Red Wine Compound Causes Protective Stress Response

A wealth of evidence-based literature has long touted the numerous health benefits associated with resveratrol—a compound found in red wine and grapes. While researchers have suggested its links to longevity, diabetes prevention, and reduced risk of age-related diseases and cardiovascular disease, it’s been unclear how exactly the compound achieves these benefits.

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Scientists from The Scripps Research Institute (TSRI) in La Jolla, CA, may now have an answer. In a new study in Nature, they suggest resveratrol may stimulate a stress response gene, activating several other protective genes in the body.

“This study uncovered a new, fundamental mechanism of action of resveratrol,” says lead study author Mathew Sajish, PhD, of the Skaggs Institute for Chemical Biology at TSRI. “This mechanism is a foundation upon which the mechanisms and pathways studied in earlier works, at higher concentrations of resveratrol, are layered over.”

Along with their laboratory team, Sajish and senior investigator Paul Schimmel, PhD, examined resveratrol’s association with an ancient family of proteins called tRNA synthetases, which help to translate genetic material into the amino-acid building blocks that make up proteins. 

In particular, they focused on how resveratrol mimics tyrosine tRNA synthetase (TyrRS), an amino acid that can relocate to the nucleus of the cell under stressful conditions and adopt a protective role. 

“This mimicry reshapes the structure and purpose of TyrRS to activate major stress signaling pathways,” Sajish explained. “The key is its activation of PARP-1, a master regulator. This connection to PARP-1 was missed in previous studies. 

Known for its role in stress response and DNA repair and its major influence on aging, PARP-1 also switched on a number of other protective genes associated with longevity and tumor suppression when it was activated by resveratrol. The team confirmed these findings when they injected mice with the compound.

Some researchers have questioned the health benefits of resveratrol exhibited in previous studies because many of them used “unrealistically high doses” of the compound, according to Sajish.

However, he and his colleagues found that the TyrRS-PARP-1 pathway can be activated with doses of resveratrol up to 1,000 times lower than the doses used in some of those studies. As low, perhaps, as the amount of resveratrol found in a couple glasses of red wine, Sajish suggested.

“Because our work showed effects of resveratrol at much lower concentrations than those typically used in earlier studies, it is possible that benefits occur at lower concentrations than previously imagined,” he said.

The team is also on the lookout for molecules that can activate the TyrRS stress response pathway even more potently than resveratrol.

“This study opened up a new area of research—we believe resveratrol’s action through TyrRS can be utilized for therapeutic purposes,” Sajish said. “Our future studies are focused to deliver TyrRS’s health benefits to society. In addition, we know that other members of the same protein family have alternative functions, which we are also exploring.”

—Colleen Mullarkey

Reference

Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature. 22 December 2014 [epub ahead of print].  doi:10.1038/nature14028