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Updated: May 5, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19
Marine Barthez1, Biyun Xue2, Jian Zheng3
1Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
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.
Insights
Aging increases COVID-19 severity. SIRT2 deficiency worsens disease in aged mice, but NAD+ boosters like 78c offer protection by regulating immune responses to SARS-CoV-2.
Area of Science:
- Immunology
- Gerontology
- Virology
Background:
- Aging is a significant risk factor for severe COVID-19, but the underlying mechanisms are not fully understood.
- Age-related decline in immune function contributes to increased vulnerability to infections like SARS-CoV-2.
Purpose of the Study:
- To investigate the role of SIRT2 in age-associated COVID-19 severity.
- To explore therapeutic strategies targeting NAD+ metabolism for protecting aged individuals from SARS-CoV-2 infection.
Main Methods:
- Utilized aged mice models lacking SIRT2 and infected them with SARS-CoV-2.
- Administered NAD+ booster (78c) to aged mice during SARS-CoV-2 infection.
- Investigated the molecular mechanisms involving SIRT2, cGAS acetylation, and ORF3a-mediated inflammation.
Main Results:
- Aged mice lacking SIRT2 exhibited exacerbated COVID-19 disease and higher mortality.
- Treatment with NAD+ booster 78c significantly protected aged mice against lethal SARS-CoV-2 infection.
- SIRT2 regulates cGAS acetylation, suppressing age-associated inflammation and immune overactivation.
Conclusions:
- SIRT2 plays a crucial role in mitigating age-associated COVID-19 severity by controlling cGAS-mediated inflammation.
- NAD+ boosting represents a promising therapeutic avenue for preventing severe outcomes in elderly populations infected with SARS-CoV-2.
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