The Best Way to Boost NAD+: Supplements vs. Diet (webinar recording)

· ·
5/5 - (27 votes)

The pros and cons of all the NAD+ supplements and what are the ways to boost NAD+ naturally with diet and lifestyle?

Discuss
Republish

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Do NAD+ Levels Decline with Age?

Our understanding of nicotinamide adenine dinucleotide (NAD+) arose from humble beginnings as a factor noted to enhance yeast fermentation in a 1906 paper unassumingly entitled “The Alcoholic Ferment of Yeast-Juice.” Little did they know that waves of NAD-related discoveries would go on to yield a total of four Nobel Prizes. NAD+ is now known as an essential molecule for all living organisms, required for the function of about 500 enzymes, including, notably, the extraction of metabolic energy from food. The 21st century has produced yet another scientific renaissance for NAD+ with the realization that it was critical for the activity of sirtuins, the “guardians of mammalian healthspan” I detail in my book, How Not to Age.

NAD+ is one of the most abundant molecules in our body. Once considered relatively stable, it’s now known to be in a constant state of synthesis, recycling, and breakdown. The entire pool of NAD+ in some of our tissues is turned over several times a day. To maintain cellular vitality in the face of this turnover, an adequate supply of NAD+ precursors and sufficiently high enzyme activity synthesizing NAD+ are critical. The importance of NAD+ is exemplified by the devastating consequences of a deficiency of NAD+ precursors like niacin (vitamin B3). The deficiency syndrome, called pellagra, is characterized by the 4 D’s: dermatitis, dementia, diarrhea, and, eventually, death.

Thankfully, since life as we know it couldn’t exist without it, NAD+ and its precursors are found in everything we eat—plant, animal, or fungi—but we need to know how to get at them. The niacin in corn, for instance, is tightly bound up, but it can be released by presoaking in alkaline lime-water. Maize was exported from Latin America to become a dietary staple without the requisite knowledge about traditional processing techniques, though, and an epidemic of pellagra ensued. An estimated 100,000 Americans died from pellagra in the first few decades of the 20th century before bread started to be fortified with niacin in 1938.

The pitch for NAD+ boosting as an anti-aging strategy goes as follows: all species, including humans, naturally experience a decline in NAD+ levels over time, and this decline is, in fact, one of the major reasons organisms age. By restoring youthful levels, the argument goes, these age-related disorders can be delayed, or even reversed. Two leaders in the field, one from Harvard and the other MIT, have said, respectively, that NAD+ boosters may “hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan,” and that sirtuin activation by NAD+ repletion “may be the most actionable item to emerge from aging research.” Of course, they have both been involved in multimillion-dollar dietary supplement companies.

The first premise, that NAD+ levels decline with age, has been called into question. For example, this 2022 review “Age-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?” concluded that, despite systemic claims to the contrary, the evidence supporting the premise is very limited. Indeed, the most comprehensive study to date found significant changes in NAD+ levels in less than half of the tested tissues in old versus young mice. The human data are similarly inconsistent.

NAD+ boosting supplement shills make claims like “By middle age, our NAD+ levels have plummeted to half that of our youth,” but the cited source only shows a drop (in brain levels) of about 13 percent between about the ages 20 to 60. A similar study estimated about an 18 percent drop from age 25 to 70, both broadly consistent with a 14 percent drop in spinal tap fluid samples taken from those over age 45 (average age 71), compared to those under age 45 (average age 34). It’s unclear if such modest differences would have any consequences, and a more recent study found no significant differences at all in brain or muscle levels between a young group (average age 21) and an older group (average age 69).

A study of skin samples found a greater than 50 percent drop in young adults compared to the skin of newborns, and a further drop of about 60 percent from young adults to middle age. However, there did not seem to be a further decline from middle to old age. There was a small study that found the NAD+ levels in the liver samples of six older individuals (average age 66) was about 30 percent lower than that of six younger individuals (average age 39). NAD+ levels also may be lower in macrophage white blood cells in older individuals, but in the blood more generally, half the studies showed a decline with age, and the other half didn’t. By far the largest study (enrolling 10 times more people than the other studies combined) found a slight drop in NAD+ in the aging bloodstreams of men, but no drop in women.

The bottom line is that given the conflicting results from the remarkably few studies on the subject, it’s misleading to say NAD+ universally decreases with age. Regardless, the proof is in the pudding. What about the second premise, that boosting levels late in life can improve health and longevity? We’ll address that question, next.

Can NAD+ Boosters Increase Lifespan and Healthspan?

The effects of NAD+ boosters on aged rodents have been described in the medical literature as “profound,” “dramatic”…“remarkable….” Treated mice had increased physical activity, improved vision, and strengthened bones while delaying or preventing muscle loss, hearing loss, cognitive decline, and ovarian aging. Benefits to nearly every organ system have been documented, including improved artery function, brain function, heart function, immune function, kidney function, liver function, and muscle function. For example, a single week of an NAD+ booster was sufficient to restore key markers of muscle health in a 22-month-old mouse to levels similar to that of a six-month-old mouse. That’s roughly the equivalent of reverting the muscle health of a 70-year-old person back to when they were just 20.

NAD+ boosters can also extend the lifespans of animals, presumed to be due to the elevation of sirtuin activity dependent on NAD+. This longevity effect was first demonstrated more than 20 years ago in yeast cells. An overexpression of the genes involved in NAD+ synthesis extended replicative lifespans by as much as 60 percent. In the microscopic worm C. elegans, NAD+ boosting compounds have been shown to extend lifespans by up to 16 percent. In mice, one NAD+ booster was able to extend lifespan by a more modest five percent, but this was accomplished even when supplementation was started late in life––which is unusual for longevity treatments. No wonder people are excited about all manner of NAD+ boosting supplements. The big question is do any of these healthspan or lifespan effects translate to benefitting humans?

There are four major NAD+ boosting supplements on the market these days: nicotinic acid (NA), also known as niacin, nicotinamide (NAM), also known as niacinamide, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). NAD+ can also be given directly, as well as its hydrogenated form NADH. There are also hydrogenated forms of NMN and NR, also known as dihydronicotinamide riboside. So, there is quite the alphabet soup: NA, NAM, NMN, NR, NAD, NADH, NMNH, and NRH. The body can also make NAD+ “from scratch” from the amino acid tryptophan.

Given the critical nature of NAD+, it is perhaps unsurprising that the body has so many different pathways utilizing a panoply of precursors.

Converting tryptophan to NAD+ requires eight steps, whereas NA, NAM, and NR can be turned into NAD+ in only two or three steps. NMN is a direct precursor of NAD+, but when NMN or NR is taken orally, it appears to just turn into NA or NAM, via rapid degradation in the bloodstream or active conversion in the liver. So, why take the more expensive NMN or NR if it’s just going to end up as NA or NAM? Bought in bulk, NA or NAM would just cost pennies a day, versus more like a dollar a day for NR or NMN. That would add up to hundreds of dollars a year for NR or NMN, compared to closer to only five bucks for a whole year’s worth of NA or NAM. But cost aside, what are the risks and benefits of all these NAD boosters? That’s exactly what I’ll cover, next.

Risks and Benefits of Nicotinic Acid (NA), a NAD+ Booster

The name nicotinic acid was changed to niacin in the 1940s to avoid any confusion with nicotine. Either name has to be better than the original moniker, though: vitamin PP (for pellagra preventing).

In the 1950s, NA became the world’s first cholesterol-lowering drug. This led to more than 20 trials involving tens of thousands of individuals taking high doses of NA for up to six years, resulting in by far the most robust safety data we have on any of the NAD+ precursors. The most striking benefit was found in the Coronary Drug Project, a trial carried out in the pre-statin drug era of the 1960s and 70s. The 15-year follow-up found that those who had been randomized to years of high-dose NA ended up with a 6.2% drop in absolute mortality (52 percent had died in the NA group versus 58 percent in the placebo group). This sparked major clinical trials that, sadly, failed so spectacularly that one was even stopped prematurely.

All in all, a Cochrane meta-analysis concluded that “no evidence of benefits from niacin therapy” was found. One possible explanation for the contrasting results is that the early promising trials used immediate-release niacin, while the newer failed trials used slow-release formulations (also known as extended or sustained release). At high doses, regular niacin commonly causes an intense flushing redness and prickly heat sensation similar to a menopausal hot flash. A slow-release version was developed to reduce this flushing reaction, catapulting it into a billion-dollar blockbuster drug, but it simply doesn’t work as well to lower cholesterol.

The major clinical trial failures led to the withdrawal of the drug in Europe and the removal from U.S. clinical guidelines for cardiovascular disease prevention. There still may be a role for niacin preparations in the treatment of heart disease among patients who cannot tolerate statin drugs, but what about use for the general public as an NAD+ booster? 

There is a series of rare genetic defects that can lead to a condition called mitochondrial myopathy that’s characterized by low NAD+ levels in the blood and muscles. In 2020, researchers demonstrated that these levels could be repleted with 750 to 1,000 mg a day of NA, which led to a significant improvement in muscle strength. This was the first and only study to show improvements in muscle NAD+ levels and performance with any sort of NAD+ booster. In a control group of individuals without the genetic defect, blood levels of NAD+ were raised by NA, but not muscle levels, suggesting that NAD+ levels are already “topped off” in normal muscles. As you’ll see, this is a recurring theme among NAD+ boosters.

We know that large doses of NA can boost NAD+ levels in human blood, but a corresponding increase in sirtuin activity has yet to be demonstrated. Why not give it a try? Because of the side effects unearthed in the cholesterol-lowering trials. NA raises blood sugars and may increase your risk of developing diabetes. Based on studies of tens of thousands of people on high-dose NA who were followed for years, one would expect that 1 in 43 people taking NA for five years would develop diabetes who otherwise wouldn’t have. It’s unclear if this risk is only limited to slow release formulations.

The safety buffer, the ratio between the tolerable upper limit and the RDA, is the lowest for NA compared to half a dozen other common vitamins. However, the upper limit is just based on the flushing reaction, which although uncomfortable, is considered harmless and tends to dissipate over time. Long-term use can have other adverse consequences, though, including stomach ulcers, vomiting, abdominal pain, diarrhea, and jaundice, a sign of liver toxicity, which is worse with slow-release formulations. There is also a theoretical concern that excessive NA intake may contribute to the development of Parkinson’s disease. Due to the unpleasant flushing and risk of more serious side effects, interest has moved towards other NAD+ enhancers.

Risks and Benefits of Nicotinamide (NAM), a NAD+ Booster

Ever since nicotinamide (NAM) was also shown to cure pellagra, both nicotinic acid, NA, and NAM have been collectively referred to as niacin or vitamin B3, though they are distinct compounds. For example, NAM is not plagued by the same kind of hot flash reaction. (Facial flushing attributed to niacinamide in some older studies was likely due to a less purified form contaminated with residual NA.)

The relative capacity of NA versus NAM to generate NAD+ is unclear. Neither has been shown to boost sirtuin activity, but both do extend the lifespan of C. elegans. I couldn’t find any longevity trials for NA in rodents; however, NAM was put to the test and failed to prolong the lives of mice. What clinical effects might we expect in people?

Previously, I explored the proven anti-aging effects for topical nicotinamide on the skin, and the remarkable ability of oral nicotinamide to help prevent skin cancer. I also noted it failed to prevent type 1 diabetes, despite promising mouse data, though it may help preserve residual function in people newly diagnosed with type 1 diabetes––but apparently not enough to affect blood sugar control. What about its use as a NAD+ booster?

In those with mitochondrial myopathy, NA raised muscle NAD+ levels, and improved mitochondrial and muscle function. But in healthy individuals, muscle NAD+ levels didn’t budge. However, the average age of individuals in the control group was 50. What about in older adults whose muscle NAD+ levels might potentially be lower? Four NAD+ precursors were tested in older adults averaging in their 70s: tryptophan, NA, NAM, and NR. All four failed to improve muscle strength or function, failed to affect mitochondrial function, and failed to even nudge NAD+ levels in their muscles. Why not give it a try anyway? Again, side effects.

Like NA, high-dose NAM can cause gastrointestinal disturbances and signs of liver toxicity…. However, NAM may result in more issues involving methylation. The first step in breaking down excess NAM is to transfer a methyl group to it, forming methylnicotinamide. Unfortunately, methylnicotinamide is neurotoxic, and can cross the blood-brain barrier. This may explain why NAM can exacerbate Parkinson’s-like symptoms in rats, and why Parkinson’s patients have higher levels of the NAM-methylating enzyme in their brains. And the same with Alzheimer’s brains for that matter. Excess NAM may also deplete the body’s pool of methyl groups.

If you read the Epigenetics chapter in my book How Not to Age, you may remember that DNA methylation is critical for the regulation of gene expression. Epigenetic changes caused by NAM-induced methyl depletion have been blamed as the reason why rats fed megadoses of NAM suffer from fatty livers and swollen kidneys, but that was at a human-equivalent dose far exceeding what people might take. Is there any evidence that more modest NAM supplementation might affect methylation in humans? Yes, and even with a single dose as low as 100 mg.

Methylation also plays a key role in breaking down fight-or-flight hormones like noradrenaline, and neurotransmitters like serotonin and histamine. Within hours of a single 100 mg dose of NAM, blood levels of all three become elevated, suggesting their metabolism was impaired by the shunting of methyl groups to deal with the excess NAM. Also noted was a significant rise in homocysteine, which is a byproduct of methylation reactions and a risk factor for cardiovascular disease and dementia.

Another potential problem with NAM is that it’s a sirtuin inhibitor. Wait, I thought the whole purpose of taking NAD+ precursors is to boost sirtuin activity. Sirtuin enzymes use up NAD+ and spit out NAM. This allows the body to recycle the NAM back into NAD+ for further sirtuin use. But it also means the body can use NAM as part of a negative feedback loop. Like a thermostat in the winter that shuts down the furnace when there’s too much heat, the body shuts down NAD+ use by sirtuins when it detects too much NAM. NAM pills didn’t exist when our bodies evolved; so, in the wake of a sudden wave of NAM, the body must think its sirtuins are churning out too much and dials them back. Perhaps this explains why NAM fails to prolong the lifespans of mice. When the sirtuin-suppressing effects of NAM were first reported 20 years ago, the researchers cautioned that this could potentially lead to “deleterious consequences of long-term nicotinamide therapy in humans.”

Risks and Benefits of Nicotinamide Riboside (NR), a NAD+ Booster

NR and NMN seem to be more promising NAD+ precursors than NA or NAM, since they don’t cause flushing; nor do they directly inhibit sirtuins. In mice, NR and NMN both raised liver NAD+ levels, but of the two, only NR significantly raised NAD+ in the muscles. Also, NR is so far the only NAD+ booster shown to prolong the lifespan of mice.

There have been at least 10 clinical trials of NR, most showing it can boost human blood levels of NAD+ by up to 168 percent. Note, though, that most doses used exceeded 300 mg, which is the daily dose approved as safe by the U.S. Food and Drug Administration and European Food Safety Authority. At the approved dose, blood NAD+ is boosted more on the order of 50 to 60 percent, but no dose was found to affect NAD+ levels in human muscle (compared to placebo). The greater preponderance of human bioavailability and safety data for NR compared to NMN has led some to proclaim NR as the preferred NAD+ precursor. And, by some, I mean employees of a chemical company that produces NR for supplements. The question after all of these human NR trials is: have any of them shown clinical benefit? Sadly, no. Let’s go through the alphabet.

After accounting for multiple testing, randomized, double-blind, placebo-controlled trials of NR in middle-aged or older adults failed to find any significant benefit over placebo for artery stiffness or artery function, BAT activation, blood pressure, blood sugar control, body weight, cardiac energy or ejection fraction, fat burning, fatty liver, exercise capacity, fatigue, insulin sensitivity, metabolic flexibility, metabolic health, metabolic rate, mitochondrial function or biogenesis, muscle blood flow, upper or lower body muscle strength, pancreatic function or the release of metabolic hormones, the treatment of Parkinson’s disease symptoms, or physical performance.

NR-hawking companies claim NR is anti-inflammatory, but in their own study, only three out of 10 markers of inflammation were affected compared to placebo, and a subsequent independent study using the same dose for twice as long found zero of 12 markers affected.

Remarkably, the opposite was found for many of these outcomes in rats and mice. In rodents, NR does raise NAD+ levels in muscle, improving insulin sensitivity and mitochondrial biogenesis, and on down much of the list. Why does NR work in rodents, but appear to almost entirely flop in people? Some have suggested inadequate dosing. The typical dose used in mouse studies was about twice that used in many human studies, but a double dose has been tried in people, to no avail.

Another possibility is sirtuin inhibition by NAM, the main degradation product of NR. In fact, based on mouse studies, NR may metabolize in the gut into NAM or NA before it even makes it in the bloodstream. Either way, unlike in mice, NR can’t seem to elevate NAD+ in human muscle; so, no wonder there’s no alteration of human sirtuin activity. Maybe that explains the disparate results. In fact, the key NAD+ synthesizing enzyme in human muscle biopsies was actually suppressed by NR supplementation. This doesn’t happen in mice, but it does in people. Presumably this downregulation is an adaptive response to the unnaturally large flood of NR coming into the system. So, what happens when you stop taking the supplement? How quickly does your enzyme activity bounce back?

In mice, not only may their microbiome affect NR, but the NR may affect their microbiome, too. Some of the benefits of NR can then be transferred between mice via fecal transplants. So, at least in mice, some of the benefits of NR may be due to modulating the mouse microbiome. The distinct differences between the gut flora of humans and rodents may offer another explanation why NR works in them, but not us.

Unlike NAM, supplementation with NR did not increase homocysteine levels, but one study of a combination of NR plus a resveratrol analogue called pterostilbene raised LDL cholesterol high enough to kill as many as 1 in 40 long-term users. However, this effect is presumed to be due to the pterostilbene, as NR alone has not been shown to raise LDL, whereas pterostilbene has.

One study did find that NR seems to cause a small reduction in hematocrit, hemoglobin, and platelet count in people within a week of starting it. This shift towards a more anemic state was suggested to account for impaired exercise performance seen in rats given NR. However, the 35 percent drop in performance did not reach statistical significance. NR did cause a significant increase in systemic oxidative stress, however, and another rodent study found a worsening of inflammation and deterioration of metabolic health. But if positive effects in rodents don’t translate to people, perhaps we shouldn’t expect that negative ones will, either.

Regulatory authorities from Australian, Canada, Europe, and the United States have all authorized NR as safe, at least up to 300 mg a day (or 230 in pregnant and lactating women). But the lack of demonstrable clinical benefit would seem to preclude NR supplementation.

Risks and Benefits of Nicotinamide Mononucleotide (NMN), a NAD+ Booster

Both NR and NMN have been shown to have beneficial effects in rodents, though they haven’t been tested side-by-side. Both precursors raise blood levels of NAD+ in people, but similarly haven’t been pitted head-to-head against one another. One potential advantage of NMN over NR is that it may be more stable in the bloodstream. In mouse blood at least, within an hour, most NR is converted into NAM, whereas NMN levels remain steady. You could also argue that NMN is better because it’s a direct precursor of NAD+, whereas NR first has to be converted to NMN; so, we might as well just take NMN in the first place. Ironically, the exact opposite argument can also be made, based on the inability of NMN to pass through cell membranes.

Structurally, NMN is just NR with a phosphate group attached to it. The phosphate charge prevents NMN from passing in and out of cells; so, to get inside a cell, NMN first has to be converted into NR. Then, once inside, the NR can turn back into NMN and make NAD+. So, if NMN first has to be converted into NR for cell entry, the argument goes, maybe you might as well just take NR to begin with, because there’s no NMN transporter. Or is there? An NMN transporter was recently described (at least in mouse intestine); so, maybe NMN is able to skip the NR step and pass directly into cells to make NAD+ after all. However, the evidence that such a NMN transporter exists remains controversial.

NMN boasts a long list of rodent healthspan benefits, but, unlike NR, has yet to demonstrate an extension of mammalian lifespan. What about in people? There have just been a few human NMN studies published to date. One small study of healthy middle-aged men found that various single doses had no apparent effect on any of the measured variables, including retinal eye function, sleep quality, heart rate, blood pressure, oxygenation, or body temperature. A 12-week study of daily NMN supplementation in middle-aged men and women similarly found no significant effects on any outcome, including lean mass, muscle mass, body fat, blood sugars, cholesterol, or insulin sensitivity. NMN did boost blood NAD+ levels, though they peaked after the first month, and then trended down for months two and three. So, there may have been an adaptive drop in NAD+ synthesis, as was suspected with NR. Like NR, NMN also fails to raise NAD+ in muscle tissue.

One study, evocatively entitled “Nicotinamide Mononucleotide Supplementation Enhances Aerobic Capacity in Amateur Runners,” tested three different doses of NMN versus placebo for six weeks among young and middle-aged recreational runners. Aerobic capacity was increased at one ventilatory threshold, but not the other. No overall benefit for aerobic capacity or peak power, or any of another ten measures of cardiopulmonary function was found. If you measure enough things, statistical outliers, both positive and negative ones, can just pop up as flukes. For example, the researchers noted significant improvement in the single-leg stance test, but the NMN had no significant effect on any of the other physical function tests. And upon closer inspection, the apparent single-leg balance benefit was only found in the middle-dose group compared to the high-dose group, because the high-dose group ended up doing slightly worse compared to baseline. No significant effect was found for any of the doses compared to placebo.

A similar issue can be found in a 12-week study of NMN supplementation in older adults. The NMN company-funded authors concluded that NMN “improved lower limb function and reduced drowsiness in older adults.” But it failed to significantly affect 16 additional measures, including other tests of lower limb function and fatigue. There are so few NMN studies that this kind of shotgun approach is understandable, casting the widest possible net for effects to be further tested, but on their own cannot be presented as convincing proof of efficacy.

All of the above NMN studies were on healthy individuals. What about testing NMN on those who are already metabolically compromised? Overweight or obese postmenopausal women with prediabetes were randomized to NMN or placebo for 10 weeks. NMN didn’t seem to affect body weight or composition, liver fat, blood pressure, or a dozen other metabolic variables, but it did improve muscle insulin sensitivity, though not enough to affect insulin levels or short- or long-term blood sugar control. This may be because insulin sensitivity in the liver and body fat remained unchanged. NMN also appeared to have no effect on mitochondrial function or muscle strength, fatigability, or recovery.

In terms of safety, NMN shills speak of it as being naturally found in fruits and vegetables, but even the most concentrated sources (edamame, avocado, and broccoli) have over a hundred times less per serving than the typical NMN supplement dose. The same could be said for NR in milk (human and otherwise).

There are safety evaluations for NMN on rats and dogs, but unlike NR, supplemental doses of NMN have yet to be shown as safe for human consumption. There are rodent studies showing that NMN may have negative metabolic consequences compared to placebo.

But the most serious concern is nerve degeneration. The accumulation of NMN in nerve cells is toxic. Since NR is converted into NMN, this is a major concern for NR supplementation as well. The type of nerve damage, axon degeneration, is a major contributor to a variety of neurodegenerative disorders. Blocking an NMN-synthesizing enzyme appeared to help damaged neurons in vitro, protection that’s abolished by adding NMN back, and adding an enzyme that chews up NMN was also found to be protective, further supporting a theory of degenerative effects of accumulating NMN. However, clinical effects remain theoretical, as these adverse effects have only been demonstrated in fish, mice, and petri dishes.

Of course, NMN supplements may not even have NMN in the first place. ChromaDex, which sells the rival supplement Tru Niagen (a form of NR), claims to have tested the 22 NMN brands with the highest market share on Amazon, and found that most had virtually no NMN at all. Ironically, many of the apparently fake NMN products displayed quote-unquote “certificates of analysis,” and carried hundreds or thousands of positive reviews. Evidently, only three out of 22 were found to contain as much NMN as advertised on their label. Of course, ChromaDex isn’t above being shady itself; it’s been accused of making hyped false claims for Tru Niagen by both the FDA and the Better Business Bureau.

In short, NR has been demonstrated to be relatively safe but not effective, and neither safety nor efficacy has been established for NMN.

Lesser- Known NAD+ Boosting Supplements—Tryptophan, NADH, NMNH, and NRH

Taking niacin, also called nicotinic acid, would be about 50 times more efficient than taking the amino acid tryptophan to boost NAD+, because only about two percent of tryptophan is converted into niacin. Also, tryptophan didn’t work to improve mitochondrial or muscle function in physically compromised older adults, even when combined with niacin or nicotinamide. And side effects of taking tryptophan include belching and gas, blurred vision, diarrhea, dizziness, drowsiness, dry mouth, headache, heartburn, and potentially a life-threatening condition known as eosinophilia-myalgia syndrome, or EMS.

There was an epidemic of EMS tied to tryptophan supplements from a single supplier back in 1989 that led to their removal from the market for about 15 years. Some sort of contaminant was suspected, but the cause remains a mystery. To this day, tryptophan supplements continue to be tainted with impurities, with at least one case of EMS reported decades after the initial epidemic. A case of EMS tied to a bizarre weight loss diet involving hundreds of cups (~50 L) of cashews, a rich source of tryptophan, suggests the syndrome can be caused by excess tryptophan directly.

If anything, tryptophan restriction may be beneficial. Nearly 50 years ago, it was demonstrated that restricting dietary tryptophan reduced cancer rates, and increased the lifespans of rats and, subsequently, mice. Vegetarians and vegans both appear to have significantly lower intakes of tryptophan. But only in vegans does this translate to lower tryptophan blood levels––though presumably not if they were to take tryptophan supplements.

What about taking NAD+ directly? This isn’t practical because of instability and poor bioavailability. NAD+ is vulnerable to heat, pH, light, and oxygen, requiring dark desiccant storage at ideally 20 degrees (-29°C) below freezing. NAD+ can be given intravenously, a practice started in the 1950s as an “underground” treatment for alcoholism, but when taken orally, NAD may be broken down in the alkaline environment of the small intestine, and NADH, the so-called “reduced” form of NAD+, is broken down in the acidic conditions of the stomach. (In organic chemistry, the gain of a hydrogen atom is said to “reduce” the molecule; so, NADH is the reduced form of NAD+).

Enteric forms of NAD+ could potentially survive the digestive tract, but, with the exception of neurons, NAD can’t cross into mammalian cells. This is why NAD+ precursor supplements, like NMN and NR, were developed. Also, there are evidently (unpublished) data showing that straight NAD+ can cause serious hyperglycemia in mice. Has it been tested in people?

NAD+ boosting supplements have been found to improve the learning and memory of rodent models of Alzheimer’s disease in the lab. In 1995, case reports of apparent benefit of NADH for Alzheimer’s disease were published. By the next year, an open-label pilot study was published, suggesting it had a protective effect. But without a placebo control group, the only conclusion that could be drawn was to study it further, especially since a similar study with the same dose over approximately the same period found no evidence of any cognitive effects.

There have been two randomized, double-blind, placebo-controlled trials of NAD precursors for Alzheimer’s. One found no benefit for memory, attention, or clinician ratings of dementia severity, but did maybe find less of a drop in one dementia-rating scale after six months of 10 mg a day of NADH. The other, a six-month study of nicotinamide, failed to find any clinical effects.

What about trying NMNH and NRH, the reduced forms of NMN and NR? They both appear to boost NAD+ higher than their non-reduced counterparts. In vitro, NMNH can raise NAD+ levels up to 10 times higher than NMN, and NRH (also known as dihydronicotinamide riboside) is up to about 50 times more potent than NR.

There are concerns about stability of NRH outside the body, since it’s sensitive to oxygen and moisture, but within the body, NRH may be more stable, not rapidly devolving into nicotinamide like NR does (at least in mouse blood). However, unlike NR, NRH does not appear to be able to significantly increase levels in mouse muscles.

NRH is said to have a “spectacular potency” for increasing NAD+ levels––perhaps the most potent precursor discovered to date. This may not necessarily be a good thing. The extreme boost afforded by NRH had detrimental consequences in human liver cells in vitro, resulting from an excessive accumulation of free radicals. In addition to oxidation, NRH was also found to promote inflammation. Pro-inflammatory effects were noted for NRH on human immune cells in vitro (but not for NMN, NAM, or NR). Because it appears that NMNH is converted to NRH to enter cells, these potentially deleterious effects may be shared by NMNH as well (though this has yet to be tested).

Risks of NAD+ Boosting Supplements

Most of the reported side effects for NAD+ precursors, like NAM, NR, and NMN, are relatively rare and minor, for example, diarrhea, nausea, rashes, hot flashes, and leg cramps. Both NR and NMN raise NAM levels, so may share in the same concerns regarding sirtuin inhibition, methyl depletion, and potential adverse effects of NAM breakdown products.

Another theoretical concern of NAD+ boosting is the exacerbation of infections by a group of bacteria called Haemophilus (from the Greek meaning “blood loving,” though they can also cause infections of the lungs, brain, throat, flesh, and joints). Haemophilus bacteria lack the ability to make NAD+, so rely on host levels, raising the possibility that higher blood levels might worsen the disease course of infected individuals. Ironically, elevated NAD+ levels may also fuel immune system overreaction in cases of auto-immune and inflammatory disease.

When fully activated, the immune system is voracious. The immune reaction to a blood infection or extensive burns can burn 4,000 calories a day, approximating military training in the Arctic. Since NAD+ is used by cells to produce energy, it’s no surprise that we find the primary NAD+ synthesizing enzyme strongly upregulated in tissues that are actively inflamed. For example, the enzyme NAMPT is elevated in colonoscopy biopsies taken from inflamed areas in patients with inflammatory bowel disease, and higher levels are correlated with greater disease severity. So, for those suffering from chronic autoimmune diseases, such as rheumatoid arthritis, NAD+ boosting could potentially have a “profound negative impact.” This explains why tamping down NAD+ with NAMPT inhibitors has been shown to ameliorate colitis and arthritis in mice. But this has yet to be tested in people. Such NAD+ depleting drugs have, however, been used in cancer patients.

Malignancy is another heavily energy-consuming process. NAD+ may, therefore, have a tumor-promoting effect by promoting cancer cell growth and spread. For example, NAMPT, the NAD+ forming enzyme, is highly expressed in cancerous brain tumors, and correlates with decreased patient survival. This has led to attempts to use NAD+ depleting therapies to try to starve cancer progression. But this approach is confounded by rapid onset injury to another energy-intensive tissue, the retina, risking blindness.

Giving NMN to mice with pancreatic cancer accelerates the progression of the cancer, thought due to the aggravation of inflammation. The researchers conclude that consumers of NAD+ supplements must “balance the advantageous anti-ageing effects with the potential detrimental pro-tumorigenic side effects.” Perhaps this explains why the best NAD+ boosters have ever been able to do is increase mice lifespan by five percent.

On the other hand, as you’ll remember, NAM successfully prevented human skin cancers, and has been found to reduce the incidence of a variety of carcinogen-induced tumors in rodents. The disparate results may in part be due to the disparate impact sirtuin activation may have on different cancers. Sirtuin activity can be overexpressed in some cancers (like thyroid carcinomas and lung metastasis), but reduced in others (like brain, bladder, prostate, and ovarian tumors).

The bottom line is that particular caution should be used for NAD+ boosting supplements by those with cancer, or a personal or strong family history of cancer, and perhaps also by those with inflammatory disorders and certain active infections.

Which NAD+ Booster Is Best?

So, which NAD+ boosting supplement is best? There’s no clear standout, as hardly any of the preclinical effects found in the lab have translated into evidence of human clinical benefit. Perhaps this failure is to be expected, given the complexity of NAD+ physiology, with its juggling of multiple precursors, production pathways, and recycling routes. The bottom line is that it’s just too early to say if NAD+ booster supplementation will ever live up to even a fraction of the hype. Many more, larger, and longer-term studies are necessary to establish safety and efficacy.

The problem is that because NA, NAM, NR, and NMN are all natural products, they can’t be patented; so, the money for well-designed clinical trials is not as available. The reason there have been comparatively more trials done on NR than NMN is that patents were originally issued for NR before being invalidated as unpatentable.

Perhaps blindly overloading the system with NAD+ precursors is not the best way to go about NAD+ restoration. The body seems too smart to allow such blunt incursion to affect tissue levels. Maybe these supplements are just profit-making distractions from more natural approaches.

Broadly, there are three main ways to increase NAD+ levels. Increasing the supply of NAD+ precursors is just the first. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, via an inhibition of excess NAD+ degradation.

The primary determinant of NAD+ synthesis in the enzyme NAMPT. An abundance of NAMPT tends to decrease with age in human muscle, dropping steadily by about 40 percent between the ages of 20 and 80. In our liver, it drops by half. However, age-related diseases––such as atherosclerosis, cancer, diabetes, and rheumatoid arthritis––have been found to exacerbate NAMPT decline, raising a chicken-or-the-egg question. There’s where interventional trials come in.

Similar NAMPT declines have been noted in aging rats and mice. Does boosting NAMPT help? Increasing NAMPT or its species equivalent increases the lifespans of yeast, fruit flies, and rodents. An NAMPT boost also increases aerobic capacity and exercise endurance in mice, in addition to helping them live longer.

Enhanced expression of NAMPT increases the NAD+ levels in the muscles in mice comparable to feeding them dietary NAD+ precursors. But if you remember, NAD+ precursors don’t seem to able to affect NAD+ muscle levels in most people. In fact, such supplements can actually suppress NAMPT, while boosting that methylating enzyme to rid the body of the excess. In addition to methyl depletion, chronic administration of these supplements could potentially then leave people worse off should they ever stop them.

There is, however, a way to naturally boost NAMPT and NAD+ levels in humans without any supplements: exercise. Athletes have about twice the NAMPT expression in their musculature compared to sedentary individuals. To prove cause and effect, sedentary men and women started a stationary bike exercise protocol, and within three weeks, NAMPT levels increased by 127 percent. Resistance training can also increase NAMPT, and this can also translate into a 127 percent increase in muscle NAD+ levels and a rise in sirtuin activity. In other words, exercise can do what NAD+ boosting supplements can’t.

The Third Way to Boost NAD+

There are three NAD boosting strategies: Increasing the supply of NAD+ precursors is just one way. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, by, for example, conserving it, by using less. Besides sirtuins, the major consumers of NAD+ are PARP-1 and CD38. PARP-1 is an enzyme that uses NAD+ to repair DNA. The more oxidative DNA damage, the more single- and double-stranded DNA breaks, the more enzymes like PARP-1 need to be activated to come to the rescue. This uses up a lot of NAD. As DNA damage accumulates with age, the rising need for repair enzymes like PARP-1 causes a major drain on NAD+ levels.

Exposing cells in vitro to DNA-damaging agents, such as gamma radiation or genotoxic chemicals, can cause an 80 to 90 percent drop in NAD+ levels within a matter of minutes. This has led to the search for PARP-1 blockers to preserve NAD+ levels. But rather than blocking DNA repair, why not work to prevent so much damage in the first place? For example, the severe oxidative stress of a high-fat diet can lead to PARP-1 activation and NAD+ depletion in mice. But NAD+ levels can be “dramatically restored” by feeding them “purple sweet potato color,” the natural anthocyanin pigments found in purple sweet potatoes. Or, of course, you can just not feed them a high-fat diet.

DNA repair is a good thing. PARP-1 may be one of the reasons NAD+ boosting interventions can improve healthspans and lifespans in laboratory animals. Greater PARP activity strongly correlates with longer lifespan across about a dozen mammalian species, and the PARP activity of human centenarians averages 60 percent higher than younger controls. However, persistent activation can lead to NAD+ depletion, and overactivation can even lead to cell death. So, we should try to keep oxidative stress to a minimum.

CD38 is another major guzzler of NAD+. It’s an enzyme that uses NAD+ found concentrated on the surfaces of immune cells, and is robustly induced in the context of inflammation. The rise of CD38 activity with age has been blamed on persistent “inflammaging” activation, the rise in systemic low-grade inflammation in our bodies when we get older, which may be a major culprit for falling NAD+ levels. For example, blocking CD38 has been found to raise NAD+ levels in old mice comparable to that of younger mice.

So, oxidation and inflammation can lead to a drop in NAD+ levels, due to the excess activation of the NAD+ consuming enzymes. This may explain why protective sirtuin activity is reduced in obesity, a condition characterized by oxidative stress and inflammation. A study of identical twin pairs in which one, on average, was obese and the other not, found significantly less sirtuin expression in the obese twin, despite having the same genetics. And, randomize people to a six-month trial of 25 percent caloric restriction, and you can show a boost in sirtuin expression, along with a decrease in DNA damage. Protein restriction may have a similar effect, since men and women with higher protein intake tend to have lower levels of NAD+ in their blood, thought to be due to the oxidative stress induced by protein breakdown byproducts.

If oxidation and inflammation are responsible for a drop in NAD+ levels, then what about the antioxidant and anti-inflammatory phytonutrients in healthy plant foods? After screening more than 14,000 compounds, almost all flavonoids were found to be effective in a test for CD38 inhibition. The two most effective were cyanidin, found in red cabbage and blackberries, and quercetagetin, found in marigold flower tea. Another study found the three most potent compounds were luteolin, kuromanin, and luteolinidin. Luteolin is found concentrated in oregano, radicchio and chrysanthemum tea. Kuromanin is found in black berries, purple corn, and hibiscus tea. Corn tortillas are surprisingly easy to make; so, why not choose blue or purple masa to make them even healthier? Luteolinidin, found to increase NAD+ in the hearts of rats, can be found in red sorghum, one of the components of my prebiotic BROL mix, when I can find it.

The flavonoid apigenin is a well-established CD38 inhibitor. When given to mice, apigenin boosts NAD+ levels by about 50 percent, which is what people would get taking the maximum tolerable daily dose of NR. The best sources are parsley and chamomile tea. A wide range of flavonoids found in green tea, turmeric, and fruits and vegetables have also been found to prevent NAD+ depletion in human cells in vitro at levels found in the blood after consumption. How much do you have to eat, though?

Proanthocyanidins have been found to lower PARP-1 and CD38 expression in rats. NAD+ and sirtuin activity was significantly boosted at the human equivalent dose of about 280 mg a day. How much is that? That’s the amount of proanthocyanidins found in a single apple. You could also reach that dose eating two plums, a half cup (75 g) of wild blueberries, a little over a teaspoon of cinnamon, or a little over a tablespoon, like four teaspoons, of cocoa powder.

Quercetin is another suppressor of PARP-1 and CD38 shown to increase sirtuin activity in mice. The concentration necessary to lower PARP-1 in vitro can be achieved by taking a quercetin supplement, but typical supplement manufacturers’ recommended doses are up to 100 times the average daily dietary intake. Thankfully, food works, too. Researchers fried up one and a half yellow onions and raised quercetin blood levels to about 75 percent there. And so, two onions might do it. There are no long-term safety data on high-dose flavonoid supplementation; so, public health researchers suggest “caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet.”

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Do NAD+ Levels Decline with Age?

Our understanding of nicotinamide adenine dinucleotide (NAD+) arose from humble beginnings as a factor noted to enhance yeast fermentation in a 1906 paper unassumingly entitled “The Alcoholic Ferment of Yeast-Juice.” Little did they know that waves of NAD-related discoveries would go on to yield a total of four Nobel Prizes. NAD+ is now known as an essential molecule for all living organisms, required for the function of about 500 enzymes, including, notably, the extraction of metabolic energy from food. The 21st century has produced yet another scientific renaissance for NAD+ with the realization that it was critical for the activity of sirtuins, the “guardians of mammalian healthspan” I detail in my book, How Not to Age.

NAD+ is one of the most abundant molecules in our body. Once considered relatively stable, it’s now known to be in a constant state of synthesis, recycling, and breakdown. The entire pool of NAD+ in some of our tissues is turned over several times a day. To maintain cellular vitality in the face of this turnover, an adequate supply of NAD+ precursors and sufficiently high enzyme activity synthesizing NAD+ are critical. The importance of NAD+ is exemplified by the devastating consequences of a deficiency of NAD+ precursors like niacin (vitamin B3). The deficiency syndrome, called pellagra, is characterized by the 4 D’s: dermatitis, dementia, diarrhea, and, eventually, death.

Thankfully, since life as we know it couldn’t exist without it, NAD+ and its precursors are found in everything we eat—plant, animal, or fungi—but we need to know how to get at them. The niacin in corn, for instance, is tightly bound up, but it can be released by presoaking in alkaline lime-water. Maize was exported from Latin America to become a dietary staple without the requisite knowledge about traditional processing techniques, though, and an epidemic of pellagra ensued. An estimated 100,000 Americans died from pellagra in the first few decades of the 20th century before bread started to be fortified with niacin in 1938.

The pitch for NAD+ boosting as an anti-aging strategy goes as follows: all species, including humans, naturally experience a decline in NAD+ levels over time, and this decline is, in fact, one of the major reasons organisms age. By restoring youthful levels, the argument goes, these age-related disorders can be delayed, or even reversed. Two leaders in the field, one from Harvard and the other MIT, have said, respectively, that NAD+ boosters may “hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan,” and that sirtuin activation by NAD+ repletion “may be the most actionable item to emerge from aging research.” Of course, they have both been involved in multimillion-dollar dietary supplement companies.

The first premise, that NAD+ levels decline with age, has been called into question. For example, this 2022 review “Age-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?” concluded that, despite systemic claims to the contrary, the evidence supporting the premise is very limited. Indeed, the most comprehensive study to date found significant changes in NAD+ levels in less than half of the tested tissues in old versus young mice. The human data are similarly inconsistent.

NAD+ boosting supplement shills make claims like “By middle age, our NAD+ levels have plummeted to half that of our youth,” but the cited source only shows a drop (in brain levels) of about 13 percent between about the ages 20 to 60. A similar study estimated about an 18 percent drop from age 25 to 70, both broadly consistent with a 14 percent drop in spinal tap fluid samples taken from those over age 45 (average age 71), compared to those under age 45 (average age 34). It’s unclear if such modest differences would have any consequences, and a more recent study found no significant differences at all in brain or muscle levels between a young group (average age 21) and an older group (average age 69).

A study of skin samples found a greater than 50 percent drop in young adults compared to the skin of newborns, and a further drop of about 60 percent from young adults to middle age. However, there did not seem to be a further decline from middle to old age. There was a small study that found the NAD+ levels in the liver samples of six older individuals (average age 66) was about 30 percent lower than that of six younger individuals (average age 39). NAD+ levels also may be lower in macrophage white blood cells in older individuals, but in the blood more generally, half the studies showed a decline with age, and the other half didn’t. By far the largest study (enrolling 10 times more people than the other studies combined) found a slight drop in NAD+ in the aging bloodstreams of men, but no drop in women.

The bottom line is that given the conflicting results from the remarkably few studies on the subject, it’s misleading to say NAD+ universally decreases with age. Regardless, the proof is in the pudding. What about the second premise, that boosting levels late in life can improve health and longevity? We’ll address that question, next.

Can NAD+ Boosters Increase Lifespan and Healthspan?

The effects of NAD+ boosters on aged rodents have been described in the medical literature as “profound,” “dramatic”…“remarkable….” Treated mice had increased physical activity, improved vision, and strengthened bones while delaying or preventing muscle loss, hearing loss, cognitive decline, and ovarian aging. Benefits to nearly every organ system have been documented, including improved artery function, brain function, heart function, immune function, kidney function, liver function, and muscle function. For example, a single week of an NAD+ booster was sufficient to restore key markers of muscle health in a 22-month-old mouse to levels similar to that of a six-month-old mouse. That’s roughly the equivalent of reverting the muscle health of a 70-year-old person back to when they were just 20.

NAD+ boosters can also extend the lifespans of animals, presumed to be due to the elevation of sirtuin activity dependent on NAD+. This longevity effect was first demonstrated more than 20 years ago in yeast cells. An overexpression of the genes involved in NAD+ synthesis extended replicative lifespans by as much as 60 percent. In the microscopic worm C. elegans, NAD+ boosting compounds have been shown to extend lifespans by up to 16 percent. In mice, one NAD+ booster was able to extend lifespan by a more modest five percent, but this was accomplished even when supplementation was started late in life––which is unusual for longevity treatments. No wonder people are excited about all manner of NAD+ boosting supplements. The big question is do any of these healthspan or lifespan effects translate to benefitting humans?

There are four major NAD+ boosting supplements on the market these days: nicotinic acid (NA), also known as niacin, nicotinamide (NAM), also known as niacinamide, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). NAD+ can also be given directly, as well as its hydrogenated form NADH. There are also hydrogenated forms of NMN and NR, also known as dihydronicotinamide riboside. So, there is quite the alphabet soup: NA, NAM, NMN, NR, NAD, NADH, NMNH, and NRH. The body can also make NAD+ “from scratch” from the amino acid tryptophan.

Given the critical nature of NAD+, it is perhaps unsurprising that the body has so many different pathways utilizing a panoply of precursors.

Converting tryptophan to NAD+ requires eight steps, whereas NA, NAM, and NR can be turned into NAD+ in only two or three steps. NMN is a direct precursor of NAD+, but when NMN or NR is taken orally, it appears to just turn into NA or NAM, via rapid degradation in the bloodstream or active conversion in the liver. So, why take the more expensive NMN or NR if it’s just going to end up as NA or NAM? Bought in bulk, NA or NAM would just cost pennies a day, versus more like a dollar a day for NR or NMN. That would add up to hundreds of dollars a year for NR or NMN, compared to closer to only five bucks for a whole year’s worth of NA or NAM. But cost aside, what are the risks and benefits of all these NAD boosters? That’s exactly what I’ll cover, next.

Risks and Benefits of Nicotinic Acid (NA), a NAD+ Booster

The name nicotinic acid was changed to niacin in the 1940s to avoid any confusion with nicotine. Either name has to be better than the original moniker, though: vitamin PP (for pellagra preventing).

In the 1950s, NA became the world’s first cholesterol-lowering drug. This led to more than 20 trials involving tens of thousands of individuals taking high doses of NA for up to six years, resulting in by far the most robust safety data we have on any of the NAD+ precursors. The most striking benefit was found in the Coronary Drug Project, a trial carried out in the pre-statin drug era of the 1960s and 70s. The 15-year follow-up found that those who had been randomized to years of high-dose NA ended up with a 6.2% drop in absolute mortality (52 percent had died in the NA group versus 58 percent in the placebo group). This sparked major clinical trials that, sadly, failed so spectacularly that one was even stopped prematurely.

All in all, a Cochrane meta-analysis concluded that “no evidence of benefits from niacin therapy” was found. One possible explanation for the contrasting results is that the early promising trials used immediate-release niacin, while the newer failed trials used slow-release formulations (also known as extended or sustained release). At high doses, regular niacin commonly causes an intense flushing redness and prickly heat sensation similar to a menopausal hot flash. A slow-release version was developed to reduce this flushing reaction, catapulting it into a billion-dollar blockbuster drug, but it simply doesn’t work as well to lower cholesterol.

The major clinical trial failures led to the withdrawal of the drug in Europe and the removal from U.S. clinical guidelines for cardiovascular disease prevention. There still may be a role for niacin preparations in the treatment of heart disease among patients who cannot tolerate statin drugs, but what about use for the general public as an NAD+ booster? 

There is a series of rare genetic defects that can lead to a condition called mitochondrial myopathy that’s characterized by low NAD+ levels in the blood and muscles. In 2020, researchers demonstrated that these levels could be repleted with 750 to 1,000 mg a day of NA, which led to a significant improvement in muscle strength. This was the first and only study to show improvements in muscle NAD+ levels and performance with any sort of NAD+ booster. In a control group of individuals without the genetic defect, blood levels of NAD+ were raised by NA, but not muscle levels, suggesting that NAD+ levels are already “topped off” in normal muscles. As you’ll see, this is a recurring theme among NAD+ boosters.

We know that large doses of NA can boost NAD+ levels in human blood, but a corresponding increase in sirtuin activity has yet to be demonstrated. Why not give it a try? Because of the side effects unearthed in the cholesterol-lowering trials. NA raises blood sugars and may increase your risk of developing diabetes. Based on studies of tens of thousands of people on high-dose NA who were followed for years, one would expect that 1 in 43 people taking NA for five years would develop diabetes who otherwise wouldn’t have. It’s unclear if this risk is only limited to slow release formulations.

The safety buffer, the ratio between the tolerable upper limit and the RDA, is the lowest for NA compared to half a dozen other common vitamins. However, the upper limit is just based on the flushing reaction, which although uncomfortable, is considered harmless and tends to dissipate over time. Long-term use can have other adverse consequences, though, including stomach ulcers, vomiting, abdominal pain, diarrhea, and jaundice, a sign of liver toxicity, which is worse with slow-release formulations. There is also a theoretical concern that excessive NA intake may contribute to the development of Parkinson’s disease. Due to the unpleasant flushing and risk of more serious side effects, interest has moved towards other NAD+ enhancers.

Risks and Benefits of Nicotinamide (NAM), a NAD+ Booster

Ever since nicotinamide (NAM) was also shown to cure pellagra, both nicotinic acid, NA, and NAM have been collectively referred to as niacin or vitamin B3, though they are distinct compounds. For example, NAM is not plagued by the same kind of hot flash reaction. (Facial flushing attributed to niacinamide in some older studies was likely due to a less purified form contaminated with residual NA.)

The relative capacity of NA versus NAM to generate NAD+ is unclear. Neither has been shown to boost sirtuin activity, but both do extend the lifespan of C. elegans. I couldn’t find any longevity trials for NA in rodents; however, NAM was put to the test and failed to prolong the lives of mice. What clinical effects might we expect in people?

Previously, I explored the proven anti-aging effects for topical nicotinamide on the skin, and the remarkable ability of oral nicotinamide to help prevent skin cancer. I also noted it failed to prevent type 1 diabetes, despite promising mouse data, though it may help preserve residual function in people newly diagnosed with type 1 diabetes––but apparently not enough to affect blood sugar control. What about its use as a NAD+ booster?

In those with mitochondrial myopathy, NA raised muscle NAD+ levels, and improved mitochondrial and muscle function. But in healthy individuals, muscle NAD+ levels didn’t budge. However, the average age of individuals in the control group was 50. What about in older adults whose muscle NAD+ levels might potentially be lower? Four NAD+ precursors were tested in older adults averaging in their 70s: tryptophan, NA, NAM, and NR. All four failed to improve muscle strength or function, failed to affect mitochondrial function, and failed to even nudge NAD+ levels in their muscles. Why not give it a try anyway? Again, side effects.

Like NA, high-dose NAM can cause gastrointestinal disturbances and signs of liver toxicity…. However, NAM may result in more issues involving methylation. The first step in breaking down excess NAM is to transfer a methyl group to it, forming methylnicotinamide. Unfortunately, methylnicotinamide is neurotoxic, and can cross the blood-brain barrier. This may explain why NAM can exacerbate Parkinson’s-like symptoms in rats, and why Parkinson’s patients have higher levels of the NAM-methylating enzyme in their brains. And the same with Alzheimer’s brains for that matter. Excess NAM may also deplete the body’s pool of methyl groups.

If you read the Epigenetics chapter in my book How Not to Age, you may remember that DNA methylation is critical for the regulation of gene expression. Epigenetic changes caused by NAM-induced methyl depletion have been blamed as the reason why rats fed megadoses of NAM suffer from fatty livers and swollen kidneys, but that was at a human-equivalent dose far exceeding what people might take. Is there any evidence that more modest NAM supplementation might affect methylation in humans? Yes, and even with a single dose as low as 100 mg.

Methylation also plays a key role in breaking down fight-or-flight hormones like noradrenaline, and neurotransmitters like serotonin and histamine. Within hours of a single 100 mg dose of NAM, blood levels of all three become elevated, suggesting their metabolism was impaired by the shunting of methyl groups to deal with the excess NAM. Also noted was a significant rise in homocysteine, which is a byproduct of methylation reactions and a risk factor for cardiovascular disease and dementia.

Another potential problem with NAM is that it’s a sirtuin inhibitor. Wait, I thought the whole purpose of taking NAD+ precursors is to boost sirtuin activity. Sirtuin enzymes use up NAD+ and spit out NAM. This allows the body to recycle the NAM back into NAD+ for further sirtuin use. But it also means the body can use NAM as part of a negative feedback loop. Like a thermostat in the winter that shuts down the furnace when there’s too much heat, the body shuts down NAD+ use by sirtuins when it detects too much NAM. NAM pills didn’t exist when our bodies evolved; so, in the wake of a sudden wave of NAM, the body must think its sirtuins are churning out too much and dials them back. Perhaps this explains why NAM fails to prolong the lifespans of mice. When the sirtuin-suppressing effects of NAM were first reported 20 years ago, the researchers cautioned that this could potentially lead to “deleterious consequences of long-term nicotinamide therapy in humans.”

Risks and Benefits of Nicotinamide Riboside (NR), a NAD+ Booster

NR and NMN seem to be more promising NAD+ precursors than NA or NAM, since they don’t cause flushing; nor do they directly inhibit sirtuins. In mice, NR and NMN both raised liver NAD+ levels, but of the two, only NR significantly raised NAD+ in the muscles. Also, NR is so far the only NAD+ booster shown to prolong the lifespan of mice.

There have been at least 10 clinical trials of NR, most showing it can boost human blood levels of NAD+ by up to 168 percent. Note, though, that most doses used exceeded 300 mg, which is the daily dose approved as safe by the U.S. Food and Drug Administration and European Food Safety Authority. At the approved dose, blood NAD+ is boosted more on the order of 50 to 60 percent, but no dose was found to affect NAD+ levels in human muscle (compared to placebo). The greater preponderance of human bioavailability and safety data for NR compared to NMN has led some to proclaim NR as the preferred NAD+ precursor. And, by some, I mean employees of a chemical company that produces NR for supplements. The question after all of these human NR trials is: have any of them shown clinical benefit? Sadly, no. Let’s go through the alphabet.

After accounting for multiple testing, randomized, double-blind, placebo-controlled trials of NR in middle-aged or older adults failed to find any significant benefit over placebo for artery stiffness or artery function, BAT activation, blood pressure, blood sugar control, body weight, cardiac energy or ejection fraction, fat burning, fatty liver, exercise capacity, fatigue, insulin sensitivity, metabolic flexibility, metabolic health, metabolic rate, mitochondrial function or biogenesis, muscle blood flow, upper or lower body muscle strength, pancreatic function or the release of metabolic hormones, the treatment of Parkinson’s disease symptoms, or physical performance.

NR-hawking companies claim NR is anti-inflammatory, but in their own study, only three out of 10 markers of inflammation were affected compared to placebo, and a subsequent independent study using the same dose for twice as long found zero of 12 markers affected.

Remarkably, the opposite was found for many of these outcomes in rats and mice. In rodents, NR does raise NAD+ levels in muscle, improving insulin sensitivity and mitochondrial biogenesis, and on down much of the list. Why does NR work in rodents, but appear to almost entirely flop in people? Some have suggested inadequate dosing. The typical dose used in mouse studies was about twice that used in many human studies, but a double dose has been tried in people, to no avail.

Another possibility is sirtuin inhibition by NAM, the main degradation product of NR. In fact, based on mouse studies, NR may metabolize in the gut into NAM or NA before it even makes it in the bloodstream. Either way, unlike in mice, NR can’t seem to elevate NAD+ in human muscle; so, no wonder there’s no alteration of human sirtuin activity. Maybe that explains the disparate results. In fact, the key NAD+ synthesizing enzyme in human muscle biopsies was actually suppressed by NR supplementation. This doesn’t happen in mice, but it does in people. Presumably this downregulation is an adaptive response to the unnaturally large flood of NR coming into the system. So, what happens when you stop taking the supplement? How quickly does your enzyme activity bounce back?

In mice, not only may their microbiome affect NR, but the NR may affect their microbiome, too. Some of the benefits of NR can then be transferred between mice via fecal transplants. So, at least in mice, some of the benefits of NR may be due to modulating the mouse microbiome. The distinct differences between the gut flora of humans and rodents may offer another explanation why NR works in them, but not us.

Unlike NAM, supplementation with NR did not increase homocysteine levels, but one study of a combination of NR plus a resveratrol analogue called pterostilbene raised LDL cholesterol high enough to kill as many as 1 in 40 long-term users. However, this effect is presumed to be due to the pterostilbene, as NR alone has not been shown to raise LDL, whereas pterostilbene has.

One study did find that NR seems to cause a small reduction in hematocrit, hemoglobin, and platelet count in people within a week of starting it. This shift towards a more anemic state was suggested to account for impaired exercise performance seen in rats given NR. However, the 35 percent drop in performance did not reach statistical significance. NR did cause a significant increase in systemic oxidative stress, however, and another rodent study found a worsening of inflammation and deterioration of metabolic health. But if positive effects in rodents don’t translate to people, perhaps we shouldn’t expect that negative ones will, either.

Regulatory authorities from Australian, Canada, Europe, and the United States have all authorized NR as safe, at least up to 300 mg a day (or 230 in pregnant and lactating women). But the lack of demonstrable clinical benefit would seem to preclude NR supplementation.

Risks and Benefits of Nicotinamide Mononucleotide (NMN), a NAD+ Booster

Both NR and NMN have been shown to have beneficial effects in rodents, though they haven’t been tested side-by-side. Both precursors raise blood levels of NAD+ in people, but similarly haven’t been pitted head-to-head against one another. One potential advantage of NMN over NR is that it may be more stable in the bloodstream. In mouse blood at least, within an hour, most NR is converted into NAM, whereas NMN levels remain steady. You could also argue that NMN is better because it’s a direct precursor of NAD+, whereas NR first has to be converted to NMN; so, we might as well just take NMN in the first place. Ironically, the exact opposite argument can also be made, based on the inability of NMN to pass through cell membranes.

Structurally, NMN is just NR with a phosphate group attached to it. The phosphate charge prevents NMN from passing in and out of cells; so, to get inside a cell, NMN first has to be converted into NR. Then, once inside, the NR can turn back into NMN and make NAD+. So, if NMN first has to be converted into NR for cell entry, the argument goes, maybe you might as well just take NR to begin with, because there’s no NMN transporter. Or is there? An NMN transporter was recently described (at least in mouse intestine); so, maybe NMN is able to skip the NR step and pass directly into cells to make NAD+ after all. However, the evidence that such a NMN transporter exists remains controversial.

NMN boasts a long list of rodent healthspan benefits, but, unlike NR, has yet to demonstrate an extension of mammalian lifespan. What about in people? There have just been a few human NMN studies published to date. One small study of healthy middle-aged men found that various single doses had no apparent effect on any of the measured variables, including retinal eye function, sleep quality, heart rate, blood pressure, oxygenation, or body temperature. A 12-week study of daily NMN supplementation in middle-aged men and women similarly found no significant effects on any outcome, including lean mass, muscle mass, body fat, blood sugars, cholesterol, or insulin sensitivity. NMN did boost blood NAD+ levels, though they peaked after the first month, and then trended down for months two and three. So, there may have been an adaptive drop in NAD+ synthesis, as was suspected with NR. Like NR, NMN also fails to raise NAD+ in muscle tissue.

One study, evocatively entitled “Nicotinamide Mononucleotide Supplementation Enhances Aerobic Capacity in Amateur Runners,” tested three different doses of NMN versus placebo for six weeks among young and middle-aged recreational runners. Aerobic capacity was increased at one ventilatory threshold, but not the other. No overall benefit for aerobic capacity or peak power, or any of another ten measures of cardiopulmonary function was found. If you measure enough things, statistical outliers, both positive and negative ones, can just pop up as flukes. For example, the researchers noted significant improvement in the single-leg stance test, but the NMN had no significant effect on any of the other physical function tests. And upon closer inspection, the apparent single-leg balance benefit was only found in the middle-dose group compared to the high-dose group, because the high-dose group ended up doing slightly worse compared to baseline. No significant effect was found for any of the doses compared to placebo.

A similar issue can be found in a 12-week study of NMN supplementation in older adults. The NMN company-funded authors concluded that NMN “improved lower limb function and reduced drowsiness in older adults.” But it failed to significantly affect 16 additional measures, including other tests of lower limb function and fatigue. There are so few NMN studies that this kind of shotgun approach is understandable, casting the widest possible net for effects to be further tested, but on their own cannot be presented as convincing proof of efficacy.

All of the above NMN studies were on healthy individuals. What about testing NMN on those who are already metabolically compromised? Overweight or obese postmenopausal women with prediabetes were randomized to NMN or placebo for 10 weeks. NMN didn’t seem to affect body weight or composition, liver fat, blood pressure, or a dozen other metabolic variables, but it did improve muscle insulin sensitivity, though not enough to affect insulin levels or short- or long-term blood sugar control. This may be because insulin sensitivity in the liver and body fat remained unchanged. NMN also appeared to have no effect on mitochondrial function or muscle strength, fatigability, or recovery.

In terms of safety, NMN shills speak of it as being naturally found in fruits and vegetables, but even the most concentrated sources (edamame, avocado, and broccoli) have over a hundred times less per serving than the typical NMN supplement dose. The same could be said for NR in milk (human and otherwise).

There are safety evaluations for NMN on rats and dogs, but unlike NR, supplemental doses of NMN have yet to be shown as safe for human consumption. There are rodent studies showing that NMN may have negative metabolic consequences compared to placebo.

But the most serious concern is nerve degeneration. The accumulation of NMN in nerve cells is toxic. Since NR is converted into NMN, this is a major concern for NR supplementation as well. The type of nerve damage, axon degeneration, is a major contributor to a variety of neurodegenerative disorders. Blocking an NMN-synthesizing enzyme appeared to help damaged neurons in vitro, protection that’s abolished by adding NMN back, and adding an enzyme that chews up NMN was also found to be protective, further supporting a theory of degenerative effects of accumulating NMN. However, clinical effects remain theoretical, as these adverse effects have only been demonstrated in fish, mice, and petri dishes.

Of course, NMN supplements may not even have NMN in the first place. ChromaDex, which sells the rival supplement Tru Niagen (a form of NR), claims to have tested the 22 NMN brands with the highest market share on Amazon, and found that most had virtually no NMN at all. Ironically, many of the apparently fake NMN products displayed quote-unquote “certificates of analysis,” and carried hundreds or thousands of positive reviews. Evidently, only three out of 22 were found to contain as much NMN as advertised on their label. Of course, ChromaDex isn’t above being shady itself; it’s been accused of making hyped false claims for Tru Niagen by both the FDA and the Better Business Bureau.

In short, NR has been demonstrated to be relatively safe but not effective, and neither safety nor efficacy has been established for NMN.

Lesser- Known NAD+ Boosting Supplements—Tryptophan, NADH, NMNH, and NRH

Taking niacin, also called nicotinic acid, would be about 50 times more efficient than taking the amino acid tryptophan to boost NAD+, because only about two percent of tryptophan is converted into niacin. Also, tryptophan didn’t work to improve mitochondrial or muscle function in physically compromised older adults, even when combined with niacin or nicotinamide. And side effects of taking tryptophan include belching and gas, blurred vision, diarrhea, dizziness, drowsiness, dry mouth, headache, heartburn, and potentially a life-threatening condition known as eosinophilia-myalgia syndrome, or EMS.

There was an epidemic of EMS tied to tryptophan supplements from a single supplier back in 1989 that led to their removal from the market for about 15 years. Some sort of contaminant was suspected, but the cause remains a mystery. To this day, tryptophan supplements continue to be tainted with impurities, with at least one case of EMS reported decades after the initial epidemic. A case of EMS tied to a bizarre weight loss diet involving hundreds of cups (~50 L) of cashews, a rich source of tryptophan, suggests the syndrome can be caused by excess tryptophan directly.

If anything, tryptophan restriction may be beneficial. Nearly 50 years ago, it was demonstrated that restricting dietary tryptophan reduced cancer rates, and increased the lifespans of rats and, subsequently, mice. Vegetarians and vegans both appear to have significantly lower intakes of tryptophan. But only in vegans does this translate to lower tryptophan blood levels––though presumably not if they were to take tryptophan supplements.

What about taking NAD+ directly? This isn’t practical because of instability and poor bioavailability. NAD+ is vulnerable to heat, pH, light, and oxygen, requiring dark desiccant storage at ideally 20 degrees (-29°C) below freezing. NAD+ can be given intravenously, a practice started in the 1950s as an “underground” treatment for alcoholism, but when taken orally, NAD may be broken down in the alkaline environment of the small intestine, and NADH, the so-called “reduced” form of NAD+, is broken down in the acidic conditions of the stomach. (In organic chemistry, the gain of a hydrogen atom is said to “reduce” the molecule; so, NADH is the reduced form of NAD+).

Enteric forms of NAD+ could potentially survive the digestive tract, but, with the exception of neurons, NAD can’t cross into mammalian cells. This is why NAD+ precursor supplements, like NMN and NR, were developed. Also, there are evidently (unpublished) data showing that straight NAD+ can cause serious hyperglycemia in mice. Has it been tested in people?

NAD+ boosting supplements have been found to improve the learning and memory of rodent models of Alzheimer’s disease in the lab. In 1995, case reports of apparent benefit of NADH for Alzheimer’s disease were published. By the next year, an open-label pilot study was published, suggesting it had a protective effect. But without a placebo control group, the only conclusion that could be drawn was to study it further, especially since a similar study with the same dose over approximately the same period found no evidence of any cognitive effects.

There have been two randomized, double-blind, placebo-controlled trials of NAD precursors for Alzheimer’s. One found no benefit for memory, attention, or clinician ratings of dementia severity, but did maybe find less of a drop in one dementia-rating scale after six months of 10 mg a day of NADH. The other, a six-month study of nicotinamide, failed to find any clinical effects.

What about trying NMNH and NRH, the reduced forms of NMN and NR? They both appear to boost NAD+ higher than their non-reduced counterparts. In vitro, NMNH can raise NAD+ levels up to 10 times higher than NMN, and NRH (also known as dihydronicotinamide riboside) is up to about 50 times more potent than NR.

There are concerns about stability of NRH outside the body, since it’s sensitive to oxygen and moisture, but within the body, NRH may be more stable, not rapidly devolving into nicotinamide like NR does (at least in mouse blood). However, unlike NR, NRH does not appear to be able to significantly increase levels in mouse muscles.

NRH is said to have a “spectacular potency” for increasing NAD+ levels––perhaps the most potent precursor discovered to date. This may not necessarily be a good thing. The extreme boost afforded by NRH had detrimental consequences in human liver cells in vitro, resulting from an excessive accumulation of free radicals. In addition to oxidation, NRH was also found to promote inflammation. Pro-inflammatory effects were noted for NRH on human immune cells in vitro (but not for NMN, NAM, or NR). Because it appears that NMNH is converted to NRH to enter cells, these potentially deleterious effects may be shared by NMNH as well (though this has yet to be tested).

Risks of NAD+ Boosting Supplements

Most of the reported side effects for NAD+ precursors, like NAM, NR, and NMN, are relatively rare and minor, for example, diarrhea, nausea, rashes, hot flashes, and leg cramps. Both NR and NMN raise NAM levels, so may share in the same concerns regarding sirtuin inhibition, methyl depletion, and potential adverse effects of NAM breakdown products.

Another theoretical concern of NAD+ boosting is the exacerbation of infections by a group of bacteria called Haemophilus (from the Greek meaning “blood loving,” though they can also cause infections of the lungs, brain, throat, flesh, and joints). Haemophilus bacteria lack the ability to make NAD+, so rely on host levels, raising the possibility that higher blood levels might worsen the disease course of infected individuals. Ironically, elevated NAD+ levels may also fuel immune system overreaction in cases of auto-immune and inflammatory disease.

When fully activated, the immune system is voracious. The immune reaction to a blood infection or extensive burns can burn 4,000 calories a day, approximating military training in the Arctic. Since NAD+ is used by cells to produce energy, it’s no surprise that we find the primary NAD+ synthesizing enzyme strongly upregulated in tissues that are actively inflamed. For example, the enzyme NAMPT is elevated in colonoscopy biopsies taken from inflamed areas in patients with inflammatory bowel disease, and higher levels are correlated with greater disease severity. So, for those suffering from chronic autoimmune diseases, such as rheumatoid arthritis, NAD+ boosting could potentially have a “profound negative impact.” This explains why tamping down NAD+ with NAMPT inhibitors has been shown to ameliorate colitis and arthritis in mice. But this has yet to be tested in people. Such NAD+ depleting drugs have, however, been used in cancer patients.

Malignancy is another heavily energy-consuming process. NAD+ may, therefore, have a tumor-promoting effect by promoting cancer cell growth and spread. For example, NAMPT, the NAD+ forming enzyme, is highly expressed in cancerous brain tumors, and correlates with decreased patient survival. This has led to attempts to use NAD+ depleting therapies to try to starve cancer progression. But this approach is confounded by rapid onset injury to another energy-intensive tissue, the retina, risking blindness.

Giving NMN to mice with pancreatic cancer accelerates the progression of the cancer, thought due to the aggravation of inflammation. The researchers conclude that consumers of NAD+ supplements must “balance the advantageous anti-ageing effects with the potential detrimental pro-tumorigenic side effects.” Perhaps this explains why the best NAD+ boosters have ever been able to do is increase mice lifespan by five percent.

On the other hand, as you’ll remember, NAM successfully prevented human skin cancers, and has been found to reduce the incidence of a variety of carcinogen-induced tumors in rodents. The disparate results may in part be due to the disparate impact sirtuin activation may have on different cancers. Sirtuin activity can be overexpressed in some cancers (like thyroid carcinomas and lung metastasis), but reduced in others (like brain, bladder, prostate, and ovarian tumors).

The bottom line is that particular caution should be used for NAD+ boosting supplements by those with cancer, or a personal or strong family history of cancer, and perhaps also by those with inflammatory disorders and certain active infections.

Which NAD+ Booster Is Best?

So, which NAD+ boosting supplement is best? There’s no clear standout, as hardly any of the preclinical effects found in the lab have translated into evidence of human clinical benefit. Perhaps this failure is to be expected, given the complexity of NAD+ physiology, with its juggling of multiple precursors, production pathways, and recycling routes. The bottom line is that it’s just too early to say if NAD+ booster supplementation will ever live up to even a fraction of the hype. Many more, larger, and longer-term studies are necessary to establish safety and efficacy.

The problem is that because NA, NAM, NR, and NMN are all natural products, they can’t be patented; so, the money for well-designed clinical trials is not as available. The reason there have been comparatively more trials done on NR than NMN is that patents were originally issued for NR before being invalidated as unpatentable.

Perhaps blindly overloading the system with NAD+ precursors is not the best way to go about NAD+ restoration. The body seems too smart to allow such blunt incursion to affect tissue levels. Maybe these supplements are just profit-making distractions from more natural approaches.

Broadly, there are three main ways to increase NAD+ levels. Increasing the supply of NAD+ precursors is just the first. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, via an inhibition of excess NAD+ degradation.

The primary determinant of NAD+ synthesis in the enzyme NAMPT. An abundance of NAMPT tends to decrease with age in human muscle, dropping steadily by about 40 percent between the ages of 20 and 80. In our liver, it drops by half. However, age-related diseases––such as atherosclerosis, cancer, diabetes, and rheumatoid arthritis––have been found to exacerbate NAMPT decline, raising a chicken-or-the-egg question. There’s where interventional trials come in.

Similar NAMPT declines have been noted in aging rats and mice. Does boosting NAMPT help? Increasing NAMPT or its species equivalent increases the lifespans of yeast, fruit flies, and rodents. An NAMPT boost also increases aerobic capacity and exercise endurance in mice, in addition to helping them live longer.

Enhanced expression of NAMPT increases the NAD+ levels in the muscles in mice comparable to feeding them dietary NAD+ precursors. But if you remember, NAD+ precursors don’t seem to able to affect NAD+ muscle levels in most people. In fact, such supplements can actually suppress NAMPT, while boosting that methylating enzyme to rid the body of the excess. In addition to methyl depletion, chronic administration of these supplements could potentially then leave people worse off should they ever stop them.

There is, however, a way to naturally boost NAMPT and NAD+ levels in humans without any supplements: exercise. Athletes have about twice the NAMPT expression in their musculature compared to sedentary individuals. To prove cause and effect, sedentary men and women started a stationary bike exercise protocol, and within three weeks, NAMPT levels increased by 127 percent. Resistance training can also increase NAMPT, and this can also translate into a 127 percent increase in muscle NAD+ levels and a rise in sirtuin activity. In other words, exercise can do what NAD+ boosting supplements can’t.

The Third Way to Boost NAD+

There are three NAD boosting strategies: Increasing the supply of NAD+ precursors is just one way. The other two are having the body make more, by activating NAD+ synthesizing enzymes, or have the body use less, by, for example, conserving it, by using less. Besides sirtuins, the major consumers of NAD+ are PARP-1 and CD38. PARP-1 is an enzyme that uses NAD+ to repair DNA. The more oxidative DNA damage, the more single- and double-stranded DNA breaks, the more enzymes like PARP-1 need to be activated to come to the rescue. This uses up a lot of NAD. As DNA damage accumulates with age, the rising need for repair enzymes like PARP-1 causes a major drain on NAD+ levels.

Exposing cells in vitro to DNA-damaging agents, such as gamma radiation or genotoxic chemicals, can cause an 80 to 90 percent drop in NAD+ levels within a matter of minutes. This has led to the search for PARP-1 blockers to preserve NAD+ levels. But rather than blocking DNA repair, why not work to prevent so much damage in the first place? For example, the severe oxidative stress of a high-fat diet can lead to PARP-1 activation and NAD+ depletion in mice. But NAD+ levels can be “dramatically restored” by feeding them “purple sweet potato color,” the natural anthocyanin pigments found in purple sweet potatoes. Or, of course, you can just not feed them a high-fat diet.

DNA repair is a good thing. PARP-1 may be one of the reasons NAD+ boosting interventions can improve healthspans and lifespans in laboratory animals. Greater PARP activity strongly correlates with longer lifespan across about a dozen mammalian species, and the PARP activity of human centenarians averages 60 percent higher than younger controls. However, persistent activation can lead to NAD+ depletion, and overactivation can even lead to cell death. So, we should try to keep oxidative stress to a minimum.

CD38 is another major guzzler of NAD+. It’s an enzyme that uses NAD+ found concentrated on the surfaces of immune cells, and is robustly induced in the context of inflammation. The rise of CD38 activity with age has been blamed on persistent “inflammaging” activation, the rise in systemic low-grade inflammation in our bodies when we get older, which may be a major culprit for falling NAD+ levels. For example, blocking CD38 has been found to raise NAD+ levels in old mice comparable to that of younger mice.

So, oxidation and inflammation can lead to a drop in NAD+ levels, due to the excess activation of the NAD+ consuming enzymes. This may explain why protective sirtuin activity is reduced in obesity, a condition characterized by oxidative stress and inflammation. A study of identical twin pairs in which one, on average, was obese and the other not, found significantly less sirtuin expression in the obese twin, despite having the same genetics. And, randomize people to a six-month trial of 25 percent caloric restriction, and you can show a boost in sirtuin expression, along with a decrease in DNA damage. Protein restriction may have a similar effect, since men and women with higher protein intake tend to have lower levels of NAD+ in their blood, thought to be due to the oxidative stress induced by protein breakdown byproducts.

If oxidation and inflammation are responsible for a drop in NAD+ levels, then what about the antioxidant and anti-inflammatory phytonutrients in healthy plant foods? After screening more than 14,000 compounds, almost all flavonoids were found to be effective in a test for CD38 inhibition. The two most effective were cyanidin, found in red cabbage and blackberries, and quercetagetin, found in marigold flower tea. Another study found the three most potent compounds were luteolin, kuromanin, and luteolinidin. Luteolin is found concentrated in oregano, radicchio and chrysanthemum tea. Kuromanin is found in black berries, purple corn, and hibiscus tea. Corn tortillas are surprisingly easy to make; so, why not choose blue or purple masa to make them even healthier? Luteolinidin, found to increase NAD+ in the hearts of rats, can be found in red sorghum, one of the components of my prebiotic BROL mix, when I can find it.

The flavonoid apigenin is a well-established CD38 inhibitor. When given to mice, apigenin boosts NAD+ levels by about 50 percent, which is what people would get taking the maximum tolerable daily dose of NR. The best sources are parsley and chamomile tea. A wide range of flavonoids found in green tea, turmeric, and fruits and vegetables have also been found to prevent NAD+ depletion in human cells in vitro at levels found in the blood after consumption. How much do you have to eat, though?

Proanthocyanidins have been found to lower PARP-1 and CD38 expression in rats. NAD+ and sirtuin activity was significantly boosted at the human equivalent dose of about 280 mg a day. How much is that? That’s the amount of proanthocyanidins found in a single apple. You could also reach that dose eating two plums, a half cup (75 g) of wild blueberries, a little over a teaspoon of cinnamon, or a little over a tablespoon, like four teaspoons, of cocoa powder.

Quercetin is another suppressor of PARP-1 and CD38 shown to increase sirtuin activity in mice. The concentration necessary to lower PARP-1 in vitro can be achieved by taking a quercetin supplement, but typical supplement manufacturers’ recommended doses are up to 100 times the average daily dietary intake. Thankfully, food works, too. Researchers fried up one and a half yellow onions and raised quercetin blood levels to about 75 percent there. And so, two onions might do it. There are no long-term safety data on high-dose flavonoid supplementation; so, public health researchers suggest “caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet.”

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Doctor's Note

NAD+ is an essential cofactor for hundreds of enzymes, as well as the purported anti-aging activities of sirtuins. Raising NAD+ levels can extend lifespan and rejuvenate health in many animals, but what about humans? The four main NAD+-boosting supplements on the market are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinic acid (NA), and nicotinamide (NAM). In this two-hour webinar, I covered the pros and cons of each of the four primary supplements, discussed the other five (NAD, NADH, NMNH, NRH, and tryptophan), and outlined three ways to naturally boost NAD levels without supplements.

All of these individual videos will eventually be added to NutritionFacts.org, but I wanted to share this full webinar with you, including the 30-minute Q&A at the end, as soon as I could.

If you haven't yet, you can subscribe to our free newsletter. With your subscription, you'll also get notifications for just-released blogs and videos. Check out our information page about our translated resources.

Subscribe to our free newsletter and receive the Purple Sweet Potato Longevity Smoothie recipe from How Not to Age.

Previous Video

Does Lion’s Mane Mushroom Powder Have Benefits for Dementia?

Next Video

Friday Favorites: Kidney Stones and Oxalates in Spinach, Chard, and Beet Greens

Pin It on Pinterest

Share This