Sci. Aging Knowl. Environ., 23 June 2004
Calorie restriction might harness life-span extension protein to stop cell suicide
Less food can mean more protein--a specific protein, that is. The life-prolonging regime of calorie restriction (CR) boosts quantities of SIRT1, a potential mammalian longevity molecule, new research shows. The protein protects cells by blocking stress-induced suicide, suggesting that CR lengthens animals' lives at least in part by preserving irreplaceable cells. The results hint that several seemingly disparate life-extending methods overlap.
Cutting calories increases longevity in multiple species (see Masoro Review), but how it works is mysterious. In yeast, a protein called Sir2p is usually required for CR to work (see Kaeberlein Perspective). Recently, researchers uncovered a clue that the mammalian version of Sir2p, SIRT1, also operates in CR: SIRT1 spurs fat breakdown--a process that promotes longevity--in mice on the austere diet (see "Counterattack"). No one, however, had determined whether CR increases SIRT1 production. Molecular biologist David Sinclair of Harvard Medical School in Boston and colleagues set out to do so.
The researchers found that various tissues--including fat--from year-old rats on the low-cal diet had more SIRT1 than normal. They then simulated CR in cultured cells by soaking them in serum--blood with its cells removed--from the dieting rodents. Such treatment prods cultured cells to activate their stress-response genes and resist suicide, or apoptosis, recapitulating events seen in cells from calorie-restricted animals (see Kristal and Paolucci Perspective). After the procedure, the cells bore twice as much SIRT1 as did cells wetted with serum from satiated animals. CR reduces the amounts of insulin and insulin-like growth factor-1 (IGF-1), so the researchers supplemented the CR-serum-fueled cultures with these molecules, expecting them to prevent SIRT1 quantities from rising. Both hormones held SIRT1 at bay, suggesting that CR jacks up SIRT1 in part by curbing insulin and IGF-1. Previous studies had suggested that SIRT1 might protect cells from stress-induced suicide (see "Death and Aging, Together at Last"). Overproducing SIRT1 in cultured cells conferred resistance to this type of self-imposed death, the researchers found. "CR might be turning on this cell defense and keeping cells alive that might otherwise rush to death" and weaken tissues in an aging body, suggests Sinclair.
Experts are intrigued by the observations but cautious about the implications. The work "elegantly" brings together insulin signaling, CR, and apoptosis, says mammalian physiologist Edward Masoro, although apoptosis is likely to be "just part of the calorie-restriction story." The new, important result, says cell biologist Leonard Guarente of Massachusetts Institute of Technology, is that CR alters SIRT1 quantities in mammalian cells. But he isn't convinced of a link between IGF-1 and SIRT1, saying that experiments in animals are needed to solidify that conclusion. William Sonntag, a neuroendocrinologist at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, says that the paper helps us understand how CR controls apoptosis but notes that the IGF-1 result is puzzling; other research has shown that IGF-1 suppresses apoptosis. In any case, a life rich in SIRT1 might sate our hunger for more time.
June 23, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150