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Jun 18, 2025;3 (1): 26.

The role of NAD metabolism and its modulation of mitochondria in aging and disease.

Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino
Author Information
  1. Khalishah Yusri: Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  2. Sandra Jose: Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  3. Karen S Vermeulen: Department of Medical Biochemistry, Amsterdam Gastroenterology Endocrinology Metabolism and Amsterdam Neuroscience Cellular & Molecular Mechanisms, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  4. Trina Chia Min Tan: Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  5. Vincenzo Sorrentino: Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. vsorrent@nus.edu.sg. ORCID
PMID: 40604314 DOI: 10.1038/s44324-025-00067-0

Abstract

Nicotinamide adenine dinucleotide (NAD) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD precursors becoming a popular supplementation approach. As increasing components of the NAD biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD-boosting therapeutics in clinical trials, and areas of further translational development.

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Grants

  1. T2EP30124-0014/Ministry of Education - Singapore
  2. NWO; 09150172110059/Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  3. NUHSRO/2022/047/Startup/11,/National University Health System
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