choose to damage ourselves, or let damage continue at a greater rate due to circumstances we can control. All of this is irrelevant and unimportant, however, when compared to the speed with which medical technologies for the repair of aging are developed. If we can make that happen rapidly enough, we're all rescued. If not, we're all doomed.

History teaches us that research prizes are a great way to drive progress in science and its application. Competition is fundamental to human endeavor and achievement. In our neck of the woods, we can see that the Mprize for longevity science has gone a long way towards turning the aging research community away from its conservatism and reluctance to discuss extending healthy human longevity. More is always better, however. Via Cosmic Log I see that the X Prize Foundation is considering a prize for longevity research: "Even as the X Prize Foundation kicks off its $10 million competition for super-efficient automobiles, it's working on plenty more prizes to come. X Prize co-founder Peter Diamandis says he’s aiming for two new prizes every year, focusing on five fields. ... Diamandis is already deep into the strategic planning for the next X Prizes. ... We've refined our strategy, and we are planning X Prizes in five vertical fields that we've defined. ... We are looking at life science-related X Prizes, where the Archon X Prize for Genomics is the first. We're looking at areas such as cancer and human longevity."

Link: http://cosmiclog.msnbc.msn.com/archive/2008/03/20/790970.aspx

Inflammation caused by long-term exposure to sunlight hastens the damage of aging in skin, much as it does in many other tissues and systems in the body. From Science News: "Older skin cells turned up production of enzymes called proteases that break down collagen and elastin, proteins that give skin its spring and structure ... As collagen breaks down, skin collapses into wrinkles. ... It's the equivalent of taking the air out of a balloon. The tension goes out of it, and it begins to sag and fold in on itself. ... Inflammation also sets off other skin-damaging processes, such as inhibiting skin's regenerative abilities and changing fatty acid and cholesterol metabolism, which lead to erosion of the protective barrier that holds in moisture. ... sun exposure hastens "this chronic march down the calendar." ... Exposure to ultraviolet radiation from the sun increases inflammation, speeding the aging process."

Link: http://www.sciencenews.org/articles/20080301/note17.asp

Telomerase, the enzyme responsible for lengthening telomeres, is important in many areas of aging and cancer research. However, as ScienceDaily reports, scientists are still working on understanding it and lowering the cost of researching it: researchers have now "identified two new proteins that make up the telomerase complex and have a lead on several more. This is the first significant step toward understanding the makeup of telomerase since 1999. ... describe two protein components of telomerase. They also show that disabling one of the proteins brings telomerase to a grinding halt. Although the work was done in cells in a lab dish, the findings suggest that a drug blocking that protein may be a useful tool against cancer. ... one problem with studying telomerase is that it's available in such small quantities. Growing huge vats of cancer cells in the lab still only results in miniscule amounts of protein. Until recently, no technology was sensitive enough to analyze proteins at such minute levels." This is the path that leads to cheaply produced telomerase for research, as well as better approaches to manipulate its actions in cells.

Link: http://www.sciencedaily.com/releases/2008/03/080320120834.htm

I'm pleased to note that the Immortality Institute folk will be offering incentive prizes to participants in the Longevity Meme Folding@Home team on a quarterly basis going forward:

The Longevity Meme has teamed up with the Immortality Institute to offer a quarterly prize to people who contribute to the Stanford Folding@home distributing computing project - aimed at curing disease through understanding the basics of protein folding.

...

Winners will be determined by how many points are accumulated over the course of three months as reported at the Stanford Folding@home statistics site. The first quarter of competition begins at 12:00 a.m. Eastern daylight time (U.S.) April 2nd and ends at 12:00 midnight, Eastern daylight time, on June 30th.

The Longevity Meme team has grown and performed very well in the years since its formation. It takes organization and active recruitment to break into the top 200 ranked teams; many of the Immortality Institute regulars have stepped up to provide that organization. Thank you all for helping to make the team a continuing success.

Futures are built, one brick at a time, on the self-organizing collaboration of many interested people. Those collaborative communities are built of many, many overlapping modest goals and projects, just like this one. I hope you'll consider joining in, contributing to the Folding@Home project, and through this effort, learning more about the greater goals of longevity science, curing age-related disease, and ultimately repairing the damage of aging.

Head on over to the Immortality Institute to learn how to register for the prize program or discuss Folding@Home in the team thread.

EurekAlert! notes a newly discovered role for insulin in metabolism: researchers report "that insulin inhibits a master gene regulator protein known as SKN-1, and that increased SKN-1 activity increases lifespan. SKN-1 controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress - damage caused by elevated levels of free radicals (byproducts of metabolism) - and various environmental toxins. The new finding was demonstrated in experiments on the digestive system of C. elegans, a microscopic worm often used as a model organism. ... You can manipulate the expression of SKN-1 and the worms live longer ... The idea down the line is that fine-tuning the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, he said. The work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications. But, today's finding may be most important for what it teaches about aging in general." It may go some way towards explaining some of the unknowns related to IGF-1 signaling and lifespan.

Link: http://www.eurekalert.org/pub_releases/2008-03/jdc-jrd031408.php

Some research groups are making the case that all roads lead to autophagy, the process of tearing down and replacing worn cellular components, when it comes to enhancing healthy longevity through adjustments to metabolism. Examples include calorie restriction (CR) - which you can manage all by yourself today - or drugs that mimic some of the effects of CR on regulatory mechanisms in our biochemistry, which you're going to have to wait a little longer for. But it's all down to increased autophagy, they say:

The better known life extension mechanisms in lesser animals are all driven by changes in autophagy - or so say the autophagy specialists. It's true that the various hyperspecialized communities of modern biology are overly cloistered and ignorant of one another's research, but the autophagy researchers are assembling compelling evidence for this position: "Here we show that mutational inactivation of autophagy genes, which are involved in the degradation of aberrant, damaged cytoplasmic constituents accumulating in all aging cells, accelerates the rate at which the tissues age in the nematode Caenorhabditis elegans. According to our results Drosophila flies deficient in autophagy are also short-lived. We further demonstrate that reduced activity of autophagy genes suppresses life span extension in mutant nematodes with inherent dietary restriction, aberrant insulin/IGF-1 or TOR signaling, and lowered mitochondrial respiration. These findings suggest that the autophagy gene cascade functions downstream of and is inhibited by different longevity pathways in C. elegans, therefore, their effects converge on autophagy genes to slow down aging and lengthen life span. Thus, autophagy may act as a central regulatory mechanism of animal aging.

Which is interesting, because other research groups are fairly sure that the enhanced longevity provided by these sorts of metabolic adjustment is accomplished through lowered levels of chronic inflammation and free radical generation:

This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species and inhibition of inflammatory pathways play a central role in the antiaging cardiovascular effects of caloric restriction.

The evidence on both sides is compelling, but it can't be both all autophagy and all inflammation and free radical reduction, and it can't be just one or the other. Conflicting evidence and theories with good experimental backing on all sides are usually a good sign that there is something important left to be discovered, some shift in the overall picture of the field. For example, a comprehensively described link between autophagy, inflammatory processes and free radical generation. For now we're still missing a unifying view of the many known metabolic and genetic changes that increase longevity in mammals - how do they work?

It's always pleasant to see the signs of greater awareness of healthy life extension and longevity science out there in the world. Here's one: a student-produced video of arguments for and against engineered longevity. It manages to catch most of the major points aired by both sides. "Here's our final video. It looks into the pros and cons of extending our human lives beyond their normal capacity. To enhance the feeling of a debate we decided to animate our parts of the script separately then link them together so that there would be a clear distinction between the arguments for (white text) and against (black text) life extension. We also agreed to leave the debate open so that the viewer is left to decide where they stand on the issue." From where I stand, the point that trumps all others is the ongoing tide of age-related death and pain. More than 100,000 people age to death each and every day, and uncounted millions more suffer terribly. There is no practical level of effort we could devote to the repair aging that would be appropriate to the loss suffered with the passing of every single day.

Link: http://fiomar.wordpress.com/2008/03/16/the-great-life-extension-debate/

Via the LEF News, a reminder that taking care of the health basics makes a big difference to the state of your biochemistry over the years: "Inactive people may be 10 years older biologically than their active counterparts, say researchers who measured the length of telomeres in the white blood cells of more than 2,400 twins (mostly women). Telomeres are sequences of DNA that cap chromosomes, protecting them from degrading. ... Each time a cell divides, its telomeres erode, so shorter telomeres are a sign of aging. Twins who were most active during their leisure time (they averaged half an hour of activity a day) had significantly longer telomeres than their twins who were least active (they averaged just two minutes a day). Scientists don't know how exercise protects telomeres from erosion, but other studies suggest that activity may help by curbing inflammation and oxidative stress. Both can shorten telomere length. What to do: Start moving. Any exercise is better than none."

Link: http://www.lef.org/news/LefDailyNews.htm?NewsID=6597

Here's a short review of the effects of calorie restriction on two important areas in the science of metabolism and aging:

This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species and inhibition of inflammatory pathways play a central role in the antiaging cardiovascular effects of caloric restriction. Particular emphasis is placed on the potential role of the plasma membrane redox system in caloric restriction-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance.

We propose that caloric restriction increases bioavailability of NO, decreases vascular reactive oxygen species generation, activates the Nrf2/antioxidant response element pathway, inducing reactive oxygen species detoxification systems, exerts antiinflammatory effects, and, thereby, suppresses initiation/progression of vascular disease that accompany aging.

Chronic inflammation and the generation of reactive oxygen species (or free radicals) are prominent in the present day view of how normal metabolic processes cause the accumulation of biochemical damage that is aging. Look back in the Fight Aging! archives for more:

• Inflammation and the Damage of Aging
• How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You

Calorie restriction reduces the rate at which damage occurs in both of these noted avenues - fewer free radicals, more antioxidant biochemistry to soak up those free radicals, and less inflammation. Given that, it shouldn't be surprising to find that the practice of calorie restriction "makes everything better" when looking at the pace of age-related degeneration. Damage yourself more slowly and your health will last longer.

Adding to the growing list of calorie restriction (CR) benefits: "CR can increase lifespan reliably in a wide range of species and appears to counteract some aspects of the aging process throughout the body. The effects on the brain are less clear, but moderate CR seems to attenuate age-related cognitive decline. Thus, we determined the effects of age and CR on key synaptic proteins in the CA3 region of the hippocampus and whether these changes were correlated with differences in behavior on a hippocampal-dependent learning and memory task. ... We also found that both CR and ad libitum (AL) fed animals exhibited age-related cognitive decline on the Morris water maze task. However, AL animals declined between young and middle age, and between middle age and old, whereas CR rats only declined between young and middle age. Thus, the decrease in key synaptic proteins in CA3 and cognitive decline occurring across lifespan are stabilized by CR. This age-related decrease and CR-induced stabilization are likely to affect CA3 synaptic plasticity and, as a result, hippocampal function."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18342310

ScienceDaily notes continued progress towards manipulating human regenerative processes: scientist "have discovered what chemical in the eye triggers the dormant capacity of certain non-neuronal cells to transform into progenitor cells, a stem-like cell that can generate new retinal cells. ... with aminoadipate, the newly minted retinal cells migrated to where they might be needed in the retina and turned into desirable cell types. Specifically, [the researchers] showed that by injecting the chemical below the retina, the cells give rise to new photoreceptors -- the type of cells that are lost in retinitis pigmentosa or macular degeneration, as a result, leading to blindness. ... This study is very significant. It means it might be possible to turn on the eye's own resources to regenerate damaged retinas, without the need for transplanting outside retinal tissue or stem cells. If our next steps work in animal disease models, we believe that clinical testing could happen fairly quickly."

Link: http://www.sciencedaily.com/releases/2008/03/080318113517.htm

Beware of people bearing either / or choices, especially when both options are terrible. Nothing in life is binary, and there exist no inescapable boxes nor walls that cannot be torn down. You'll always find other choices, other paths forward, if you care to search hard enough.

Here is a charming either / or choice, posed by someone with surprisingly little vision for a medical research:

Controversially, Brown also suggests that wiping out cancer and heart disease might be misguided, because these are swifter, and therefore relatively desirable, ways to die. It would be easy to think him heartless, were it not for his moving and vivid descriptions in the book of watching his own father die from pancreatic cancer. Brown writes how he “returned one last time to the hospice on a vile rainy day - I hadn't seen him for a week - and it was like something from a horror movie. I had never seen someone so dead who was still alive.”

Brown admits “the experience of seeing my father in pain and being in a degraded state was very difficult. But, although it was awful, in the grander scheme, it was a relatively easy death. My father had expressed a fear of dying with dementia, and so that would have been much harder, and that's partly why I believe we shouldn't remove these acute forms of death (like cancer). We'll just be exposing ourselves to longer, more drawn-out forms of death.

It is utterly false to present a choice of working to prevent dementia or working to prevent cancer and heart disease. All can be done - there's no shortage of resources in the world. But this fellow is well with the cage of his preconceived limits: in his world, we must all suffer and die from some age-related disease. Not doing so isn't even a possibility. How odd to hear a researcher argue this point; one might almost think about pushing him back a century to argue about whether consumption or yellow fever is best to be adopted as the death of choice, and therefore no cures should be sought.

We live in an age on the verge of repairing the damage of aging, preventing all age-related disease, and extending the healthy human lifespan through other means besides. How can any medical researcher be debating which age-related degeneration should be left alone as the accepted mode of suffering and death? The strongest bars are found in the cages of the mind that we build for ourselves by accepting the world in its present form.

Ultimately, limits to action and endeavor - and in this case, limits to what can be achieved through medical research - stem from our preconceptions of what those limits should be. An incurable disease, known to all as a death sentence, is only an incurable disease until a group of vision raises the funds, performs the work, and develops a therapy. So too with age-related degeneration, suffering and death. One person's notion of the absolute wall to progress is a red flag to those more inclined to charge ahead and make progress happen.

MSNBC looks at where exponentially growing computational power leads us - why run ten experiments in the real world if you could run a thousand in simulation for the same cost in time and money? Medicine will move to look much more like other branches of engineering today in that respect: "I would predict that this century is going to be dominated by our ability to handle biomedical problems in a computational domain ... The increasing ability of computers and biochips to mimic brain chemistry, internal organs, and the interactions between drugs and viruses such as HIV could help reduce the reliance on animal testing to understand the potency and side effects of pharmaceuticals. A more informed leap between experiments on dish-grown cells and lab animals, in turn, could lead to a better drug development process. And eventually, the technology could usher in a new era of personalized medicine in which rapid tests tell doctors which treatments have the best chances of success for individual patients. ... Devices that look at what happens within the body as a whole could eventually take over many roles played by the lab rat [and] the range of simulations being worked on now will increasingly approach reality."

Link: http://www.msnbc.msn.com/id/23447395/

An update on research into the enhanced regenerative mechanisms of lower animals: "Tiny wonders of the aquarium world, zebrafish can regenerate organs and tissues, including hearts, eye parts and fins. When a fin is lost, the fish regenerates a perfect copy in two weeks by orchestrating the growth of many tissue types, including bone, nerves, blood vessels, connective tissue and skin. ... In zebrafish, one or more microRNAs appear to be important to keep regeneration on hold until the fish needs new tissue ... In response to an injury, the fish then damp down levels of these microRNAs to aid regrowth. The team discovered that the ability of zebrafish to replace amputated fins is particularly sensitive to levels of a particular microRNA called miR-133. ... They probably need to have mechanisms to reduce the potential for unwelcome growth. The implication is that in order to make human tissue regenerate more effectively, we might want to look at some of these microRNAs as potential targets."

Link: http://www.dukehealth.org/HealthLibrary/News/10257

If you haven't visited the Immortality Institute recently, you should head on over and take a look. The latest redesign is up, intended to better focus visitors on the Institute mission, as well as to present the latest science of longevity and aging and happenings in the healthy life extension community. As always, you'll find an interesting mix of folk in the Institute forums, still a watering hole for people from across the range of the community. Recent functional additions include a wiki for FAQs and other documents: "The Immortality Institute is a non-profit organization with the goal of defeating the disease we call aging. Our official mission is 'to conquer the blight of involuntary death.' We think that this has the possibility of being accomplished through a variety of means, some more radical than others. We try to further the goal of defeating aging through a variety of means, including debate and discussion [amongst] scientists and researchers in the various anti-aging related fields, the production of various informational materials (films, books, etc.), the hosting of conferences dedicated solely to various aspects about the war on aging, funding of research related to curing aging, and many other ways that we think will provide the most benefit to curing aging as quickly as possible."

Link: http://www.imminst.org

The responsible practice of calorie restriction with optimal nutrition (CR) has nothing whatsoever to do with eating disorders like anorexia. The former is engaged methodically in order to meaningfully and measurably improve your health and longevity, while the latter is engaged carelessly and relentlessly in order to damage oneself, slaved to an impossible ideal.

There is a world of difference between those extremes. That is self-evident to anyone who's taken a serious shot at practicing CR for the health benefits, as well as anyone who's spent any time in the online or offline CR communities. But you'll always find some idiot - and some academic idiots in past years - who can't see eating in a more planned fashion as anything other than a mental illness, no matter how many facts to the contrary are right under their noses. CR practitioners need no help to send idiots packing, but it's nice to see that some of the folk involved in the ongoing CALERIE study of human CR recently published a more scholarly refutation than the idiots deserve.

Is caloric restriction associated with development of eating-disorder symptoms? Results from the CALERIE trial:

This study tested a secondary hypothesis of the CALERIE trial (Heilbronn et al., 2006) that a 12-month period of intentional dietary restriction would be associated with an increase in eating disorder symptoms.

...

All three dietary restriction arms were associated with increased dietary restraint and negative energy balance, but not with increased ED symptoms or other harmful psychological effects. Participants in the three calorie restriction arms lost significant amounts of body weight. The psychological and behavioral effects were maintained during a 6-month follow-up period. ... These results did not support the hypothesis that caloric restriction causes increased eating disorder symptoms in overweight adults. In general, caloric restriction had either benign or beneficial psychological and behavioral effects.

So hopefully we'll be hearing less of the anorexia association nonsense in the years ahead. People who exercise in a planned fashion so as to be healthy don't have to put up with nonsensical accusations of mental illness, so why should people who eat in a planned fashion so as to be healthy?

Immortality is a much abused word, often used in the healthy life extension community as shorthand for physical immortality, the state of not suffering from degenerative aging - being well repaired on a regular basis by use of future medical technologies, in other words. Anne C. has some thoughts: "I don't see longevity advocacy, or longevity medicine, as having anything to do with Infinite Invulnerable Indestructuble-ness or any other metaphysical fantasy. No matter what amazing medical technologies are developed, there's never going to be any guarantee that any person exists in a state wherein continued existence forever is somehow assured. ... In other words, when I talk about life being wonderful, and about the necessity of making medicine as effective as possible for old people as well as for young people - in fact, even when I talk about the notion of mitigating things presently considered 'part of the aging process' - I am not talking about 'making people immortal'. Just, you know, in case that wasn't clear."

Link: http://www.existenceiswonderful.com/2008/03/longevity-is-lovely-but-immortality-is.html

It was something like two years ago that I noted the pointlessness of trying to use the term "anti-aging" to describe longevity science or research into the repair of aging.

Unfortunately, some topics just can't be discussed well in email, blog and website; they are drowned out by the efforts of those trying to make money. So it is with scientific anti-aging research and the vast sea of static produced by the purveyors of useless, all brand and no cattle "anti-aging" products. Just take a look at what is seen when searching for any sane, non-monetary, responsible discussion of anti-aging science on Google, Google News, Google Blog Search and Technorati - a blizzard of junk and nonsense. It's the same everywhere you look, a storm of short-termist profit seeking that destroys the primary utility of the internet for these concepts, making it impossible for diverse groups to collaborate, exchange ideas and build new organizations as a part of a serious, ongoing cultural conversation on anti-aging science.

...

Anti-aging is beyond salvage as a term for discussion; we should move on and use other language to describe the technologies of healthy life extension and advanced medicine to extend healthy life spans.

But I'm stubborn, and so kept at it for a while, to see what the balance of voices looked like. Ultimately I took my own advice and moved on to terms like "repair of aging" and "longevity science." You need a bigger foghorn to compete with the folk presently engaged in efforts to define "anti-aging," either implicitly or explicitly. The term has solidly come to mean Revlon, skin cream, potions and the art of patching over the cracks so as to look younger, while doing absolutely nothing about the damage of aging. The forgery of the mirror and makeup, the magic show in which we expect to be entertained while understanding that none of it is real.

Oh well, move on. There is nothing to be gained by trying to talk to that marketplace by redefining "anti-aging" to mean serious longevity science. That is a hard path:

If there really was a significant spill-over of sentiment and support from consumers of "anti-aging" brands to meaningful, scientific anti-aging research - or even between different "anti-aging" brands in the marketplace - I don't think we'd be seeing quite the same sort of hostile confrontation between brand-holders and scientists as takes place today. More to the point, I suspect that volunteer organizations like the Methuselah Foundation would be having far less of an uphill struggle than has been the case to attain their present level of success, and scientists backing rapid progress towards working anti-aging therapies would not be struggling to raise large-scale funding and fight conservatism within their ranks.

The hundreds of thousands (millions?) of devoted purchasers of useless "anti-aging" products translates into very, very few people who understand and give support to serious attempts to repair the damage of aging through modern science. We advocates for longevity science may as well direct our educational and awareness efforts to the population at large - there is no special leverage to be had in speaking to Revlon customers. If there was, we'd have seen it already.

Not to hammer on the point too much, but excess body fat held over the years causes chronic inflammation, which enrages your immune system, which leads to atherosclerosis, which tends to kill you abruptly and without warning. All very avoidable. To make matters worse, excess fat - or rather all the food you ate in order to create the excess fat - creates a feedback mechanism that leads to insulin resistance and diabetes, and this makes the atherosclerosis-generation process run faster: "Experts once believed that atherosclerosis, or hardening of the arteries, developed when too much cholesterol clogged arteries with fatty deposits called plaques. When blood vessels became completely blocked, heart attacks and strokes occurred. Today most agree that the reaction of the body's immune system to fatty build-up, more than the build-up itself, creates heart attack risk. Immune cells traveling with the blood mistake fatty deposits for intruders, akin to bacteria, home in on them, and attack. This causes inflammation that makes plaques more likely to swell, rupture and cut off blood flow. ... In part because diabetes increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke. ... Inflammation is blood vessels is one of the main drivers of atherosclerosis, and diabetes makes it much worse."

Link: http://www.eurekalert.org/pub_releases/2008-03/uorm-sic031308.php

Some core components of metabolism - and, by extension, the rate at which that metabolism damages itself into aging - are very ancient, changing comparatively little as species evolved radically. That's why gerontologists focused on metabolism can obtain useful data from animals as diverse as zebrafish, flies, mice and primates. From EurekAlert!: researcher "have identified 25 genes regulating lifespan in two organisms separated by about 1.5 billion years in evolutionary change. At least 15 of those genes have very similar versions in humans ... Several of the genes that the scientists identified as being involved in aging are also connected to a key nutrient response pathway known as known as the Target of Rapamycin, or TOR. That finding gives more evidence to the theory that calorie intake and nutrient response affect lifespan by altering TOR activity. ... To find these lifespan-controlling genes, the scientists took a genomic approach to comprehensively examine genes that affect aging in yeast and worms. Based on published reports, they first identified 276 genes in C. elegans that affected aging, and then searched for similar genetic sequences in the yeast genome. Of the 25 aging-related genes they found in both worms and yeast, only three had been previously thought to be conserved across many organisms."

Link: http://www.eurekalert.org/pub_releases/2008-03/uow-sin031108.php

I've posted on RAGE before, a cell receptor structure that binds to a range of biochemicals, including the undesirable advanced glycation endproducts or AGEs (hence RAGE - receptor for AGEs). RAGE binds to other materials too, and presumably has an important role in the normal operation of your tissue, but the accumulation of AGEs with age turns it into a problem.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

At least some of the degenerations brought on by AGE buildup can be laid at the feet of the interaction with RAGE, and the resulting actions then taken by your cells. Cell receptors are like keyboards or buttons - hit them with the right sort of molecules and you're instructing the cell to take action. Here are a couple of papers on RAGE and age-related degeneration:

RAGE and its Ligands in Retinal Disease

Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

Let's work out how to interfere in the reaction of AGEs with RAGE, in other words, as it looks like this will help prevent or slow the onset of common causes of age-related blindness. More of thes same in the next paper:

Receptor for Advanced Glycation Endproducts (RAGE): A Formidable Force in the Pathogenesis of the Cardiovascular Complications of Diabetes & Aging

Unifying mechanisms for the consequences of aging and chronic diabetes are coming to light with the identification that common to both settings is the production and accumulation of the largely irreversible Advanced Glycation Endproducts (AGEs). AGEs impart multiple consequences in the tissues; a key means by which they exert maladaptive effects is via their interaction with and activation of their chief cell surface receptor, Receptor for AGE or RAGE.

Although the time course, rate and extent of AGE generation and accumulation in diabetes and aging may be distinct, unifying outcomes of the ligand-RAGE interaction in the vasculature and heart are linked to upregulation of inflammatory and tissue-destructive mechanisms.

Consistent with these concepts, administration of the ligand-binding decoy of RAGE, soluble or sRAGE, suppresses early initiation and progression of atherosclerosis in diabetic mice; suppresses exaggerated neointimal expansion consequent to arterial injury; and mitigates the adverse impact of ischemia/reperfusion injury in the heart. Importantly, the RAGE ligand repertoire upregulated in these settings is not limited to AGEs. The key finding that RAGE was a multi-ligand receptor unified the concept that in diabetes and aging, innate and adaptive inflammatory mechanisms contribute to the pathogenesis of tissue injury.

We all know just how bad chronic inflammation is over the years, don't we?

All that excess fat hanging around over the years generates [inflammation which generates] atherosclerosis, which then kills you.

Now neutralizing the AGEs with another biochemical that prevents them from triggering cellular RAGE is a good plan - but a better plan is to break down the AGEs and remove them from the body. Various groups are working on that. The presence of AGEs is an important difference between young and old tissue, and we should be working to repair any such significant difference as a part of developing true rejuvenation medicine.

Is seems to be the case that the accelerated aging of progeria (HGPS) results from one minor component of "normal" aging run wild - the defects resulting from mutant lamin A. So it is plausible that therapies for progeria will have some value for the rest of us in due time. It is worth paying attention to the research: "Lamins are essential to maintain nuclear integrity and loss of lamin A/C results in increased cellular sensitivity to mechanical strain ... We found that skin fibroblasts from HGPS patients developed progressively stiffer nuclei ... fibroblasts from HGPS patients had decreased viability and increased apoptosis under repetitive mechanical strain, as well as attenuated wound healing, and these defects preceded changes in nuclear stiffness. Treating fibroblasts with farnesyltransferase inhibitors (FTI) restored nuclear stiffness in HGPS cells and accelerated the wound healing response in HGPS and healthy control cells [but] did not improve cellular sensitivity to mechanical strain. These data suggest that increased mechanical sensitivity in HGPS cells is unrelated to changes in nuclear stiffness and that increased biomechanical sensitivity could provide a potential mechanism for the progressive loss of vascular smooth muscle cells under physiological strain in HGPS patients."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18331619

Thoughs from Ouroboros: "When we think of the ways in which oxidation contributes to age-related decline, it's usually in the context of individual cells: Throughout the body, oxygen radicals accumulate within cells, perhaps as a result of damage to mitochondria, and these reactive oxygen species in turn wreak havoc throughout the cell. This happens, certainly, but the picture is incomplete until we take into account the active cellular response to oxidative damage. ... [researchers] describe how a failure in antioxidant defenses [causes] angiogenesis in the pancreas. The increase in blood flow causes hyperinsulinemia, which causes downregulation of pro-longevity factors throughout the body ... One wonders whether chronic hyperinsulinemia might further stress pancreatic beta cells, as cells throughout the body downregulate the insulin response and become insulin resistant, generating a vicious cycle in which even more insulin resistance is required. Such a mechanism could provide a bridge between oxidation and late-life diabetes, one of the scourges of old age."

Link: http://ouroboros.wordpress.com/2008/03/12/oxidative-damage-in-the-pancreas/

Aging is a set of changes in your biochemistry, in the arrangement of atoms and molecules in and around your cells. Cells and the cellular environment are a connected web of delicate machinery - mess up their arrangement, and they stop working quite so well. One of the changes seen in our cells over time is an accumulation of chemicals that the body cannot break down. Eventually, this causes severe damage in cells due to a failure of recycling mechanisms, but issues arise well prior to that point.

Lipofuscin is the name given to a mix of many different types of chemical byproducts found in cells, long known to researchers. In particular, it is associated with a common cause of age-related blindness:

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

The Methuselah Foundation funds a group working on the use of bacterial enzymes to safely degrade components of lipofuscin. One of those components is A2E, an early target for this research given the level of interest in this chemical in various branches of the scientific community. From last December's progress report:

In summer 2007, six undergraduate research assistants and one additional PhD candidate joined the effort at Biodesign Institute. They helped with synthesizing additional target compunds, such as A2E and CML (a major AGE). This veritable army of volunteers also was able to culture six independent degraders of CML, and identify two enzymes which break A2E in different ways.

Today, researchers at the Biodesign lab are working on identifying the enzyme initiating the breakdown of 7KC and CML. They are also characterizing the A2E-degrading enzymes further, and are preparing to move them into a cell model of age-related macular degeneration for initial safety and efficacy testing.

I noticed a paper today that explores biochemical mechanisms by which acculumated A2E leads to the damage of macular degeneration:

Although it remains unsubstantiated clinically, experimental results support that the accumulation of lipofuscin is related to an increased risk of choroidal neovascularization (CNV) due to age-related macular degeneration, a leading cause of legal blindness.

Here, we report that a major lipofuscin component, A2E, activates the retinoic acid receptor (RAR). In vitro [experiments] strongly suggest that A2E [induces] sustained activation of RAR target genes. A2E induced vascular endothelial growth factor (VEGF) expression in a human retinal pigment epithelial cell line [and] RAR antagonist blocked the upregulation of VEGF.

...

These results suggest that A2E accumulation results in the phenotypic alteration of retinal pigment epithelial cells, predisposing the environment to CNV development. This is mediated through the agonistic function of A2E, at least in part.

So A2E appears to drive the errant blood vessel formation of wet macular degeneration. Interesting.

As I often point out, all knowledge is useful, but we don't need to know exactly how lipofuscin accumulation contributes to age-related degeneration to know that it should be on the list of things to address as a part of any comprehensive repair of aging. Indeed, we don't even have to know exactly how it damages us in order to develop working methods of preventing that damage. More knowledge will make the task of eliminating lipofuscin-related damage easier - by narrowing the set of chemicals to target, by finding ways to render liopfuscin harmless without the effort of removing it, and so on. But by virtue of lipofuscin accumulation being a fundamental difference between young tissue and old tissue, we know that we should reverse it, and we have enough information at hand to start work on that problem immediately.

Why are humans so very long-lived - albeit nowhere near as long-lived as we'd like - in comparison to other similarly-sized mammals? "The grandmother hypothesis proposes that postreproductive longevity evolved because it is selectively advantageous for females to stop reproducing and to help raise their grandchildren. The mother hypothesis states that postmenopausal longevity evolved because it is advantageous for women to cease reproduction and concentrate their resources and energy in raising the children already produced. ... we test the mother and the grandmother hypotheses with a historical data set from which we bootstrapped random samples of women from different families who lived from the 1500s to the 1900s in the central valley of Costa Rica. ... Here we show that although longevity positively affects a woman's fertility, it negatively affects her daughter's fertility; for this reason, the heritability of longevity is unexpectedly high. Our data provide strong grounds for questioning the universality of the grandmother hypothesis and for supporting the mother hypothesis as a likely explanation for the evolution of human postreproductive longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18322917

February's volume 11 number 1 issue of Rejuvenation Research is presently freely available online. These promotions tend not to last forever, so jump on in while the opportunity is there. Of note beyond the science is an interview with David Sinclair of Sirtris Pharmaceuticals: "I see my work as part of an ongoing struggle for improving human life. If I am lucky, I can add one piece to the puzzle, but clearly there will be many more that need to be discovered if we are going to extend lifespan dramatically. I am optimistic that the piece of puzzle we are working on could add a number of healthy years to people’s lives beyond what is currently possible in medicine. And you are correct, that could help people gain access to future technologies. My primary goal, though, is not to extend lifespan so that other technologies will be available, although that may happen as a fortunate consequence. If my work leads to people living an extra five years of healthy life, I would be a very happy person, and perhaps other people can then pick up the baton from that point."

Link: http://www.liebertonline.com/toc/rej/11/1

We know that age-related changes in the cellular microenvironment are at least as important as changes within stem cells when it comes to declining regenerative capacity with aging. Can we do anything about that with the biotechnologies of today? Perhaps so: "When human umbilical cord blood cells (UCBC) were injected into aged laboratory animals, researchers [found] improvements in the microenvironment of the hippocampus region of the animals' brains and a subsequent rejuvenation of neural stem/progenitor cells. ... In the brain, there are two stem cell pools, one of which resides in the hippocampus. As in other stem cell pools, the stem cells in the brain lose their capacity to generate new cells. A potent stressor of stem cell proliferation is inflammation ... We think that UCBCs may have a similar potential to reduce inflammation and to restore some of the lost capacity of stem/progenitor cells to proliferate and differentiate into neurons ... Our results raise the possibility that a cell therapy could be an effective approach to improving the microenvironment of the aged brain and restoring some lost capacity."

Link: http://www.eurekalert.org/pub_releases/2008-03/uosf-ioh031008.php

Another good transcript from Future Current: biomedical gerontologist Aubrey de Grey was asked "to present a case for the feasibility of defeating aging, but of course within the context of the discussion that we are having today overall about the longevity dividend and perhaps more generally about the way we might influence political thinking and public policy in this general area. There is a good deal of dispute among mainstream gerontologists not only as to whether the things that I think are feasible are feasible, but also whether - even if they are - we should really talk about them. I'm going to try and address both of those issues today. ... We all know the study of the biology of aging has consequences for biological disease and suffering. The amount of the bang for the buck, so to speak, that one would get by even very modest interventions to postpone aging is vastly in excess of what is represented by the something in the region of 3% of the public biomedical budget that goes towards the study of aging. If you have a more careful definition as to what is being done to understand aging with a view of doing something about it, then the proportion of public funding that is going toward that is absolutely negligible."

Link: http://www.acceleratingfuture.com/people-blog/?p=1870

If you want a good idea as to the future rate of progress in a field of medicine, keep your eye on improvements in infrastructure - in common, widely used technologies, techniques and processes. When you see rapid introduction of new methods, or order of magnitude improvements in existing methods, you can be sure that new therapies and other medical applications will be arriving that much more rapidly. A couple of examples from the fields of regenerative medicine, cell therapy and tissue engineering caught my eye today:

Researchers Control Growth Rate Of Replacement Blood Vessels, Tissues

Researchers have discovered a way to control the growth rate of replacement tissue and the formation of new blood vessels, which solves one of the vexing problems of growing replacement tissue to treat injuries and trauma in humans.

...

"Growth factor is typically dumped in and releases over a period of hours," said Giannobile, who also directs the Michigan Center for Oral Health Research. "With certain wounds you might want a lot (of growth factor) in the beginning, and with others you might want a little released over a longer period of time. We've basically found a way to dial up or dial down the release rate of these growth factors."

New Stem Cell Technique Improves Genetic Alteration

UC Irvine researchers have discovered a dramatically improved method for genetically manipulating human embryonic stem cells, making it easier for scientists to study and potentially treat thousands of disorders ranging from Huntington’s disease to muscular dystrophy and diabetes.

...

The new approach is up to 100 times more efficient than current methods at producing human embryonic stem cells with desired genetic alterations.

A greatly lowered cost of production for tailored pluripotent cells will go a long way to expanding and speeding research. It means more experiments per unit outlay in dollars, and more research groups able to afford to employ pluripotent cells for their research. This is the early part of the fall in cost and rise in efficiency that will lead to the blossoming of open source biotechnology - when the cost of entry is so low that tens of thousands of skilled and motivated amateur biotechnicians around the world will collaborate in hundreds of diverse projects to meaningfully advance science and produce new medical technologies.

Well, this is disappointing, to say the least:

According to Senior Vice President, David Dollar, "This is a revolutionary face cream - a product so different and innovative, we believe it could generate enormous consumer interest."

So much for that company, you know, the one that was promising really interesting things in telomere and mitochondrial science not so long ago:

Telomolecular Corporation [recently] acquired a new technology from Stanford Leland Jr. University. The technology, called Mitofusin 1, allows for the repair of damaged mitochondrial DNA. Damage to mitochondrial DNA leads to forms of aging and a variety of diseases.

What do we get out of the far end of the pipe? Another useless "anti-aging" potion manufacturer - as through we had a deficit of those, not enough salespeople clogging up public understanding of what is plausible in longevity research. While recognizing that we all thrive only by paying our respects at the temple of Mammon, it is disheartening to see yet another organization taking the path of least resistance and least promise. It is a shame, a tragedy, that the oppressive state of medical regulation in the developed world makes this an almost expected outcome. It is far, far easier to make a living unmolested in the provision of bread and circuses than to build something new and valuable with a boot pressed to your neck.

Incentives matter - and the FDA refuses to approve anything that might actually repair some form of age-related damage. Any medical application that might actually be approved to treat an FDA-approved disease is forced through insanely expensive, unnecessary and overwrought trial processes - unless of course it is one of the many, many new medical technologies that is discarded as not cost-effective in the face of this huge barrier.

So it is we have an ocean of "anti-aging" nonsense, bread and circuses with only the most tenuous connection to science of interest, because government regulators have made that the best road to a profit. Ultimately, venture investors will, as for most people, demand profits over the warm feeling of altruism and frustrations of trying to do good that unelected, unaccountable government employees have decided should not be done.

The systems and organizations of medicine and medical research are nothing short of insane in their structure and actions; a sea of waste and walls to block those best placed and eager to turn dreams into reality. It is long overdue a revolution.

The San Francisco Chronicle looks at a strangely popular branch of regenerative research: "Some may feel sheepish raising the question, given the weightier problems needing a scientific fix. ... Industry sources estimate that Americans spend more than $1 billion a year on approved drugs for hair loss and hair transplants. That explains why a small but determined bunch of companies and academics are mining the hair shaft for clues to the molecular mechanisms of balding. They're throwing an arsenal of high-tech tools at the condition: genome studies, stem cell stimulation, gene therapy, a type of tissue engineering often called 'hair cloning' and even robotics. ... Experiments are challenging the long-held notion that new follicles are never formed in humans and that follicles can never be revived once they become inactive. ... If new follicles form on top of a bald scalp, will they have the decadeslong lifespan of a baby's follicles, or will they quickly succumb to the male hormones that caused the baldness in the first place? ... We view it as a very early, very high-risk project. But if it works, it would be great."

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2008/03/07/BU4IVBIV2.DTL

Via EurekAlert!, a look at the results of neglecting your health: "The islet cells in the pancreas can compensate with increased insulin production only for so long when confronted with chronic obesity and inactivity. As a result glucose levels start to rise causing a host of problems ... Continually revved up insulin production, the kind that results from overeating and obesity, slowly dulls the body's response to insulin. As a result, blood sugar levels start to creep up, setting the stage for diabetes-associated complications such as blindness, stroke and renal failure. To make matters even worse, chronically elevated blood sugar concentrations exacerbate insulin resistance. The vicious circle gets rolling [when] out-of-control blood sugar levels disable the molecular switch that normally shuts off sugar production in the liver in response to rising levels of insulin." This is a personal future you can avoid through diet and exercise - nothing complicated about it. Why risk shortening your life and missing out on the era of working rejuvenation medicine that is just around the corner?

Link: http://www.eurekalert.org/pub_releases/2008-03/si-ceb030308.php

It's very rewarding to see folk out there broadening the conversation electric on the topic of healthy life extension: the science that will see us to many more healthy years, and the advocacy needed to build a research community, fund it, and turn research into results. Here's Scott Wainner speaking from the far side of the blogosphere:

One area that I have become particularly passionate about is longevity research - not just the idea of living longer, but the idea of biologically living as a 20-something indefinitely without experiencing age related disease or decay. Despite many advances in research over the past decade, this important concept has not yet been widely embraced by the public ... Why are we happy to continue pushing the envelope of age by relying on technological advancements in one breath, and in the next breath failing to become adamant supporters of anti-aging research?

A good question, and several thoughts are given on that topic. More pertinently, Wainner does more than just hold up his end of the conversation, he steps up to make something happen:

Never before in human history have we had the technological means to even begin to address this difficult problem. Our ancestors (around 60 billion people by some estimates) died in order to make this world a better place and so that we could learn and build on their accomplishments. Surely there is nothing more important than the massive reduction in human suffering (losing loved ones, or experiencing chronic disease), aging, and death, if it is within our technological capability to do so. We have an obligation to pursue such a challenge with all available means (not just a handful of well-intentioned researchers) to honor those who came before us and to prevent the unnecessary deaths of most people living today.

The $20 Blogging Challenge

So here’s my challenge to you: think about this issue [and] make a post to support this issue on your blog. In exchange, I’ll do follow up posts here at wrevenue.com linking back to you from my PR6 blog and I’ll even do one better: the first 100 bloggers who do a blog post about this issue to voice their demand for serious research to stop the aging process, and who write me to give me a link to their post, will each earn $20 paid via Paypal by yours truly - don’t delay to write your post and claim your easy $20!

The conversation electric - the vast and many-threaded discourse built of blogs, old media, scientific publications, private discussions, lectures, and every other form of communication imaginable - is the foundation upon which activist communities and organizations like the Methuselah Foundation can be built. Without the conversation, always present for reference, how will newcomers learn about healthy life extension, or be convinced of the supporting science by patient advocates for longevity research? How will these groups forge their legitimacy and grow large enough to create real change? From activist communities come funding, education and persuasion of the broader public towards the end goal of the defeat of aging. That is the road to large and well-supported longevity research communities, big enough to rival the cancer establishment, working hard to move the technologies capable of repairing the damage of aging from laboratory to clinic.

It's a long road ahead, but that didn't stop the cancer patient advocates in past decades, did it? Many hands make light work - so do something today to spead the word about the viability of greatly extending the healthy human life span within our lifetimes. Contribute to the conversation electric, and the future of longevity, healthier lives, understood, welcomed and supported by all.

Thoughts on bias prompted by the film "Do You Want To Live Forever?" can be found at Quiet Please: "As I already explained when I reviewed Radical Evolution, it is interesting that the people who tend to be opposed to a drastically increased or to an unlimited lifespan tend to view those who seek to abolish death as mad geniuses who will do the world more harm than good. They also believe that today's definition of normal is the one that must be upheld forever, the one that must endure. This obviously implies a complete disregard for what used to be considered normal (a very slippery concept when appraised in the context of history and within cultural considerations), and naturally, for what could become normal. It also implies, in my view, a total selfishness and narrow-minded belief that what we have today is as good as it is ever going to get and that our 20th and 21st century values (or rather, their values) are better and more appropriate than past or future values."

Link: http://www.yume.co.uk/do-you-want-to-live-forever

Future Current posts another presentation transcript from last year's Securing the Longevity Dividend symposium: "I am speaking today about the most popular arguments for and against longevity. This is not going to be a discussion of the scientific arguments that are put forth - I will leave that to the biogerontologists and the specialists. These are the kind of arguments that do come out of academia and some of the political lobbies, but these are also the kind of arguments you hear from the person on the street that you bump into. If you mention this in casual conversation, you can almost assuredly expect these kinds of retorts and objections to these sorts of issue of life extension. ... One of the most common arguments that is put forth in opposition to life extension is the appeal to nature. I'm sure we are all familiar with this - the suggestion that what is natural is inherently good or right, and that what is unnatural is somehow bad or wrong. A number of critics make the claim that life extension is a violation of the natural order - that humanity is tampering with nature, which is inherently good." Critics are always willing to overlook any number of accepted unnatural portions of the modern human condition to strike at the one they don't like.

Link: http://www.acceleratingfuture.com/people-blog/?p=9

Replication is a cornerstone of the scientific method, as we are reminded in this paper: "The exceptional longevity of centenarians is due in part to inherited genetic factors, as deduced from data that show that first degree relatives of centenarians live longer and have reduced overall mortality. In recent years, a number of groups have performed genetic association studies on long-living individuals (LLI) and young controls to identify alleles that are either positively or negatively selected in the centenarian population as consequence of a demographic pressure. Many of the reported studies have shown genetic loci associated with longevity. Of these, with the exception of APOE, none have been convincingly reproduced. ... Our results show that, at present, except for APOE, none of the selected genes show association with longevity if carefully tested in a large cohort of LLI and their controls, pointing to the need of larger populations for case-control studies in extreme longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18034366

Many bird species enjoy far greater longevity than mammals of a similar size. Some modestly-sized birds, such as crows and ravens, can live for almost half a century when sheltered from the harsh realities of a wild life. What is the root of this avian longevity? A recent paper makes the case for greater resistance to oxidative damage:

Current mechanistic theories of aging would predict that many species of birds, given their unusually high metabolic rates, body temperatures, and blood sugar levels, should age more rapidly than mammals of comparable size. On the contrary, many avian species display unusually long life spans.

This finding suggests that cells and tissues from some avian species may enjoy unusually robust and/or unique protective mechanisms against fundamental aging processes, including a relatively high resistance to oxidative stress. We therefore compared the sensitivities of presumptively homologous epithelial somatic cells derived from bird and mouse kidneys to various forms of oxidative stress.

When compared to murine cells, we found enhanced resistance of avian cells from three species (budgerigars, starlings, canaries) to 95% oxygen, hydrogen peroxide, paraquat, and gamma-radiation. Differential resistance to 95% oxygen was demonstrated with both replicating and quiescent cultures. Hydrogen peroxide was shown to induce DNA single-strand breaks. There were fewer breaks in avian cells than in mouse cells when similarly challenged.

You might recall that greater resistance to oxidative damage - due to differing rations of biochemicals in cell membranes - is also the present consensus explanation for the outsize longevity of naked mole-rats in comparison to other rodent species.

As noted at EurekAlert!: "Scientists now can take embryonic stem cells, the cells that can become any tissue type in the body, and coax them into becoming all the cells in the blood supply ... However, they can't make blood stem cells that [self-renew] and don't differentiate prematurely when transplanted into patients. The only way this currently can be achieved is by manipulating the cell's nuclear regulatory machinery with genes using retroviruses. To generate blood stem cells that are safe for use in patients [scientists must] learn how to generate self-renewing blood stem cells in a more natural way, by providing the correct developmental cues from the environment in which the cells develop. ... This recent study indicates that the first niche for expansion of blood stem cells is the placenta's vascular labyrinth, where oxygen and nutrients are exchanged between the mother and the fetus. The findings show the placenta harbors two different microenvironments, one area where blood stem cells originate and another area, the labyrinth, that nurtures them, allowing them to expand in number. ... The labyrinth is a source of many growth factors and cytokines. We just need to identify what those signaling molecules and cues are that are nurturing those cells when in the placenta."

Link: http://www.eurekalert.org/pub_releases/2008-03/uoc--urf030308.php

Continuing the targeted anti-cell therapy theme for the day, the BBC looks at the use of magnet-producing bacteria in the role of cell destroyer: "bacteria-produced magnets are better than man-made versions because of their uniform size and shape ... It is hoped one day the magnets could be guided to tumour sites and then activated to destroy cancerous cells. ... They could be guided to the site of a tumour magnetically. Once there, applying an opposite magnetic field would cause the nanomagnets to heat up, destroying cells in the process. They could also potentially be used to carry drugs directly to the cancerous tissue." Great breadth of present initiatives is a key sign of impending progress in any field. The range of potential types of targeted therapy presently explored in the laboratory is broad indeed - bacteria, engineered nanoparticles and viruses, lasers, magnetic fields and combinatory compounds, to name but a few. The more competing methodologies the better, given the importance of this technology to the medicine of the near future.

Link: http://news.bbc.co.uk/2/hi/health/7270913.stm

The ability to safely and quickly destroy very specific types of cell in a living body will be a core technology for the new medicine of the next few decades. There's no shortage of potential targets in the aging body: cancer, senescent cells pumping out damaging biochemicals, malconfigured immune cells, and so forth. Researchers are making good progress on this technology base: "Now, we're engineering sophisticated nanostructures to elude the body's natural defenses, locate tumors and other diseased cells, and release a payload of therapeutics, contrasting agents, or both over a controlled period. ... Getting intravenous agents to their intended targets is no easy task. ... To overcome this problem, we hypothesized and developed a multifunctional [multistage delivery system (MDS)] comprising stage 1 mesoporous particles loaded with one or more types of stage 2 nanoparticles, which can in turn carry either active agents or higher-stage particles. We have demonstrated the loading, controlled release and simultaneous in vitro delivery of quantum-dots and carbon nanotubes to human vascular cells. ... Once on site, the molecules can be released in a controlled way and then the MDS will degrade in 24 to 48 hours, be transformed into orthosilicic acid and leave no trace in the body." The medicine of tomorrow, arriving soon.

Link: http://www.sciencedaily.com/releases/2008/03/080303093556.htm

Bacteria once thought immortal do in fact age, a fact discovered fairly recently. In essence, a bacterium seems to push off more of its biochemical damage onto the "older" of the two new daughter bacteria created when it divides. Aging, recall, is defined as the accumulation of biochemical damage - that "older" daughter bacterium is "older" because it is more damaged.

So, while interesting, why should we care about all this? What is the relevance of this asymmetrical division process to aging in multicelled organisms, or the relevance to age-related degeneration in humans? A few strands of research are touched on in a recent PNAS paper:

Aging is a fundamental characteristic of all living organisms. Recent work in our laboratory has identified and quantified aging in Escherichia coli, where cells progressively decline in growth rate and reproductive ability with increasing cell pole age, establishing this organism as a simple experimental model of aging.

In this outwardly symmetrically dividing bacterium, the cell inheriting the old pole after division grows more slowly and divides less frequently, therefore exhibiting aging. Thus, the dividing cell partitions its resources and/or damaged components in a biased fashion, leading to differential growth potential distinguishing the old-pole aging cell and its young-pole counterpart.

To shed light on the molecular mechanism underlying aging in E. coli, we focus here on the partitioning of damaged, aggregated proteins in wild-type bacterial cells growing in a nonstressing favorable environment.

Aggregated proteins are linked to cellular degeneracy in many age-related diseases [e.g., Huntington's disease, Alzheimer's disease, spongiform encephalopathies, Parkinson's disease, and cataracts]. In addition, numerous reports link protein maintenance and repair functions (e.g., folding and disaggregation-related chaperones and proteases) to aging. Consequently, considerable effort has been invested in the study of protein aggregation, resulting in a better understanding of aggregation in vitro and in the identification of a number of genes involved in this process, many of which are widely conserved in all kingdoms of life. In contrast, less is known about the aggregation process in vivo, its causes, and its direct consequences on cell fate; such understanding has been hindered by the inability to follow in vivo the formation and outcome of inclusion bodies under native conditions.

Advances in biotechnology make these and many other complex projects possible. The researchers found that, as expected, "old pole" bacteria retain more of the damaging protein aggregates than "young pole" bacteria. It seems likely that bacterium-by-bacterium analysis of other measures of damage will show similar results.

As the paper notes, there are all sorts of similarities between asymmetric division in bacteria and related processes in our cells:

Intriguing is the similarity between aggrosome localization to the eukaryotic centrosome and the inclusion bodies to the bacterial division plane. In the former model, putative stem cells exhibited a lower aggregation level as compared with differentiated cells. It remains to be seen whether, as in bacteria, germ-line cells use the same mechanism to ensure their optimal survival. Is the unknown segregation mechanism common across kingdoms? Is the bacterial mechanism a precursor (possibly "passive," e.g., non-energy consuming?) mechanism or rather evolutionarily converged to the same optimal solution?

...

although cells can potentially invest more in maintenance and repair during growth phase, this may not be cost-effective, prevailing in cycles of aging and rejuvenation by damage segregation. Interestingly, in terminally differentiated postmitotic cells such as neurons, aggregate accumulation correlates with diseases. Because all organisms face challenges of protein folding and aggregation, it is unsurprising that the genes coding for the machinery for protein folding quality control are highly conserved across the domains of life. Given the newly apparent universality, E. coli may provide a powerful system for studying the formation and prevention of toxic aggregates, such as those responsible for a number of degenerative diseases.

At the end of this road may be methodologies for rejuvenating cell populations, such as aging stem cells, through manipulating the processes of asymmetric division - passing off biochemical damage to a daughter population that is then discarded. Or not. As Aubrey de Grey points out, these experiments really should be repeated in cell populations or single-celled organisms before we get too excited - there are, after all, significant differences between a cell and a bacterium.

The New Scientist reports on more results of the study of Ashkenazi Jewish centenarians: researchers have "identified gene variants that make people live longer. Men may miss out, as all carriers identified so far are women. They are also slightly shorter than average. ... Both mutations affect the receptor for insulin-like growth factor 1 (IGF1), a driver of bodily growth and maturity, especially during puberty. By making the receptor slightly faulty, the mutations may disrupt IGF1 binding and decelerate the process of maturation and ageing. In support, they found circulating levels of IGF1 to be 37% higher in carriers of the mutation, probably to compensate for the underperforming receptor. Carriers were also 2.5 centimetres shorter on average than the general population. ... This milestone result will no doubt stimulate a worldwide search for IGF1 mutations in other centenarian populations." As the short piece notes, the research community has ammassed a wide range of results on IGF-1 and longevity in lower animals.

Link: http://www.newscientist.com/article/dn13403-longlife-genes-found-in-100yearold-humans.html

Ethan Zuckerman was blogging biomedical gerontologist Aubrey de Grey's presentation at the BIL conference. Scroll down in his post for that section:

Gerontologist Aubrey de Grey has spoken at TED previously, and presented this year at TED University, a preconference event that focuses on short, practical talks. He gives this talk, called “Not the TED Commandments, or How to Be a Successful Heretic” to the BIL stage. de Grey is a phenomenally successful heretic - he’s the [cofounder of the Methuselah Foundation], and he’s been systematically challenging thinking about life extension for the past dozen years.

The set of thoughts on successful organized heresy - otherwise known as bringing about radical, lasting change in a community - is a good insight into the DNA of the Methuselah Foundation. The Foundation might be viewed as an organized heresy in the making that aims to reform gerontology into a goal-oriented community working to repair aging. It's also good advice for anyone seeking to build an organization around a vision that manages to Get Stuff Done.

1. Be right (diligence before oratory). He quotes Sean Carroll: "Being a heretic is hard work". It’s not enough to disagree with mainstream thinking - you actually have to be correct. "Galileo was a heretic, but understood the reigning orthodoxy at the time better than anyone else." Very few people work that hard: "Many casual heretics can’t be bothered."

...

3. Be a doer (as well as a talker). One reason to take de Grey seriously is the number of people who’ve taken him seriously, pledging huge sums to support his research. (I plan to steal his methodology for Global Voices.) You have to work very hard to raise these sorts of sums… and fundraising is a form of doing, even if it doesn’t feel like it.

...

8. Be inspirational (and have a team that’s organizational). (Oh man, is this one true.)

9. Be selfless (remember that control is only a means to an end) - Don’t control all your work too carefully - you make progress by reliquishing control to other people to take your idea forward.

Those last two above are particularly important in the history of the Methuselah Foundation and the development of now ongoing Strategies for Engineered Negligible Senescence research. They quite accurately encapsulate how to be successful as the point of the spear, the tip of a change process that, in the end, will lead to a growing, self-sustaining community with its own vision and ownership of the progress made.

Via ScienceDaily, researchers postulate that the biochemical root of HPGS, or progeria, causes accelerated aging by affecting stem cell populations: "The cause of HGPS, a mutated protein called progerin, was identified in 2003. However, the mechanism by which progerin causes the widespread clinical effects of HGPS has been unclear. ... [researchers have now] found that progerin activates genes involved in the Notch signaling pathway, a major regulator of stem cell differentiation - the process by which stem cells give rise to the mature cells that make up different tissues. ... Their experiments revealed that progerin profoundly affects the fate of these stem cells, greatly skewing the rate at which they mature into different tissues. ... Progerin is present at low levels in the cells of healthy people. One could envision a scenario in which progerin's effects on the Notch pathway and, by extension, on adult stem cells could, over time, lead to many of the tissue changes we commonly associate with the aging process."

Link: http://www.sciencedaily.com/releases/2008/03/080302150715.htm