CellMar 5, 2026

Restoring daily body clock signals in a key brain control center reverses aging signs and extends life in male mice

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 28, 2026

Abstract

Essence

Timed 3'-deoxyadenosine restored hypothalamic circadian rhythms, improved aging biomarkers, and extended lifespan in aged male mice.

Evidence

This mechanistic mouse study used transcriptomic, hormonal, epigenetic, knockout, and chemogenetic experiments to show that circadian-phase-optimized 3dA increased paraventricular nucleus circadian amplitude, reduced epigenetic age, and required PVN Ruvbl2 for benefit.

Caveat

The evidence is limited to aged male mice and a PVN-specific mechanism, so relevance to other sexes and humans is unproven.

Simplified

Age-related circadian disruptions accelerate physiological decline and shorten lifespan. Enhancing circadian amplitude has emerged as a promising strategy for ameliorating age-associated disorders. Here, we show that the circadian-phase-optimized administration of 3'-deoxyadenosine (3dA) strengthens circadian amplitude in hypothalamic paraventricular nucleus (PVN) neurons, mitigates aging biomarkers, and extends mouse lifespan. 3dA restores clock synchrony and hormonal rhythms, including corticosterone, and reduces epigenetic age as measured by DNA methylation clocks. Transcriptomic, hormonal, and epigenetic profiling reveal robust increases in PVN circadian amplitude following timed 3dA administration, and the PVN-specific knockout of RuvB-like ATPase 2 (Ruvbl2) establishes its genetic necessity by abolishing 3dA's benefits. Similarly, chemogenetic PVN activation reproduces 3dA's metabolic and physiological benefits. These findings identify the PVN clock as a pharmacological node linking circadian amplitude to organismal aging, suggest that targeting RUVBL2-dependent circadian transcription enhances network synchrony, and indicate that circadian interventions are promising therapeutic candidates for delaying aging and improving healthspan in aged male mice.