Molecular Mechanisms of Genotype-Dependent Lifespan Variation Mediated by Caloric Restriction: Insight from Wild Yeast Isolates.

is an energy-balanced nutrient intake without malnutrition to reduce food intake by 20-40%. CR leads to distinct metabolic reprogramming and adaptive changes in gene expression and, as a result, increases health and lifespan in various model organisms, from yeast to most likely primates. Besides extending lifespan, CR also holds great promise for treating many human age-onset pathologies, and the molecules underlying its effects are sought as targets of pharmaceutical aging therapeutics. However, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. In addition, several studies in different aging models have now demonstrated that the longevity effect of CR can vary dramatically across different genotypes within a population. As such, CR might be beneficial for some yet detrimental for others, and the mechanisms underlying such genotype-dependent variation are not clear. In this study, we meet these challenges by dissecting molecular response to CR in diverse wild isolates of yeast strains, aiming to characterize pathways and molecules mediating CR's effects on replicative lifespan (RLS) diversity. We found that the RLS significantly differs across genetically diverse wild yeast isolates under CR conditions. Examining the relationships among the RLS phenotypes under CR and non-CR conditions, transcript, and metabolite provided insights into the role of mitochondrial functions in CR-mediated lifespan extension.