2. Academic Validation
  3. SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19

SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19

  • Cell Rep. 2025 Apr 22;44(4):115562. doi: 10.1016/j.celrep.2025.115562.
Marine Barthez 1,  Biyun Xue 2,  Jian Zheng 3,  Yifei Wang 4,  Zehan Song 4,  Wei-Chieh Mu 5,  Chih-Ling Wang 1,  Jiayue Guo 1,  Fanghan Yang 5,  Yuze Ma 1,  Xuetong Wei 4,  Chengjin Ye 6,  Nicholas Sims 1,  Luis Martinez-Sobrido 6,  Stanley Perlman 7,  Danica Chen 8
Affiliations

Affiliations

  • 1 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 2 Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
  • 3 Department of Microbiology and Immunology, Center for Predictive Medicine, University of Louisville, Louisville, KY, USA.
  • 4 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 5 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 6 Texas Biomedical Research Institute, San Antonio, TX, USA.
  • 7 Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA; Department of Pediatrics, University of Iowa, Iowa City, IA, USA. Electronic address: stanley-perlman@uiowa.edu.
  • 8 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: danicac@berkeley.edu.
PMID: 40220296 DOI: 10.1016/j.celrep.2025.115562
Abstract

Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal Infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of Cyclic GMP-AMP Synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 Infection.

Keywords

COVID-19; CP: Immunology; CP: Microbiology; NAD; ORF3a; SARS-CoV-2; SIRT1; SIRT2; SIRT3; SIRT6; SIRT7; aging; cGAS; inflammation; mitochondria; sirtuin.

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