Heat-induced longevity in budding yeast requires respiratory metabolism and glutathione recycling

Heat-induced hormesis is a well-known conserved phenomenon in aging, traditionally attributed to the benefits conferred by increased amounts of heat shock (HS) proteins. Here we find that the key event for the HS-induced lifespan extension in budding yeast is the switch from glycolysis to respiratory metabolism. The resulting increase in reactive oxygen species activates the antioxidant response, supported by the redirection of glucose from glycolysis to the pentose phosphate pathway, increasing the production of NADPH. This sequence of events culminates in replicative lifespan (RLS) extension, implying decreased mortality per generation that persists even after the HS has finished. We found that switching to respiratory metabolism, and particularly the consequent increase in glutathione levels, were essential for the observed RLS extension. These results draw the focus away solely from the HS response and demonstrate that the antioxidant response has a key role in heat-induced hormesis. Our findings underscore the importance of the changes in cellular metabolic activity for heat-induced longevity in budding yeast.