SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19
Summary: 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 inc...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500333X |
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| Summary: | Summary: 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. |
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| ISSN: | 2211-1247 |