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The end of the year is closing in, and this is about when I usually make an annual donation to the Methuselah Foundation. I prefer the periodic lump sum donations over monthly contributions as it's a good way to force an occasional check on whether you're still making a good choice. In the years since the Foundation's inception, I've donated to the Mprize fund. The fund predates the option to directly sponsor Strategies for Engineered Negligible Senesence (SENS) research aimed at repairing the damage of aging, but I've continued to put money towards the research prize, as I consider it to be important.

Time for a change, I think. This year's donation will go towards SENS research - but not because I think the Mprize is any less worthy. At this point, it looks like the best plausible growth path for the Methuselah Foundation over the next few years is based on following through with present initiatives to establish and publicize a steady stream of modest SENS research achievements. I've long said that advocacy and tangible results have to go hand in hand for optimal progress; when one gets too far ahead of the other, it tends to slow down.

You get what you pay for in this life - so if we want to see that steady stream of research achievements, we have to fund the research. Other people hang around in the wings waiting for more confirmation and mass of support for these projects, but those of us who better understand the science and potential of SENS are the ones who must pay to start the ball rolling. My contributions aren't large, but then no one person can form a crowd. I would hope that discussing this topic moves those of you yet to donate to make that small effort to help progress towards engineered longevity.

The Millard Foundation has been moving towards earnest funding of longevity science over the past few years: there have been initial donations, conference attendances, meetings with movers and shakers. All the normal activities and preparation by people who take investing very seriously. Much like the Glenn Foundation, which I would consider an analogous force in the philanthropic funding space, the Millard family have donated generously to the Methuselah Foundation. But where Paul Glenn opted to place his first major funding initiatives firmly in the present mainstream - calorie restriction research, understanding metabolism, and attempts to slow aging through metabolic and genetic manipulation - the Millard family is more inclined towards the Strategies for Engineered Negligible Senescence (SENS) viewpoint. This approach is to reverse aging without altering the workings of our metabolism by identifying and repairing damage: the engineering approach.

Long-time readers will know that I consider the debate over the methods used to engineer longevity in humans to be the most important scientific battle of this century. If it goes the right way - towards SENS, presently the minority viewpoint - then I believe significant results in applied longevity science will arrive decades sooner than they might, and will include therapies capable of rejuvenating the elderly. If development of metabolic manipulation therapies to slow aging continues to dominate, progress towards enhanced longevity will be much slower, and the resulting therapies will be of no use to those already aged.

From what I've seen, the Millards have money, influence, and the intelligence to use it well. That is good news for SENS-style research over the next few years. Going by the latest news from the Methuselah Foundation, things are moving forward more rapidly now:

Back in June at Aging '08 I met Barbara Logan of the Millard Foundation having previously met her father William Millard at SENS 2. ... Over the following months she became a resource for me and I introduced her to some efforts with the Alberta Government where I had proposed the development of regenerative medicine programs which are under consideration. It soon became clear that there were some strong synergies and I was invited to participate in the efforts of the Millard Foundation in developing a strategy to serve the mission. Unsurprisingly, Aubrey [de Grey] is a consultant on the project and will play an increasingly important role as we move forward - the ideas of SENS are part of the project's DNA. More than that I'm afraid I can't speak to at this time, but suffice to say, it is one of the most exciting efforts (other than the Methuselah Foundation) that I have been involved with.

Diversification in the growth of the money-bearing and money-raising side of the healthy life extension community, and the wider adoption of the ideas of SENS in that group, is a very encouraging sign. Of all the things I'd want to see in a movement primed for growth in the years ahead, diversity amongst the movers and shakers tops the list. Diversity implies competition, and competition is the way to success.

Deuterium and engineered longevity are in the popular press again:

[The method] centres on fortifying the body's tissues and cells against attack and decay caused by free radicals, dangerous chemicals produced when food is turned into energy. Such 'attacks' on proteins are particularly damaging and have been linked to cancer, Alzheimer's and Parkinson's.

Dr Shchepinov's theory is based on deuterium, a naturally-occurring isotope, or form of hydrogen, that strengthens the bonds in between and around the body's cells, making them less vulnerable to attack.

He found that water enriched with deuterium, which is twice as heavy as normal hydrogen, extends the lifespan of worms by 10 per cent. And fruitflies fed the 'water of life' lived up to 30 per cent longer.

Heavy water is toxic to mammals at very high concentrations, and as I mentioned in response to a paper from Rejuvenation Research in 2007:

Shchepinov argues that isotopes would only be incorporated in the sites that need to be protected from oxidation. 'Ideally, they will slow down the oxidation reaction so much that they will never be released to take part in other reactions. If some of them do break free, they will only occur in small concentrations,' he said.

As for the other folk quoted in [a science press article at the time], I'm dubious - it seems to me that the level of technology required to target the isotopes reliably (and keep them targeted) would enable far more effective methdologies of repairing rather than preventing oxidative damage.

I suspect that the main benefit to come out of this research will be an increased understanding of free radical biochemistry and its interaction with degenerative aging.

UPDATE 11/27/2008: You'll find a much better article on this research at the New Scientist.

The message to take away from much of the research into obesity is "don't let it happen to you." Fortunately for most of us, that is well within our power: obesity is almost always a choice.

While smoking reduces life by an average of ten years, the research says being seriously overweight can cut life expectancy by as much as 13 years.

As for any complicated survey of human health, you'll find dissenting studies, or studies that show widely different results for different studied groups. Here's one that shows no real difference to life expectancy for obese versus non-obese old people:

Total, active, and disabled life expectancy in Americans aged >/=70 is estimated, with and without obesity and arthritis. Results indicate that neither obesity nor arthritis is related to the length of life for older men and women, alone or in combination. However, both conditions are significantly individually associated with increased length of disabled life in older men (1.4 years attributable to obesity; 1.2 years to arthritis at age 70) and women (1.7 years attributable to obesity; 2.1 years to arthritis at age 70). In addition, the combination of the two is significantly related to decreased active life, with nearly 50 and 60% of remaining life for 70-year-old men and women lived with disability, respectively.

I suspect there's some survivorship bias in studying people who are sufficiently inured to obesity by luck of genes or more active lifestyle to make it past 70 - despite the nasty effects that all that visceral fat has on your metabolism. Even if this you're not losing years, it certainly takes its toll in other ways. Disability and age-related disease of any sort is an unpleasant, very expensive experience, yet many people ensure they will suffering more of it by way of the lifestyle they lead and the calories they consume.

Damaged mitochondria accumulate in your cells with advancing age, and their malfunctions cause all sorts of further harm to your biochemistry. All in all they are a bad thing, and a strong candidate for the most important cause of degenerative aging. So it is with interest I notice that researchers working on Parkinson's disease are uncovering more of the cellular mechanisms that - when working properly - cull damaged mitochondria so that they can be replaced:

Parkin, the product of the Parkinson's disease-related gene Park2, prompts neuronal survival by clearing the cell of its damaged mitochondria.

...

Several lines of evidence suggest that Parkin loss is associated with mitochondrial dysfunction, but exactly how was unknown. To learn more about Parkin's role in cells, Narendra et al. examined the protein's subcellular location. They found that Parkin was present in the cytoplasm of most cells, but translocated to mitochondria in cells that had undergone mitochondrial damage such as membrane depolarization.

Damaged mitochondria can trigger cell death pathways; indeed, dysregulation of mitochondrial health was already thought to be a possible cause of the neuronal cell death associated with Parkinson's disease. The relocation of Parkin to damaged mitochondria, the team showed, sends these defunct organelles to autophagosomes for degradation. Parkin may thus prevent the damaged mitochondria from triggering cell death. Because neurons are not readily replicable, disposing of damaged mitochondria may be especially important in the adult brain.

I'm not so interested in the association with Parkinson's, since the cell death mechanisms for the dopamine-producing neurons that die off in Parkinson's appear to be further downstream in the chain of cause and effect than accumulation of alpha-synuclin. I am, however, very interested any mechanism that shows potential for enhancement to clear out more damaged mitochondria.

If you look back at the details of how damaged mitochondria eventually replace undamaged mitochondria in a cell, however, it isn't clear whether Parkin is involved in such a mechanism. The crucial point is whether Parkin is only involved in responding to damage to mitochondrial membranes, as the type of internal mitochondrial damage that contributes to aging leaves the membranes intact. The devil, as always, is in the details - and biochemistry has no shortage of details.