Loss of mitochondrial DNA accelerates the early-age decline in stress resistance during yeast replicative aging

Baker’s yeast is a well-established model for studying fundamental mechanisms of aging. Due to asymmetric division, yeast mother and daughter cells are distinguishable, and mother cells typically cease division after 15–25 budding events. Meanwhile, yeast suspensions consist predominantly of young cells. Here we studied whether, under harsh environmental conditions, replicative aging — defined by the number of buds produced — manifests at early replicative ages. To test this, we adopted a flow-cytometry-based pulse-chase labeling method to trace survival of yeast age cohorts from daughter cells up to mothers that had produced several — on average up to eight — buds. We found that stress-induced mortality increased with replicative age across all nine stress conditions tested. Mitochondrial dysfunction, caused by depletion of mitochondrial DNA, increased the regression coefficient of replicative age against mortality induced by acetic acid stress, oxidative stress induced by menadione, and sugar-induced cell death. Deletion of SIR2 — a genetic perturbation known to extend replicative lifespan under optimal conditions — also steepened the age–mortality slope under acetic acid stress. Together, our data indicate that aging manifests early in life under extreme environments and that genetic factors influencing this process partially overlap with those limiting lifespan in optimal conditions.