| RESEARCH |
The mammalian version of Sir2 is SIRT1. This protein is an important component of a complex network of reactions that control an organism's response to the environment. "In mammals, it is becoming increasingly apparent that SIRT1 is a key regulator of cell defenses and survival in response to stress," write Sinclair and colleagues in a recent article [Science, 305, 390 (2004)]. "In response to damage or stress, cells attempt to repair and defend themselves, but if unsuccessful, they often undergo programmed cell death, or apoptosis. Numerous studies show that aging is associated with increased rates of stress-induced apoptosis. ... Consistent with this, rodents subjected to caloric restriction and long-lived genetic mutants ... are typically less prone to stress-induced apoptosis." In the Science paper, the Sinclair team reports that SIRT1 expression is higher in rats with restricted diets than in animals that eat as much as they want. In addition, cells grown in serum from rats on restricted diets are less vulnerable to stress-induced apoptosis than cells grown in serum from well-fed rats. The scientists believe that SIRT1 operates through its interaction with the DNA repair factor Ku70. Ku70 ordinarily binds to the protein Bax, interfering with Bax's ability to promote apoptosis. Under stressful conditions, however, two lysines in Ku70 become acetylated, and it loses its hold on Bax. That allows Bax to migrate from the cell's cytoplasm into the mitochondria, where it initiates apoptosis. The Sinclair team discovered that SIRT1 maintains the two Ku70 residues in a deacetylated state "to keep Bax sequestered from mitochondria. Thus, caloric restriction induces SIRT1 expression in a wide array of tissues, and this shifts the balance away from cell death toward cell survival." The researchers also note that levels of insulin and another hormone called insulin-like growth factor 1 (IGF-1) are lower in rodents that are fed less than normal. And they found that cells grown in serum from underfed rats reduced SIRT1 expression when treated with insulin or IGF-1. Sinclair's team concludes that these data "indicate that the systemic regulation of mammalian SIRT1 is mediated, in part, by insulin and IGF-1, two serum factors that are involved in life span regulation in a variety of species" including worms, flies, and mice. Sinclair and his colleagues believe that other targets of SIRT1 may also be affected by caloric restriction and other stresses. For instance, Sinclair has collaborated with Michael E. Greenberg, director of the neuroscience division at Children's Hospital Boston, to explore the connection between SIRT1 and FOXO3, a member of the FOXO family of Forkhead transcription factors. These proteins serve as sensors of the insulin signaling pathway and also activate genes related to DNA repair, detoxification of reactive oxygen species, cell cycle arrest, and cell death. SIRT1 apparently controls the cellular response to stress by regulating the FOXO transcription factors, report Greenberg, Sinclair, and their colleagues [Science, 303, 2011 (2004)]. In response to oxidative stress, SIRT1 deacetylates FOXO3, which "increases FOXO3's ability to induce cell cycle arrest ... possibly allowing more time for cells to detoxify reactive oxygen species and to repair damaged DNA." Deacetylation also "inhibits FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance." |
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