Tuesday, August 18, 2009

A Program for Aging?

In the science section of today's New York Times, Nicholas Wade skillfully reviews progress toward drugs to extend human lifespan. As he notes, researchers have known for decades that severe caloric restriction extends the life of many animals. Beginning in the 1990s they realized that changing the action of even one gene, for example by mutation or drugs, can have a similar effect. I've written on incremental advances for Scientific American in 2004 and for The Scientistin 2005, but there has been steady progress before and since.

I do, however, question Wade's assertion that "Evolutionary biologists, the experts on the theory of aging, have strong reasons to suppose that human life span cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, like roundworms, fruit flies and mice." Although I'm sure some evolutionary biologists would be skeptical, others have devised coherent ways to understand how a reprogrammable lifespan could evolve.

The first thing to recognize is that immortality is perfectly normal, in the following sense: your cells are the surviving members of an unbroken line of succession going back billions of years. Sure, along the way, many individual animals died without offspring. Even in the animals that reproduced to pass on the torch, most cells died along with their bodies. But their sacrifice doesn't alter the overall continuity of life, any more than the billions of skin cells you lose each day.

So practically speaking, cellular processes are quite capable of self-renewal that makes organisms immortal. There's nothing inherent about death, in a properly self-maintained body. The idea that we just "wear out" after a while is an oversimplification, partly based on analogy with the flawed machines that we build. There is accumulating damage to the telomeres at the end of chromosomes and oxidative damage resulting from metabolism, but clearly there are ways to evade them.

Why then do our bodies die at all, to be replaced by new generations? This is where it gets interesting, and speculative. One reason could be that periodic sexual scrambling of our genetic material is important for evolutionary innovation. No doubt there's some truth to that, but asexual species also have a fixed, relatively short lifespan. Whatever the reason, it seems that there are benefits to building a new body from scratch. As Thomas Jefferson said, "a little rebellion, now and then, is a good thing."

But how much? How often should generations turn over? The optimum must be a tradeoff between the benefits of new bodies (whatever they may be) and the cost of making them, such as energy and nutrients. The growing offspring are also vulnerable to predators and harsh living conditions.

From this point of view, it hardly seems shocking that we would have ways of recalculating the tradeoff between reproduction and longevity, and there's lots of experimental support for this view. Think of the calorie-reduction effect: when resources are short, all sorts of animals live longer. It makes sense to conserve scarce resources and reproduce when times get better. The widely studied roundworm C. elegans even goes into a long-lived dormant state, something like the spores of some plants, when conditions are bad. Researchers have also found direct that reproducing causes changes that reduce lifespan. (It's not entirely a myth that your kids make you age prematurely--although they also make you young.)

What's particularly interesting is that the biochemical pathways that underlie these responses--the specific molecules and the ways they influence one another--have many common elements in creatures ranging from humans to worms and flies and even to single-celled yeast. Each of these species lives longer when food is drastically reduced, even though the specific ways in which they eventually die are completely different. (Few yeast die of heart attacks, for example.) This suggests to many researchers that there may be a "program" that modifies lifespan in response to environmental and reproductive conditions, and that that program has been adopted and adapted over hundreds of millions of years of evolution.

If so, the question is whether we can hack into this ancient program. And should we?

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