The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.

Authors

Ying Yang, Da Eun Kang, Qi Fan, Eric A Hanse, Hosung Bae, Rocio A Barahona, Xiyu Shen, Bryan I Ruiz, Shelly H Lee, Katherine R Pasterczyk, Nainpriya Babbar, Katherine G Waldvogel, Roberto Tinoco, Kim N Green, Qin Yang, Cholsoon Jang, Mei Kong

Published in

Science advances. Volume 11. Issue 43. Pages eadt3879. Oct 24, 2025. Epub Oct 24, 2025.

Abstract

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-¹³C₆-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.

PMID:
41134908
Bibliographic data and abstract were imported from PubMed on 25 Oct 2025.

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