Multi‐Omics Reveals Mechanisms of Metabolic Rejuvenation in Aged Mice and Pre‐Frail Older Men by Losartan

Aging is associated with significant alterations in systemic metabolism across species. We employed targeted metabolomics to investigate the effects of losartan, an angiotensin II receptor blocker, on the serum metabolome of aged mice and pre-frail older men. Losartan treatment resulted in a shift in serum metabolome aging signature to a more youthful state. This rejuvenation effect appears to be contingent on the presence of functional angiotensin II receptors, with receptor knockout mice showing no rejuvenation effect with treatment. Additionally, we observed a similar rejuvenation effect of losartan in the cardiac proteome of aged mice, with the most pronounced changes occurring in proteins involved in oxidative phosphorylation. While our study did not encompass a full lifespan analysis, in alignment with previous reports of lifespan extension in other models, we noted a statistically significant improvement in survival among geriatric mice treated with losartan. In parallel, we analyzed serum metabolomics data from pre-frail older men from a phase 2 randomized placebo-controlled trial of losartan, which indicated a dose-dependent metabolic rejuvenation effect. Correlation network analysis revealed divergent aging effects between species, with mice exhibiting broad decreases in metabolite concentrations and humans showing increases, particularly across lipid species. Principal component analysis further highlighted a global shift in metabolite levels, potentially linked to changes in lipoprotein metabolism, plasma volume, and amino acid metabolism with age. In summary, our results suggest that losartan can partially reverse age-related metabolomic changes in both male mice and humans, with distinct species-specific responses.