You Live What You Eat? Connecting Metabolism to Lifespan

Includes: ELXR, SIRT
by: Derek Lowe

I didn’t note it at the time here, but back in November there was a very interesting paper in Nature that bears on aging and life extension. A group at the Hutchinson Center in Seattle did a survey of compounds, looking for whatever might show up that seemed to extend lifespan (that’s just the sort of see-what-falls-out screen that C. elegans is good for, since the little beasts are so small, and they only live for about 20 days or so).

They screened 88,000 compounds - by far the largest direct survey ever run for longevity, as far as anyone knows, but (I should point out) still a tiny run by industrial standards. But they came up with a few hits: 1083 compounds made the first cut (roundworms still alive longer than they should be), and 115 of those repeated with statistical significance. 13 compounds increased lifespan by 30 to 60%. Interestingly, I don't think that they list all of them in the paper, but they did note that one of the strong hits looked very much like a known hit set of serotinergic antagonists.

They ran a set of analogs through the assay, and had a high hit rate. All the compounds that worked were 5-HT2 antagonists, such as marketed drug mianserin, although they each have some other activities as well (it should be noted that the reuptake inhibitors, the Prozac/Zoloft type compounds, had no effect). But the 5-HT2 subtype, particularly 5-HT2c, has long been regarded as important in food intake, so the guess is that these compounds also tie into the whole caloric restriction story for aging.

Restricting food intake and giving one of these drugs at the same time didn't add anything, the group found. It may be that these compounds set off metabolic signals that tell the roundworms that they’re short of food, even though they really aren’t, and thus do a sort of fake caloric restriction on them. At any rate, mutant nematodes that can't make serotonin showed no lifespan extension with exposure to these compounds, so one way or another, it seems to be involved.

Now, I wouldn’t advocate running out and trying this on a human being just yet, though, since we’ve come up with several higher brain functions for our serotinergic receptors that roundworms don’t have much call for. There’s also the question of what this strategy would feel like in a higher animal: would you want to live longer, but always feel as if you were starving, for example? I know that the people who are trying CR on themselves say that this isn’t the case, at least after the first few weeks or months (!), but there’s no telling what would happen with a pharmacological approach.

What this study does point out, though, is something that I think that a lot of people haven’t really caught on to yet: first, it’s increasingly clear that there are deep connections between metabolism and lifespan. All sorts of genes related to food intake and insulin signaling affect how long model organisms live, and there’s every reason to expect that the same is true of us.

Second, the settings for our lifespans may not be optimal – or what we’d now consider optimal. There’s every reason to expect that this relationship has been under very heavy selection pressure. Evolutionarily, this would be the balance between reproductive fitness and everything else an organism might do, and evolutionarily, reproductive fitness is going to be the big winner every time. But there’s no reason that we necessarily have to accept whatever tradeoffs were made during the development of our species.

We’re going to have to be very careful, of course. There may be all kinds of catches to extending lifespan – susceptibility to cancer and other diseases being the first one that everyone thinks of. But ever since our brains became large and complex enough for language and culture, and ever since we started growing our own food, we’ve been altering the evolutionary bargains that all other species have had to make – predator/prey relationships, availability of food, and so on. We may yet be able to draw a black line through another paragraph of the contract, and make it stick.

I don’t think that many people realize that this is possible, or that it’s an area of active research. Most of the large drug companies, in fact, seem to be staying away from it for now, content to let the smaller ones take on the (considerable) risks. Some people may not be able to get past Aubrey de Grey’s hair, and may have decided the whole subject is out on the fringe. But, increasingly, I don’t think it is. This stuff could work, eventually, and if it does, it’ll be one of the biggest inflection points in the history of the species.