Chapter 193
Other NAD+ Boosters as Supplements
A similar problem emerged in a twelve-week study of NMN supplementation in older adults. The authors, funded by an NMN manufacturer, concluded that NMN "improves lower-limb function and reduces drowsiness" in older adults, but it had no significant effects on 16 other measures, including other tests of lower-limb function and fatigue. There are so few NMN studies that the scattershot approach is understandable—you want to cast the widest net possible to find additional effects worth studying further—but taken on its own, such a study is not convincing evidence of the product’s efficacy.
All of the NMN studies mentioned above were conducted in healthy subjects. What would happen if NMN were tested in people with metabolic disorders? Overweight or obese postmenopausal women with prediabetes were randomized for ten weeks to NMN or a placebo. NMN did not appear to produce changes in weight or body composition, liver fat, blood pressure, or a dozen other metabolic parameters, but it improved muscle insulin sensitivity—though not enough to affect insulin levels or short- or long-term blood sugar regulation. Perhaps because insulin sensitivity in the liver and in body fat did not change. NMN also did not appear to have any effects on mitochondrial function, muscle strength, fatigability, or recovery.
As for safety, NMN enthusiasts emphasize that the substance occurs naturally in fruits and vegetables, but even the most concentrated sources (edamame, avocado, and broccoli) contain less than one hundredth of the typical NMN supplement dose per serving. The same applies to NR in milk (human and otherwise). There are studies in rats and dogs on the safety of NMN, but unlike NR, the safety of NMN in supplement-typical doses for human consumption has yet to be established. As I write this in early 2023, the sale of NMN as a dietary supplement is still in legal limbo.
There are rodent studies showing that NMN can negatively affect metabolism, but the most serious caveat concerns neurodegeneration. The accumulation of NMN in nerve cells is toxic. Since NR is converted into NMN, this is also a problem with NR supplementation. The type of nerve damage (axonopathy) is a major contributor to a number of neurodegenerative diseases, including glaucoma. In vitro, it seemed to help damaged neurons to block an NMN-synthesizing enzyme—a protection that was reversed by adding NMN—and adding an NMN-degrading enzyme also proved protective. But clinical effects remain theoretical, since these harms have been observed only in fish, mice, and in the petri dish.
Sometimes NMN supplements even come without any NMN at all. ChromaDex, the seller of the competing product "Tru Niagen" (a form of NR), claims to have analyzed 22 NMN products with the largest market shares on amazon.com and found that in most of them the NMN content was below the limit of detection—meaning practically not present at all. Ironically, many of these apparently counterfeit NMN products came with a "certificate of analysis" and had hundreds or even thousands of positive customer reviews. Apparently, only 3 of 22 products contained as much NMN as stated on the label. Of course, ChromaDex itself is also questionable; both the FDA and the Better Business Bureau accused the company of making exaggerated, false claims about Tru Niagen. In short: NR has proven relatively safe but ineffective, and NMN was neither safe nor did it have any effect.
Other NAD+ Boosters as Supplements
What about tryptophan, NAD+, NADH, NMNH, and NRH? I describe all of them in detail at see.nf/othernad. In summary, if anything, tryptophan restriction would be useful; taking NAD+ directly is largely ineffective because of instability and poor bioavailability; and although NMNH and NRH are more potent, that is not necessarily a good thing, because NRH can promote inflammation and oxidation—harmful effects that NMNH presumably also brings with it (because it has to be converted into NRH to get into cells).
Potential Side Effects on Inflammation and Cancer
Most side effects of NAD+ precursors such as NAM, NR, and NMN are relatively rare and minor—for example diarrhea, nausea, rash, hot flashes, and leg cramps. Both NR and NMN increase NAM levels, so the same concerns regarding sirtuin inhibition, methyl deficiency, and potential side effects apply to them as to NAM breakdown products. I discuss this in detail in see.nf/nadprecautions, but basically it boils down to the fact that cancer patients, cancer survivors, and people with cancer in the family—and perhaps also those with inflammatory diseases or an active Haemophilus infection—should be especially cautious with NAD+ boosters.
Which Booster Is the Best?
Among NAD+ boosters as supplements, none clearly stands out, because hardly any of the preclinical effects from the lab have translated into evidence of clinical benefit in humans. But perhaps this lack of efficacy was to be expected given the complexity of NAD+ physiology, which juggles many precursors, biosynthetic pathways, recycling routes, and countless enzymes. It is simply too early to say whether supplementation with NAD+ boosters will ever live up to even a fraction of its hype. Many more, larger, and longer-term studies are still required to demonstrate safety and efficacy.
The problem is that NA, NAM, NR, and NMN are natural products and cannot be patented, so there is not enough money available for well-designed clinical studies. The fact that more studies have been carried out on NR than on NMN is because patents were initially granted before NR was deemed not patentable in 2021.
Maybe blindly flooding the system with NAD+ precursors is not the best way to restore NAD+ levels. The body seems too clever to allow such a blunt intrusion to change NAD+ levels in tissues. These supplements may be only a profitable distraction from more natural options.
Natural Ways to Increase NAD+ Levels
Generally speaking, there are three ways to increase NAD+ levels. Consuming more NAD+ precursors is only one of them. The other two are to get the body to make more by activating NAD+-synthesizing enzymes, and to make it use up less by inhibiting the breakdown of excess NAD+.
Upregulating NAMPT
The most important factor for NAD+ synthesis is the enzyme NAMPT, whose amount in human muscle declines with age. Between ages 20 and 80 it steadily decreases by about 40 percent. In the liver, NAMPT drops by half. It has been shown that age-related diseases such as atherosclerosis, cancer, diabetes, and rheumatoid arthritis amplify the decline in NAMPT, which raises the chicken-and-egg question. This is where intervention studies come in.
A similar decline in NAMPT has also been found in aging rats and mice. Would it help to boost this enzyme? Increasing NAMPT—or its equivalent in other species—extends the lifespan of yeast, fruit flies, and rodents. In mice, increased NAMPT can also improve aerobic capacity and endurance, and they live longer.
Increased expression of NAMPT raises NAD+ levels in the muscles of mice to the same extent as providing dietary NAD+ precursors, but you may recall that in most people NAD+ precursors do not affect NAD+ levels in muscle. In fact, such supplements even suppress NAMPT and ramp up the methylating enzyme to rid the body of the excess. Long-term use of such a supplement not only leads to methyl deficiency, but can also leave you worse off if you discontinue it one day. But there is a way to increase NAMPT and NAD+ levels naturally and entirely without supplements: exercise.