Metabolic Profiling Reveals Organ-Specific Molecular Pathologies and Aging-Associated Biomarkers in Progeroid...

The molecular mechanisms linking premature and physiological aging remain incompletely understood. Here, we present a cross-species, multi-organ metabolic atlas of progeroid laminopathy (PL) generated through integrated lipidomic and metabolomic profiling of heart, lung, skin, and serum from Hutchinson-Gilford progeria syndrome (HGPS) mouse models and human PL cohorts. We identify organ-specific metabolic alterations, with the most pronounced changes observed in the skin at the omics level. Notably, we uncover disruption of a taurine-TCA-TUDCA cytoprotective axis, suggesting a coordinated metabolic vulnerability in PL. Serum profiling further reveals candidate circulating biomarkers, including increased LPC(18:1e) and LysoPA along with decreased D-glucose 1-phosphate and NAD. These alterations are conserved across species and, importantly, display concordant trends in independent cohorts of physiologically aged healthy individuals. This overlap indicates a partial convergence between PL-associated and normal aging-related metabolic changes. Together, our findings provide a metabolic framework for understanding PL pathophysiology and highlight clinically accessible biomarkers that warrant future longitudinal validation.