Does NAD+ Level Decline With Age?

The advertising promise for NAD+ as an anti-aging strategy is this: In all species, including humans, NAD+ levels naturally decline over time, and this decline is one of the most important reasons why every organism ages. By restoring a youthful NAD+ level, the claim goes, such age-related disorders could be delayed or even reversed. Two experts in the field, one from Harvard and the other from MIT, said NAD+ boosters delivered on “the promise of boosting the body’s resilience not just against one, but against many diseases and thereby extending the human healthy lifespan,” and that sirtuin activation through NAD+ supplementation was “perhaps the most practically implementable insight of aging research,” respectively. Of course, both were entangled with multimillion-dollar dietary supplement companies.

The first prerequisite—namely that NAD+ levels decline with age—was called into question. In 2022, for example, the review “Age-dependent decline of NAD+—universal truth or biased consensus?” found that despite systematic claims to the contrary, the evidence for this premise is very sparse. In fact, in the most comprehensive study to date, significant changes in NAD+ levels were found in only about half of the tissue samples examined from old mice compared to young ones. The data from studies with human subjects, which I describe at see.nf/nadecline, are similarly inconsistent.

Ultimately, given the contradictory results of the surprisingly few studies on this topic, it is misleading to claim that NAD+ decreases with increasing age. But regardless, the proof of the pudding is in the eating. What about the second prerequisite—that raising NAD+ levels in old age promotes health and longevity?

Longer healthspan and lifespan in rodents

The effects of NAD+ boosters on old rodents have been described in the medical literature as “dramatic” and “remarkable.” The treated mice were physically more active and had greater endurance, could see better, and had stronger bones; muscle wasting, hearing loss, ovarian aging, and cognitive decline were delayed, prevented, or reversed. Benefits were documented for virtually every organ system, including improved functioning of arteries, brain, heart, immune system, kidneys, liver, and muscles. For example, just a single week with an NAD+ booster was sufficient to bring important markers of muscle health in a 22-month-old mouse to the level of a 6-month-old mouse. Roughly speaking, that is about like turning a 70-year-old back into a 20-year-old.

NAD+ boosters can also extend the lifespan of other animals, presumably because of increased NAD+-dependent sirtuin activity. This life-extending effect was first demonstrated more than 20 years ago in yeast cells. Overexpression of the genes involved in NAD+ synthesis extended their replicative lifespan by up to 60 percent. In the microscopic worm C. elegans, NAD+-boosting compounds extended lifespan by up to 16 percent. In mice, an NAD+ booster was able to extend lifespan by a modest 5 percent—but even when supplementation was started late in the animals’ lives, which is unusual for life-extending therapies.

No wonder many people are enthusiastic about all kinds of NAD+-promoting dietary supplements. The big question is whether any of these effects on human healthspan or lifespan can be translated to humans.

NAD+ boosters as dietary supplements

Today, mainly four supplements are on the market as NAD+ boosters: nicotinic acid (NA), also known as niacin; nicotinamide (NAM), also known as niacinamide; nicotinamide riboside (NR); and nicotinamide mononucleotide (NMN). NAD+ can also be administered directly, as can the reduced form NADH. In addition, there are also reduced forms of NMN (NMNH) and NR (NRH). So a whole alphabet soup comes together: NAD, NA, NAM, NR, NMN, NADH, NMNH, and NRH. Our bodies can also produce their own NAD+ from the amino acid tryptophan. Given the indispensability of NAD+, it is not surprising that the body can produce it in so many different ways from so many different precursor substances.

To convert tryptophan into NAD+ requires eight steps, whereas NA, NAM, and NR can be converted into NAD+ in only two or three steps. NMN is a direct precursor of NAD+, but when NMN or NR are taken orally, they appear to be converted directly into NA or NAM via rapid breakdown in the bloodstream, or through active conversion in the liver, or by the microbiome. So why take the more expensive NMN or NR if they end up as NA or NAM anyway? If you buy NA or NAM in larger quantities, it costs only a few cents per day, whereas NR or NMN tends to cost more like a dollar per day. That would add up to hundreds of dollars per year for NR or NMN, as opposed to less than five dollars for NA or NAM. But is it worth taking any of it at all?

Nicotinic acid (NA)

The name nicotinic acid was changed to niacin in the 1940s to avoid confusion with nicotine. Both designations are probably still better than the original name: vitamin PP, an English abbreviation for pellagra prevention.

In the 1950s, NA became the world’s first cholesterol-lowering drug. That led to about two dozen studies with tens of thousands of participants who took high-dose NA for up to five years, and it ended with by far the most reliable safety data on one of the NAD+ precursors. The most impressive benefit was discovered in the Coronary Drug Project, a study conducted in the 1960s and 1970s, before the statin era. The 15-year follow-up showed that absolute mortality among participants who had taken high-dose NA for 15 years fell by 6.2 percent (52 percent in the NA group versus 58.2 percent in the placebo control group). This was the trigger for several large clinical trials, which unfortunately failed so spectacularly that one was even terminated early.

Overall, a meta-analysis by the nonprofit organization Cochrane concluded that “no evidence of benefit from niacin therapy” was found. One possible explanation for the contradictory results is that the promising early studies used immediate-release niacin, whereas the newer, unsuccessful studies used slow (extended or delayed) release preparations. At high doses, regular niacin typically causes intense flushing and a sensation of heat, similar to hot flashes in menopause. A delayed-release version was developed to reduce the hot flashes, making niacin a multibillion-dollar blockbuster drug, but to lower cholesterol, it simply does not work as well.

The failures in the large clinical trials led to the drug being taken off the market in Europe and removed from clinical guidelines in the U.S. for the prevention of cardiovascular disease. Niacin preparations continue to play a role in treating heart patients who cannot tolerate statins, but what about their use as NAD+ boosters for the general population?