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
  • 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: [email protected].
  • 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: [email protected].
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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