NAD levels are critically important to your body's immune response
Viruses knock down your NAD levels, and your innate immune system needs that NAD to fight back. That's why replenishing NAD before and during a viral attack can support your immune system.
Keep in mind that health supplements like NAD precursors such as nicotinamide riboside are not intended to treat, cure, or prevent any disease, and they cannot be sold or marketed for that purpose.
Indeed, the science does not tell us that boosting your NAD levels will prevent you from catching a virus or that improving NAD levels will cure the illness caused by the virus. But an NAD boost might nonetheless be extremely helpful to your body to support the immune system by making sure that the cells that are fighting the virus have the fuel they need to do what they need to do.
COVID Lowers NAD Levels
Viral infections in general, and COVID-19 infections in particular, do not hit everyone equally. Scientists have identified numerous "co-morbidities" -- unhealthful conditions that correlate with worse outcomes in COVID, including old age, obesity, diabetes, pregnancy, and a number of other conditions that suspiciously correlate with NAD deficiency.
But not only do people with lower NAD levels do worse when they get COVID, but infection itself actually lowers NAD levels:
We have found that [a viral infection] results in the massive depletion of NAD+.
NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger.
Moreover, studies of coronaviruses generally, and COVID-19 in particular, reveal an interesting drama in the immune system. When a COVID infection is detected, the cell's innate immune system releases an enzyme called a PARP (Poly-ADP Ribose Polymerase). The PARP attaches an ADP-Ribose molecule to the coronavirus. The purpose of the ADP-Ribose molecule is to interfere with the virus's ability to reproduce.
_____________________________
NAD boosters cannot prevent
or cure COVID; but they might
help your immune system fight back.
_____________________________
Where does the PARP get the ADP-Ribose molecule? You can see here that ADP-Ribose is most of an NAD molecule -- everything but nicotinamide:
That means that every time a PARP attaches an ADP-Ribose to a coronavirus, it uses one of the cell's NAD molecules in order to do it.
The problem is that coronaviruses have a counterattack. It is an enzyme called CARH (Coronavirus ADP-R Hydrolase), which removes the ADP-Ribose that the PARP just attached. That process of attachment and removal burns up the cell's NAD:
Infected cells expend NAD+ in antiviral ADP-ribosylating activities while the virus attempts to reverse these modifications. Indeed, coronavirus infection strikingly depletes cellular NAD+ level
By the virtue of its high capacity to actively reverse antiviral ADP-ribosylation, this virus accentuated pre-existing states of NAD+ deficiency
It is speculated that SARS-CoV-2 depletes cellular NAD+ levels by overexpressing a set of PARPs, all of which compete for the same NAD+ pool....which ultimately reduces NAD+ levels
If it weren't for CARH, coronaviruses might not be much of a problem, because replication could be adequately impaired by the PARP. Instead, the PARP defenses are reversed, and NAD levels crash by three-fold. Because NAD levels crash, PARPs aren't able to continue defending against the virus (and, as we shall see, other aspects of the immune response are also impaired).
Here is how the scientists say it:
From their earliest replication intermediates, coronaviruses elicit an attack on cellular NAD+. Cellular NAD+ becomes a battlefield in which the innate immune system and the virus struggle for the upper hand.
Our data established that noncanonical PARPs are consistently induced by Coronavirus infection, can depress cellular NAD+ and have their MARylation activities limited by cellular NAD+, and have known antiviral activities...The >3-fold depression [of NAD] seen in this study is precedented in HIV and herpesvirus infections... ["MARylation" is adding the ADP-Ribose to the virus]
NAD Boosters Might Help
If depressed NAD levels are impairing the body's innate immune system, then perhaps boosting NAD levels would allow the PARPs to continue their work and more effectively fight back against the coronavirus and depress viral replication.
A group of scientists found that several different NAD-boosting approaches significantly improved PARP function and decreased the rate of viral replication, most of all nicotinamide (NAM) and nicotinamide riboside (NR). However, they were less certain that nicotinamide would work as well in practice because at high doses nicotinamide can inhibit PARPs, which would defeat the enterprise. Here is how they said it:
Here we showed that boosting NAD+ through the NR and NAMPT pathways depresses replication...Based on gene expression data as well as MHV cellular infection data, NAM, NAMPT activators, and NR have similar potential to be strongly protective in vivo. However, there are a few caveats. First, that at pharmacological doses, NAM has the potential to function as a PARP inhibitor. Second, NAMPT is considered a driver of pulmonary vascular remodeling and potentially a target to be inhibited to maintain lung health of some people at risk for COVID-19. Thus, to maximize the likelihood of success in human Coronavirus prevention and treatment trials, care should be taken to carefully compare efficacy and dose-dependence of NR, SBI [a NAMPT activator that increases the expression of NAMPT], and NAM with respect to control of cytokine storm and antiviral activities in vivo.
That study was published about two years ago in the Journal of Biological Chemistry. It is important to understand how these molecules interact, but it's not clear how seriously to take the study, because they used mice, ferrets, and a lung biopsy from someone who died of COVID. That's some distance from a human clinical trial.
However, in the following two years, clinical studies have been run to test whether NAD boosting strategies would in fact improve outcomes for humans with COVID infections, including the Phase 2 and Phase 3 clinical trials summarized here:
Our study shows that [CMA - a combined metabolic activator including NR] and standard therapy significantly reduces the mean recovery time of ambulatory patients with COVID-19 as compared with placebo and standard therapy (6.6 vs 9.3 d in phase-2) and (5.7 vs 9.2 d in phase-3)...by improving immune response, and regulating antioxidant, amino acid and lipid metabolism. After having a positive result on the phase 2 study with 93 patients, we designed a double-blinded placebo-controlled Phase 3 study with 304 patients. We have shown that administration of the CMA accelerates the recovery of the patients independent of standard therapy...Our analysis showed that administration of CMA is an effective and safe treatment for COVID-19 patients.
Participants who took the supplements recovered from COVID in 5.7 days, compared to 9.2 days for those on the placebo.
Therefore, as a more recent study summarized, the strength of the body's initial immune response to COVID depends on NAD levels, and so the disease will be more serious in people whose NAD levels are already low:
The strength of the initial immune response to SARS-CoV-2, to restrain its replication, depends on the cellular NAD+ level. High potency of SARS-CoV-2 in reversing antiviral ADP-ribosylation confers higher resistance of this virus to the restriction of replication and permits the development of serious disease in patients with pre-existing, subclinical NAD+ deficiency
Moreover, consistent with other studies involving high doses of NR, this study also found that inflammatory cytokine levels were improved (decreased).
Cytokine Storm
That finding of reduced inflammation was important, because depressed PARP activity isn't the only problem with reduced NAD levels in viral infection. Severe COVID cases commonly exhibit an over-reaction by the immune system, called a "cytokine storm." Instead of the immune system failing to react to the viral infection, this is the immune system gone into overdrive, and this over-reaction is itself deadly.
Inflammatory responses are themselves antiviral, although the severe cytokine storm associated with acute and chronic viral disease is considered a pathological overreaction.
So which is it -- is the immune system getting regulated up or down? Both. The up-regulation and down-regulation of the immune response normal -- in fact, it is essential for properly managing infection response. But the immune system wants to be activated and calmed by the right amounts at the right time, and that's what's not happening in severe COVID.
Some of the molecules that can calm the immune response also depend on the presence of NAD to do their work:
NAD+ may contribute to the resolution of inflammation, and to limiting or preventing the effects of cytokine storms; it might do so by increasing the activity of sirtuins...
That means that low NAD levels can both prevent the immune system from working the way it should, and also cause it to work in ways that it should not. And that's why it is so bad that coronaviruses can rapidly deplete NAD levels.
Scientists sum it up thus:
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. 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. 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.... We argue that since PARP enzymatic activity requires NAD+, maintaining a sufficient NAD+ concentration may be crucial for achieving PARP-related antiviral mechanisms...We argue that providing more NAD+ to fuel the activity of PARPs might shift the antiviral balance back in favor of host cells...
Multiple independent lines of evidence point to NAD+ metabolism as a potential target of intervention. Viral infections are known to cause cellular NAD+ depletion. Indeed, declined levels of NMN, an NAD+ precursor, have been detected in the blood of COVID-19 patients. Furthermore, the upregulations of PARP genes and NAD+ biosynthetic gene nampt were observed in SARS-CoV-2 infected individuals. PARPs play key roles in antiviral immune response. The induction of PARPs that are known to use NAD+ as the co-substrate to catalyze mono-ADP-ribosylation (MARylation) further decreased the cellular NAD+ contents. Moreover, the upregulation of NAMPT, the rate-limiting enzyme of the salvage pathway, can be viewed as a compensative mechanism in response to the increased demand for NAD+. Boosting intracellular NAD+ pool using precursors such as NR has been shown to block the replication of murine hepatitis virus (MHV) sensitive to MARylation PARP activity, lending support to the idea that restoration of NAD+ homeostasis may mitigate COVID-19 severity.
A Phase 4 human clinicial study, assessing just nicotinamide riboside alone in the context of long COVID, is underway. But we likely won't have the results until 2024.
There are other ways to boost NAD, such as nicotinamide, tryptophan and niacin (also known as "nicotinic acid"). However, high doses of nicotinamide can cause adverse side effects, and the metabolic pathways that are used by to make NAD from tryptophan and niacin appear to be downregulated during COVID infection:
These data indicate that the same noncanonical PARPs induced by MHV are induced by SARS-CoV-2 and that in vivo infection with SARS-CoV-2 down-regulates synthesis of NAD from tryptophan and nicotinic acid (NA) while up-regulating synthesis capacity from NAM and NR.
Conclusion
Antibiotics will stop a bacterial infection, but only your immune system can reverse a viral infection. Vaccines are one way to help your immune system, by preparing it for particular types of threats. But there are other ways to provide immune support, and one of them is by ensuring that the immune system has enough energy to do its job.
Many different viruses cause NAD depletion, including flu, Zika, and coronaviruses, like COVID. Both animal and human studies suggest that you would want to both have and maintain robust NAD levels when COVID comes calling. Indeed, worse COVID outcomes seem to correlate with conditions of age and metabolic stress that depress NAD levels.
Although anything that boosts NAD levels in tissues that are under viral attack will probably help, the studies suggest that tryptophan and niacin will be less effective, because COVID infection down-regulates the metabolic pathways by which those precursors become NAD.
Nicotinamide (NAM) and Nicotinamide Riboside (NR) both worked well in vitro, but in practice there is a risk that NAM will boost NAD and simultaneously suppress PARP and sirtuin activity, which would defeat the purpose. Thus, nicotinamide riboside may turn out to be the NAD precursor of choice for immune support in response to viral attack. Clinical tests to confirm are underway.
Research involving NAD and viral infection...
Comments