Healthy Aging with NAD+

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 Ds: 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 nor 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.

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.

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 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 one 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.