After winning tenure at MIT in 1986, biology professor Leonard Guarente did some soul-searching.
He had made his mark by studying gene regulation in yeast, but that field was getting overrun with researchers, and he wanted to pursue a riskier project, where success would have a dramatic scientific impact.
He thought about delving into HIV — the virus had just been identified — but found biologists already flocking to that line of research. Studying the biological and molecular basis of memory and consciousness also sounded appealing, but the problem seemed too huge to tackle.
With the help of some bright graduate students who arrived in his lab in 1991, he hit on the idea of looking for genes that control aging in yeast. At the time, it was a plan with little prospect for success: Few scientists believed that aging might be controlled by a single gene (or small group of genes).
Guarente turned that view around — and pioneered a new field of study — with his discovery of so-called longevity genes, which dramatically boost the lifespan of yeast, worms, mice and potentially humans. The human version of the gene, known as SIRT1, is now the target of several drugs in development to treat the diseases of aging, including diabetes, Alzheimer's and cardiovascular disease.
"This is a radical, new type of medicine, where you don't treat just one disease, but many," says David Sinclair, a former postdoctoral associate in Guarente's lab and now a professor of pathology at Harvard Medical School.
Sirtris Pharmaceuticals, a company started by Sinclair, is conducting two clinical trials of drugs based on Guarente's discoveries, in patients with Type II diabetes and cancer. Results of the Phase II trials are expected next year.
A risky venture
In the early 1990s, when he first identified SIR2, the master gene that controls aging in yeast, Guarente thought it unlikely that his work would eventually finger the same anti-aging genes in worms and mammals, much less humans. "The notion that the same gene could control aging across species - we didn't think it was possible," he recalls.
But Sinclair, who joined the lab in 1995, remembers Guarente's unwavering dedication to the work. "He could see [the potential] while most people, even in our lab, were highly skeptical that this was going anywhere," Sinclair says.
Guarente, now in his mid-50s, says doesn't expect his research to yield a fountain of youth. Instead he relies on old-fashioned strategies for staying healthy: He exercises daily, doesn't smoke, and roughly follows a Mediterranean diet. He also drinks red wine, which has high levels of resveratrol, a compound that Sinclair showed activates SIRT1.
His penchant for taking on difficult challenges kicked in at an early age. Growing up in Revere, a gritty suburb north of Boston, Guarente devoted himself to school and worked at a local grocery store to help pay his tuition at Boston College High School. After graduating at the top of his class, he entered MIT in 1970, becoming the first in his family to attend college.
In high school, he had never been interested in biology, but he decided to study molecular biology at MIT after hearing some upperclassmen talk about how exciting the new field was. At the time, genetic engineering was an emerging field, and the new techniques offered a world of opportunities for a young, eager scientist.
Before launching his aging studies in 1991, he shared most scientists' views that aging was something that happened inevitably, bringing along its assortment of diseases such as cancer and Alzheimer's. If that was true, it could take decades to identify all of the genes involved in aging. However, if the conventional wisdom was wrong, then identifying the gene (or small group of genes) could have an enormous impact. Guarente decided to take the risk.
Not everyone thought his new research program was a good idea, including some of his MIT colleagues. However, Guarente's new focus paid off: In 1995, he showed that longevity genes, which help organisms withstand stressful conditions such as starvation, offer protective benefits that can extend lifespan and improve overall health if activated long enough.
The longevity genes produce proteins called sirtuins, which control a myriad of cell activities by removing acetyl molecules from proteins, activating or de-activating the proteins. Using this mechanism, sirtuins can act as master regulators of a cell's response to stress. When faced with DNA damage, inflammation or limited food supply, sirtuins coordinate a variety of hormonal networks, regulatory proteins and other genes, with a net effect of keeping cells alive and healthy.
However, sirtuins are not likely to extend lifespan indefinitely. Indeed, even in yeast and roundworms, sirtuin genes or calorie restriction can extend the life span at most 50 percent. In mice or rats, again calorie restriction can exert up to a 50 percent extension in life span. Given the likelihood that any sirtuin drug will not be perfect, Guarente envisions a modest effect on life span, but a major effect in health span (the period during which we are healthy and active). "I think of sirtuins as the key to approaching late-onset diseases in a systematic and global way," he says. "I don't think we will see a change in how long people live, but I think we'll see an improvement in how long people stay healthy."
Guarente also solved a longstanding mystery by linking sirtuins to the effects of extreme calorie restriction on longevity. It has been known for decades that cutting normal calorie consumption by 30 to 40 percent can boost lifespan and improve overall health in animals such as worms and mice. Guarente showed that calorie restriction boosts levels of a co-enzyme called NAD, which in turn activates SIRT1.
Some biologists have questioned whether the benefits of caloric restriction seen in yeast, worms and mice apply to humans. If not, trying to reproduce those effects with drugs could prove futile. It's difficult to answer the question definitively, because studies in calorie restriction in primates take a very long time, and for humans, the diet is unpleasant and impossible for most people to sustain.
Though no long-term human studies have been done, a recent study in rhesus monkeys that spent 20 years on a calorie restricted diet showed that they were less likely to suffer diabetes, cancer and heart disease. However, average lifespan was extended only if the researchers excluded deaths they deemed unrelated to aging.
Guarente is quick to point out that drawback in the study, and says he doesn't believe the work offers significant support for the idea that calorie restriction can extend lifespan in primates. However, he is still hopeful that sirtuin-boosting drugs will help fight diseases of aging, mimicking some of the effects of calorie restriction without the negative side effects.
If the ongoing efforts to develop such drugs pan out, it's safe to say Guarente will have achieved the dramatic impact he set out to make back in the early 1990s when he started to study aging. "If these new drugs are safe and effective in humans, that will really bring us to another level in terms of treating potentially all of the major diseases of aging, like diabetes and Alzheimer's," he says.