By James Odell, ND, OMD, LAc
When it comes to fighting aging at the cellular level, two supplements stand out for their ability to boost NAD+, with profound anti-aging effects.
What Is Nicotinamide Adenine Dinucleotide?
Life as we know it cannot exist without the nucleotide nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential cellular component from the simplest organisms, such as bacteria, to the most complex multicellular organisms. NAD is found in two forms in the body, NAD+ and NADH, both of which are also molecules. The main difference between NAD+ and NADH is that the NAD+ molecule is oxidized and the NADH molecule is not. NADH stands for "nicotinamide adenine dinucleotide (NAD) + hydrogen (H). NAD+ directly and indirectly influences many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell function.1
The Vital Roles of NAD+
These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and healthy aging. NAD+ is abundant in most living cells and has been described as a cofactor in electron transfer during oxidation-reduction reactions. In addition to participating in these reactions, NAD+ has also been shown to play a vital role in cell signaling, regulating several pathways from intracellular calcium transients to the epigenetic status of chromatin.
Primarily, NAD+ is a nucleotide molecule that provides energy for mitochondria which are intracellular powerhouses that produce ATP and carry out diverse functions for cellular energy metabolism. Both mitochondrial ATP production and membrane potential require the universal cofactor NAD+.
The Benefits of NAD+ in the Aging Process
At a biochemical level aging is marked by oxidative stress, epigenetics affecting genomic stability, dysregulated intercellular communication, telomere attrition, cellular senescence, stem cell exhaustion, and importantly, mitochondrial dysfunction. Mitochondrial dysfunction has now been associated with over 40 major diseases and health problems including type 2 diabetes, cancer, Alzheimer’s disease, and other neurodegenerative diseases.2, 3, 4, 5
Most importantly, it has now been demonstrated that cellular NAD+ levels decline during chronological aging. In fact, by middle age, our NAD+ levels have plummeted to half that of our youth.6, 7, 8, 9, 10 Furthermore, numerous studies have shown that increasing NAD+ levels enhance insulin sensitivity, reverses mitochondrial dysfunction, and extends lifespan.11, 12, 13, 14, 15, 16
Four Ways NAD+ Is Biosynthesized in the Body
NAD+ levels can also be increased by activating enzymes that stimulate the synthesis of NAD+, by inhibiting an enzyme (CD38) that degrades NAD+.17 Specifically, in mammals, NAD+ biosynthesis can proceed via four different routes: 18, 19, 20, 21
de novo synthesis from tryptophan (TRP),
synthesis from either form of vitamin B3, nicotinamide (NAM) - also known as niacinamide,
synthesis from nicotinic acid (NA) - also known as niacin,
or conversion of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
Although NAD+ (Nicotinamide Adenine Dinucleotide) biosynthesis in humans occurs through multiple pathways, as mentioned above, we'll only focus on how the body converts nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) into NAD+. These two precursors have gained significant attention in recent years due to their potential role in boosting NAD+ levels, particularly as we age and our natural NAD+ production declines.
Supplementing Nicotinamide Riboside (NR) To Biosynthesize NAD+
Nicotinamide riboside (NR) is a form of vitamin B3 (niacin) and a precursor to NAD+. NR has recently become one of the most studied NAD+ precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. Accumulating evidence on NR’sNRs’ health benefits has validated its efficiency across several animal and human studies for treating several cardiovascular, neurodegenerative, and metabolic disorders.22, 23, 24, 25, 26
NR effects are currently being investigated in clinical trials, including research into diverse cardiovascular diseases, neural and cognitive functions, metabolic disturbances, muscular and kidney injuries, aging, and chemotherapy. In addition, fundamental research on NR transport and metabolic pathways will further support a rapid translation to effective therapeutic use.27, 28
Nicotinamide Riboside Dosage
The standard dose of NR can vary depending on several factors, including the specific formulation, the manufacturer’s recommendations, and the intended use (whether for research or therapeutic purposes). Typical oral doses used in research studies range from 100 to 1000 mg/day. Most practitioners recommend 500 to 1000 mg daily.29, 30
Supplementing Nicotinamide Mononucleotide (NMN) To Biosynthesize NAD+
Nicotinamide mononucleotide (NMN) is another precursor to NAD+ that has been studied for its many potential health benefits, including antiaging effects.31, 32, 33, 34, 35 When taken orally, NMN is rapidly absorbed and converted to NAD+. In numerous mouse models of disease and aging, NMN has demonstrated many remarkable effects, benefitting conditions ranging from diabetes to Alzheimer’s disease to ischemia.36
NMN and NR work synergistically together. NMN can be converted by the body to NR, which then enters cells, and is converted back to NMN by an enzyme called nicotinamide riboside kinase (NRK).37
Supplementation with NMN has increasesd NAD+ biosynthesis, suppressesd age-related adipose tissue inflammation, enhancesd insulin secretion and insulin action, improvesd mitochondrial function, and improvesd neuronal function in the brain.38, 39 Thus, supplementing NMN and NR is an effective nutraceutical anti-aging intervention with beneficial effects on various physiological functions. NMN levels fall with age, and aging itself has also been shown to compromise the body’s conversion of NMN to NAD+ significantly.40
NMN is naturally found in small amounts in fruits and vegetables such as avocados, broccoli, cabbage, edamame, and cucumbers. However, these are small amounts and to obtain levels needed to significantly enhance NAD+, it is necessary to supplement NMN. Most NMN is synthesized from vitamin B3 in the form of nicotinamide. At the center is nicotinamide phosphoribosyltransferase (NAMPT), an essential rate-limiting enzyme. This enzyme catalyzes the conversion from nicotinamide to NMN, which exists in both an intracellular (iNAMPT) and extracellular form (eNAMPT).41 The extracellular form has higher enzymatic activity than the intracellular form and has been found in blood plasma, seminal plasma, and cerebrospinal fluid in humans. 42, 43
Like NAD+ and NMN, eNAMPT declines with age. Both white and brown adipocytes actively secrete eNAMPT, suggesting that fatty tissue may be a modulator of NAD+ biosynthesis.44 Researchers speculate that the gut microbiome, and certain resident bacteria within it, may produce NMN.45 NMN has been able to suppress age-associated weight gain, enhance energy metabolism and physical activity, improve insulin sensitivity, improve eye function, improve mitochondrial metabolism, and prevent age-linked changes in gene expression.46 NMN is likely a good supplement to suppress inflammation associated with aging since studies show it lowers adipose tissue inflammation associated with age. Interestingly, older mice appear more responsive to NMN, than younger mice.47
NMN Dosage
Like NR, the standard dose of NMN can vary depending on several factors, including the specific formulation, the manufacturer’s recommendations, and the intended use (whether for research or therapeutic purposes). Typical oral doses used in research studies range from 100 to 1000 mg/day. Most practitioners recommend 500 to 1000 mg/day. A liposomal version of NMN may well mimic the body’s transport system, enhancing uptake and delivery, as science advances its understanding of the holy grail of reversing aging.
Conclusion
Advancing age and many disease states are associated with declines in nicotinamide adenine dinucleotide (NAD+) levels. Preclinical studies suggest that boosting NAD + abundance with precursor compounds, such as nicotinamide riboside or nicotinamide mononucleotide, profoundly affects physiological function in aging and disease models. Supplementation with these compounds is safe and tolerable and can increase the abundance of NAD+ and related metabolites in multiple tissues. Dosing regimens and study durations vary greatly across interventions, and small sample sizes limit data interpretation of physiological outcomes.
References
Covarrubias, Anthony J., Rosalba Perrone, Alessia Grozio, and Eric Verdin. "NAD+ metabolism and its roles in cellular processes during aging." Nature Reviews Molecular Cell Biology 22, no. 2 (2021): 119-141.
Szendroedi, Julia, Esther Phielix, and Michael Roden. "The role of mitochondria in insulin resistance and type 2 diabetes mellitus." Nature Reviews Endocrinology 8, no. 2 (2012): 92-103.
Solaini, Giancarlo, Gianluca Sgarbi, and Alessandra Baracca. "Oxidative phosphorylation in cancer cells." Biochimica et Biophysica Acta (BBA)-Bioenergetics 1807, no. 6 (2011): 534-542.
Kristian, Tibor, Irina Balan, Rosemary Schuh, and Mitch Onken. "Mitochondrial dysfunction and nicotinamide dinucleotide catabolism as mechanisms of cell death and promising targets for neuroprotection." Journal of Neuroscience Research 89, no. 12 (2011): 1946-1955.
H. Reddy, P., and T. P. Reddy. "Mitochondria as a therapeutic target for aging and neurodegenerative diseases." Current Alzheimer Research 8, no. 4 (2011): 393-409.
Szendroedi, Julia, Esther Phielix, and Michael Roden. "The role of mitochondria in insulin resistance and type 2 diabetes mellitus." Nature Reviews Endocrinology 8, no. 2 (2012): 92-103.
Solaini, Giancarlo, Gianluca Sgarbi, and Alessandra Baracca. "Oxidative phosphorylation in cancer cells." Biochimica et Biophysica Acta (BBA)-Bioenergetics 1807, no. 6 (2011): 534-542.
Kristian, Tibor, Irina Balan, Rosemary Schuh, and Mitch Onken. "Mitochondrial dysfunction and nicotinamide dinucleotide catabolism as mechanisms of cell death and promising targets for neuroprotection." Journal of Neuroscience Research 89, no. 12 (2011): 1946-1955.
H. Reddy, P., and T. P. Reddy. "Mitochondria as a therapeutic target for aging and neurodegenerative diseases." Current Alzheimer Research 8, no. 4 (2011): 393-409.
Zhu, Xiao-Hong, Ming Lu, Byeong-Yeul Lee, Kamil Ugurbil, and Wei Chen. "In vivo NAD assay reveals the intracellular NAD contents and redox state in the healthy human brain and their age dependences." Proceedings of the National Academy of Sciences 112, no. 9 (2015): 2876-2881.
Lin, Su-Ju, and Leonard Guarente. "Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease." Current opinion in cell biology 15, no. 2 (2003): 241-246.
Yaku, Keisuke, Keisuke Okabe, and Takashi Nakagawa. "NAD+ metabolism: Implications in aging and longevity." Aging research reviews 47 (2018): 1-17.
Yang, Yue, and Anthony A. Sauve. "NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy." Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics 1864, no. 12 (2016): 1787-1800.
Lee, Chi Fung, Arianne Caudal, Lauren Abell, G. A. Nagana Gowda, and Rong Tian. "Targeting NAD+ metabolism as interventions for mitochondrial disease," Scientific Reports 9, no. 1 (2019): 3073.
Sauve, Anthony A. "NAD+ and vitamin B3: from metabolism to therapies." Journal of Pharmacology and Experimental Therapeutics 324, no. 3 (2008): 883-893.
Katsyuba, Elena, Mario Romani, Dina Hofer, and Johan Auwerx. "NAD+ homeostasis in health and disease." Nature Metabolism 2, no. 1 (2020): 9-31.
Aksoy, Pinar, Thomas A. White, Michael Thompson, and Eduardo N. Chini. "Regulation of intracellular levels of NAD: a novel role for CD38." Biochemical and biophysical research communications 345, no. 4 (2006): 1386-1392.
Imai, Shin-ichiro. "Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases." Current pharmaceutical design 15, no. 1 (2009): 20-28.
Chini, Eduardo N. "CD38 as a regulator of cellular NAD+ : a novel potential pharmacological target for metabolic conditions." Current pharmaceutical design 15, no. 1 (2009): 57-63.
Camacho-Pereira, Juliana, Mariana G. Tarragó, Claudia CS Chini, Veronica Nin, Carlos Escande, Gina M. Warner, Amrutesh S. Puranik et al. "CD38 dictates age-related NAD+ decline and mitochondrial dysfunction through an SIRT3-dependent mechanism." Cell metabolism 23, no. 6 (2016): 1127-1139.
Longo, Valter D., Adam Antebi, Andrzej Bartke, Nir Barzilai, Holly M. Brown‐Borg, Calogero Caruso, Tyler J. Curiel et al. "Interventions to slow aging in humans: are we ready?." Aging cell 14, no. 4 (2015): 497-510.
Mehmel, Mario, Nina Jovanović, and Urs Spitz. "Nicotinamide riboside—the current state of research and therapeutic uses." Nutrients 12, no. 6 (2020): 1616.
Damgaard, M. V., & Treebak, J. T. (2023). What is really known about the effects of nicotinamide riboside supplementation in humans? Science advances, 9(29), eadi4862.
Alegre, Gabriela Fabiana Soares, and Glaucia Maria Pastore. "Nad+ precursors nicotinamide mononucleotide (nmn) and nicotinamide riboside (nr): Potential dietary contribution to health." Current nutrition reports 12, no. 3 (2023): 445-464.
Birkisdóttir, María B., Ivar van Galen, Renata MC Brandt, Sander Barnhoorn, Nicole van Vliet, Claire van Dijk, Bhawani Nagarajah et al. "The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside." Frontiers in Aging 3 (2022): 1005322.
Sharma, Chiranjeev, Dickson Donu, and Yana Cen. "Emerging role of nicotinamide riboside in health and diseases." Nutrients 14, no. 19 (2022): 3889.
Biţă, Andrei, Ion Romulus Scorei, Maria Viorica Ciocîlteu, Oana Elena Nicolaescu, Andreea Silvia Pîrvu, Ludovic Everard Bejenaru, Gabriela Rău et al. "Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives." Molecules 28, no. 16 (2023): 6078.
Birkisdóttir, María B., Ivar van Galen, Renata MC Brandt, Sander Barnhoorn, Nicole van Vliet, Claire van Dijk, Bhawani Nagarajah et al. "The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside." Frontiers in Aging 3 (2022): 1005322.
Freeberg KA, Craighead DH, Martens CR, You Z, Chonchol M, Seals DR. Nicotinamide riboside supplementation for treating elevated systolic blood pressure and arterial stiffness in midlife and older adults. Front Cardiovasc Med 2022;9:881703.
Trammell, Samuel AJ, Mark S. Schmidt, Benjamin J. Weidemann, Philip Redpath, Frank Jaksch, Ryan W. Dellinger, Zhonggang Li, E. Dale Abel, Marie E. Migaud, and Charles Brenner. "Nicotinamide riboside is uniquely and orally bioavailable in mice and humans." Nature communications 7, no. 1 (2016): 12948.
Poddar, Saikat Kumar, Ali Ehsan Sifat, Sanjana Haque, Noor Ahmed Nahid, Sabiha Chowdhury, and Imtias Mehedi. "Nicotinamide mononucleotide: exploration of diverse therapeutic applications of a potential molecule." Biomolecules 9, no. 1 (2019): 34.
Rahman SU, Qadeer A, Wu Z. Role and potential mechanisms of nicotinamide mononucleotide in aging. Aging Dis 2024;15:565-83.metabolic regulation[10
Mills, Kathryn F., Shohei Yoshida, Liana R. Stein, Alessia Grozio, Shunsuke Kubota, Yo Sasaki, Philip Redpath et al. "Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice." Cell metabolism 24, no. 6 (2016): 795-806.
Igarashi, Masaki, Yoshiko Nakagawa-Nagahama, Masaomi Miura, Kosuke Kashiwabara, Keisuke Yaku, Mika Sawada, Rie Sekine et al. "Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men." npj Aging 8, no. 1 (2022): 5.
Alegre, Gabriela Fabiana Soares, and Glaucia Maria Pastore. "Nad+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR): Potential dietary contribution to health." Current nutrition reports 12, no. 3 (2023): 445-464.
Okabe, Keisuke, Keisuke Yaku, Kazuyuki Tobe, and Takashi Nakagawa. "Implications of altered NAD metabolism in metabolic disorders." Journal of Biomedical Science 26, no. 1 (2019): 34.
Poljsak, Borut. "NAMPT-mediated NAD biosynthesis as the internal timing mechanism: in NAD+ world, time is running in its own way." Rejuvenation research 21, no. 3 (2018): 210-224.
Loreto, Andrea, Christina Antoniou, Elisa Merlini, Jonathan Gilley, and Michael P. Coleman. "NMN: the NAD precursor at the intersection between axon degeneration and anti-aging therapies." Neuroscience Research 197 (2023): 18-24.
Yoshino, Jun, Joseph A. Baur, and Shin-ichiro Imai. "NAD+ intermediates: the biology and therapeutic potential of NMN and NR." Cell metabolism 27, no. 3 (2018): 513-528.
Imai S. Diagnostic and therapeutic applications of a novel plasma metabolite, Nicotinamide Mononucleotide (NMN), for age-associated metabolic complications in humans. Longer Life Foundation 2011.
Mills, Kathryn F., Shohei Yoshida, Liana R. Stein, Alessia Grozio, Shunsuke Kubota, Yo Sasaki, Philip Redpath, et al. "Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice." Cell metabolism 24, no. 6 (2016): 795-806.
Hallschmid, Manfred, Harpal Randeva, Bee K. Tan, Werner Kern, and Hendrik Lehnert. "Relationship between cerebrospinal fluid visfatin (PBEF/Nampt) levels and adiposity in humans." Diabetes 58, no. 3 (2009): 637-640.
Friebe, D., M. Neef, J. Kratzsch, S. Erbs, K. Dittrich, A. Garten, S. Petzold-Quinque et al. "Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans." Diabetologia 54 (2011): 1200-1211.
Imai, Shin-ichiro. "The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control." NPJ systems biology and applications 2, no. 1 (2016): 1-9.
Grozio, Alessia, Kathryn F. Mills, Jun Yoshino, Santina Bruzzone, Giovanna Sociali, Kyohei Tokizane, Hanyue Cecilia Lei et al. "Slc12a8 is a nicotinamide mononucleotide transporter." Nature Metabolism 1, no. 1 (2019): 47-57.
Mills, Kathryn F., Shohei Yoshida, Liana R. Stein, Alessia Grozio, Shunsuke Kubota, Yo Sasaki, Philip Redpath et al. "Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice." Cell metabolism 24, no. 6 (2016): 795-806.
Caton, Paul William, Julius Kieswich, M. M. Yaqoob, M. J. Holness, and M. C. Sugden. "Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function." Diabetologia 54 (2011): 3083-3092.
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