Miércoles 12 de Abril de 2006, Ip nº 148

The Fountain of Health -- Part 2
Por David Rotman

Look Up

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.

Risk Factor

At Elixir and Sirtris, there is little talk about slowing down the aging process. Rather, both companies are intensely focused on the discovery and development of drugs for various age-related diseases, such as type 2 diabetes. Sirtris's Westphal puts it bluntly: "I was never interested in a company that would try to prolong life. I was interested in a company that was going to use genes involved in diseases of aging and in finding an FDA-approved path to get those drugs approved for important disorders like diabetes and neurological disorders."

Nevertheless, antiaging research and drug discovery efforts like Sirtris's and Elixir's are closely linked and share a common premise; a few master genes are thought to regulate both the body's ability to fight off diseases associated with aging and the extension of life span. Though it is still a controversial hypothesis, Sinclair and Guarente believe that in times of adversity or stress -- when food is scarce, for instance -- sirtuins somehow marshal an organism's natural defenses. They argue that, among other things, activated SIRT1 triggers changes in cells that mobilize repair mechanisms and increase energy production. It is, perhaps, these enhanced natural defense mechanisms that explain why animals on a calorie-restricted diet live longer and are healthier.

The idea that the genetic and molecular causes of aging and of many diseases are connected could provide a powerful new way of thinking about medicine, suggests Toren Finkel, a cardiologist at the National Heart, Lung, and Blood Institute in Bethesda, MD. Walk down the corridors of any hospital, he says, and you can't help but notice that many of the patients are elderly. "As cardiologists, we target what we view as causes of diseases -- clearly involved risk factors like hypertension." While that approach is effective, he says, it has largely ignored the most obvious factor in many diseases: age.

"It is obvious....We get sicker as we get older," says Finkel. He says he's not sure whether that observation "is so obvious it is stupid, or so obvious it is profound." But either way, he says, new research explaining the genetic and molecular events behind the aging process is, for the first time, raising the possibility of treating a broad range of diseases by intervening in that process. "No one had really thought about controlling aging as a practical way to control these diseases," says Finkel. "But it could be a powerful way of treating patients."

Our understanding of why people grow old is still primitive, but researchers say the drug discovery effort can push ahead regardless. "We don't understand a damn thing about aging," admits Helfand. But he's quick to add that the health benefits of calorie restriction are well documented in many organisms. And that, he says, "is very exciting from a drug discovery perspective."

The goal is clear: the discovery of drugs that will delay the onset of many of our most devastating diseases, the kind of illnesses that frequently turn the golden years into years of chronic ill health. "Everybody associates caloric restriction with longevity and life span, but the effects on diseases are much more immediate and important," says Guarente. "If only we understood how [calorie restriction] works, such knowledge would guide us in drug development. We would have a drug that would favorably impact many of the common diseases."

  04/04/2006. MIT's Technology Review.