Sinclair says the finding also provides a plausible explanation for two well-known phenomena: that DNA damage accelerates aging, and that patterns of gene expression tend to go awry as an animal gets older.
The sirtuins have received considerable attention in recent years for their apparent role in aging. An overabundance of sirtuins extends the life spans of yeast, nematodes, and flies. In addition, molecules that seem to activate sirtuins–such as resveratrol, found in red wine–have a protective effect against some age-related diseases in mice. Sinclair cofounded Sirtris Pharmaceuticals in Cambridge, MA, to investigate the therapeutic possibilities of highly potent resveratrol-like molecules. The company is testing a series of products, including a treatment for treating type 2 diabetes.
The new study adds to this growing body of evidence for the many ways sirtuins contribute to aging and age-related disease. “SIRT1 is reported to do so many different things now; the challenge is going to be figuring out which of those it really does, and which of those are really important for diseases,” says Brian Kennedy, another former member of Guarente’s lab. Kennedy, now an associate professor of biochemistry at the University of Washington, was not involved in the study.
Guarente also emphasizes the broad importance of sirtuins, beyond the newly discovered SIRT1 mechanism. “The universal in aging we already know is sirtuins; they do so many things,” he says. “The best way to approach this is to be able to trigger sirtuins so that you get all of the outputs and all of the benefits that they can bestow,” he adds, noting that many of those outputs are unrelated to the new mechanism.
Sinclair and his colleagues also found evidence of a link between the SIRT1 mechanism and cancer, a disease strongly associated with old age. When dosed with resveratrol or beefed up with an extra copy of the SIRT1 gene, mice normally prone to cancer developed fewer tumors. Both of these interventions increased the available amount of SIRT1, likely enhancing the protein’s ability to repair the DNA damage that leads to cancer without compromising its function as a gene regulator.
SIRT1 was already known to regulate a handful of mouse genes, but the new study revealed hundreds more. Many of these genes were found to be overexpressed in the brains of aging mice, underlining the potential importance of SIRT1-based gene deregulation in the aging process.
While the striking parallel between mice and yeast suggests that sirtuins’ competing dual roles may be relevant in a wide variety of organisms, it remains to be seen just how that mechanism fits into the larger picture of mammalian aging, says Vijg. Nonetheless, Sinclair is confident that his group has uncovered a potentially universal mechanism. “Life, in general, has an Achilles heel,” says Sinclair, “and this is it.”