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Loss of sirtuin 3 disrupts cellular senescence signaling pathways.

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Title: Loss of sirtuin 3 disrupts cellular senescence signaling pathways.
Authors: Kura N; Jean Mayer USDA Human Nutrition Research On Aging at Tufts University, Boston, MA, 02111, USA.; Graduate School of Biological Sciences, Tufts University, Boston, MA, 02111, USA., Mogck BA; Jean Mayer USDA Human Nutrition Research On Aging at Tufts University, Boston, MA, 02111, USA., Jezak ST; Jean Mayer USDA Human Nutrition Research On Aging at Tufts University, Boston, MA, 02111, USA.; Friedman School of Nutrition Science & Policy, Tufts University, Boston, MA, 02111, USA., Velarde MC; Institute of Biology, College of Science, University of the Philippines, 1101, Quezon City, Philippines., Wiley CD; Jean Mayer USDA Human Nutrition Research On Aging at Tufts University, Boston, MA, 02111, USA. christopher.wiley@tufts.edu.; Graduate School of Biological Sciences, Tufts University, Boston, MA, 02111, USA. christopher.wiley@tufts.edu.; Friedman School of Nutrition Science & Policy, Tufts University, Boston, MA, 02111, USA. christopher.wiley@tufts.edu.; Department of Medicine, School of Medicine, Tufts University, Boston, MA, 02111, USA. christopher.wiley@tufts.edu.
Source: GeroScience [Geroscience] 2026 Jun; Vol. 48 (3), pp. 3483-3495. Date of Electronic Publication: 2026 May 06.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Springer International Publishing Country of Publication: Switzerland NLM ID: 101686284 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2509-2723 (Electronic) Linking ISSN: 25092723 NLM ISO Abbreviation: Geroscience Subsets: MEDLINE
Imprint Name(s): Original Publication: Cham : Springer International Publishing, [2017]-
MeSH Terms: Sirtuin 3*/genetics , Sirtuin 3*/deficiency , Sirtuin 3*/metabolism , Cellular Senescence*/physiology , Cellular Senescence*/genetics , Signal Transduction* , Senescence-Associated Secretory Phenotype*, Fibroblasts/metabolism ; Wound Healing/physiology ; Tumor Suppressor Protein p53/metabolism ; Animals ; Mice, Knockout ; Mice ; Aging
Abstract: Cellular senescence is a multifaceted stress response marked by stable proliferative arrest and the secretion of diverse biologically active factors, collectively known as the senescence-associated secretory phenotype (SASP). The senescent phenotype is remarkably variable and subject to various regulatory influences. We previously demonstrated that mitochondrial dysfunction induced by diverse stimuli, including the loss of sirtuin 3 (SIRT3), leads to the hyperactivation of AMPK and p53, culminating in senescence while concurrently suppressing much of the proinflammatory SASP. Here, we extend our findings by revealing that the absence of SIRT3 can suppress segments of the SASP even in the absence of p53. Intriguingly, SIRT3 deficiency renders cells resistant to stimulation by exogenous cytokines, such as interleukin-1. Fibroblasts derived from Sirt3 knockout mice exhibit a diminished SASP, including reduced levels of Pdgfa, and these mice display impaired wound healing and a more expansive granulation area. Furthermore, aged Sirt3 knockout mice show disrupted patterns of senescence relative to wild type controls, including increases in senescence markers in adipose tissue, but surprisingly also decreases in liver and heart. Collectively, these data underscore a role for SIRT3 in orchestrating cellular senescence phenotypes, shedding light on its regulatory influence beyond the p53-dependent pathway.
(© 2026. The Author(s).)
Competing Interests: Declarations. Competing interests: CW holds patents related to the detection, modification, and elimination of senescent cells and declares no non-financial interests. NK, BM, SJ, and MV declare no competing financial or non-financial interests.
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Grant Information: R01 AG051729 United States AG NIA NIH HHS; T32 DK124170 United States DK NIDDK NIH HHS; DK124170 United States DK NIDDK NIH HHS; 8050-10700-003 Agricultural Research Service; AG051729 United States AG NIA NIH HHS; USDA-ARS 58-8050-9-004 Agricultural Research Service
Contributed Indexing: Keywords: Cellular senescence; Fibroblasts; Mitochondria; Senescence-associated secretory phenotype; Sirtuin 3; Wound healing
Substance Nomenclature: EC 3.5.1.- (Sirtuin 3)
0 (Sirt3 protein, mouse)
0 (Tumor Suppressor Protein p53)
Entry Date(s): Date Created: 20260505 Date Completed: 20260714 Latest Revision: 20260819
Update Code: 20260819
PubMed Central ID: PMC13356147
DOI: 10.1007/s11357-026-02284-x
PMID: 42086890
Database: MEDLINE
Description
ISSN:2509-2723
DOI:10.1007/s11357-026-02284-x