Question of the Month #12: Energy-Carrying Molecules to Boost Aging Mitochondria?

Posted by Michael Rae on November 23, 2015 | Chief Science Officer's Team

Q: In recent months, I’ve seen quite a lot of promotional material — and some coverage from well-established news venues — for a dietary supplement called nicotinamide riboside (NR). The companies involved say that Harvard researchers showed that this supplement restores mitochondrial function in the cells of aging mice, completely reversing the aging process in muscles. Some of them add that other research has shown that it improves metabolism, fights fat and obesity, and is protective of brain function. What do you think of this supplement?

A: Before getting into the matter of nicotinamide riboside (NR)’s potential benefits to humans, it must be clarified that the substance used in the Harvard research was not actually NR, but another compound called nicotinamide mononucleotide (NMN)[1]. But NMN is unsuitable for oral supplementation, as it is rapidly hydrolyzed in the intestine, so the Harvard researchers (like a previous team of scientists from the Washington University School of Medicine at St. Louis[2] and others thereafter[3]) injected their mice with NMN rather than giving it to them in their feed.

With the excited coverage that greeted the Harvard NMN research, supplement companies have promoted NR as a substitute, because it was already in production and can be taken orally. Because NR is a precursor to NMN, which in turn is used for the synthesis of the energy shuttle molecule nicotinamide adenine dinucleotide (NAD), many supplement vendors assert or imply that the results with NMN can also be gained with NR. Promoters of NR also point to studies showing that NR yields improvements in metabolic health in rodent models of diabetic obesity promoted by a high-fat/high sugar diet that are similar to those reported for injected NMN. These vendors furthermore note positive results of NR supplementation in mouse models of genetic neurological and mitochondrial disorders, and in mice genetically engineered to develop liver cancer.

That all may sound promising, and it certainly makes for effective marketing copy. But no study has actually been done demonstrating that NR has similar effects to NMN in the muscles of otherwise-healthy aging mice. In fact, one study found that high-dose NR supplementation was unable to increase NAD levels in muscle tissue or the mitochondrial fraction of normal, healthy mice.[4] Additionally, overexpressing the gene that converts NR to NMN in these animals’ muscles still didn’t affect muscle mitochondrial function in the way that the Harvard researchers reported with NMN, suggesting that the effects observed with injected NMN may involve some kind of systemic response to having NMN itself circulating in the bloodstream.[4] This casts considerable doubt on the assumption that either NR, or some other supplement that raises cellular NAD levels, will replicate the effects of NMN on aging muscle.

Moreover, even if NR supplements do provide an immediate jolt to muscle mitochondrial metabolism in the way that the Harvard NMN studies suggest, it’s not clear that doing so is a good idea in the long term. NMN injections don’t improve mitochondrial function by repairing molecular damage wrought by the aging process in the organelles, nor in other cells and biomolecules whose damage with age results in a dampening-down of mitochondrial activity (see discussion in Question of the Month #11: “Are Mitochondrial Mutations Really All That Important?”). Instead, NMN injections leave the existing damage in place, and induce the still-functional mitochondria to work harder and pump out more energy. This is rather like pushing harder on the gas pedal when your car is not running at full power due to damage to its cams and push rods: it may make the car go faster in the short term, but the underlying damage hasn’t been fixed, and will likely get even worse from the excessive wear.

Because the Harvard study of NMN-treated mice only lasted a week, it did not examine the long-term effects of NMN treatment on the mice. Previous studies with other dietary supplements, however, have revealed that the potential for such effects does exist and cannot be neglected in risk/benefit evaluations. In one noteworthy study, spiking the drinking water of aging rats with the dietary supplement acetyl-L-carnitine boosted cellular energy production, but it also increased the cells’ production of free radicals,[5] likely setting them up for more mitochondrial mutations in the future. Later studies tried to counteract this problem by coadministering antioxidants, but despite the higher energy levels, the combination failed to extend the lifespan of otherwise-normal aging mice — the best integrated measure for effects of a treatment on the aging process.

It’s also important for readers of the press coverage of the Harvard report to understand just what was involved when such stories reported that NMN treatment “reversed the effects of aging” on the mice’s muscles. Readers would be forgiven for imagining the muscles of frail, elderly mice suddenly swelling to youthful size, able to perform tiny rodent bench presses with the strength and endurance of much younger animals. In reality, though, as the investigators were careful to point out in the original scientific paper, while their treated animals’ muscle cells exhibited biochemical evidence of improved (“rejuvenated”) metabolism and insulin-stimulated glucose uptake, “we did not observe an improvement in muscle strength (data not shown), indicating that 1 week of treatment might not be sufficient to reverse whole-organism aging and that longer treatments might be required.”[1]

This important detail was missing from almost all of the reporting in the popular press. While it’s possible, as the scientists speculate, that longer-term treatment would have led to some recovery of muscle function, the lack of any observed improvement in actual muscle strength calls into question the functional significance of the biochemical “rejuvenation” they report.

Additionally, interpretation of the Harvard report is greatly hampered by the lack of information of the animals’ weight or food intake, which raises the possibility of effects mediated by Calorie restriction or (contrariwise) by the simple overfeeding of all the animals in the study. Also, an earlier report by Dr. Shin-ichiro Imai of the Washington University School of Medicine at St. Louis,[2] who was a pioneer in working with this compound, had identified some gender-discordant effects of NMN on glucose metabolism, and unfortunately the Harvard report does not disclose the sex of the animals. In fact, some of the reported findings in the new report seem to be contradicted by Dr. Imai’s earlier studies. It will be good to see these issues clarified and ironed out in future research.

Finally, to put the question into practical consumer terms: while we are not advocating self-experimentation with NR conducted prior to the resolution of these issues, any realistic attempt to translate the actual methods used in the rodent studies would be very expensive. The studies showing benefits of NR supplementation in mouse models of disease have used doses of 400-500 milligrams of NR per kilogram of mouse body weight. Even after adjusting for the different metabolic rates of mice and humans, an approximate equivalent adult dose would range from 2000 to 4000 milligrams of NR per day. Commercially-available NR supplements contain between 75 and 125 mg NR per capsule, at a cost of roughly 0.6-0.8 cents per milligram of NR; to experiment with even the lower end of the human-equivalent dosage range would thus involve swallowing 18-30 NR pills a day, at a cost of $400-550 a month.

[1] Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013 Dec 19;155(7):1624-38. doi: 10.1016/j.cell.2013.11.037. PubMed PMID: 24360282; PubMed Central PMCID: PMC4076149.

[2] Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011 Oct 5;14(4):528-36. doi: 10.1016/j.cmet.2011.08.014. PubMed PMID: 21982712; PubMed Central PMCID: PMC3204926.

[3] Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol. 2015 Mar 1;15:19. doi: 10.1186/s12883-015-0272-x. PubMed PMID: 25884176; PubMed Central PMCID: PMC4358858.

[4] Frederick DW, Davis JG, Dávila A Jr, Agarwal B, Michan S, Puchowicz MA, Nakamaru-Ogiso E, Baur JA. Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism. J Biol Chem. 2015 Jan 16;290(3):1546-58. doi: 10.1074/jbc.M114.579565. Epub 2014 Nov 19. PubMed PMID: 25411251; PubMed Central PMCID: PMC4340401.

[5] Hagen TM, Wehr CM, Ames BN. Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone. Ann N Y Acad Sci. 1998 Nov 20;854:214-23. PubMed PMID: 9928432.