Combinatorial lipidomics and proteomics underscore erythrocyte lipid membrane aberrations in the development of adverse cardio-cerebrovascular complications in maintenance hemodialysis patients

TL;DR

This study explores how aging affects kidney function and metabolism, revealing a link between lipid changes and kidney decline, with implications for lifespan and sex differences.

Contribution

The study identifies a novel metabolic link between glucosylceramide accumulation and kidney aging, mediated by mTOR signaling.

Findings

Elevated glucosylceramides correlate with kidney functional decline and higher mortality in aged individuals.

GluCer-mTOR signaling disrupts mitophagy and mitochondrial respiration in the kidney.

The effect is conserved between humans and mice and is more pronounced in females.

Abstract

Age-associated deterioration of physiological functions occur 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 that were recapitulated in mice, on which we further characterized the aging phenome across five peripheral organs. Our multi-omics analyses connected systemic aging profiles primarily to kidney metabolism, uncovering a metabolic association between localized glucosylceramide (GluCer) accretion and renal functional decline. Elevated GluCers were also associated with higher risk of deaths in an independent cohort of aged individuals (n = 271). We report GluCer-mTOR signaling commencing at late middle-age that disrupts mitophagy and undermines mitochondrial respiration in kidney. Conserved between human and mice, GluCer-mediated renal dysfunction is female-biased and modulated by intracellular purines. Our work provides molecular basis for the sexually disparate effects of mTOR inhibition on mammalian lifespan, possibly ascribed to the evolutionary cost of female reproduction.