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NAD + metabolism: A therapeutic target for age-related metabolic disease
Open accessAbstract
Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor by virtue of its redox capacity, and as such regulates a wealth of metabolic transformations. However, the identification of the longevity protein silent regulator 2 (Sir2), the founding member of the sirtuin protein family, as being NAD⁺-dependent reignited interest in this metabolite. The sirtuins (SIRT1-7 in mammals) utilize NAD⁺ to deacetylate proteins in different subcellular compartments with a variety of functions, but with a strong convergence on optimizing mitochondrial function. Since cellular NAD⁺ levels are limiting for sirtuin activity, boosting its levels is a powerful means to activate sirtuins as a potential therapy for mitochondrial, often age-related, diseases. Indeed, supplying excess precursors, or blocking its utilization by poly(ADP-ribose) polymerase (PARP) enzymes or CD38/CD157, boosts NAD⁺ levels, activates sirtuins and promotes healthy aging. Here, we discuss the current state of knowledge of NAD⁺ metabolism, primarily in relation to sirtuin function. We highlight how NAD⁺ levels change in diverse physiological conditions, and how this can be employed as a pharmacological strategy.
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“They observed that the reduced level of NAD+ downregulated SIRT1, a NAD+- dependent deacetylase involved in regulating mitochondrial homeostasis and XPA repair activity 91–93.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [93]
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“Nicotinamide riboside, nicotinamide mononucleotide, and nicotinic acid are pursued as strategies to boost metabolic flexibility through increased NAD+ and consequent activation of SIRTs (261, 262) (Fig. 5).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [262]
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3 retracted
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“The nuclear sirtuin SIRT1 is the best-known member of the family especially after it was described as the target of the polyphenol, resveratrol (Howitz et al., 2003), which is found in low quantities in red wine (see section ‘‘Pharmacological control of NAD+ levels’’).”
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“During fasting and exercise, the level of NAD+ increases (Canto et al., 2009, 2010).”
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Zheng, D., Zhang, Y., Zheng, M., Cao, T., Wang, G., Zhang, L., Ni, R., Brockman, J., Zhong, H., Fan, G., et al. (2019) · Clinical Science · doi:10.1042/cs20181022 · Cited by 51
Kasai, S., Yoshihara, T., Lopatina, O. L., Ishihara, K., & Higashida, H. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00075 · Cited by 50
“CD157/BST-1 has a variety of roles in the humoral immune response, neutrophil transmigration and hematopoietic stem cell support (Ishihara and Hirano, 2000; Funaro et al., 2004; Podestà et al., 2005; Malavasi et al., 2006; Mouchiroud et al., 2013).”
BackgroundNew Therapeutic Concept of NAD Redox Balance for Cisplatin Nephrotoxicity
Oh, G., Kim, H., Shen, A., Lee, S., Yang, S., Shim, H., Cho, E. Y., Kwon, K., Kwak, T. H., & So, H. (2016) · BioMed Research International · doi:10.1155/2016/4048390 · Cited by 48
NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging
Micó, V., Berninches, L., Tapia, J., & Daimiel, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18050915 · Cited by 50
“For that reason, before these activators could be implemented, the precise role of SIRT1 in lifespan extension needs to be further clarified [85].”
BackgroundInnate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy
Ginefra, P., Lorusso, G., & Vannini, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124441 · Cited by 48
Zamporlini, F., Ruggieri, S., Mazzola, F., Amici, A., Orsomando, G., & Raffaelli, N. (2014) · FEBS Journal · doi:10.1111/febs.13050 · Cited by 48
Ruan, Q., Ruan, J., Zhang, W., Qian, F., & Yu, Z. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.08.010 · Cited by 44
Lippi, L., Uberti, F., Folli, A., Turco, A., Curci, C., D’Abrosca, F., Alessandro de, S. I. R. E., & Invernizzi, M. (2022) · Aging Clinical and Experimental Research · doi:10.1007/s40520-022-02203-y · Cited by 43
“L-Trp, NA, and NAM are involved in the NAD+ metabolisms pathway, functioning as precursors in the biosynthesis process and enhancing NAD+ formation [47].”
BackgroundNAD+ in Cancer Prevention and Treatment: Pros and Cons
Poljšak, B. (2016) · Journal of Clinical & Experimental Oncology · doi:10.4172/2324-9110.1000165 · Cited by 45
“Additionally, it was reported that SIRT3 can repress the Warburg effect by regulating HIF - 1α and reprogramming cancer cell metabolism; from highly glycolytic to a shift toward oxidative phosphorylation [117,118,130,131].”
BackgroundPodocytopathy: The role of actin cytoskeleton
Ahmadian, E., Eftekhari, A., Atakishizada, S., Valiyeva, M. N., Ardalan, M., Khalilov, R. I., & Kavetskyy, T. S. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113920 · Cited by 48
Preyat, N., Rossi, M., Kers, J., Chen, L., Bertin, J., Gough, P. J., Moine, A. L., Rongvaux, A., Gool, F. V., & Léo, O. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.60 · Cited by 42
Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration
Jadeja, R. N., Thounaojam, M. C., Bartoli, M., & Martin, P. M. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/2692794 · Cited by 45
Zhang, H., Li, J., Cao, C., Zhang, B., Yang, W., Shi, B., & Shan, A. (2020) · Food & Function · doi:10.1039/c9fo02609f · Cited by 39
Liu, Y., Luo, C., Li, T., Zhang, W., Zong, Z., Liu, X., & Deng, H. (2021) · Journal of Proteome Research · doi:10.1021/acs.jproteome.0c01037 · Cited by 42
Drugs in Development for Acute Kidney Injury
Hulse, M., & Rosner, M. H. (2019) · Drugs · doi:10.1007/s40265-019-01119-8 · Cited by 39
van der Velpen, V., Rosenberg, N., Maillard, V., Teav, T., Chatton, J., Gallart‐Ayala, H., & Ivanišević, J. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15362 · Cited by 39
“…the NAD+ production (Katsyuba et al., 2018; Rajman et al., 2018; Shi et al., 2017), considered as essential for the mitochondrial function and to improve the health outcome of age- associated metabolic diseases, such as AD (Hikosaka et al., 2021; Mitchell et al., 2018; Mouchiroud et al., 2013).”
BackgroundThe metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans
Wu, N., Ma, Y., Gong, X.-Q., Zhao, P., Jia, Y.-J., Zhao, Q., Duan, J.-H., & Zou, C. (2023) · Nature Communications · doi:10.1038/s41467-023-35899-1 · Cited by 41
Vidugirienė, J., Leippe, D. M., Sobol, M., Vidugiris, G. J. A., Zhou, W., Meisenheimer, P. L., Gautam, P., Wennerberg, K., & Cali, J. J. (2014) · Assay and Drug Development Technologies · doi:10.1089/adt.2014.605 · Cited by 38
“Given the important role of nicotinamide adenine dinucleotides as redox factors in cellular metabolism and substrates in various signaling pathways, NAD(P)/NAD(P)H metabolism is a therapeutic target for novel drug development.(14,15) However, the lack of widely accepted high-throughput screening (HTS) assays for monit…”
Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges
Begum, M. K., Konja, D., Singh, S., Chłopicki, S., & Wang, Y. (2021) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001154 · Cited by 40
Nie, H., Zhang, Y., Yu, H., Xiao, H., Li, T., & Yang, Q. (2021) · Drug Delivery · doi:10.1080/10717544.2021.1886198 · Cited by 37
“More importantly, it has been reported to increase NMNAT activity and enhance NADþ biosynthesis (Grant, 2010; Mouchiroud et al., 2013; Mathieu et al., 2016).”
BackgroundChandrasekaran, K., Najimi, N., Sagi, A. R., Yarlagadda, S., Salimian, M., Arvas, M. I., Hedayat, A. F., Kevas, Y., Kadakia, A., & Russell, J. W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094887 · Cited by 37
“The maintenance of NAD+ levels is central to axonal degeneration and regeneration pathways and to Mt homeostasis, including Mt oxidative phosphorylation, Mt biogenesis, and nuclear–mitochondrial communication [34,35].”
BackgroundOxidative Status Predicts Quality in Human Mesenchymal Stem Cells
Bertolo, A., Capossela, S., Fränkl, G., Baur, M., Pötzel, T., & Stoyanov, J. (2017) · Stem Cell Research & Therapy · doi:10.1186/s13287-016-0452-7 · Cited by 36
Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis
Cao, T., Ni, R., Ding, W., Ji, X., Fan, G., Zhang, Z., & Peng, T. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04767-3 · Cited by 37
“NAD + is generated through three pathways in mammals: the de novo pathway from the L-tryptophan amino acid precursor; the salvage pathway; and the Priess-Handler pathway from precursors such as nicotinamide, niacin, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) [2].”
Mahon, R. N., & Hafner, R. (2015) · Clinical Infectious Diseases · doi:10.1093/cid/civ621 · Cited by 37
Jia, Q., Cui, C., Deng, Q., Wang, L., Chen, R., Zhai, D., Xie, L., & Yu, J. (2018) · Oncology Letters · doi:10.3892/ol.2018.9400 · Cited by 37
“NMNAT2 is a sensitive enzyme marker for NAD levels that reflects the intracellular redox equilibrium and cellular energy state, acting as a sensor for cells with a high energy demand, including cancer cells (20,21).”
Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies
Djouadi, F., & Bastin, J. (2019) · Cells · doi:10.3390/cells8040289 · Cited by 36
Reductive stress: The key pathway in metabolic disorders induced by overnutrition
Zhang, S., Wang, N., Gao, Z., Gao, Z., Wang, X., Xie, H., Wang, C.-Y., & Zhang, S. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.01.012 · Cited by 37
“Therefore, upregulation of sirtuins may lead to competition for NAD + with other NAD + -consuming enzymes, leading to more severe NAD + depletion, and thus aggravating reductive stress [94,95].”
Recent Advances in Inhibitors of Sirtuin1/2: An Update and Perspective
Zhou, Z., Ma, T., Zhu, Q., Xu, Y., & Zha, X. (2018) · Future Medicinal Chemistry · doi:10.4155/fmc-2017-0207 · Cited by 34
Connell, N., Grevendonk, L., Fealy, C., Moonen-Kornips, E., Bruls, Y., Schrauwen-Hinderling, V., de Vogel, J., Hageman, R., Geurts, J., Zapata-Perez, R., et al. (2021) · The Journal of Nutrition · doi:10.1093/jn/nxab193 · Cited by 33
Self-citationNeutrophil Maturation and Survival Is Controlled by IFN-Dependent Regulation of NAMPT Signaling
Siakaeva, E., Pylaeva, E., Spyra, I., Bordbari, S., Höing, B., Kürten, C. H. L., Lang, S., & Jabłońska, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225584 · Cited by 32
“As NAD+ is needed in many critical cellular processes, such as transcription, cell-cycle progression, DNA repair, and regulation of apoptosis [31,32], maintaining NAD+ content in cells prevents their death [33].”
BackgroundNovel role of PKR in palmitate-induced Sirt1 inactivation and endothelial cell senescence
Li, Y., Peng, Z., Wang, C., Li, L., Leng, Y., Chen, R., Yuan, H., Zhou, S., Zhang, Z., & Chen, A. F. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00038.2018 · Cited by 32
Nutritional Epigenetic Regulators in the Field of Cancer
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“Furthermore, nicotinamide adenine dinucleotide (NAD+) is a hydrogen carrier for redox enzymes with important roles in redox homeostasis and has emerged as a critical signaling molecule and essential substrate for sirtuins (SIRT), a class of enzymes that mediate several beneficial effects related to ageing [246], inclu…”
BackgroundTherapeutic potential of nicotinamide adenine dinucleotide (NAD)
Arenas‐Jal, M., Suñé-Negre, J. M., & García‐Montoya, E. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173158 · Cited by 30
Metadata
- Authors
- Mouchiroud, L., Houtkooper, R. H., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Auwerx, Johan
- Venue
- Critical Reviews in Biochemistry and Molecular Biology
- Publisher
- Informa UK Limited
- Published
- 2013-06-06
- Volume
- 48
- Issue
- 4
- Pages
- 397-408
- ISSN
- 0045-6411 (ISSN-L)
- 1040-9238
- 1549-7798
- PMC
- PMC3858599
- OpenAlex
- W2089838011
- Cited by
- 193
- References
- 137
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 11 · 2023: 8 · 2022: 9 · 2021: 25 · 2020: 16 · 2019: 18 · 2018: 18 · 2017: 19 · 2016: 15 · 2015: 22 · 2014: 14 · 2013: 2
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Critical Reviews in Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (136201, 124713)
- ZonMw (91613050)
- National Heart, Lung, and Blood Institute (R01HL106511)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- NAD+ metabolism, sirtuins, Sir2, NAD+ precursors, PARP inhibition, mitochondrial function, aging, healthy aging, NAD+ supplementation, protein deacetylation
- MeSH terms
- Animals, Humans, Metabolic Diseases, NAD, Sirtuins
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