The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism

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

doi:10.1126/sciadv.adt3879

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The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism

Journal article

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The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism

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, …

Science advances, Vol.11(43), pp.eadt3879-14

10/24/2025

DOI: 10.1126/sciadv.adt3879

PMID: 41134908

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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- 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.

Aging - genetics

Aging - metabolism

AMP-Activated Protein Kinases - metabolism

Animals

Cellular Senescence - genetics

Citric Acid Cycle

Glycolysis

Longevity - genetics

Mice

Mice, Knockout

Phosphoprotein Phosphatases - genetics

Phosphoprotein Phosphatases - metabolism

Details

Title: Subtitle: The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism
Creators: Ying Yang - University of California, Irvine
Da Eun Kang - University of California, Irvine
Qi Fan - University of California, Irvine
Eric A Hanse - University of California, Irvine
Hosung Bae - University of California, Irvine
Rocio A Barahona - University of California, Irvine
Xiyu Shen - University of California, Irvine
Bryan I Ruiz - University of California, Irvine
Shelly H Lee - University of California, Irvine
Katherine R Pasterczyk - University of California, Irvine
Nainpriya Babbar - University of California, Irvine
Katherine G Waldvogel - University of California, Irvine
Roberto Tinoco - University of California, Irvine
Kim N Green - University of California, Irvine
Qin Yang - University of California, Irvine
Cholsoon Jang - University of California, Irvine
Mei Kong - University of California, Irvine
Resource Type: Journal article
Publication Details: Science advances, Vol.11(43), pp.eadt3879-14
DOI: 10.1126/sciadv.adt3879
PMID: 41134908
ISSN: 2375-2548
eISSN: 2375-2548
Grant note: P30 CA062203 / NCI NIH HHS R35 GM153227 / NIGMS NIH HHS
Language: English
Date published: 10/24/2025
Academic Unit: Internal Medicine
Record Identifier: 9985217135202771

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