Longevity Meme Newsletter, November 09 2009

November 09 2009

The Longevity Meme Newsletter is a weekly e-mail containing news, opinions, and happenings for people interested in healthy life extension: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives.



- Evaluating an Industry that Doesn't Exist
- Genetic Polymorphisms of Human Longevity
- Two Videos of Interest
- Discussion
- Latest Healthy Life Extension Headlines


The industry of repair technologies for the biochemical damage of aging doesn't yet exist; only the foundations of laboratory work and early signs in advocacy, organization, and fundraising are presently in evidence:


"Imagine an industry poised to burst into existence. The signs are there: the advocates, the tinkerers, the potential business models and user demand, the promising early scientific work yet to be fully exploited. But how you determine whether this is real or all an illusion? How to find out whether an explosion of progress and growth is just about to happen, or whether the seeds of this nascent industry will continue to germinate at low levels of activity for years longer? There is only one useful method: invest a significant amount of money and see how much interest, activity, and follow-on investment it attracts.

"This is one of the lines of reasoning behind the most adventurous of venture capital deals, behind research prizes, and behind large philanthropic donations to young fields of research. Today I have in mind Peter Thiel's $3 million matching fund for SENS research, a donation made back in 2006 when the Methuselah Foundation and SENS Foundation were one and the same. The terms of this donation made it a very explicit fishing expedition, a tool for evaluating the state of the longevity science industry that has yet to exist - an industry based on the SENS approach to repair and reversal of aging versus the present mainstream approach of metabolic manipulation to slow aging."

You can read more about the donation in the Fight Aging! archives here:


The terms of Thiel's matching fund are set to end at the close of 2009, less than two months from now. In the past three years, $3 million has been raised and pledged, and a little less than $1.5 million of the matching fund remains. That is success, but not the level of success we would have liked:

"A lot of progress and networking has happened behind the scenes, both inside and outside the scientific community. A number of Methuselah Foundation volunteers and associates have gone on to found and assist in diverse other efforts, such as Genescient, the LifeStar Institute, and the Biogerontology Research Foundation. But it's hard to evaluate the value of advocacy and increasing diversity in organizations that carry the SENS ideas; it's easy to evaluate dollars raised. By that standard we as a community are not as far advanced as we thought we were, even though progress and growth is ongoing. The lion's share of all investment and philanthropic donation to longevity science in the past few years has not gone to SENS-like research, but towards metabolic manipulation instead. Consider the Sirtris acquisition, the Paul F. Glenn Laboratories, and so forth. From my perspective, the increase in scientific understanding of metabolism and aging produced by those efforts will have great value in the long term, but I don't see that applied biotechnology that merely slows aging will have any great impact on our longevity.

"As I've pointed out numerous times in the past, we in middle age today only get one shot at a twenty year development cycle for longevity-enhancing medical technology. If by 2030 all that has been achieved is a reliable slowing of aging, then we will benefit very little from that. The only way to significantly enhance healthy life expectancy in the old is to aim for rejuvenation: repair and restoration, not slowing down the accumulation of damage.

"So SENS and SENS-like ideals for longevity science are not where we'd like to be. Growth is slower, and fundraising has not hit the heights we'd like. A large matching fund looks likely to expire only half-used, and not through any lack of effort on the part of fundraisers. Take five minutes to mope, and then think about what we can do to change this state of affairs."


The studies showing small differences in human genes to be associated with small differences in life expectancy are rolling in these days:


"Some people have better genes than other people; such is the luck of the draw. The effects of most genetic differences on human longevity appear to be small in comparison to the effects produced by lifestyle choices, however. You are still the master of your own destiny in that regard. Time wasted in wishing you had a better variant of FOXO3A would be better spent exercising.

"A great deal of modern life science research is focused on deciphering the operation of our genes and metabolism. Along the way, researchers are digging up many statistical associations between human life span and specific genetic polymorphisms, such as different alleles of a single gene. This is happening rapidly enough that individual results are no longer newsworthy; this is a data gathering phase in the broader research community, and the data is rolling in. Relentless gains in the cost effectiveness of genetic biotechnologies mean that databases of these associations will grow far faster than they are mined for potential applications and cross-references in the years ahead."


In the following Fight Aging! post, you'll find both an unofficial advocacy video for the work of the SENS Foundation in advancing longevity science, and a recording of Aubrey de Grey's presentation at the recent Singularity Summit:



The highlights and headlines from the past week follow below.

Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!




Researchers are occasionally surprised when a genetic modification expected to reduce life span in fact extends it. In this example, a defense against lipid peroxidation is disabled in mice. (You might recall that lipid peroxidation is one of the ways in which oxidative damage originating in the mitochondria spreads throughout the body). Rather than reducing the life span of these mice due to greater damage, this actually has the effect of galvanizing further defensive mechanisms to greater activity. So in fact, such a mouse winds up with more effective repair and protection mechanisms over the long term. This is an example of hormesis - regular application of a little damage provokes an ongoing and massive response from the body's repair mechanisms, which leads to a longer healthy life span. From the paper: "The lipid peroxidation product 4-hydroxynonenal (4-HNE) forms as a consequence of oxidative stress. ... A major route of 4-HNE disposal is via glutathione conjugation, in the mouse catalyzed primarily by glutathione transferase mGSTA4-4. Unexpectedly, mGsta4-null mice, in which 4-HNE detoxification is impaired, have an extended life span. This finding could be explained by the observed activation of the transcription factor Nrf2 in the knockout mice, which in turn leads to an induction of [a] detoxification mechanism that contributes to enhanced longevity."

It isn't completely clear exactly how many longevity genes affect our biochemistry. For example: "The researchers studied a family of transcription factors called FoxO known to be involved in proliferation, differentiation and programmed cell death. FoxO genes are required for the extreme longevity seen in some strains of laboratory roundworms, and a single mutation in the FoxO3 gene has recently been associated with long life in Japanese, German, American and Italian populations. ... We wanted to know if FoxO3 could be involved in regulating the pool of neural stem cells ... researchers examined laboratory mice in which the FoxO3 gene was knocked out. ... the few stem cells found in the adult mice without FoxO3 more rapidly churned out neural cell precursors - those cells destined to become new neurons - than did the mice with normal FoxO3 levels. In fact, the brains of the mice that lacked FoxO3 were heavier than the control group, perhaps because they were burning through their pool of neural stem cells by making too many new nerve cells. ... It's intriguing to think that genes that regulate life span in invertebrates may have evolved to control stem cell pools in mammals. ... [researchers] are working on creating a mouse in which FoxO3 levels are artificially elevated. If their theory about the function of the protein in the brain is correct, it's possible that the neural stem cell pools of these mice will be protected from the ravages of time. ... We're very interested in understanding how everything unravels during the aging process."

From the MIT Technology Review: "Traditionally, treatment for severe second-degree burns consists of adding insult to injury: cutting a swath of skin from another site on the same patient in order to graft it over the burn. The process works, but causes more pain for the burn victim and doubles the area in need of healing. Now a relatively new technology has the potential to heal burns in a way that's much less invasive than skin grafts. With just a small skin biopsy and a ready-made kit, surgeons can create a suspension of the skin's basal cells - the stem cells of the epidermis - and spray the solution directly onto the burn with results comparable to those from skin grafts. ... After removing a small swatch of skin near the burn site (the closer the biopsy, the better for precise matching of color and texture), the surgeon places it in the kit's tiny incubator along with an enzyme solution. The enzyme loosens the critical cells at the skin's dermal-epidermal junction, and the surgeon harvests them by scraping them off the epidermal and dermal layers and suspending them in solution. The resulting mixture is then sprayed onto the wound, repopulating the burn site with basal cells from the biopsy site."

The use of targeting mechanisms makes existing anti-cancer methodologies, such as radiation or toxic chemicals, work far more effectively and inflict less harm upon the patient. Via EurekAlert!: researchers used "a radiolabeled antibody to deliver targeted doses of radiation, followed by a stem cell transplant, to successfully treat a group of leukemia and pre-leukemia patients for whom there previously had been no other curative treatment options. All fifty-eight patients, with a median age of 63 and all with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome - a pre-leukemic condition - saw their blood cancers go into remission. ... The key to success in this study was use of a radiolabeled antibody that has therapeutic iodine 131 attached and is designed to target leukemic bloods cells that carry a marker on the surface of the cell known as CD45. ... Delivered intravenously, the radiation looks for the CD45 antigen receptor on the surface of blood cells. This approach results in a two- to four-fold increase in the amount of radiation that reaches cancerous cells as compared to standard external beam radiation, which also radiates normal surrounding organs and tissue. The more radiation that can be applied, the more cancer cells will be killed in preparation for donor stem cells to take over the diseased immune system and kill off the remaining cancer cells." The survival rate after 3 years is around a third - somewhat better than the expected zero for existing options.

Researchers are delving deeper into the mechanisms that link fat tissue with chronic inflammation, a source of damage to the body that raises the risk of age-related disease: "Researchers have new evidence to explain how saturated fatty acids, which soar in those who are obese, can lead the immune system to respond in ways that add up to chronic, low-grade inflammation. The new results could lead to treatments designed to curb that inflammatory state, and the insulin resistance and type 2 diabetes that come with it. One key [is] an immune receptor (called Toll-like receptor 4 or Tlr4) at the surface of blood cells, including a particularly 'angry' class of macrophages known to pump out toxic molecules and spur inflammation. It now appears that fatty acids may in essence 'hijack' those immune cells via Tlr4. ... Tlr4 is out there to sense bacterial products, but one of those looks a lot like fatty acids. They don't know it's not bacteria. ... Scientists had suspected that Tlrs might be the 'sensors' linking obesity to inflammation. Indeed, earlier studies had supported that notion. In the new study, the researchers show that this interaction is particularly important in the bloodstream. Mice lacking Tlr4 only in blood cells grew obese when they were fed a high-fat diet, but they were largely spared the metabolic consequences of their obesity. The mice were fat, but metabolically they continued to 'look pretty normal.'"

Kevin Perrott of the LifeStar Institute is featured in this Edmonton Sun article: "Kevin Perrott sees a future without heart disease, arthritis or cancer. And it's right around the corner ... if people can get over their unfounded fear of stem-cell research. 'The potential is totally limitless,' Perrott says, his eyes widening with enthusiasm, 'But we have to get everybody on the same wavelength.' The problem, he says, is that the ethical debate over stem cells hasn't kept up with the research. Perrott, a local businessman and PhD student, hopes to change that. Earlier this year he founded the LifeStar Institute Canada to build public support for stem-cell research. ... In the near future, someone needing a kidney transplant could have a new organ manufactured out of cells taken from their own skin, potentially bringing an end to organ donor wait lists. It also opens the door for 'personalized cell replacement therapies.' For example, heart attack victims who've suffered permanent organ damage could be treated so that the dead tissue regenerates itself. Parkinson's disease, Alzheimer's disease and other incurable conditions could potentially be reversed."

THE CASE FOR AUTOPHAGY (November 03 2009)
This open access review paper looks at the evidence pointing towards the process of autophagy as a central metabolic determinant of longevity: "The accumulation of cellular damage is a feature common to all aging cells and leads to decreased ability of the organism to survive. The overall rate at which damage accumulates is influenced by conserved metabolic factors (longevity pathways and regulatory proteins) that control lifespan through adjusting mechanisms for maintenance and repair. Autophagy, the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles, is implicated in aging and in the incidence of diverse age-related pathologies. Recent evidence has revealed that autophagic activity is required for lifespan extension in various long-lived mutant organisms, and that numerous autophagy-related genes or proteins are directly regulated by longevity pathways. These findings support the emerging view that autophagy is a central regulatory mechanism for aging in diverse eukaryotic species."

A good article from h+ Magazine: "'Daddy, when are you going to die?' asks my daughter Zenobia, age five. 'Yeah, how much longer do you really think you can live?' says big sister, Tallulah, age nine. I'm only 57, and healthy, but my two larvae are obsessed with my expiration date because their grandfather passed away last summer. I am twelve years older than their mother, so the kids know I'm scheduled - in the traditional societal view - as the next family member to croak. 'Hey, you brats!' I retort. 'I'm not going anywhere. I'm going to boss you around forever.' ... 'You can't,' scoffs Tallulah. 'Every animal dies. Even whales and trees.' I contemplate emailing her teacher to suggest up-to-date science books by Aubrey de Grey and K. Eric Drexler. 'If my body dies,' I announce, 'I'm going to have scientists freeze me immediately, because my brain will still be alive. I'll stay frozen until future smart people wake me up in a world where everybody lives forever.' ... I show my daughters the website of a cryonics organization in Silicon Valley. 'When I die,' I instruct them. 'I'll have a medal around my neck that says 'Cool Me Off.' On that medal there's a phone number. Call it and somebody will tell you what to do.'"

Here is a glance at why protein folding is important: "Research indicates that ALS, in common with other neurological disorders, such as Alzheimer's and Parkinson's disease, is caused by our own proteins, which form aberrant aggregates that are fatally toxic to our nerve cells. However, it has not been known what causes these proteins to aggregate. [Researchers] have now revealed what happens with proteins during the very first, critical step towards forming larger aggregates.
It turns out that the protein superoxide dismutase interchanges between its normal structure and a misfolded form. During a brief moment the structure becomes partially misfolded to expose sticky patches that normally are hidden in the interior. These patches cause two or several protein molecules to stick together, thereby forming the cornerstone of the larger structures that are believed to underlie ALS. ... Knowledge of the misfolded protein structure potentially makes possible future efforts to rationally design drugs that prevent the misfolding event and hence the development of ALS." This is why projects like Folding@home are important to the future of medical science: understanding a misfold makes it possible to work towards correcting it.

Some thoughts on humanism and longevity science from a social justice variety of bioethicist: "If humanists reflected critically and consistently upon their basic moral convictions, I believe they would become strong advocates of aging research and the aspiration to decelerate human aging. However, most humanists are not (at least yet) strong advocates of this scientific research; indeed many probably oppose this research or at the least do not think it an important priority. In this post I will explain why this is a mistake given the foundational moral premises of humanism. ... A 21st century humanist recognizes the fact that no person, regardless of race, gender, nationality or *age*, deserves to suffer morbidity and mortality. And thus we ought to aspire to reduce these risks when it is feasible to do so, whether it be by providing access to clear drinking water, bed nets to protect against malaria or developing new drugs that re-programme our metabolism and help protect against chronic diseases. ... The average age of life expectancy, at birth, in the world today is 67. This means that most people born today will live long enough to suffer one of the chronic diseases of aging, like cancer or heart disease. This is a fate suffered by millions every year now, especially in the developing world (contrary to what most people in the developed world think). 21st humanists ought to be among the strongest and loudest advocates of biogerontology."



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