A review paper I noticed today reminded me of the relationship between body temperature and longevity. Calorie restriction leads to lowered body temperature - as well as extended healthy life - in mice, but unrelated methods of lowering body temperature over the long run also seem to extend longevity to some degree. For example, see this research from a couple of years ago:

Was calorie restriction itself responsible for longer lifespan, with reduced body temperature simply a consequence? Or was the reduction of core body temperature a key contributor to the beneficial effects of calorie restriction? Conti and colleagues wanted to find out. To tackle the problem, the scientists decided to try to lower core body temperature directly, without restricting food intake.

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Conti and colleagues decided to focus their efforts on the preoptic area of the hypothalamus, a structure in the brain that acts as the body’s thermostat and is crucial to temperature regulation. Just as holding something warm near the thermostat in a room can fool it into thinking that the entire room is hotter so that the air conditioning turns on, the Scripps Research team reasoned that they could reset the brain’s thermostat by producing heat nearby.

To do so, they created a mouse model that produced large quantities of uncoupling protein 2 in hypocretin neurons in the lateral hypothalamus, which is near the preoptic area. The action of uncoupling protein 2 produced heat, which diffused to other brain structures, including the preoptic area. And, indeed, the extra heat worked to induce a continuous reduction of the core body temperature of the mice, lowering it from 0.3 to 0.5 degrees Celsius.

The scientists were then able to measure the effect of lowered core body temperature on lifespan, finding that the mice with lowered core body temperature had significantly longer median lifespan than those that didn’t. While this effect was observed in both males and females, in this study the change was more pronounced in females - median lifespan was extended about 20 percent in females and about 12 percent in males.

Some researchers would like to pin temperature-dependent longevity on the rate of chemical reactions in the body (reaction speeds generally being proportional to temperature), but I suspect that's too simplistic. An alteration in the rate at which mitochondrial processes generate damaging free radicals sounds more plausible, driven by some temperature-sensitive signaling and control process.

The interesting question with regard to this is what proportion of calorie restriction benefits stem from this mechanism - as opposed to, say, the loss of visceral fat, changes in metabolic control pathways, increased autophagy, other regulatory changes in cells, and so forth. None? A tenth? A third? What? As we look at ongoing work to produce calorie restriction mimetic drugs, based on manipulating the biochemical pathways researchers discovered through research into calorie restriction, how much benefit will these mimetics provide for people who still have visceral fat and a high body temperature?

As I mentioned over at the Longevity Meme, SAGE Crossroads seems to be putting forth new material on policy and longevity science once more. Looking at some of the podcasts uploaded this year, I notice one on the Longevity Dividend initiative with Daniel Perry of political advocacy groups Alliance for Aging Research and CAMR, amongst others.

#35-Longevity Science-Setting the stage, the longevity dividend:

All you have to do is go into any bookstore in this country and go to the health section and you’ll see lots of titles about ending aging or immortality or stopping aging in its tracks. I think there is a lot of debate over whether that’s conceivable, but I think there is an emerging belief that we can slow down the processes of aging and make real achievements within a reasonable period of time, the next 10-15 years, that could buy back for people now living 5-7 years of healthy, productive life. As one gerontologist said, it ought to take 80 years to get to 60. Now that may be a bit more ambitious that what I’m talking about. I’m talking about seven years not 20 years, but there is a growing feeling among leading scientific authorities that based upon what we know works in laboratory animals, including apparently based on recent data, rhesus monkeys, a very close cousin to human beings. It could be possible that we could engineer healthier, more vital, more satisfying life for people in their 70s, 80s, and 90s in our lifetime.

Institutional outlooks are usually incrementalist, aiming for the smallest set of changes possible under present circumstances, as the incentives within institutions discourage any other course. In that respect, the Longevity Dividend is the output of institutional thinkers. What you see above this is more or less the view from inside the government funding monolith, where suggesting even a modest target for increasing healthy life span is a major advance, hurdle and negotiation.

Meanwhile, outside the institutional gates is where you'll find the serious attempts to create revolutionary change in the aging research community and develop disruptive technologies from the latest longevity science. As I said at the time the Longevity Dividend was first put forward:

this proposal is late to the party, fails to acknowledge those who have been advocating similar approaches for some years, and touts a target for gains in healthy life span that is somewhat less than the actuaries and system biologists think will be attained in the next 10 to 20 years by present trends and research directions.

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The Longevity Dividend proposal is primarily a political position - which should instantly explain most of its deficiencies to those who follow the way in which funding politics works. It's the first step in a long engagement with large-scale government funding sources (such as the National Institute on Aging) in an attempt to steer future funds into the sorts of moderate programs supported by its authors. That Miller, et al, are doing this at all illustrates, amongst many other things, a concern that future funding will dry up in favor of groups presently moving to advocate healthy life extension - such as those system biologists, or supporters of the Strategies for Engineered Negligible Senescence.

My prediction for the next decade: the trail to radical life extension, and to increasing public understanding and support for medicines to repair aging, will be blazed by philanthropic and private venture funding.

I've been meaning to mention that molecular biologist and healthy life extension advocate Attila Chordash is in the midst of blogging the construction of his PhD thesis. His long term interest is in what he calls partial immortalization (or, alternately, systemic regenerative medicine) - as much healthy life extension as possible attained through period replacement of organs and vital cell populations, as well as via manipulation of stem cells in situ. I have been varyingly skeptical of the degree to which this alone is sufficient for radical life extension:

• Regeneration Is Not Rejuvenation
• Inserting Repair of Aging Into Tissue Engineering

But it is still an interesting concept, and will clealry be explored in the years ahead, given the massive levels of funding and research interest justifiably directed towards stem cell science.

But back to the thesis, which is a good insight for those interested in what is presently going on down in the trenches of the research community:

During my PhD work I’ve done various stem cell transplantations (local and systemic) into brain, heart, muscle tissues using different stem cell sources, just like freshly isolated bone marrow derived cells (hematopoietic, mesenchymal stem cells), murine embryonic stem cells, cultured hematopoietic stem cells. And I was heavily involved in the mechanisms by which exogenous stem cells can contribute to host tissues and the way these exogenous cells and lesion models can motilize the built in endogenuous stem and progenitor cell populations.

So for me the unifying concept behind is a kind of systemic approach, that is to collect many stem cell data from various tissues, organs, compare them to each other and derive some unifying principles from them that could be adapted to other tissue environments too.

Chordash is not the only person engaged in online thesis building in the regenerative medicine space. I view this as a facet of the overall trend in scientific work towards more open access, meritocratic open review, a gift economy of information, and incremental publication by release. The present information infrastructure in the scientific community - much of it still geared to and informed by an era of paper libraries and hand-delivered mail - isn't up to the task of enabling efficient management and utilization of data at scale. Change is underway, and must go a lot further if the pace of research is to keep up with the pace of data generation. As Chordash puts it:

after all, scientists should conduct nice experiments and publish their results in short, inforich and accessible research papers in order to share it ASAP with the research community, not in book-length, otherwise unaccessible PDFs

The ideal infrastructure would look - from above the API layer - something like a vast distributed and cross-referenced database, constantly updated and constantly accessible to automated discovery and correlation agents, raw data neatly split out from conclusions and theories about that data. As even small fields grow far beyond the ability of one researcher - or one small team - to encompass and understand, automation of the time-consuming parts of academic research will become increasingly necessary.