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

## TL;DR

The kidney contributes to aging by accumulating fats, especially in females, which leads to mitochondrial dysfunction and systemic aging.

## Contribution

The study reveals a sex-specific mechanism linking kidney metabolism to systemic aging through glycosphingolipid accumulation and mTORC1 signaling.

## Key findings

- Age-related accumulation of glucosylceramide in the kidney correlates with systemic uremic toxins and mortality risk.
- Female-specific GluCer accumulation disrupts mitochondrial function via purine-dependent mTORC1 activation.
- Pharmacological purine depletion rescues mitochondrial dysfunction and reduces systemic aging effects.

## Abstract

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 (n = 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.

Female‐specific renal GluCer accumulation disrupts mitochondrial quality control via a conserved purine‐mTORC1 pathway, triggering a wave of uremic toxins into the systemic circulation that constitutes a female‐biased vulnerability toward renal‐driven multiorgan senescence. As estrogen levels fall in late middle‐age, GluCer accumulates in female kidneys. Elevated purines activate mTOR, disrupt mitophagy, suppress PGC1α, and impair mitochondrial–lysosome untethering, leading to mitochondrial dysfunction and reduced ATP production. Renal failure promotes systemic accumulation of uremic toxins and multiorgan senescence. Purine inhibition attenuates mTOR activation and restores mitochondrial homeostasis, highlighting a potential senotherapeutic strategy.