Significance The free radical theory of aging remains controversial. Accumulation of mitochondrial damage is commonly accepted as an age-related phenomenon associated with the inescapable side effects of oxidative metabolism. However, to date, molecular determinants of this phenomenon have not been identified. Previous evidence indicates that engineered mice deficient in the denitrosylase S -nitrosoglutathione reductase (GSNOR) show features of aging. Here, we show that due to epigenetic events, GSNOR expression declines with age, ultimately resulting in the accumulation of damaged mitochondria. By contrast, centenarians maintain high GSNOR expression. Collectively, these data suggest that GSNOR may act as a longevity protein countering defects in mitochondrial physiology that arise from age-related epigenetic deregulation.