Raising NAD+ Levels With Niagen® (Nicotinamide Riboside) Inhibits Coronavirus Replication in Preclinical Cell Model
New preclinical research shared on scientific publishing website bioRxiv.org has demonstrated that increasing NAD+ levels can boost the activity of protective enzymes called PARPs and reduce coronavirus replication in a mouse cell model.
NAD+, Immunity and Viral Replication
With over 11 million cases, 500,000 deaths, and no curative interventions to date [1], COVID-19 has proven a formidable challenge for healthcare and biomedical research.
SARS-CoV-2, the virus that causes COVID-19 has been shown to wreak havoc on lung cells in part by depleting levels of the metabolite NAD+, which is essential in helping to repair inflammatory DNA damage and support cell survival [2]. NAD+ depletion may be a key factor in innate immunity and thus may be implicated in COVID’s spread and fatal symptoms, making NAD+ an interesting target for antiviral support.
Researchers at the University of Iowa, Oregon Health & Science University, and the University of Kansas had previously reported in an in vitro model that levels of NAD+ in cells were decreased by 80% after infection with a form of coronavirus [3]. The loss of NAD+ appeared to worsen cell survival and impair immune cells such as macrophages from optimally combatting the virus [4].
Raising NAD+ Slows Coronavirus Replication
The hypothesis driving this latest research was that if NAD+ depletion further deteriorated the cells’ defenses, thus promoting viral replication, raising NAD+ levels with NAD+ boosting interventions may reduce replication.
These latest in vitro results validated their hypothesis by demonstrating that mouse cells infected with coronavirus murine hepatitis virus (MHV, a viral “cousin” of SARS-CoV-2) had decreased viral proliferation when supplemented with the NAMPT (the enzyme that converts nicotinamide into NAD+) activator SBI-797812 (SBI), niacinamide (NA), nicotinamide (NAM), or Niagen® nicotinamide riboside (NR). Importantly, SBI, NAM, and NR had significantly greater effects on blunting replication than NA.
The Mechanisms Behind the Results
As part of this research, the team also confirmed that the activity of antiviral PARP enzymes, key to a strong innate immune response, were upregulated by boosting NAD+. NAD-dependent poly(ADP-ribose) polymerases (PARPs) are a class of repair enzymes, several of which are known to help prevent viruses from hijacking cellular machinery for replication [5]. Coronaviruses respond with their own countermeasure with an enzyme called poly-ADP ribose glycohydrolase (PARG), that functions to disable PARPs [3, 6]. This cat and mouse game depletes NAD+ levels in the cell and weakens PARPs, allowing the virus greater opportunity to replicate.
Proper NAD+ levels may also play a role in maintaining a proportional inflammatory response to infection. It is hypothesized that NAD+ depletion may worsen the “cytokine storm” that results in the fatal acute respiratory distress syndrome (ARDS) seen in some COVID patients [7-9].
In summary, while NAD+ is essential to appropriately modulate the inflammatory response and inhibit coronavirus replication, its levels are depleted with infection. In fact, the virus seems to target high energy expenditure organs, like lungs, kidneys and intestines [7]—organs that need all the NAD+ they can get.
Not All Interventions Are Created Equal
While gene expression data identified NAM, NAMPT activators and NR to have similar potential to be strongly protective in vivo, there are a few caveats to be aware of. First, at pharmacological doses, NAM has the potential to function as a PARP inhibitor which is the exact opposite effect of its intended use [10]. Second, overactive NAMPT is implicated in a condition that may reduce lung capacity and adversely affect the lungs and heart, suggesting that its use may not be an appropriate strategy to maintain lung health in some people at risk for COVID-19 [11].
The study authors suggest that, “In order to maximize the likelihood of success in human CoV prevention and treatment trials, care should be taken to carefully compare efficacy and dose-dependence of NR, SBI and NAM with respect to control of cytokine storm and antiviral activities in vivo.”
Onward, Against COVID-19
These results pave the way for further investigations into the immunity-promoting potential of NAD+ boosting interventions. As the study co-author Dr. Charles Brenner stated, “Our data now establish the potential of NR and other NAD-boosting technologies to block infection. The next steps are animal and human trials against SARS-CoV-2.”
Dr. Brenner and team will continue their investigations into the antiviral potential of NR to validate if findings from the lab translate to the clinic. Ultimately, clinical trials are required to determine whether NR and other NAD-boosting nutrients are effective in helping fight COVID-19 infection in humans.
References
Medicine, J.H.U. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). 2020; Available from: https://coronavirus.jhu.edu/map.html.
Shi, Y., et al., COVID-19 infection: the perspectives on immune responses. Cell Death Differ, 2020.
Wang, X., et al., Sirtuins and Immuno-Metabolism of Sepsis. Int J Mol Sci, 2018. 19(9).