Losartan Reverses Age-Related Metabolic Decline in Mice and Older Men
A common blood pressure drug shifts the aging metabolome toward a more youthful state in both aged mice and pre-frail older men.
Summary
Researchers used multi-omics tools to study losartan, a widely prescribed blood pressure medication, in aged mice and pre-frail older men. They found that losartan shifted the serum metabolome — the full profile of small molecules in the blood — toward patterns seen in younger individuals. The effect depended on functional angiotensin II receptors, since knockout mice showed no benefit. In the heart, losartan improved proteins involved in energy production. Geriatric mice on losartan also showed improved survival. In a phase 2 human trial, pre-frail older men showed dose-dependent metabolic rejuvenation. Interestingly, aging affected metabolites differently across species, but losartan partially reversed these changes in both, suggesting a shared mechanism with species-specific nuances.
Detailed Summary
Aging reshapes the body's metabolic landscape in ways that accelerate frailty and disease. Identifying drugs that can reverse these changes — not just slow them — is a central goal of longevity medicine. This study investigates whether losartan, an angiotensin II receptor blocker (ARB) already approved for hypertension, can do exactly that.
Researchers from Johns Hopkins and the National Institute on Aging applied targeted metabolomics and proteomics to aged mice and pre-frail older men enrolled in a phase 2 randomized placebo-controlled trial. In mice, losartan treatment shifted the serum metabolome toward a younger signature. The cardiac proteome also improved, with the most significant changes in proteins governing oxidative phosphorylation — the mitochondrial process central to cellular energy. Treated geriatric mice showed statistically significant survival improvements.
Critically, the rejuvenation effect was absent in angiotensin II receptor knockout mice, confirming the mechanism is receptor-dependent rather than off-target. This specificity strengthens the biological plausibility of the findings and points toward the renin-angiotensin system as a genuine aging pathway.
In human participants, serum metabolomics data revealed a dose-dependent metabolic rejuvenation effect with losartan. However, the aging metabolic signature differed between species: mice showed broad decreases in metabolite concentrations with age, while humans showed increases, particularly in lipid species. Principal component analysis suggested global shifts tied to lipoprotein metabolism, plasma volume, and amino acid metabolism.
The implications are significant. Losartan is inexpensive, widely available, and has a well-established safety profile. If these metabolic rejuvenation effects translate to clinical outcomes, it could represent a low-barrier longevity intervention — particularly for older adults already managing cardiovascular risk. Larger, longer trials are needed to confirm functional and survival benefits in humans.
Key Findings
- Losartan shifted the serum metabolome of aged mice and pre-frail older men toward a younger metabolic state.
- The rejuvenation effect required functional angiotensin II receptors — knockout mice showed no benefit.
- Cardiac proteome improvements centered on oxidative phosphorylation proteins, suggesting mitochondrial benefits.
- Geriatric mice on losartan showed statistically significant survival improvements.
- Human participants showed dose-dependent metabolic rejuvenation in a phase 2 randomized controlled trial.
Methodology
The study used targeted metabolomics in aged mice and proteomics of cardiac tissue, alongside serum metabolomics from a phase 2 randomized placebo-controlled trial of losartan in pre-frail older men. Angiotensin II receptor knockout mice served as mechanistic controls. Principal component and correlation network analyses were used to characterize species-specific aging and treatment effects.
Study Limitations
This summary is based on the abstract only, as the full text was not available. The mouse study did not encompass a full lifespan analysis, limiting survival conclusions. The human trial was phase 2 and likely underpowered for definitive clinical outcome endpoints; species-specific metabolic differences complicate direct translation.
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