Calorie restriction extends life span in a wide spectrum of organisms, and has been shown to delay the onset or reduce the incidence of many age-related diseases, including cancer and diabetes. No one is sure why it works.
MIT Biology Professor Leonard P. Guarente discovered in 2000 that calorie restriction activates the silenced information regulator (SIR2) gene, which has the apparent ability to slow aging during the low-calorie diet. This gene makes a protein called Sir2, which is normally activated by the coenzyme molecule NAD. Guarente has shown that SIR2 is integrally tied to extending life span in yeast and in the roundworm. Humans carry a similar gene.
This latest study probes how Sir2 is activated by calorie restriction. The authors report that a coenzyme related to NAD, called NADH (nicotinamide adenine dinucleotide) inhibits Sir2 by blocking the action of NAD. During calorie restriction, levels of NADH decline in cells. This decrease in NADH allows NAD to better activate Sir2 and thereby extend life span.
"These findings provide a simple model for activation of Sir2 and extension of life span by calorie restriction," the authors write. "Our findings suggest that the NAD/NADH ratio can serve a critical regulatory function, determining the life span of yeast mother cells. A reduction in this nucleotide activates Sir2 to extend the life span in calorie restriction."
In previous research, Guarente found that rather than a slower metabolism leading to a slower rate of respiration, it turns out that respiration in yeast cells under calorie restriction goes up, not down. "A high respiration rate is intimately connected with calorie restriction in yeast," he said. "A high respiration rate activates SIR2. When respiration goes up, NADH goes down and SIR2 goes up. When SIR2 goes up, longevity happens."
NADH, a coenzyme or enzyme helper, is present in all living cells. (An enzyme is a protein that works like a catalyst in the body to prompt chemical changes; for instance, turning food into energy.) NADH, an activated form of the B vitamin niacin, helps produce energy through a series of chemical reactions in the cell.
In cells, NADH stimulates the production of ATP (adenosine triphosphate), a compound that represents chemical energy in cells. The more NADH a cell has, the more stored energy it has. It remains to be seen whether these findings about yeast and NADH will relate to the extension of life span in mammals by calorie restriction.
In addition to Guarente, authors include Su-Ju Lin, now at the University of California at Davis; Ethan Ford, MIT postdoctoral associate in biology; Marcia Haigis, MIT postdoctoral fellow in biology; and MIT biology graduate student Gregory B. Liszt.
This work is supported by the National Institutes of Health, the Ellison Medical Foundation, the Seaver Institute and the Howard and Linda Stern Fund.