A new study gives insight into how resveratrol—a compound found in grapes, red wine and nuts—may ward off several age-related diseases. The findings could help in the development of drugs to curtail some of the health problems that arise as we get older.
Certain metabolic diseases, including type 2 diabetes and heart disease, tend to strike as we age. In animal studies, severely restricting calories can help prevent some of these diseases. Over a decade ago, researchers found that resveratrol can mimic calorie restriction in some ways and extend the lifespans of yeast, worms, flies and fish.
Resveratrol affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. Resveratrol is only one of many natural and synthetic sirtuin-activating compounds (STACs) now known. Whether these STACs directly interact with sirtuins or affect them indirectly, however, has been a subject of debate.
A research team led by Dr. David Sinclair of Harvard Medical School — including researchers from NIH’s National Heart, Lung and Blood Institute (NHLBI) — set out to explore whether STACs can directly activate the sirtuin SIRT1. The study, funded in part by NIH’s National Institute on Aging (NIA), appeared on March 8, 2013, in Science.
SIRT1 works in the cell by removing an acetyl chemical group from its protein substrates. Previous research found that STACs increased SIRT1 activity toward substrates tagged with fluorescent compounds. However, they didn’t affect SIRT1 activity on untagged substrates. The scientists hypothesized that the fluorescent chemical group, typically used to track cells, might mimic some property that SIRT1 requires for its activity.
The scientists tested SIRT1 substrates tagged with compounds similar to the fluorescent tags. They discovered that STAC activation of SIRT1 depends on the presence of certain amino acids at particular positions on SIRT1 substrates. When they removed or changed these amino acids, the effect of STACs on SIRT1 activity was abolished.
The researchers screened for SIRT1 mutant proteins that couldn’t be activated by resveratrol. One mutant, with a lysine instead of a glutamate at one particular position, blunted the enzyme’s activation by more than 100 chemically diverse STACs. The glutamate normally found at this position in SIRT1 is conserved in species ranging from flies to humans. The lysine substitution didn’t significantly alter any aspect of the enzyme’s activity other than its activation by STACs.
STACs ultimately increase the activity of mitochondria, the organelles that produce the cell’s energy. Some believe that this may be how STACs affect age-related diseases. In mouse cells with the mutant SIRT1, the effects of STACs on mitochondria were blocked.
“Now that we know the exact location on SIRT1 where and how resveratrol works, we can engineer even better molecules that more precisely and effectively trigger the effects of resveratrol,” Sinclair says.
The scientists found no evidence for the involvement of other biological pathways that were previously linked to the effects of STACs. These results suggest that resveratrol and other STACs act, at least in part, through direct interactions with SIRT1 and its substrates. Further research will be needed to understand which of these pathways are responsible for the effects of STACs in the body.
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