Regulation of endogenous hydrogen sulfide production by dietary restriction and the GH/IGF-I axis
Abstract: Dietary restriction (DR), defined loosely as reduced nutrient/calorie intake without malnutrition, and reduced signaling through the growth hormone/insulin-like growth factor I (GH/IGF-I) pathway are both associated extended longevity, improved metabolic fitness and increased stress resistance across evolutionary boundaries. However, downstream effector mechanisms of DR and reduced GH/IGF-1 benefits remain poorly characterized, particularly in mammals. Previously, we have found that DR increases endogenous production of the gas hydrogen sulfide (H2S), and that this can confer some benefits of DR, including protection from the acute stress of ischemia reperfusion injury. Recently, we found that GH is a negative regulator of H2S production through the transsulfuration pathway enzyme, cystathionine gamma lyase (CGL). Long-lived dwarf mice lacking GH or GH receptor displayed increased CGL expression and hepatic H2S production. In addition to protection from ischemic injury, increased H2S is associated with pleiotropic benefits including reduced blood pressure, improved insulin sensitivity and increased angiogenic potential. Implications for increased transsulfuration pathway activity and H2S production on stress resistance, metabolic fitness and aging in the context of DR and hypopituitary dwarfism will be discussed.
About James Mitchell:
James R. Mitchell completed his doctoral training at UC Berkeley on human telomerase biochemistry and his post-doctoral studies at Erasmus University in Rotterdam, the Netherlands on the genetics of DNA repair and aging. He is currently an Associate Professor in the Department of Genetics & Complex Diseases at the Harvard T. H. Chan School of Public Health. The Mitchell lab is focused on elucidating the underlying mechanisms of the phenomenon known as dietary restriction, an intervention involving reduced nutrient/energy intake that slows aging, improves metabolic fitness and increases resistance to a variety of clinically relevant acute stressors, including major surgery. Recent work has focused on the beneficial role of increased endogenous production of hydrogen sulfide gas, and its regulation by nutrient and neuroendocrine mechanisms. Dr. Mitchell’s long-term goal is translate knowledge of these anti-aging mechanisms towards the goal of improving human health.