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

作者：Marine Barthez, Biyun Xue, Jian Zheng, Yifei Wang, Zehan Song, Wei‐Chieh Mu, Chih-Ling Wang, Jiayue Guo, Fanghan Yang, Yuze Ma, Xuetong Wei, Chengjin Ye, N.A. Sims, Luis Martínez‐Sobrido, Stanley Perlman, Danica Chen · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.115562 · 被引用次数：10 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Cytomegalovirus and herpesvirus research

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.