COVID-19, NAD, and the B3 Vitamins
[UPDATED OCTOBER 6, 2020:]
Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19. The Brenner-Fehr-Heer team had already shown that coronavirus infection attacks the NAD system, and that four defensive PARP enzymes activated by viral infection can have their activities increased by boosting NAD. A new Phase 2 clinical study in Istanbul followed 93 patients with mild-to-moderate COVID-19 infections. Seventy one patients received a nutritional cocktail that included nicotinamide riboside; 22 patients received a placebo. The results (preprint) were that patients receiving the nutritional cocktail recovered in an average of 6.6 days, versus 9.3 days on the placebo. The nutritional cocktail also lowered liver enzymes. Dr. Brenner said "The results were statistically significant, and the intervention was safe. In mice, NR lowers liver enzymes. In people, NR lowers IL6. In cells, NR increases innate antiviral activities. Thus, I expect NR was the driver of the beneficial effects in people."
[UPDATED July 9, 2020] This new preclinical study posted July 8, 2020, suggests that Coronaviruses including COVID-19 deplete cellular NAD; Depleted NAD impairs the body's innate immune system's ability to fight the virus; Replenishing NAD with NR rescues innate immune function and slows viral replication. Therefore, "nutritional and pharmacological interventions to enhance NAD-based defenses may boost innate immunity." These are still cell studies, not human studies, but the direction is promising. The authors note that Nicotinamide (NAM) and Nicotinamide Riboside (NR) both performed well at slowing viral replication, but cautioned that at pharmacological doses, NAM has the potential to function as a PARP inhibitor, so NR may be superior overall. The authors also note that, although it's too early to be confident -- we lack human studies -- but "NAD boosting approaches have the potential to support the innate immune system and address the age-, smoking- and comorbid conditions associated with worse SARS-CoV-2 outcomes (37). The potential societal benefit of a safe and readily available molecule to support prevention and public health is hard to overstate, especially as new outbreaks of COVID-19 emerge."
[UPDATED May 14, 2020] On a television interview on May 14, Dr. Charles Brenner summarized the research thus: "What we discovered is that the NAD system comes under a specific attack during a viral infection. So in a coronavirus infection NAD levels get cut down by more than three-fold, and a number of genes that control the NAD system are disturbed. Our early stage research suggests that boosting the NAD status of a cell and maybe even of a person may allow them to boost their innate immunity against the virus...We also know that in many of the conditions of metabolic stress in which NAD levels decline the NR gene pathway to make more NAD gets boosted up. So it looks as though when a cell is damaged or challenged by a viral infection that cell and tissue is looking for NR in order to potentially support its innate immunity."
New research suggests that the process by which COVID-19 damages lung tissues includes NAD depletion. And so people ask whether Vitamin B3-based NAD precursors, which replenish NAD, might protect against tissue harm caused by COVID-19?
First, an important disclaimer: There is no scientific study that says that NAD replenishment by any method treats, cures, or prevents any disease, including COVID-19. The human evidence only shows that B3 vitamins like Niagen are safe and effective at replenishing NAD. The effect of that replenishment in humans remains unproven. It is only in animal studies that we consistently see NAD replenishment having a positive effect on physical conditions involving NAD depletion.
One more thought before we get to the research. Niacin is the most famous of the B3 vitamins. It was identified early on as a cure for the wasting disease Pellagra, which was very common in the first half of the 20th century. Today Pellagra is rare because flour and cereals are enriched with Niacin.
But the US government's RDA for Niacin is only what's necessary to prevent pellagra (15mg). Now there is evidence not only that other forms of B3 may be more effective, but that the optimal dose for human health may be far more than the minimum to prevent pellagra, which means that Americans may not be getting enough B3, or the best kind.
This article compares the different NAD precursors. And this article compares the two NAD precursor finalists, NR and NMN.
BACK TO THE SCIENCE
Here is the emerging science on COVID-19, and why it points toward the potential of NAD precursors. It turns on "Cytokine Storms." According to this study, "It has been widely accepted that" excessive inflammation and cytokine storms "greatly contribute to the severity and lethality of COVID-19."
Cytokines are small proteins, like interferon, released by the immune system. When the virus that causes COVID-19 enters the lungs, cytokines are released, causing inflammation. But in some patients too many cytokines are released -- an uncontrolled storm. This severe overreaction can cause deadly levels of inflammation. Cytokine storms are more likely to occur in older patients, who have both well-developed immune systems and diminished levels of NAD.
The science we are going to look at suggests that what ends as a cytokine storm may start as an NAD deficiency.
Last year, a 21-day placebo-controlled, randomized, double-blind, crossover human study showed a direct connection between the NAD-replenishing B3 vitamin Nicotinamide Ribose and cytokine levels. according to the study, supplementation with Nicotinamide Riboside (NR) "depressed levels of circulating inflammatory cytokines."
Vitamin B3 should be used
as soon as coughing begins
This Editorial published in the prestigious journal Nature on March 23, 2020, says,
"We propose some simple, but largely ignored, approaches to the treatment of COVID-19 patients...Since Vitamin B3 is highly lung protective, it should be used as soon as coughing begins..." (emphasis added)
That editorial may be enough by itself for some people to act. As usual, the best NAD precursor, NR, is also the most expensive, but Nicotinamide might do the job, and the Nature editorial does not suggest otherwise.
But let's go deeper and try to understand WHY Vitamin B3s are recommended.
The World Health Organization says that alcohol use can increase the risk of catching COVID-19 and make it worse if you do get it.
Why might that be? It turns out that drinking alcohol reduces your body's NAD+ levels. And NAD+, in turn, powers the mitochondria that power your cells, and is crucial for your innate immune system.
So what if COVID-19, as part of its attack, drives down NAD , like alcohol does, only worse?
The journal Aging says maybe: "COVID-19 patients may benefit tremendously from [NAD boosters like NR], as SARS-CoV-2-infected patients have increased levels of [the NAD+-consuming enzyme] CD38+, and NAD has been shown to enhance DNA repair via PARP pathways."
But how does COVID-19 depress NAD?
A recent paper in the journal Viruses explains the general mechanism. Viral infections cause cells to release Interferon. The Interferon triggers molecules called PARPs. PARPS attempt to interfere with the virus by attaching an ADP-Ribose molecule to the virus. This is called ADP-ribosylation.
However, according to a study published in the journal PLOS Pathogens, "all members of the coronavirus family, encode a macrodomain to reverse ADP-ribosylation and combat this immune response." And this new study from Dr. Fehr agrees. In other words, coronaviruses, including the virus that causes COVID-19, have evolved a defense against the PARPs: The viruses have an enzyme that removes the ADP-ribose that was just attached to virus.
A new study pre-released on April 18, 2020, by a rock-star team including some of the world's leading experts on NAD and on coronavirus, examines this process in the context of COVID-19 infections, and explains how NAD is implicated.
Specifically, the study finds that COVID-19 infection "consistently and strikingly dysregulates" the NAD system. The natural immune response in COVID-19 activates a number of PARPs that try to prevent the virus from replicating. The coronavirus then undoes what the PARPs did, which re-starts the cycle.
Those PARPS rely on NAD to attack the virus, so the repeating cycle initiated by the viral infection significantly depresses NAD levels.
The study then examines a number of different potential methods of restoring NAD levels to support PARP activity, concluding that (1) augmenting NAD synthesis appears preferable to reducing NAD consumption, (2) the NAD synthesis pathways for Niacin and Tryptophan are suppressed during COVID-19 infection; and (3) the NAM and NR pathways look good, but NR may be better than NAM because NAM at high doses has the potential to block PARP activity.
COVID-19 upsets the NAD system in powerful and potentially actionable ways
Dr. Brenner, on Twitter, characterizes this new research as follows: "This is our 1st of several works on #SARSCoV2 [the virus that causes COVID-19]. We show that the virus upsets the NAD system in powerful & potentially actionable ways...The infected cell [as part of its innate immunity] uses PARPs to try to shut down (viral) replication. The virus tries to shut down the innate immune defense with its ADPribosylhydrolase. It is cellular warfare & the battleground is NAD...We now know that coronaviruses initiate a tug-of-war over cellular NAD...Coronavirus infection knocks down cells' NAD and NADP by about three-fold."
Coronavirus infection knocks down
cells' NAD by about three-fold
Another way of thinking about it, according to Dr. Brenner, is that NAD-boosting will give the PARPs more ammunition for the battle, while also supporting the mitochondrial functions needed for the function of our cells and tissues.
That again may be enough to suggest for some people Nicotinamide, or Nicotinamide Riboside as a prophylactic. [I do not think NMN makes any sense at this time, despite Dr. Sinclair's enthusiasm, for reasons explained here. If nothing else, the commercially available versions of NMN are expensive and may be unstable.]
The details of the tug-of-war get complex. There are 15 different PARPs that participate in the cell's innate immune system, and not all of them are involved in the process of ADP-ribosylation. ADP-ribosulation can be reversed by an enzyme called PARG ( ("Poly(ADP-Ribose) Glycohydrolase") or in the case of COVID-19, CARH ("CARH" stands for "COV ADP-ribosylhydrolase").
There is good evidence that this tug of war is real, because in coronaviruses in which CARH gets turned off, the virus replicates poorly. But with CARH active, the virus not only replicates but uses up NAD consistent with the predicted ribolation/deribolation war.
COVID-19 is cellular warfare
and the battleground is NAD
Even before COVID-19, researchers were focusing on NAD repletion as a method of preventing lung damage from inflammation.
For example, in this ongoing study that began before the COVID-19 outbreak, the researchers noted that "supplementing mice with the unique NAD+ precursor nicotinamide riboside (NR)" reduced both age-related and induced fibrosis, and therefore the researchers hypothesized that attempts to "boost NAD+ bioavailability will restore SIRT activity and limit fibrosis" including in inflammation-dependent models of systemic sclerosis. That study is a mouse study, it isn't complete, and their method of NAD repletion is to inhibit CD38 (because CD38 also depletes NAD). But the general idea that excess inflammation can result in NAD depletion, which in turn can cause lung damage, which in turn can be prevented by replenishing NAD, predates COVID-19. COVID-19 is just be the most recent example of an NAD-depleting illness that could potentially be addressed with NAD-replenishing strategies.
In summary, there is zero evidence that any vitamin can prevent COVID-19 infection. But there is emerging science that suggests that preventing NAD depletion might be an important strategy in mitigating the effects of COVID-19 infection, and that NAM or NR might be good ways to prevent depletion.
There is now one human Phase 2 clinical study that suggests NAD replenishment might speed recovery in mild-to-moderate cases of COVID-19 infection, which is consistent with prior animal studies.
I will continue to update this article as new COVID-19 studies emerge that support or contradict the NAD replenishment hypothesis.
UPDATE MAY 21, 2020: In a news interview on May 18, Dr. Brenner described the new research on the viruses and NAD as follows:
"We found that within 12 hours of a coronavirus infection cellular NAD gets cut down by more than three-fold, and that the gene set that controls the NAD system is greatly disturbed. A number of genes are turned on whose function is to provide an anti-viral defense for those cells, to stop the possibility of establishment of a viral infection. That leads to a greater use of NAD -- a greater demand for NAD.
"The other thing we discovered in this study is that the gene pathways to make and maintain NAD levels are disturbed by the coronavirus infection. We increase our capacity to make NAD from some vitamins; we lose our capacity to make NAD from other vitamins. And that's something that we needed to know in order to figure out how to get the potential benefit from this basic foundational research that we've been conducting...
"We also know now that viral infection depletes NAD. And this is really important because you need NAD for repair processes and cellular resiliency. And so you need NAD levels high in order to do things like fight infection and repair DNA and avoid complications of many of these metabolic stresses that are associated with worse COVID-19 outcomes."
Interviewer: What's the best way to replenish NAD levels?
"You can do it with a vitamin. Niacin has been known as an NAD precursor vitamin for 70 years or more. But one of the problems with Niacin is that is causes a flush reaction, and also the Niacin gene pathway is depleted -- when NAD levels go down, the ability of a cell to use Niacin goes down also.
"But NR, the NAD precursor vitamin that we discovered, looks like it potentially has a high activity to restore healthy NAD levels because the NR pathway goes up during a coronavirus infection. So we're not making a disease claim, but we have expectations that NR will potentially safely boost NAD levels in the face of a coronavirus infection and potentially have preventative activity."
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