Comparative metabolomics identifies recurrent age-associated pathway remodeling across species

<h4>ABSTRACT</h4> Aging is accompanied by widespread metabolic change, but it remains unclear which features are shared across species with different physiology, lifespan, and sampling contexts. To address this, we employed a pathway-centered comparative metabolomics framework to evaluate age-associated metabolic remodeling across wild African savanna elephant, mouse, and Drosophila melanogaster . Drosophila provided a controlled adult time course to map age-associated metabolite trajectories, while mouse and elephant plasma datasets allowed us to test whether these pathway signatures extended to mammalian aging. Adult Drosophila showed extensive metabolomic remodeling, with significant metabolites organizing into distinct temporal trajectory classes. Although individual metabolite overlap across species was limited, robust correspondence at the pathway-level overlap was observed. Pathway scores derived from Drosophila increased progressively with fly age, successfully distinguished young and old mice, and captured age-associated stratification across the elephant lifespan. Notably, lipid metabolism, particularly carnitine and fatty acid metabolism, together with nucleotide-related pathways, consistently emerged as the core features of aging across analyses. These findings suggest pathway-level metabolic remodeling is a recurrent feature of cross-species aging.