Leonard Guarente

This description of aging is incomplete, said Guarente, who spoke as part of the "Dean’s Distinguished Lecture Series." The series draws scientific leaders to HSPH to address crosscutting research. A missing piece of the aging story, he said, is a gene called SIR2 in yeast. Humans possess a similar gene.

In 2000, researchers in Guarente's lab discovered that a low-calorie diet alters metabolism, which activates SIR2 and lengthens the lives of yeast.. Later, his group demonstrated that SIR2 serves a similar function in roundworms. His group is now investigating the role of the gene in mice.

"SIR2 seems to exist in nature to promote survival and slow aging in the face of scarcity," Guarente said. "Even though aging has many and variable causes, it is regulated by SIR2. If conditions are poor, it has the ability to slow down aging and perhaps reproduction to weather the storm. Evolutionarily, it makes sense."

The mechanistic details of how SIR2 regulates aging may help scientists harness benefits of calorie restriction–longer lives, thinner bodies –while excluding downsides such as diminished sex drive and fewer meals.

In the nucleus of cells, DNA is wrapped around a string of protein beads. To duplicate itself or make proteins, DNA needs to be unwrapped from its chromatin packaging. SIR2 plucks an acetyl compound off the protein bead, which effectively silences the DNA.

"Interestingly, SIR2 doesn’t know where to go [on the chromosome]," Guarente said. "It’s not a DNA-binding protein. It binds to partner proteins that bring it to the DNA. We think that’s what has allowed it to evolve and regulate different pathways and different processes. It’s part of the answer of why this gene is so adaptable in different systems."

In yeast, Guarente’s group discovered that to promote longevity, SIR2 needs a co-factor called NAD, a chemical involved in metabolism. He explained in a previous talk on the topic, "Without NAD, SIR2 is Clark Kent. With NAD, SIR2 is Superman."

Recently, Guarente and his colleagues added to the model. They reported that calorie restriction decreases the level of a related molecule called NADH, which works like Kryptonite to inhibit SIR2. Yeast whose NADH levels were lowered through genetic tweaking lived longer, showing that the combination of more NAD and less NADH stimulates SIR2. A paper describing this work was published in the January 1 issue of Genes & Development.

In mouse studies about to be published, Guarente focused on the role of a similar gene, SIRT1, in body fat. "Calorie restriction impacts first on fat," he said. "Fat accumulates during aging, about one pound per year. Fat accretion causes age-associated diseases, such as diabetes. Lean mice live long. What better way to measure conditions, good or bad, than by the body fat we carry?"

In fat cells of mice, reduced calories seem to stimulate SIRT1, which works with a partner to bind to and shut down a key fat-production gene called ppar-gamma. Guarente argues that the mechanism does not just slow down or stop the accumulation of fat, but it actively helps the animal shed fat, slowing down aging and increasing the lifespan.

The next "Dean’s Distinguished Lecture Series" will be on April 1. Samuel Thier, former President and CEO of Partners HealthCare, will speak on health care policy and the elections.

–CCM