Philanthropy For Basic Science: Longevity Genes

Chemical Genetic Approaches to Aging

CHEMICAL GENETICS relies on using small, cell-permeable molecules that interact with proteins and create a loss or a gain of function of proteins similar to genetic mutations. The active compounds are obtained by in vivo screening of libraries of chemicals, a process similar to finding mutants in traditional genetic screens. Dr. Bedalov is using this technique to find molecules that inhibit Sir2 enzymes, which have been shown to play a role in regulating the lifespan of yeast and nematodes. Working with yeast, he has identified splitomicin as one such inhibitor and has analyzed its structure. He has also found a naphtol derivative and several lead compounds that appear to inhibit mammalian Sir2; their greater stability in aqueous solutions makes them promising as reagents in mammalian cells. By exploiting the ability to inactivate Sir2 with such compounds, Dr. Bedalov plans to dissect Sir2 pathways that promote longevity in higher organisms, including mammals.