Science advancesOct 24, 2025

The protein SAPS3 influences lifespan by controlling metabolism

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Deleting SAPS3 extended lifespan and improved age-related metabolic and functional measures in mice.

Evidence

This mouse and cellular preclinical study tested SAPS3 deletion with lifespan, behavior, cognition, motor, AMPK, senescence, glucose-tracing, and metabolomic analyses in aging models.

Caveat

The abstract reports preclinical mouse and cellular evidence, so whether targeting SAPS3 improves human longevity or healthy aging is unknown.

Simplified

Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice. We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-C-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging. 13 6