Trans‐Omics Integration Reveals That the Kidney Contributes to Systemic Aging via Sexually Dimorphic Accumulation of Glycosphingolipids

Age-associated deterioration of physiological functions occurs at heterogeneous rates across individual organs. A granular evaluation of systemic metabolic mediators of aging in a healthy human cohort (<i>n</i> = 225) identified prominent increases in circulating uremic toxins, a finding recapitulated in mice. We connected these systemic aging profiles to renal metabolism, specifically linking glucosylceramide (GluCer) accretion to renal functional decline at late middle-age that coincides with the temporal surge in uremic toxins. Importantly, age-associated increases in circulating GluCer, largely contributed by the kidneys, are conserved from mice to humans, and are significantly associated with enhanced risk of multiple causes of mortality in aged individuals. We further showed that GluCer accumulation, commencing in late middle-age of females, impairs mitophagy via disrupting mitochondria-lysosome untethering, and undermines mitochondrial respiratory function via purine-dependent activation of mTORC1 signaling that can be rescued by pharmacological purine depletion. The resulting age-associated renal dysfunction is female-biased, likely due to sexually dimorphic GluCer handling. Our work provides a molecular basis for the sex-specific benefits of mTOR inhibition on lifespan, and highlights clinically relevant inhibitors of purine metabolism as potential senotherapeutics to mitigate kidney-driven systemic aging.