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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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BackgroundSmall molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
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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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“, 1986; Rine & Herskowitz, 1987), which was originally described as a NAD-dependent class III histone deacetylases (Imai et al., 2000).”
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“During fasting and exercise, the level of NAD+ increases (Canto et al., 2009, 2010).”
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“The level of these metabolites depend on a complex series of energetic (Xiao et al. 2007, Hardie et al. 2012) and redox pathways (Cantó & Auwerx 2012, Mouchiroud et al. 2013), along with a reliance on the quantity, type, and location of available energy substrate stores.”
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“NAD + precursors have received much scientific attention (9, 19) and hold therapeutic value in numerous diseases including cardiovascular (71, 72) , neurodegenerative (21) , and metabolic conditions (73, 74) as well as ageing per se (8) .”
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Gu, W., Liu, D., Wei, L., Yang, Z., Jiang, S., Dai, S., Cao, T., & Shen, Z. (2025) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/10742484251369609 · Cited by 2
Multitasking Roles for Poly(ADP-ribosyl)ation in Aging and Longevity
Mangerich, A., & Bürkle, A. (2015) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-14151-0_6 · Cited by 2
“NAD+ is a central metabolic cofactor by functioning as an important redox factor and serving as a substrate for enzymes, such as PARPs as well as the class III deacetylases known as sirtuins [273].”
BackgroundPrasanth, M. I., Sivamaruthi, B. S., Kesika, P., Rosmol, P. S., & Tencomnao, T. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819590-1.00002-1 · Cited by 2
Genetik und Epigenetik des Alterns
Menzel, A., & Weber, B. (2022) · Springer eBooks · doi:10.1007/978-3-662-61417-4_10 · Cited by 1
Enhancing Type 1 Diabetes Care by Embracing an Integrative Approach
Neville, L. (2023) · Integrative and Complementary Therapies · doi:10.1089/ict.2023.29088.lne · Cited by 1
The role of nicotinamide adenine dinucleotide salvage enzymes in cardioprotection
Kibria, F., DAS, S. K., & Arefin, M. S. (2024) · Polish Journal of Cardio-Thoracic Surgery · doi:10.5114/kitp.2024.141145 · Cited by 1
“Interestingly, the major NAD + synthesizing enzymes nicotinamide riboside kinase 1 (NRK1), nicotinamide riboside kinase 2 (NRK2) [90], and nicotinate phosphoribosyl transferase (NAPRT) are identified in the cy - tosol only [91].”
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Translational Geroscience Strategies for Delaying Multimorbidity
Khanal, P., Chand, J., Patil, V. S., Singh, L., & Bhattacharya, K. (2026) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.6c00026 · Cited by 1
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“Beyond its canonical role in redox reactions, NAD + serves as an essential substrate for NAD + -consuming enzymes, including sirtuins and ADP-ribosyltransferases (PARPs), thereby directly linking cellular metabolism to epigenetic and post-translational modification signaling [ 7, 8 ].”
Bianchi, A. R. (2014) · Journal of Microbial & Biochemical Technology · doi:10.4172/1948-5948.1000148 · Cited by 1
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“Besides, 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 [13,21] But whether NMNAT2 have neuroprotective effect in TBI is still unconfirmed.”
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Redox Dynamic Homeostasis and Aging
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Chronic mTOR Inhibition by Rapamycin and Diabetes
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Uchiumi, F., Arakawa, J., Takihara, Y., Akui, M., Hamada, H., & Tanuma, S. (2018) · InTech eBooks · doi:10.5772/intechopen.71095
“Several drugs that induce an increase in the intracellular NAD level are expected to contribute to the establishment of novel therapeutics for treating age-related diseases, including cancer [168].”
BackgroundElectrochemical Characterization of Nicotinamide Riboside
Goines, S., & Dick, J. E. (2019) · ChemElectroChem · doi:10.1002/celc.201901435
Nature Versus Nurture: What Can be Learned from the Oldest-Old's Claims About Longevity?
Poljšak, B., Kovač, V., Levec, T., & Milisav, I. (2021) · Rejuvenation Research · doi:10.1089/rej.2020.2379
“42,43 Yet, PARPs directly compete with sirtuins for the NAD + bioavailability 44,45 and NAD + depletion was found to increase oxidative stress and inflammation and can be restored by lifestyle choices like calorie restriction and exercise.”
Skeletal muscle health in aging
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The use of Nicotinamide in Parkinson’s disease; A Possible path to the future. Review Article
Fahmy, S., Alshahawy, M., Mohamed, N., Gamal, N., Abdelazim, S., Abdelsalam, N., Abdelrahim, H., Shehab, R., & Wakeel, L. M. E. (2023) · Archives of Pharmaceutical Sciences Ain Shams University · doi:10.21608/aps.2023.204521.1116
Multifactorial microbial networks shape aging and neurodegeneration
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Metabolic Plasticity in Embryogenesis Throughout the Lens of NAD+
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“…interaction with NMN-NAD + at the STXBP1/syntaxin interface, as indicated by computational modeling, or from indirect mechanisms such as systemic metabolic enhancement, mitochondrial support, or modulation of synaptic energetics (Mouchiroud et al. 2013), or both direct and indirect mechanisms.”
Investigation of BACE1 as a stress-induced regulator of neuronal metabolism
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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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