Sex-specific regulation of lifespan and metabolic health by AMP biosynthesis

During aging, the loss of metabolic homeostasis drives a myriad of age-related pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex have so far produced detrimental phenotypes in vertebrates. Here, as an alternative approach, we manipulate the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and demonstrate a male-specific lifespan extension. To explore the observed sexual dimorphism, we use an integrated omics approach and identify that metabolic plasticity, which is deregulated with age, is restored in old heterozygous males. These phenotypes are accompanied by a fasting-like metabolic switch, and resistance to high-fat diet. On the cellular level, heterozygous cells experienced inhibited mitochondrial functions, increased sensitivity to nutrient levels, reduced ATP levels, and an activated AMPK pathway. Finally, lifelong intermittent fasting reversed the male-specific longevity benefits. Together, we identify the AMP/AMPK axis as a sexually dimorphic regulator of vertebrate lifespan, and APRT as a novel target for promoting metabolic health.