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

Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among the closely related species or strains of a single species. Since mitochondrial-mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect. Author summaryCaloric restriction (CR) 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 CRs 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.