Emerging strategies, applications and challenges of targeting NAD⁺ in the clinic

Jianying Zhang^#^{1

2

3}, He-Ling Wang^#^{1

3}, Sofie Lautrup^{1

3}, Hilde Loge Nilsen^{4

5

6}, Jonas T Treebak⁷, Leiv Otto Watne^{8

9}, Geir Selbæk^{4

10

11}, Lindsay E Wu¹², Torbjørn Omland^{13

14}, Eija Pirinen^{15

16

17

18}, Tin Cho Cheung¹⁹, Jun Wang¹⁹, Mathias Ziegler²⁰, Ole-Bjørn Tysnes^{21

22}, Rubén Zapata-Pérez²³, Santina Bruzzone²⁴, Carles Canto²⁵, Michela Deleidi²⁶, Georges E Janssens²⁷, Riekelt H Houtkooper²⁷, Morten Scheibye-Knudsen²⁸, Masaya Koshizaka^{29

30}, Koutaro Yokote^{29

30}, Eric Verdin^{31

32}, Vilhelm A Bohr^{28

33}, Charalampos Tzoulis^{21

22

34}, David A Sinclair³⁵, Evandro Fei Fang^{36

37}

Affiliations

¹ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
² Key Laboratory of Oral Health Research in Hunan Province, Xiangya School of Stomatology, Central South University, Hu'nan, China.
³ The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway.
⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ Centre for Embryology and Healthy Development (CRESCO), University of Oslo, Oslo, Norway.
⁶ Department of Microbiology, Oslo University Hospital, Oslo, Norway.
⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Institute of Clinical Medicine, Campus Ahus, University of Oslo, Lørenskog, Norway.
⁹ Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway.
¹⁰ Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
¹¹ Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹² School of Biomedical Sciences, UNSW Sydney, Sydney, New South Wales, Australia.
¹³ Department of Cardiology, Akershus University Hospital, Lørenskog, Norway.
¹⁴ K.G. Jebsen Center for Cardiac Biomarkers, University of Oslo, Oslo, Norway.
¹⁵ Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁶ Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹⁷ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁸ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁹ Hong Kong Longevity Science Laboratory Limited, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China.
²⁰ Department of Biomedicine, University of Bergen, Bergen, Norway.
²¹ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
²² Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.
²³ Group of Metabolism and Gene Regulation, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, Guadalupe de Maciascoque, Murcia, Spain.
²⁴ Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova, Italy.
²⁵ Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
²⁶ Mechanisms and Therapy of Genetic Brain Diseases Institut Imagine, INSERM UMR 1163- Paris Cite' University, Paris, France.
²⁷ Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism (AGEM), Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
²⁸ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁹ Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.
³⁰ Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan.
³¹ UCSF Department of Medicine, San Francisco, CA, USA.
³² Buck Institute for Research on Aging, Novato, CA, USA.
³³ Section on DNA Repair, National Institute on Aging, Baltimore, MD, USA.
³⁴ K.G. Jebsen Center for Translational Research in Parkinson's disease, University of Bergen, Bergen, Norway.
³⁵ Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA.
³⁶ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway. e.f.fang@medisin.uio.no.
³⁷ The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway. e.f.fang@medisin.uio.no.

^# Contributed equally.

PMID: 40926126
DOI: 10.1038/s43587-025-00947-6

Review

Emerging strategies, applications and challenges of targeting NAD⁺ in the clinic

Jianying Zhang et al. Nat Aging. 2025 Sep.

. 2025 Sep;5(9):1704-1731.

doi: 10.1038/s43587-025-00947-6. Epub 2025 Sep 9.

Authors

Affiliations

¹ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
² Key Laboratory of Oral Health Research in Hunan Province, Xiangya School of Stomatology, Central South University, Hu'nan, China.
³ The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway.
⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ Centre for Embryology and Healthy Development (CRESCO), University of Oslo, Oslo, Norway.
⁶ Department of Microbiology, Oslo University Hospital, Oslo, Norway.
⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Institute of Clinical Medicine, Campus Ahus, University of Oslo, Lørenskog, Norway.
⁹ Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway.
¹⁰ Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
¹¹ Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹² School of Biomedical Sciences, UNSW Sydney, Sydney, New South Wales, Australia.
¹³ Department of Cardiology, Akershus University Hospital, Lørenskog, Norway.
¹⁴ K.G. Jebsen Center for Cardiac Biomarkers, University of Oslo, Oslo, Norway.
¹⁵ Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁶ Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹⁷ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁸ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁹ Hong Kong Longevity Science Laboratory Limited, Hong Kong Science Park, Pak Shek Kok, Hong Kong SAR, China.
²⁰ Department of Biomedicine, University of Bergen, Bergen, Norway.
²¹ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
²² Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.
²³ Group of Metabolism and Gene Regulation, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, Guadalupe de Maciascoque, Murcia, Spain.
²⁴ Department of Experimental Medicine, Section of Biochemistry, University of Genova, Genova, Italy.
²⁵ Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
²⁶ Mechanisms and Therapy of Genetic Brain Diseases Institut Imagine, INSERM UMR 1163- Paris Cite' University, Paris, France.
²⁷ Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism (AGEM), Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
²⁸ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁹ Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.
³⁰ Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan.
³¹ UCSF Department of Medicine, San Francisco, CA, USA.
³² Buck Institute for Research on Aging, Novato, CA, USA.
³³ Section on DNA Repair, National Institute on Aging, Baltimore, MD, USA.
³⁴ K.G. Jebsen Center for Translational Research in Parkinson's disease, University of Bergen, Bergen, Norway.
³⁵ Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA.
³⁶ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway. e.f.fang@medisin.uio.no.
³⁷ The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway. e.f.fang@medisin.uio.no.

^# Contributed equally.

PMID: 40926126
DOI: 10.1038/s43587-025-00947-6

Abstract

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD⁺-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD⁺ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD⁺ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.

PubMed Disclaimer

Conflict of interest statement

Competing interests: E.F.F. is a co-owner of Fang-S Consultation AS (organization no. 931 410 717) and NO-Age AS (organization no. 933 219 127); has a material transfer agreement with LMITO Therapeutics (South Korea), a CRADA arrangement with ChromaDex (USA), a commercialization agreement with Molecule AG/VITADAO and material transfer agreements with GeneHarbor (Hong Kong) Biotechnologies Limited and Hong Kong Longevity Science Laboratory (Hong Kong); is a consultant for MindRank AI (China), NYO3 (Norway), AgeLab (Vitality Nordic AS, Norway) and Hong Kong Longevity Science Laboratory (Hong Kong). H.L.N. is an owner of NilsenRepairAge Consulting (organization no. 932146797) and NO-Age AS (organization no. 933219127); has a CRADA arrangement with ChromaDex (USA) and is a consultant for Ambr Institute (Norway), MitoTerapeutics (Norway) and AgeLab (Vitality Nordic AS, Norway). C.T. is listed as inventor on international patent applications relating to the use of NR as a treatment for PD. These patents have been filed by the Technology Transfer Office ‘Vestlandets Innovasjonsselskap As (VIS)’ on behalf of Haukeland University Hospital, Bergen, Norway (PCT/EP2022/067408, PCT/EP2022/067412 and PCT/EP2023/060962). G.S. has received honoraria for giving lectures at symposia sponsored by Eisai and Eli Lilly and has participated at advisory board meetings for Eisia, Roche and Eli Lilly concerning the manufacture of disease-modifying therapies for AD. T.O. has received institutional research support from ChromaDex (USA). E.P. reports a relationship with ChromaDex that includes speaking and lecture fees. M.Z. is chief scientist at Blue Helix Health AS. K.Y. and M.K. have received research support from ChromaDex (USA) via their institution. V.B. is a member of the Chromadex Scientific Advisory Board. T.C.C. and J.W. are inventors and consultants in the Hong Kong Longevity Science Laboratory. D.A.S. is a consultant, inventor, board member and, in some cases, an investor in Atai (2021–present) I; Galilei Biosciences SIRT6 activators (2014–present) F, I, E, A, B; InsideTracker (Segterra), Cambridge, MA I, A, IP (2011–present) B (2011–2017); Zymo Research Irvine, CA, molecular biology (2017–present) A; MetroBiotech, an EdenRoc company also known as Bauhaus; NAD boosters (2015–present) F, I, E, A, B (EdenRoc), IP; Life Biosciences Boston, and affiliates, Cantata Bio (formerly Dovetail Genomics and Arc Bio), Delavie Sciences (2017–present) F, I, E, A, B, IP; Levels (2021–present) E, A; Bold Capital (2021–present) E, A; Falcon Edge Capital (2021–present) E; AFAR (American Federation for Aging Research) B, A, F; Life Extension Advocacy Foundation (LEAF) A; Animal Biosciences (2017–present) I, E; Immetas (2018–present) F, I, E, A, B; Jumpstart Fertility, a Life Biosciences Company, F, I, E, A, B, IP; Fully Aligned Co, F, E, B, IP. F, founder; I, investor; E, equity; A, advisor/consultant; B, board of directors; IP, inventor on licensed patents; L, funding for laboratory (for further information about the affiliations of D.A.S., including those judged not relevant to this work, see https://sinclair.hms.harvard.edu/david-sinclairs-affiliations/ ). L.E.W. is a scientific advisor and shareholder in Metro Biotech and Jumpstart Fertility. The other authors declare no competing interests.

References

1. Navas, L. E. & Carnero, A. NAD⁺ metabolism, stemness, the immune response, and cancer. Signal Transduct. Target. Ther. 6, 2 (2021). - PubMed - PMC - DOI
1. Xiao, W., Wang, R. S., Handy, D. E. & Loscalzo, J. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid. Redox Signal. 28, 251–272 (2018). - PubMed - PMC - DOI
1. Braidy, N. et al. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid. Redox Signal. 30, 251–294 (2019). - PubMed - DOI
1. Verdin, E. NAD⁺ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015). - PubMed - DOI
1. Covarrubias, A. J., Perrone, R., Grozio, A. & Verdin, E. NAD⁺ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol. 22, 119–141 (2021). - PubMed - DOI

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Emerging strategies, applications and challenges of targeting NAD⁺ in the clinic

Affiliations

Emerging strategies, applications and challenges of targeting NAD⁺ in the clinic

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical