March 2006

The Fountain of Health

Continued from page 3

By David Rotman

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Elixir Pharmaceuticals and Sirtris have much in common. Both firms were founded to discover drugs for age-related diseases, using core technology built around antiaging genes. Both feature rosters of star antiaging researchers, with Elixir counting Guarente and Kenyon among its founders. Just a few miles apart, Elixir is at the edge of MIT's campus, while Sirtris is next to Harvard University.

But despite their similarities, the two companies seem to have radically different outlooks. At Elixir, which was founded in 1999, there is no evidence of the kind of youthful bravado that characterizes Sirtris. On the whiteboard in his small office, Peter DiStefano, Elixir's chief scientific officer, patiently and meticulously diagrams some of the metabolic pathways that the company is investigating. Some directly involve SIRT1; some don't. Arrows overlap in a complicated mesh; some arrows just wander off, pointing to unknown territory. DiStefano's point is clear: these molecular mechanisms are immensely complicated and still not completely understood.

"It's hard to say when we will get to a drug development candidate [based on sirtuins]. It's a little early," he says. He points to a small sign above his door, positioned so that it's the last thing you see as you leave the office. It reads, "The animal is always right." The challenge, says DiStefano, is translating the knowledge of mechanisms at the cellular level into an understanding of effects on the whole organism. "You have to look at the entire animal. You can do a lot of cell-based experiments and see a lot of effects in cells, and those are absolutely important starting points, but you really need to glue it all together and figure out what happens at the organismal level."

Indeed, many questions about sirtuins remain unanswered. The genetic and molecular pathways involved in aging are complex, and their details remain much in dispute. Whether sirtuins are central to them is still, in fact, controversial: other labs are studying different genetic candidates for such a master role in the aging process. "It is still a very young field, and it suffers from lack of consensus," says Stephen Helfand, a professor of biology at Brown Medical School and discoverer of an aging gene called indy (for "I'm not dead yet") in fruit flies. "People don't agree on many things."

Even strong believers in sirtuins point out that scientists are just beginning to understand the genes' biology and their metabolic role. In particular, it's uncertain whether sirtuins act in mammals the same way they do in lower organisms. The experiments in which adding extra copies of SIRT1 to mice failed to extend the life span of the animals are particularly troubling to some. Labs studying mice are also struggling to prove that the beneficial effects of calorie restriction require the activity of sirtuins -- something that Guarente showed for yeast and Helfand for fruit flies but that hasn't been demonstrated in mammals.

The Fountain of Health

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