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

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<sup>+</sup>-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD<sup>+</sup> 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.

Authors

Institutions

Publication Details

Journal
Cell Reports
Published
2025-04-01
DOI
https://doi.org/10.1016/j.celrep.2025.115562
Citations
6
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
4.78

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Jian Zheng, Fanghan Yang, Marine Barthez, Zehan Song et al.
6 citations
Cell Reports
interferon and immune responses
4.78
article

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

Jian Zheng, Fanghan Yang, Marine Barthez, Zehan Song, Stanley Perlman, Biyun Xue, Luis Martínez‐Sobrido, Chih-Ling Wang, Danica Chen, Jiayue Guo, Yuze Ma, Yifei Wang, Xiaoli Wei, Chengjin Ye, Wei-Chieh Mu, N.A. Sims
article en
6 citations

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<sup>+</sup>-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD<sup>+</sup> 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.

Cell ReportsVol. 44(4)
University of Iowa (US), Texas Biomedical Research Institute (US), University of Louisville (US), University of California, Berkeley (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases
Zero hunger
Openalex Percentile: Top 5%
interferon and immune responses
4.78
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.