Protein chaperones elicit a caloric restriction-like response to extend replicative lifespan

The involvement of protein chaperones in aging is intriguing and their potential contribution has, so far, been attributed solely to their central role in proteostasis. Here we show that four protein chaperones from different cellular compartments extend replicative lifespan (RLS) in budding yeast by a common mechanism akin to caloric restriction. The RLS extension relies on the increased direct activation of Snf1 kinase by Hsp90, thereby bypassing the signal on the environmental glucose level. The chaperone-related RLS extension is accompanied by the uncoupling of the respiratory chain. A genomic approach confirmed the repression of glycolysis and cytoplasmic translation, and contrary, activation of gluconeogenesis and fatty acid oxidation. Our results set a novel paradigm for the role of protein chaperones: by modulation of the chaperone expression level one can affect metabolic features such as glucose sensing, fatty acid consumption, respiration rate, and, consequently, modify lifespan. We expect the described mechanism to open new avenues for research in aging and age-related diseases.