If it’s up to some pharmaceutical companies, in some countries the vitamin B3 analog nicotinamide mononucleotide (NMN) may soon no longer be available as a supplement, but as an undoubtedly expensive drug that reduces aging symptoms and extends life. We doubt whether the companies in question will succeed in this aim. But when it comes to the biological effects of NMN, we have to admit that the greedy drug companies have a point. Although you should not exaggerate its effect, NMN does seem to be able to slow down parts of the aging process.

 

By Willem Koert

 

In scientific literature, NMN appears for the very first time in an article from 1906. The paper has nothing to do with longevity, but everything with yeast and fermentation.[1] In this article, two British biochemists describe how they find vulnerable molecules in yeast cells that convert sugars into alcohol. These were, as we now know, enzymes. If the temperature rises too high, the enzymes break down and stop working.

The British discovered that yeast cells also contain substances that are resistant to heat. One of the substances they describe is NMN. The enzymes need NMN, plus its analogues, to do their job, the British discovered. If they mix the NMN analogues with the yeast cells, the fermentation of glucose proceeds more quickly.

 

NAD+

At that time, no one suspected that the British discoveries were also relevant to humans. Only about ten years later will the Polish biochemist Casimir Funk discover the first vitamin in rice germ.[2] It’s vitamin B3. In experiments in orphanages and prisons, American clinical epidemiologist Joseph Goldberger discovered that a deficiency of vitamin B3 causes pellagra.[3]

After the Second World War, biochemists gradually elucidated what vitamin B3 exactly is during a few decades. The vitamin, which is present in various forms in food, metabolizes in the body into more complex molecules such as NMN. NMN then metabolizes into nicotinamide adenine dinucleotide [NAD+]. NAD+ is a coenzyme. That means enzymes need NAD+ to function.

These enzymes that utilize NAD+ as a coenzyme also include a number of enzymes that repair vital parts of cells. One of these is PARP, which repairs damaged genetic material such as DNA, among other things. Another group of enzymes that require NAD+ are the sirtuins, of which SIRT1 is probably the most important.

You can compare SIRT1’s role in the cell to pressing a reset button on a computer that has crashed. If infections, toxic substances, a long-term high glucose level or other stressors have caused the cell to switch on or off all kinds of parts of the DNA, the DNA must eventually return to a normal state. That’s what SIRT1 and other sirtuins are supposed to do.

In this way, sirtuins allow cells to grow and develop, inflammatory reactions are inhibited, mitochondria continue to produce energy and cells that have become hopelessly aged or damaged kill themselves. A high activity of sirtuins is therefore synonymous with longevity.

 

Anti-aging

At the end of the 20th century, researchers at Washington University School of Medicine, who – like their British colleagues a century earlier – studied yeast cells, discovered that sirtuins needed NAD+ to function.[4] After it became clear that this was also true in mammals, the researchers suggested that supplementation with NAD+ precursors such as NMN or other interventions that increase cellular NAD+ biosynthesis may slow aging.[5]

Animal studies pointed in this direction. For example, as organisms age, the activity of sirtuins decreases. According to research with old lab mice, supplementation with NMN returns the activity of sirtuins to a level that you would expect from young laboratory animals. As a result, in old lab mice, the body’s ability to get cells to take up glucose improves.[6] This ability tends to decrease with age.

Aging also reduces muscle function. The ability to perform long-term exercise is therefore reduced in older organisms. In animal experiments, NMN also largely reverses this aging effect, probably by improving the functioning of the mitochondria.[7]

Researchers achieved similar successes when they used NMN supplementation to rejuvenate the blood vessels in older laboratory animals,[8] prevent the development of type 2 diabetes[9], reduce the risk of a murine equivalent of Alzheimer’s disease[10] and reduce osteoporosis[ 11] and cognitive decline [12]. It even proved possible to increase the fertility of older laboratory animals by supplementing with NMN.[13]

A problem that should not be underestimated with these animal studies is the dosage. If the test animals in the studies had been human adults, they would have taken 2-4 grams of NMN daily over a long period of time. The foods with the highest concentrations of NMN, such as young soybeans, cucumber peel and avocado, contain only about one milligram of NMN per hundred grams. (Some websites say that a large 100-gram tomato would contain tens of milligrams of NMN, but the analyses we’ve read so far don’t mention such quantities.)

 

78c

The human equivalent of the doses used in the promising animal studies is extreme. For this reason, some research departments studying anti-aging and NAD+ have opted not to further invest in research into the effects of NMN supplementation. Instead, they focus on developing pharmacological interventions that inhibit the activity of minor enzymes that deplete NAD+ in cells. This increases the amount of NAD+ that PARP and sirtuins can use to slow cell aging.

American researchers, for example, are studying the anti-aging effects of a substance they call 78c. 78C inhibits the enzyme cyclic ADP ribose hydrolase [spatial structure below], which uses NAD+.

Mice that receive 78c are more active in old age and have a healthier glucose metabolism and cardiovascular system than mice that do not receive 78c.[14] 78c also extends the lifespan of male mice by 10 percent and protects their muscle mass against degradation when mice reach old age.[15]

It remains to be seen whether safe and effective pharmacological anti-aging drugs such as 78c will ever come onto the market. And if it happens, the question is when. It could take decades. For the time being, the question of whether supplementation with NMN can slow down aging in humans appears therefore to be more relevant.

 

Human data

At the moment, in all, about a dozen trials have been published in which people have used NMN. There are also various trials whose results have not yet been published, and trials that are still ongoing. In these trials, subjects receive doses of up to 250-900 milligrams per day. Reported effects are often modest, and it is not always clear whether they are clinically relevant, but NMN supplementation seems to make people fitter. Side effects do not seem to occur.

In a Japanese study, conducted with healthy subjects over the age of 65, endurance improved through daily supplementation with 350 milligrams of NMN.[16] There was no effect on insulin action and body composition, but the study may have been too short for this.

In another study, conducted by researchers at the Washington University School of Medicine, overweight postmenopausal prediabetic women were given 250 milligrams of NMN daily for 10 weeks.[17] In this study, NMN improved insulin action. Supplementation also increased the concentration of platelet-derived growth factor [PDGF]. This could mean that NMN supplementation can bring about muscle growth in the long run. PDGF is involved in the process in which muscle tissue recruits new stem cells and then grows them into mature muscle cells.[18]

In yet another Japanese study, conducted among healthy adults, researchers found a trend toward an increase in muscle mass.[19] The Japanese provide little information about their test subjects, but their biometrics suggest that they are people who were frequently physically active.

The anti-aging effects of NMN supplementation may only become apparent after a longer period of time. Although you would expect, based on the animal studies, that the effective doses of NMN are in the order of magnitude of a few grams per day, there are still few human studies that point in that direction. An exception in this regard is a recent and sponsored trial, in which a daily dose of 300 mg NMN had no significant effects in middle-aged subjects, but daily doses of 600 and 900 did.[20] These effects were – yet again – modest. In addition, in their tables, the researchers report a mild deterioration in glucose metabolism when the higher doses of NMN were administered, although the values remained in the normal range in most subjects.

 

Co-supplementation?

One possibility to make supplementation with NMN more effective is co-supplementation with natural substances that increase the activity of sirtuins, researchers from the Swiss Institute of Translational Medicine suggested in a review.[21] An interesting candidate, which has also been extensively researched, is resveratrol, according to the Swiss. But that’s something for a subsequent blog.

 

 

 

[1] Harden A, Young JW. The alcoholic ferment of yeast-juice. Part II. The co-ferment of yeast-juice. Proc R Soc Lond B. 1906;78(526):78369-375.

[2] Funk C. Who discovered vitamines? Science. 1926 Apr 30;63(1635):455-6.

[3] Nutrition classics from Public Health Reports. The prevention of pellagra. A test of diet among institutional inmates. Nutr Rev. 1973 May;31(5):152-3.

[4] Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb 17;403(6771):795-800.

[5] Imai S. A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis. Pharmacol Res. 2010 Jul;62(1):42-7.

[6] Ramsey KM, Mills KF, Satoh A, Imai S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell. 2008 Jan;7(1):78-88.

[7] Mendelsohn AR, Larrick JW. Partial reversal of skeletal muscle aging by restoration of normal NAD⁺ levels. Rejuvenation Res. 2014 Feb;17(1):62-9.

[8] De Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016 Jun;15(3):522-30.

[9] Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia. 2011 Dec;54(12):3083-92.

[10] Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016 Jul 15;1643:1-9.

[11] Lu Z, Jiang L, Lesani P, Zhang W, Li N, Luo D, Li Y, Ye Y, Bian J, Wang G, Dunstan CR, Jiang X, Zreiqat H. Nicotinamide Mononucleotide Alleviates Osteoblast Senescence Induction and Promotes Bone Healing in Osteoporotic Mice. J Gerontol A Biol Sci Med Sci. 2023 Feb 24;78(2):186-94.

[12] Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Süle Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019 Jun;24:101192.

[13] Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, Jin XL, Mahbub S, Campbell JM, Habibalahi A, Loh WN, Youngson NA, Maniam J, Wong ASA, Selesniemi K, Bustamante S, Li C, Zhao Y, Marinova MB, Kim LJ, Lau L, Wu RM, Mikolaizak AS, Araki T, Le Couteur DG, Turner N, Morris MJ, Walters KA, Goldys E, O’Neill C, Gilchrist RB, Sinclair DA, Homer HA, Wu LE. NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep. 2020 Feb 11;30(6):1670-1681.e7. 

[14] Tarragó MG, Chini CCS, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN. A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell Metab. 2018 May 1;27(5):1081-1095.e10.

[15] Peclat TR, Thompson KL, Warner GM, Chini CCS, Tarragó MG, Mazdeh DZ, Zhang C, Zavala-Solorio J, Kolumam G, Liang Wong Y, Cohen RL, Chini EN. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell. 2022 Apr;21(4):e13589.

[16] Igarashi M, Nakagawa-Nagahama Y, Miura M, Kashiwabara K, Yaku K, Sawada M, Sekine R, Fukamizu Y, Sato T, Sakurai T, Sato J, Ino K, Kubota N, Nakagawa T, Kadowaki T, Yamauchi T. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging. 2022 May 1;8(1):5.

[17] Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021 Jun 11;372(6547):1224-9.

[18] Contreras O, Córdova-Casanova A, Brandan E. PDGF-PDGFR network differentially regulates the fate, migration, proliferation, and cell cycle progression of myogenic cells. Cell Signal. 2021 Aug;84:110036.

[19] Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T, Tobe K, Nakagawa T. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Front Nutr. 2022 Apr 11;9:868640.

[20] Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, Thasma S, Andhalkar N, Avhad G, Kumbhar V. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. Geroscience. 2023 Feb;45(1):29-43.

[21] Sharma A, Chabloz S, Lapides RA, Roider E, Ewald CY. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients. 2023 Jan 14;15(2):445.