NAD+ in COVID-19 and viral infections

Updated: Jun 9

Minyan Zheng, Michael B. Schultz & David A. Sinclair1

Abstract NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD+ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD+ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD+-mediated actions via genes that remove NAD+ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD+ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation.

NAD+ as a modulator of viral infection outcomes Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viral infections render the body a battlefield, requiring mobilization of vast resources to mount an effective defense. These defenses can backfire when uncontrolled, resulting in deadly cytokine storms (see Glossary). A key to effective interventions is to trigger robust antiviral defenses but with checked inflammation. Therefore, molecules that suppress both viral replication and inflammation may be particularly important for fighting severe COVID-19 [1]. A growing body of evidence shows that the metabolite NAD+ is a mediator of both antiviral and anti-inflammatory mechanisms. Based on this evidence, we posit that therapies that boost NAD+ concentrations might play a role in preventing and treating severe COVID-19 and other viral infections. First described as a yeast fermentation factor over a century ago, today, NAD+ has risen to prominence as a regulator of healthy aging. Low levels of NAD+ in tissues and organs are associated with aging, metabolic syndrome, and inflammation, while dietary interventions that slow age-related diseases increase NAD+ concentrations [2]. Here, we review the epidemiological and mechanistic data supporting a role for NAD+ in modulating the outcomes of viral infections, with a focus on SARS-CoV and SARS-CoV-2. We also explore ongoing approaches to boost NAD+ levels for therapeutic benefit in the clinic.

NAD+ and risk factors for severe COVID-19 Aging A tragic and poorly understood aspect to COVID-19 is the increased susceptibility of the elderly to severe forms of the disease [3]. Rates of hospitalization, intensive care unit (ICU) admission, and death increase with age, while the young are often left relatively unscathed [4]. Most infectious diseases afflict both the very old and young, making this demographic pattern for COVID-19 susceptibility unusual [5]. A better understanding of the mechanisms that render older individuals more susceptible to developing severe disease could lead to new candidate strategies for therapeutic intervention. We posit that one culprit may be a deficiency in NAD+, the concentration of which decreases during aging in nearly every tissue studied across species [6]. In rodents, this decrease has been observed in tissues and cells that are relevant to COVID-19 infection, such as the skeletal muscle, liver endothelial cells, and macrophages [7., 8., 9., 10.]. A growing body of human data corroborates an association between age and low NAD+ concentrations across multiple tissues including the skin, blood, liver, and muscle.

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