Scientists have long hypothesized that the antioxidant resveratrol, the red-wine ingredient sometimes touted as an elixir of youth, could make humans live longer. However, previous studies had suggested the amount of resveratrol needed to produce beneficial effects far exceeded the amount available through moderate consumption of red wine.
Paul Schimmel, PhD, is a professor and member of the Skaggs Institute for Chemical Biology at The Scripps Research Institute.
Now a TSRI team has discovered that resveratrol activates an ancient stress response mechanism in human cells that guards against DNA damage – a finding that should dispel much of the mystery and controversy about how resveratrol can indeed work in moderate doses.
“This stress response represents a layer of biology that has been largely overlooked, and resveratrol turns out to activate it at much lower concentrations than those used in prior studies,” said senior investigator Paul Schimmel, a professor and member of the Skaggs Institute for Chemical Biology at TSRI.
“With these findings we have a new, fundamental mechanism for the known beneficial effects of resveratrol,” said lead author Mathew Sajish, a Senior Research Associate in the Schimmel laboratory.
Resveratrol is a compound produced in grapes, cacao beans, Japanese knotweed, and some other plants in response to stresses, including infection, drought, and ultraviolet radiation. Researchers have reported that it extended lifespan and prevented diabetes in obese mice and vastly increased the stamina of ordinary mice running on wheels. The question was how.
The TSRI team found that resveratrol triggers the stress response by targeting a family of enzymes called tRNA synthetases that promote protein synthesis. Earlier work led by TSRI professor Xiang-Lei Yang, a TSRI professor in the Departments of Chemical Physiology and Cell and Molecular Biology and former member of Schimmel's laboratory, found that one member of this enzyme family, TyrRS, also protects DNA during stress. The enzyme does this by moving to the cell nucleus. Dr. Sajish noted that resveratrol appeared to have stress-response properties similar to TyrRS and also resembled TyrRS's normal binding partner tyrosine.
For the new study, Drs. Sajish and Schimmel put TyrRS and resveratrol together. Tracking the resveratrol-bound TyrRS in the nucleus, the researchers determined that it activates the protein PARP-1, a major stress response and DNA-repair factor thought to have a significant influence on lifespan. TyrRS's activation of PARP-1 led, in turn, to the activation of a host of protective genes, including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6.
“Based on these results, it is conceivable that moderate consumption of a couple glasses of red wine would give a person enough resveratrol to evoke a protective effect via this pathway,” Dr. Sajish said.
Why would resveratrol, a protein produced in plants, be so potent and specific in activating a major stress response pathway in human cells? Probably because it does much the same in plant cells, and probably again via TyrRS – a protein so fundamental to life that it hasn't changed much in the hundreds of millions of years since plants and animals went their separate evolutionary ways. “We believe that TyrRS has evolved to act as a top-level switch or activator of a fundamental cell-protecting mechanism that works in virtually all forms of life,” said Dr. Sajish.
“We think this is just the tip of the iceberg,” said Dr. Schimmel. “We think there are a lot more amino-acid mimics out there that can have beneficial effects like this in people. And we're working on that now.” Dr. Schimmel and his laboratory also are searching for molecules that can activate the TyrRS stress response pathway even more potently than resveratrol does.