Is NAD+ the future of longevity?
Dr. Nandana Bhardwaj
Aging is associated with changes in biological and physiological processes, with some reports suggesting that aging and metabolism are strongly interconnected. Crucial metabolic changes associated with aging include less efficient cellular regeneration, DNA repair defects, and decline in mitochondrial number and functions.
Longevity researchers are focusing on NAD+ (nicotinamide adenine dinucleotide), as it fuels various biological processes, and declines gradually with age.
Various nutrients and supplements such as collagen, fisetin, nicotinamide riboside (a precursor of NAD+ and NADH), polyphenols, whey protein, curcumin, and various vitamins are reported to play a significant role in delaying aging, and support longevity.
NAD+ (nicotinamide adenine dinucleotide) is a cofactor in all living cells, and is needed for biological processes such as DNA repair, metabolic functions, cellular senescence, boosting immune function, gene expression, maintaining circadian rhythm (sleep-wake up cycle), controlling inflammation, and improving longevity. All above-mentioned processes are indispensable for metabolic balance and healthy ageing.
The first report demonstrating the medical importance of NAD+ was in the treatment of pellagra, with niacin (vitamin B3), a NAD+ precursor. Research has highlighted the role of NAD and its deterioration is linked to various chronic illnesses such as heart disease, diabetes, obesity, vision loss, neurodegenerative diseases and several cancers. In contrast, dietary supplementation that supports NAD levels, upregulates NAD resulting in beneficial effects against conditions associated with aging.
NAD+ markedly declines with age, with the concentration of NAD+ within the cells of newborns being around three times more compared to young adults, and around eight times that of the elderly, over 71 years of age. As such, maintaining sufficient NAD+ levels may be a solution for age related conditions, and extending lifespan. The main functions of NAD+ include promotion of DNA repair, modulation of immune response and chromosome stability.
As cells are unable to absorb NAD directly, dietary supplementation with NAD+ precursors such as nicotinamide riboside (NR), nicotinamide (NAM), nicotinic acid (NA), tryptophan and nicotinamide mononucleotide (NMN) are used to efficiently increase NAD levels. Among these precursors, much focus has been placed on NMN and NR to increase cellular NAD levels.
Recent human trials show health benefits of supplementation of NAD+ precursors, such as NMN or NR. The recommended dose of NMN and NR in humans ranges between 1000-2000 mg per day, without any side effects. Though both precursors show beneficial health effects, there are significant differences in them.
- A study conducted by University of Pennsylvania, USA, oral supplementation of 200 mg/kg NR demonstrated raised NAD+ levels in the liver only but not in other body tissues. In contrast, NMN supplementation reported raised NAD levels in multiple body tissues such as skeletal muscle, blood vessels, kidneys, pancreas, adipose tissues, and even the heart.
- Previously, it was unclear whether NMN crosses the blood brain barrier, however, a study whereby NMN was administered via the abdominal cavity showed a rapid increase in NAD+ levels in the brain, within 15 minutes. This suggests that NMN does cross the blood brain barrier.
- Various reports show improvement in cognition and memory with NMN administration in mouse and rat models of Alzheimer’s disease.
- Dose-response studies using NMN supplementation indicate the beneficial role of NMN, even at lower doses (100 mg/kg) in terms of neuronal outcomes and physical activity.
- In a recent report, NMN supplementation has demonstrated improvement in vascular aging by stimulating anti-aging micro-RNA gene expression in aged mice with restoration of NAD levels.
Currently, there are several major human clinical trials looking at NMN supplementation to increase NAD levels. Institutions running these trials include Washington School of Medicine in St. Louis, USA, Keio University Medical School in Tokyo, Japan and Brigham and Women's hospital in Boston under Harvard longevity scientists. The initial data from phase I and phase II clinical trials results are very encouraging, and support its beneficial health benefits related to aging.
Maintaining optimal levels NAD+ is essential for maintaining metabolic health in the elderly, and may potentially improve lifespan and healthspan. Dietary measures combined with NMN supplementation, are potential therapeutic strategies to alleviate age-related decline and support longevity.
Dr. Nandana Bhardwaj
Dr. Bhardwaj is currently working as Senior Research Scientist with STANVAC group. She has received her Ph. D and Post-doctoral research in Biomedical Engineering from Indian Institute of Technology (IIT) Kharagpur, India and School of Materials Science and Engineering, Nanyang Technological University (NTU), Singapore. Her research interests stretching from Biomaterials, Tissue Engineering, Stem cells, drug delivery, wound healing, 3D bioprinting, disease tissue/organ models to regenerative medicine. She has published 35+ articles in top tier journals of biomedical engineering and multiple awards in her name with ~6000 citations and H-index of 19. She has also been featured in “Top 2% Scientist” globally and in biomedical engineering research in a list prepared by Stanford University (published in PLoS Biology, October16, 2020).
- Barzilai, N., Huffman, D.M., Muzumdar, R.H., Bartke, A., 2012. The critical role of metabolic pathways in aging. Diabetes 61, 1315–1322.
- Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021 Feb;22(2):119-141.
- Verdin E. NAD⁺ in aging, metabolism, and neurodegeneration. Science. 2015 Dec 4;350(6265):1208-13.
- Johnson S, Imai SI. NAD + biosynthesis, aging, and disease. F1000Res. 2018 Feb 1; 7:132.
- Canto, C., Menzies, K.J., Auwerx, J., 2015. NAD (+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22,31–53.
- D. J. Lanska, The discovery of niacin, biotin, and pantothenic acid. Ann. Nutr. Metab. 61, 246–253 (2012).
- Yaku K, Okabe K, Nakagawa T. NAD metabolism: Implications in aging and longevity. Ageing Res Rev. 2018 Nov; 47:1-17.
- Rajman, L., Chwalek, K., Sinclair, D.A., 2018. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 27, 529–547.
- Yoshino, J., Baur, J.A., Imai, S.I., 2017. NAD (+) intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 27, 513–528.
- P. Gomes, N. L. Price, A. J. Y. Ling et al., “Declining NAD+ induces a pseudohypoxic state disrupting nuclear mitochondrial communication during aging,” Cell, vol. 155, no.7, pp. 1624–1638, 2013.
- H. Massudi, R. Grant, N. Braidy, J. Guest, B. Farnsworth, and G. J. Guillemin, “Age-associated changes in oxidative stress and NAD+ metabolism in human tissue,” PLoS ONE, vol. 7, no. 7, 2012.
- Zocchi E, Usai C, Guida L, Franco L, Bruzzone S, Passalacqua M, De Flora A. Ligand-induced internalization of CD38 results in intracellular Ca2+ mobilization: role of NAD+ transport across cell membranes. FASEB J. 1999; 13(2):273–83.
- Yoshino J, Baur JA, Imai SI. NAD (+) intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;27(3):513–28. https://doi.org/10.1016/j.cmet.2017.11.002.
- Heidinger BJ, Blount JD, Boner W, et al. Telomere length in early life predicts lifespan. Proc Natl Acad Sci U S A. 2012;109(5):1743-8.
- Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071-8.
- Ying W, Garnier P, Swanson RA. NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem Biophys Res Commun. 2003;308(4):809-13.
- Bai P, Canto C, Oudart H, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011;13(4):461-8.
- Wang S, Xing Z, Vosler PS, et al. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke. 2008;39(9):2587-95.
- Pittelli M, Felici R, Pitozzi V, et al. Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol Pharmacol. 2011;80(6):1136-46.
- Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153(6):1194-217.
- Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016;24(6):795-806.
- Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016; 7:12948.
- Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging. 2013;34(6):1581-8.
- Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459.
- Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286.
- Kiss, T., Nyúl-Tóth, Á., Balasubramanian, P., Tarantini, S., Ahire, C., Yabluchanskiy, A., Csipo, T., Farkas, E., Wren, J. D., Garman, L., Csiszar, A., & Ungvari, Z. (2020). Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. GeroScience, 42(2), 527–546.
- Liu L, Su X, Quinn WJ 3rd, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E, Migaud M, Mitchison TJ, Baur JA, Rabinowitz JD. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab. 2018 May 1;27(5):1067-1080.e5. doi: 10.1016/j.cmet.2018.03.018.
- Poddar, S. K., Sifat, A. E., Haque, S., Nahid, N. A., Chowdhury, S., & Mehedi, I. (2019). Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules, 9(1), 34. https://doi.org/10.3390/biom9010034.
- Stein, L.R., and Imai, S. (2014). Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. EMBO J. 33, 1321–1340.
- Yoon, M.J., Yoshida, M., Johnson, S., Takikawa, A., Usui, I., Tobe, K., Nakagawa, T., Yoshino, J., and Imai, S. (2015). SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD (+) and function in mice. Cell Metab. 21, 706–717.
- 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. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806.
- Long, A.N., Owens, K., Schlappal, A.E., Kristian, T., Fishman, P.S., and Schuh, R.A. (2015). Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 15, 19.
- Yao, Z., Yang, W., Gao, Z., and Jia, P. (2017). Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci. Lett. 647, 133–140.