Anti-Aging Effects of NR and NMN

Healthful Vitality | 02/16/2021 By Dr. Gunjan Chauhan | Anti-Aging Effects of NR and NMN

In the past few years, an increased life expectancy has been observed in the overall population of America, with a subsequent increase in elderly citizens. Notably, studies have revealed numerous benefits of NR & NMN on anti-aging. To identify the anti-aging effects of NR and NMN, first, let us examine aging. Not to mention, aging is a natural process characterized by a decline in normal body’s metabolism and functions (1). To put it differently, there is a shift in the energy production as you age, involving downregulation of mitochondria, and in insufficient supply of nicotinamide adenine dinucleotide (NAD) in the body. In fact, all the cellular respiratory processes in the body are controlled by NAD, therefore its depletion affects the activities of various organs such as liver, skin, adipose tissue, pancreas, skeletal muscle and brain (2).

Anti-Aging Effects of NR and NMN: Role of Sirtuins in aging process

In order to prolong the lifespan, few interventions have shown promising results in both animal and human studies. Important to realize, the main target evaluated in majority of the anti-aging studies are sirtuins. Sirtuins were first detected in yeasts and considered as transcription repressors. Furthermore, they have also been identified in bacteria and eukaryotes, such as mammals. Humans consist of seven different members of sirtuins, and they play an important role in cellular metabolism and oxidative stress. Additionally, research has shown that sirtuins improve the body’s response against aging process as it maintains the appropriate length of the telomers. To explain, telomers are specialized proteins located at the end of chromosome, which protect it from damage and prevent unraveling of chromosomes. Indeed, the length of telomere is directly related to the lifespan, so longer the length of telomere, greater the life expectancy (3).

Nicotinamide adenine dinucleotide (NAD+) and its metabolites

Nicotinamide adenine dinucleotide (NAD+) is an important molecule that serves as an enzyme cofactor and plays a key role in energy metabolism by accepting and donating electrons (4). Notably, the level of NAD+ depends on our dietary intake and how much energy we consume through food and other nutrients. Also, research has demonstrated that it modulates an individual’s lifespan as well health (5). As mentioned earlier, sirtuins are regulated by NAD+ ensuring that appropriate response is induced during stressful situations such as fasting, DNA impairment and excessive free radical formation. Notably, activation of sirtuins result in stimulation of transcription processes to increase the efficiency of metabolic functions and mitochondrial oxidative metabolism. In addition, response to oxidative stress is also enhanced, as sirtuins upregulate the antioxidant pathways (6).

In particular, studies have demonstrated that in aged mice, the level of NAD+ decreased in multiple organs such as liver and skeletal muscle tissues (7,8). Clearly, the cellular activities controlled by sirtuins depend on the supply of NAD+. In fact, during normal aging phenomenon, the amount of NAD+ decreases inside the cells, affecting the functions of sirtuins. Besides, it is reported that NAD+ level can be adequately restored in the nucleus and the mitochondria of cells with appropriate supplementation of NAD+ metabolites (9). Vitamin B, in the form of Vitamin B3 might enter the rescue pathway via food and serve as a NAD+ precursor (10).

The two important NAD+ metabolites

Notably, there are two important NAD+ metabolites, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) that can enhance NAD levels. These two metabolites are types of vitamin B3 which have shown anti-aging properties in animal and human studies. In fact, NR has showed significant effective outcome in humans, while NMN is being evaluated for its safety in human consumption. Indeed, both NR and NMN have demonstrated potential capacities, to improve the physiological processes associated with aging in animal studies (11).

Anti-Aging Effects of NR and NMN Pharmacological activities

NR and NMN have shown strong anti-aging properties, opening a new horizon of novel therapeutics. In detail, both the molecules have demonstrated enhanced performance in several disease models including neurodegenerative disorders like Alzheimer’s disease, cerebral ischemia, myocardial infarction and diabetes (12). Admittedly, NR has already proved its effectiveness in human trials, whereas NMN has showed life-span prolonging properties in animal model. This highlights the anti-aging characteristics of two potential therapeutic candidates (13). Apparently, most of the pharmacological actions of NR and MNM are facilitated by synthesis of NAD+. NMN has a higher penetration capability through plasma membrane compared to NR (14).

Studies have mentioned that NAD+ has regenerative capacity, as it enhanced the growth of muscle stem cells in older mice. Similarly, NR and NMN have also demonstrated neurogenesis, prevented decline in melanocyte stem cells and increased life span in mice (15).

Nicotinamide mononucleotide or Nicotinamide riboside: Which one is better?

Although there are various types of NAD+ precursors, in the past decade NR and NMN have gained a lot of popularity due to their unique pharmacokinetic and pharmacological properties. Currently, both of these NAD+ metabolites are used in clinical studies. Evidently, research findings have shown that both are effective, with their own specific properties, however, the question which is yet to be answered is, which one performs better?

Investigators have their own preferences and supporting views regarding each. NR is available to a greater extent in food sources, has a better cell permeability compared to NMN, as it does not undergo any transformation to an intermediate product. NR has showed beneficial outcomes, and is safe for human use, while NMN has not been evaluated for safety in human trials [16].

In order to analyze which one is better, let’s take a closer look at the studies where NR and NMN were used

A study conducted a 12-week investigation in obese subjects to assess the changes in glucose metabolism and insulin sensitivity after they were given 2000 mg of NR supplementation daily. The results showed that treatment with NR supplement was safe to use, however no improvement in glucose metabolism and insulin sensitivity was noticed [17]. Like, in another study, the investigators aimed to evaluate the effectiveness on cardiovascular and other physiological functions after increasing the NAD+ bioavailability, by expanding level of NAD+ precursors in aging subjects. The outcomes of the clinical trial showed that NR supplementation for a long-term improved the NAD+ metabolism, and was well-tolerated in middle-aged and older adults [18].

Several studies have mentioned beneficial properties of NMN, where it was reported to be as effective as NR. For example, a recent study where therapeutic approach for Friedreich’s Ataxia (FRDA), a rare type of congenital heart disease was assessed, NMN proved to be advantageous where treatment with NR failed (19). In fact, FRDA occurs due to accelerated acetylation of frataxin, a mitochondrial protein and decreased activity of SIRT3, causing heart enlargement.

Therefore, a significant improvement in the diastolic as well as systolic function was seen in the mice when 500 mg/kg of NMN supplements were given two times each week for a period of six weeks. In another animal study, result from a microarray analysis found that in skeletal muscle, 76.3% of 300 compromised genes were upregulated, in liver 41.7% of 513 compromised genes were activated, and in white adipose tissue 73.1% of 360 compromised genes were stimulated, after performing NMN treatment on mice (20).

The Process of Aging

The process of aging commonly involves impairment of the vascular system, with increased release of free radicals that causes oxidative stress. Studies performed on mice models have found NMN to be effective in the management of such vascular alterations (21).

Studies involving cognitive decline in Alzheimer’s disease, where the main cause of dementia and cognitive impairment was due to accumulation of beta- amyloid plaques, supplementation with NMN led to a decline in the level of beta amyloid plaques. In a recent study, treatment with NR at a dose of 12 mM in drinking water in rodents, reduced the DNA damage and the neuronal cell-death in the hippocampus area of the brain. An improved cognitive ability was also observed due to increased activity of SIRT3 in the brain, however no change in the level of beta amyloid plaques was reported (22). NMN has led to significant improvement in brain activities in aged animal models, such as it enhanced cognitive functions, improved condition of neurons and reduced inflammation by preventing the formation of beta amyloid protein in brain.

Indeed, various studies on anti-aging effects of NR and NMN have shown effective anti-aging properties, making it difficult to choose and justify as to which one performs better. NMN has proved to be beneficial in promoting body’s metabolism and cellular response in animal studies, though these findings still need to be validated in human clinical studies. The manufacturing cost of NMN is expensive and the expenses has to be borne by the patients. NR has few advantages compared to NMN, nevertheless NMN has immense capacity that makes it suitable as an anti-aging supplement. It can be used for the treatment of heart diseases, Alzheimer’s disease, diabetes and other types of age-related disorders (23).

Conclusion

In sum, it is fair to conclude that NR and NMN have overlapping activities, but each has its own pharmacological and pharmacokinetic properties that can make them potential anti-aging supplements.

References

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7. Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Canto C, et al. The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 2013;154:430–441: https://www.cell.com/fulltext/S0092-8674(13)00755-1

8. Mouchiroud L, Houtkooper RH, Auwerx J. NAD(+) metabolism: a therapeutic target for age-related metabolic disease. Crit Rev Biochem Mol Biol. 2013;48:397-408: https://pubmed.ncbi.nlm.nih.gov/23742622/

9. Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz Jr SC, Suthammarak W, Gong G, et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 2013;18:239-250. Retrieved from https://pubmed.ncbi.nlm.nih.gov/23931755/

10. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9:1286. Available online at https://pubmed.ncbi.nlm.nih.gov/29599478/

Related Article: Benefits of NR & NMN on Aging and Overall Health

11. 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;14:528-536. Retrieved from https://pubmed.ncbi.nlm.nih.gov/21982712/

12. Park, J.H.; Long, A.; Owens, K.; Kristian, T. Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol. Dis. 2016, 95, 102–110. [CrossRef] Available at: https://pubmed.ncbi.nlm.nih.gov/27425894/

13. Tsubota, K. The first human clinical study for NMN has started in Japan. NPJ Aging Mech. Dis. 2016, 2, 16021.Retrieved from https://www.nature.com/articles/npjamd201621

14. Pittelli, M.; Felici, R.; Pitozzi, V.; Giovannelli, L.; Bigagli, E.; Cialdai, F.; Romano, G.; Moroni, F.; Chiarugi, A. Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair, and Apoptosis. Mol. Pharmacol. 2011, 80, 1136–1146. Available online at: https://pubmed.ncbi.nlm.nih.gov/21917911/

15. Zhang, H.; Ryu, D.; Wu, Y.; Gariani, K.; Wang, X.; Luan, P.; D’Amico, D.; Ropelle, E.R.; Lutolf, M.P.;  Aebersold, R.; et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016, 352, 1436–1443. Retrieved from https://pubmed.ncbi.nlm.nih.gov/27127236/

16. Poddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I. Nicotinamide mononucleotide: exploration of diverse therapeutic applications of a potential molecule. Biomolecules. 2019;9:34. Retrieved from https://www.mdpi.com/2218-273X/9/1/34/htm

17. Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: Safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr. 2018;108:343-353.Available at: https://pubmed.ncbi.nlm.nih.gov/29992272/

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18. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9:1286. Retrieved from https://pubmed.ncbi.nlm.nih.gov/29599478/

19. Martin AS, Abraham DM, Hershberger KA, Bhatt DP, Mao L, Cui H, et al. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight. 2017;2:93885. Available at : https://pubmed.ncbi.nlm.nih.gov/28724806/

20. Mills, K.F.; Yoshida, S.; Stein, L.R.; Grozio, A.; Kubota, S.; Sasaki, Y.; Redpath, P.; Migaud, M.E.; Apte, R.S.; Uchida, K.; et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016, 24, 795–806. Available at: https://pubmed.ncbi.nlm.nih.gov/28068222/

21. De Picciotto, N.E.; Gano, L.B.; Johnson, L.C.; Martens, C.R.; Sindler, A.L.; Mills, K.F.; Imai, S.; Seals, D.R. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 2016, 15, 522–530. Retrieved from https://pubmed.ncbi.nlm.nih.gov/26970090/

22. Stram AR, Pride PM, Payne RM. NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease. FASEB J. 2017;31:602.

23. Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, et al. NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci USA. 2018;115:e1876– e1885. Retrieved from https://www.pnas.org/content/115/8/E1876