UCLA

With increasing age comes increasing susceptibility to age-related diseases, including cancer and neurodegenerative diseases. A novel approach to treating such diseases is to treat aging itself. However, not much is known about the molecular targets of the aging pathway. Utilizing the Drug Affinity Responsive Target Stability (DARTS) approach developed by our laboratory, we have been working to identify the molecular targets of the aging pathway and to analyze the anti-aging mechanisms of various small molecules that have been shown to increase life expectancy. One such small molecule, resveratrol (RSV), a polyphenol found in the skin of red grapes, has been shown to possess various health benefits, including the extension of lifespan, in several different model organisms. However, the underlying molecular mechanisms of RSV’s beneficial effects remain unclear and highly controversial. My thesis work entails the identification of a novel molecular target of resveratrol, deleted in breast cancer 1 (DBC1), and analysis of its mechanism of action through the protein deacetylase sirtuin 1 (SIRT1), which has been shown to be required for some of RSV’s various health benefits. I have also identified DBC1 as a target of RSV’s metabolites, the 3- and 4’-glucuronides and sulfates, and analyzed the metabolites’ mechanisms of action through SIRT1. And finally, I have discovered that resveratrol induces the phosphorylation of DBC1 and activates a distinct ATM-dependent but DBC1-independent DNA damage response from etoposide that does not result in apoptosis. Taken together, my thesis provides a novel molecular mechanism of resveratrol and its metabolites through the novel molecular target DBC1, resolving some of the controversy surrounding resveratrol’s SIRT1-dependent mode of action, and identifies a distinct ATM-dependent and DBC1-independent DNA damage response that resveratrol activates, suggesting another novel molecular mechanism of resveratrol that could contribute to its beneficial health effects.