May 9, 2021

Treatments

Does NMN improve metabolic health in humans?

Thoughts on the first efficacy trial recently published

Read Time 4 minutes

A paper was recently published in Science by investigators from Washington University that tested the effect of a high dose of nicotinamide mononucleotide (NMN) in overweight or obese postmenopausal pre-diabetic women. It was a tiny study — 13 in the treatment group and 12 in the placebo group — but it found one statistically significant difference between the placebo and treatment groups: improved muscle insulin sensitivity.

NMN, like nicotinamide riboside, or NR for short (commercially sold as “Basis,” “Tru Niagen,” and probably others), is an oral precursor to NAD+. As we age, cellular NAD+ levels decline. Because NAD+ is an important substrate for sirtuins, which play an important role in DNA repair, it is hypothesized that replacing NAD+ will be geroprotective (i.e., slow the aging process). In fact, the university press release referred to NMN as an “anti-aging” compound in its headline due to some beneficial effects seen in mice. (Nota bene: few terms irk me more than “anti-aging.” The correct term here is geroprotective if, indeed, NMN protects one from the process of aging.)

It’s not clear if NAD+ declines with age because we’re using more to repair increasingly damaged DNA, or if it declines for some other reason, which limits its availability for repair, but it does seem highly plausible that more cellular NAD+ is a good thing. It’s also hypothesized the NMN might be a more stable way (i.e., less prone to degradation) to deliver this precursor than NR. (If you want to learn more about this, and this broader topic in general, listen to episodes #27 and #70 of The Drive podcast, both of which feature discussions with David Sinclair, an expert on this topic.)

Unfortunately, you can’t just give NAD+ intravenously. Well, you can, and no shortage of clinics do, but IV NAD+ doesn’t actually make it into the cells in any meaningful way, so this approach is at best a marketing ploy, and at worst, a scam. Instead, people have turned to taking NR or NMN orally in the hopes that they will be converted by the body into NAD+ in the place it matters most: inside cells.

Back to the study: commercial doses of NMN are typically sold at 50 to 150 mg, but the treatment group took 250 mg per day for 10 weeks versus a placebo group. At the conclusion of the study, the investigators repeated something called a hyperinsulinemic-euglycemic clamp which is considered the gold standard to measure how well muscles take up glucose. (I discuss this in the AMA podcast on insulin resistance.) 

The Figure below (Figure 2A from the paper) — the glucose disposal rate — shows what they found. On the left is the placebo group. With basal amounts of insulin (in white bars) compared with insulin infusions (in gray bars), there was a noticeable rise in glucose disposal rate. But if you compare the pre-treatment (in white circles) to the post-treatment (in dark circles), there is no difference. Translation: the placebo treatment did not increase glucose disposal rates. Next, look at the right side of the Figure, the NMN group. Same idea, except there is a small, statistically significant difference in glucose disposal post insulin infusion. Translation: the NMN group was better at putting at least some amount of glucose into their muscles post-treatment, when insulin is present.

Figure. Muscle insulin sensitivity, assessed as glucose disposal rate during basal conditions (white bar) and insulin infusion (gray bar) of a hyperinsulinemic-euglycemic clamp procedure. Image credit: Yoshino et al., 2021

But while this difference, about 20% more insulin-mediated glucose disposal, is statistically significant, is it necessarily clinically significant? That is, is it enough of an increase to really matter in the real world? With such a small number of participants, including a massive response in one individual, which may have skewed the average glucose disposal rate in the NMN group upward (see the black circle at the upper right of Figure), I’m not sure you can apply these results outside the context of this study. There were also several findings in the study that call into question the efficacy of the intervention.

Consider the Table below (Table 1 from the paper) entitled, “Body composition and basal metabolic variables.” In the words of one of my snarkier colleagues, a better title might be, “All the things NMN doesn’t do.” Typically, when a treatment improves insulin sensitivity, there are improvements in other related markers of metabolic health, including body composition, liver and abdominal fat content, blood pressure, glucose, and insulin, but that didn’t happen in this study, except for one metric, which is surprising given a duration of 10 weeks. (I would have liked to have seen a 24-hour area under the curve or AUC for insulin, or a 24-hour urinary C-peptide, which is almost as good, to see if there was less overall secretion over the course of the day. If that were the case, it would lend more credence to NMN improving overall insulin sensitivity.)

Table. Body composition and basal metabolic variables. Image credit: Yoshino et al., 2021

So, what is the upshot here? Well, I still remain unconvinced that supplementing NR or NMN is geroprotective in a meaningful way. I can think of several compounds I’d rather be taking to achieve that goal. (For a list of those compounds, the Rich Miller episode is the best place to start.) Is it possible the dose was still too low in this study, or that more time is needed? Yes, and that’s worth more investigation. Is it also possible that the benefits are not quantifiable by the measurements used here? Of course. But consider the recent results from the Interventions Testing Program (ITP), which sought to test this rigorously using NR (though not NMN). 

A good geroprotective candidate will have several lines of evidence pointing to its efficacy, including human studies showing improvements in outcomes related to quality of life and even mortality (consider metformin in cancer patients) and animal studies finding extension of lifespan (consider rapamycin in virtually every test model). The best place to find the latter is the ITP, which rigorously tests compounds to see if they extend lifespan in mice. The ITP uses hundreds of mice for each study, they carry out parallel studies at multiple sites, they use genetically heterozygous mice, and they have an open invitation for anyone to suggest a molecule to be studied. In fact, a company that was interested in making an NR supplement recommended it for testing by the ITP several years ago. 

When I discussed this topic on the podcast with Rich Miller, one of the architects of the ITP, the data was not yet published. It is now, and the results show that NR failed to increase lifespan. While genetically variable mice are not furry little people, they can give us insight into what might work for humans. Look at rapamycin’s history with the ITP — multiple cohorts, different doses, administered from early to late-life, all extending lifespan — as well as studies in yeast, worms, flies, (other) mice, monkeys, and humans all suggesting geroprotection. When you compare its results to date to NR and NMN, they’re just not in the same ballpark.

So for now I remain a skeptic of this approach for “life extension,” which is (indirectly) how it’s touted commercially (it’s illegal for such companies to make direct claims of this nature). I’m happy to be proven wrong as more data emerges.

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  1. Fate of the IV NAD+ is an important question. I think it is too soon to label this a scam – particularly given the older reports of very positive effects on alcohol and opiate withdrawal. Plus, see the paper below tracking blood and urine parameters during a 6hr infusion. Too small a sample to say much…but worth additional research.

    AUTHOR=Grant Ross, Berg Jade, Mestayer Richard, Braidy Nady, Bennett James, Broom Susan, Watson James

    TITLE=A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+

    JOURNAL=Frontiers in Aging Neuroscience

    VOLUME=11

    YEAR=2019

    PAGES=257

    URL=https://www.frontiersin.org/article/10.3389/fnagi.2019.00257

    DOI=10.3389/fnagi.2019.00257

    ISSN=1663-4365

    ABSTRACT=Accumulating evidence suggests that active maintenance of optimal levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) is beneficial in conditions of either increased NAD+ turnover or inadequate synthesis, including Alzheimer’s disease and other neurodegenerative disorders and the aging process. While studies have documented the efficacy of some NAD+ precursors such as nicotinamide riboside (NR) in raising plasma NAD+, no data are currently available on the fate of directly infused NAD+ in a human cohort. This study, therefore, documented changes in plasma and urine levels of NAD+ and its metabolites during and after a 6 h 3 μmol/min NAD+ intravenous (IV) infusion. Surprisingly, no change in plasma (NAD+) or metabolites [nicotinamide, methylnicotinamide, adenosine phosphoribose ribose (ADPR) and nicotinamide mononucleotide (NMN)] were observed until after 2 h. Increased urinary excretion of methylnicotinamide and NAD+ were detected at 6 h, however, no significant rise in urinary nicotinamide was observed. This study revealed for the first time that: (i) at an infusion rate of 3 μmol/min NAD+ is rapidly and completely removed from the plasma for at least the first 2 h; (ii) the profile of metabolites is consistent with NAD+ glycohydrolase and NAD+ pyrophosphatase activity; and (iii) urinary excretion products arising from an NAD+ infusion include NAD+ itself and methyl nicotinamide (meNAM) but not NAM.

  2. Its not just about longevity. I have myalgic encephalomyelitis/chronic fatigue syndrome, triggered by chemotherapy. I have been taking NMN sublingually to increase my energy, so that I can be more active, so I don’t have to spend the day in bed.

    Within 15 minutes of taking it, my head feels clearer, I’m more alert and can exercise more.

    IV NAD+ also helped, irrespective of what you say. The increased energy I got from it lasted for about 36 hours.

    Nicotinamide riboside does absolutely nothing for me, even though I know patients who do feel energy from it. I think it depends on ones NMRK genes.

  3. Do you have any thoughts about the company Nadovim which promotes a product that delivers NAD+ in oral form along with some precursors like riboflavin and herbals such as bacopa? Can oral NAD+ get to the cells if IV can’t?

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