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NAD + repletion improves mitochondrial and stem cell function and enhances life span in mice
Open accessAbstract
A dietary supplement protects aging muscle: The oxidized form of cellular nicotinamide adenine dinucleotide (NAD + ) is critical for mitochondrial function, and its supplementation can lead to increased longevity. Zhang et al. found that feeding the NAD + precursor nicotinamide riboside (NR) to aging mice protected them from muscle degeneration (see the Perspective by Guarente). NR treatment enhanced muscle function and also protected mice from the loss of muscle stem cells. The treatment was similarly protective of neural and melanocyte stem cells, which may have contributed to the extended life span of the NR-treated animals. Science , this issue p. 1436 ; see also p. 1396
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“Mounting evidence supports a critical role for NAD+ in stem cell rejuvenation, including in HSCs, endothelial stem cells, muscle stem cells, and melanocyte stem cells (Das et al., 2018; Vannini et al., 2019; Zhang et al., 2016).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Zhang et al., 2016
In the citing paper
“Similarly, NR treatment of aged mice resulted in increased proliferation and increased neurogenesis in both the subventricular zone and the dentate gyrus of the hippocampus in aged mice (Zhang et al., 2016).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Zhang et al., 2016
In the citing paper
“In primary cell culture, supplementation with NR delays cellular senescence (Wiley et al., 2016), and NR treatment also reduces the senescent state in both NSCs and other stem cell types (Zhang et al., 2016).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Zhang et al., 2016
In the citing paper
“NR supplementation delayed senescence of adult NSCs in 2-year-old mice (Zhang et al., 2016), suggesting a role for a deficit in NAD+ or one or more of the enzymes it supports in neural-cell senescence.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Zhang et al., 2016
In the citing paper
“NR administration in old mice showed a small but significant increase in lifespan (5%)198.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [198]
In the citing paper
“Treatment with NR also improved muscle stem cell functions by regulating mitochondrial metabolism in a mouse model of muscular dystrophy197,198.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [198]
In the citing paper
“In mice, NR causes a wide range of beneficial effects, including a moderate lifespan extension [202].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [202]
In the citing paper
“Additionally, nicotinamide riboside treatment in aging mice increased skeletal muscle function by preventing stem cell senescence, improved mitochondrial function, and a higher expression of genes involved in the TCA cycle and OXPHOS (266).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [266]
In the citing paper
“Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance49,50,52,53”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [53]
In the citing paper
“the conversion of these precursors to NAD+ bypasses the rate limited enzyme NAMPT”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [53]
In the citing paper
“new therapeutic strategies have emerged to restore NAD+ levels in muscle by administration of dietary NAD+ precursors such as NR or NMN46,53,54”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [53]
In the citing paper
“For example, some old MuSCs become senescent, a state characterized by irreversible cell cycle arrest and secretion of cytokines and other proteins (senescence-associated secreted phenotype)39–43.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [39]
In the citing paper
“NAD precursors such as nicotinamide riboside can restore ageing defects in ISCs120, as well as in MuSCs, NSCs and melanocyte stem cells39.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [39]
In the citing paper
“The administration of NAD precursors, in particular nicotinamide riboside and nicotinamide mononucleotide, has shown benefits in terms of healthspan219 and lifespan39.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [39]
In the citing paper
“Nicotinamide riboside also has a beneficial effects on old MuSCs, NSCs and melanocyte stem cells, in part by rescuing mitochondrial function39.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [39]
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Self-citationBiological aging processes underlying cognitive decline and neurodegenerative disease
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“The critical importance of balanced mitochondrial activity is evidenced by data demonstrating lifespan extension both by the increasing of cellular metabolism and antioxidant capacity in models (79, 80) and by interventions designed to decrease mitochondrial function or enhance ROS production (81, 82).”
BackgroundLukjanenko, L., Karaz, S., Stuelsatz, P., Gurriaran-Rodriguez, U., Michaud, J., Dammone, G., Sizzano, F., Mashinchian, O., Ancel, S., Migliavacca, E., et al. (2019) · Cell stem cell · doi:10.1016/j.stem.2018.12.014 · Cited by 374
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
Mehr, A. P., Tran, M. T., Ralto, K. M., Leaf, D. E., Washco, V., Messmer, J., Lerner, A., Kher, A., Kim, S. H., Khoury, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0138-z · Cited by 373
The role of mitochondria in aging
Jang, J. Y., Blum, A., Liu, J., & Finkel, T. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120842 · Cited by 358
Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging
Sato, S., Solanas, G., Peixoto, F. O., Bee, L., Symeonidi, A., Schmidt, M. S., Brenner, C., Masri, S., Benitah, S. A., & Sassone‐Corsi, P. (2017) · Cell · doi:10.1016/j.cell.2017.07.042 · Cited by 366
“Liver-Specific Elevation of NAD and Related Metabolites NAD and its biosynthetic pathway through the enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a critical regulator of aging, and rescuing the levels of NAD is reported to modulate lifespan and/or healthspan extension (Belenky et al., 2007b; Gomes et al.,…”
BackgroundMigliavacca, E., Tay, S. K. H., Patel, H. P., Sonntag, T., Civiletto, G., McFarlane, C., Forrester, T., Barton, S. J., Leow, M. K., Antoun, E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13694-1 · Cited by 365
Self-citationRepairing mitochondrial dysfunction in disease
Sorrentino, V., Menzies, K. J., & Auwerx, J. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104908 · Cited by 337
Tissue Stem Cells: Architects of Their Niches
Fuchs, E., & Blau, H. M. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.09.011 · Cited by 332
“Thus, metabolic and epigenetic regulation work hand in hand to determine MuSC fate choices during regeneration and changes in nutrient availability can trigger changes in MuSC function in regeneration, aging, and muscular dystrophies (Cerletti et al., 2008; Zhang et al., 2016).”
BackgroundMitochondrial Sirtuins and Molecular Mechanisms of Aging
van de Ven, R. A. H., Santos, D., & Haigis, M. C. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.02.005 · Cited by 312
Dollerup, O. L., Christensen, B., Svart, M., Schmidt, M. S., Sulek, K., Ringgaard, S., Stødkilde-Jørgensen, H., Møller, N., Brenner, C., Treebak, J. T., et al. (2018) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqy132 · Cited by 282
Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses
Phang, J. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7350 · Cited by 302
“which takes nicotinamide (NAM) back to nicotinamide mono nucleotide with PRPP as the cosubstrate (107).”
BackgroundNAD+ homeostasis in renal health and disease
Ralto, K. M., Rhee, E. P., & Parikh, S. M. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0216-6 · Cited by 293
The role of mitochondria in stem cell fate and aging
Zhang, H., Menzies, K. J., & Auwerx, J. H. (2018) · Development · doi:10.1242/dev.143420 · Cited by 291
“Supplementing mouse chow with nicotinamide riboside has been shown to induce the UPRmt to prevent MuSC, NSC and melanocyte stem cell (McSC) senescence (Zhang et al., 2016).”
BackgroundInfluentialSelf-citationCastro-Portuguez, R., & Sutphin, G. L. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.110841 · Cited by 296
“, 2012), muscular dystrophy (Zhang et al., 2016), ataxia telangiectasia (Fang et al.”
BackgroundInfluentialPirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., Hakkarainen, A., Kuula, J., Heinonen, U., Schmidt, M. S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.04.008 · Cited by 286
“The revelation of disturbed NAD homeostasis in muscle and metabolic diseases (Gariani et al., 2016; Khan et al., 2014; Ryu et al., 2016; Trammell et al., 2016; Yoshino et al., 2011; Zhang et al., 2016) in animals has generated a high interest whether NAD metabolism aberrations occur in degenerative diseases in humans…”
BackgroundInfluentialCellular and epigenetic drivers of stem cell ageing
Ermolaeva, M., Neri, F., Ori, A., & Rudolph, K. L. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0020-3 · Cited by 272
The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore
Rottenberg, H., & Hoek, J. B. (2017) · Aging Cell · doi:10.1111/acel.12650 · Cited by 275
“…is critical for proliferation of stem cells (Shin et al., 2015), and therefore, the inhibition of sirt3 in aging (Brown et al., 2013) as well as depletion of its substrate NAD+ in stem cells (Zhang et al., 2016) is predicted to enhance mPTP activation in aging stem cells and inhibit proliferation.”
BackgroundNAD metabolism: Implications in aging and longevity
Yaku, K., Okabe, K., & Nakagawa, T. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.05.006 · Cited by 269
Regulation of Stem Cell Aging by Metabolism and Epigenetics
Ren, R., Ocampo, A., Liu, G., & Belmonte, J. C. I. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.019 · Cited by 286
Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme
Pissios, P. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.02.004 · Cited by 259
NAD + Metabolism in Cardiac Health, Aging, and Disease
Abdellatif, M., Sedej, S., & Kroemer, G. (2021) · Circulation · doi:10.1161/circulationaha.121.056589 · Cited by 267
Zhu, Y., Liu, X., Ding, X., Wang, F., & Geng, X. (2019) · Biogerontology · doi:10.1007/s10522-018-9769-1 · Cited by 255
Human trials exploring anti-aging medicines
Guarente, L., Sinclair, D. A., & Kroemer, G. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.007 · Cited by 266
NAD + repletion improves muscle function in muscular dystrophy and counters global PARylation
Ryu, D., Zhang, H., Ropelle, E. R., Sorrentino, V., Mázala, D. A. G., Mouchiroud, L., Marshall, P. L., Campbell, M. D., Ali, A. S., Knowels, G. M., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf5504 · Cited by 256
“1A) [reviewed in (19)]—could have a multifaceted influence on the development of muscle weakness and fatigue in DMD and potentially other neuromuscular diseases (17).”
BackgroundMethodInfluentialSelf-citationSaccon, T. D., Nagpal, R., Yadav, H., Cavalcante, M. B., Nunes, A. D. D. C., Schneider, A., Gesing, A., Hughes, B., Yousefzadeh, M., Tchkonia, T., et al. (2021) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glab002 · Cited by 247
“Some of the most studied senolytics include navitoclax (ABT-263) (5), danazol (6), nicotinamide riboside (7), fisetin (8), curcumin (9), dasatinib (D), and quercetin (Q) (4).”
BackgroundExercise and bone health across the lifespan
Santos, L., Elliott-Sale, K. J., & Sale, C. (2017) · Biogerontology · doi:10.1007/s10522-017-9732-6 · Cited by 274
“…is caused by depletion of nicotinamide adenine dinucleotide (NAD?) and downregulation of the tricarboxylic acid and oxidative phosphorylation (OXPHOS) pathways (Zhang et al. 2016), leading to a decline in respiratory function and stem cell senescence (Wiley et al. 2016; Zhang et al. 2016).”
BackgroundNAD+ homeostasis in human health and disease
Perez, R. Z., Wanders, R. J. A., van Karnebeek, C., & Houtkooper, R. H. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202113943 · Cited by 244
“…NAD+-enhancing molecules was successful in ameliorating the outcomes of these conditions, including neurodegenerative disorders (Liu et al, 2013; Zhou et al, 2015; Schondorf et al, 2018), metabolic diseases (Revollo et al, 2007; Yoshino et al, 2011; Canto et al, 2012; Lee et al, 2015; Katsyuba…”
BackgroundAutophagy in Cardiovascular Aging
Abdellatif, M., Sedej, S., Carmona-Gutierrez, D., Madeo, F., & Kroemer, G. (2018) · Circulation Research · doi:10.1161/circresaha.118.312208 · Cited by 239
“Furthermore, late-in-life dietary supplementation of nicotinamide riboside, which activates sirtuins by replenishing nicotinamide adenine dinucleotide stores, prolongs mouse lifespan.(70) However, the role of sirtuins per se in lifespan extension is matter of discussion because SIRT1 transgenic mice, despite being hea…”
BackgroundGuan, Y., Wang, S.-R., Huang, X.-Z., Xie, Q.-H., Xu, Y.-Y., Shang, D., & Hao, C.-M. (2017) · Journal of the American Society of Nephrology · doi:10.1681/asn.2016040385 · Cited by 238
Pleiotropic effects of mitochondria in aging
de Lima, T. I., Li, T. Y., Mottis, A., & Auwerx, J. H. (2022) · Nature Aging · doi:10.1038/s43587-022-00191-2 · Cited by 254
Self-citationMitochondria in the signaling pathways that control longevity and health span
Akbari, M., Kirkwood, T. B. L., & Bohr, V. A. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100940 · Cited by 234
“…targets, including senescent cells and SASP (Arriola Apelo et al., 2016; Bai et al., 2011; Fang et al., 2016a, a; Kirkland et al., 2017; Kraig et al., 2018; Lin and Hardie, 2018; Zhang et al., 2016), which can also be modified by lifestyle changes (Di Francesco et al., 2018; Mattson et al., 2018).”
Human skeletal muscle aging atlas
Kedlian, V. R., Wang, Y., Liu, T., Chen, X., Bolt, L., Tudor, C., Shen, Z., Fasouli, E. S., Prigmore, E., Kleshchevnikov, V., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00613-3 · Cited by 218
“Several other putative muscle aging factors, such as stem cell senescence, denervation, metabolic dysregulation and chronic inflammation, were also investigated 8–11 .”
BackgroundSelf-citationImplications of altered NAD metabolism in metabolic disorders
Okabe, K., Yaku, K., Tobe, K., & Nakagawa, T. (2019) · Journal of Biomedical Science · doi:10.1186/s12929-019-0527-8 · Cited by 223
Sarcopenia and Muscle Aging: A Brief Overview
Dao, T., Green, A. E., Kim, Y.-A., Bae, S., Ha, K., Gariani, K., Lee, M.-R., Menzies, K. J., & Ryu, D. (2020) · Endocrinology and Metabolism · doi:10.3803/enm.2020.405 · Cited by 249
“NAD replenishment using NAD boosters, including nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinamide (NAM), CD38 inhibitors and PARP inhibitors, protects from age- or congenital disease-related muscle phenotypes [51-55].”
BackgroundSelf-citationThe Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging
Chini, E. N., Chini, C. C. S., Espindola Netto, J. M., de Oliveira, G. C., & van Schooten, W. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.02.001 · Cited by 227
“Importantly, decline in cellular NAD levels has emerged as a potential key player in the pathogenesis of several diseases including age-related conditions (Table 1) [1-32].”
InfluentialVannini, N., Campos, V., Girotra, M., Trachsel, V., Rojas-Sutterlin, S., Tratwal, J., Ragusa, S., Stefanidis, E., Ryu, D., Rainer, P. Y., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.02.012 · Cited by 218
“…because it has been characterized as a means of activating the SIRT1 axis via the induction of the mitochondrial stress response in the context of aging, liver, and muscle regeneration (Imai et al., 2000; Belenky et al., 2007; Canto´ et al., 2012; Mouchiroud et al., 2013; Zhang et al., 2016).”
Self-citationModulating NAD+ metabolism, from bench to bedside
Katsyuba, E., & Auwerx, J. H. (2017) · The EMBO Journal · doi:10.15252/embj.201797135 · Cited by 231
“…as mitochondrial dysfunction (Gomes et al , 2013; Mouchiroud et al , 2013; Mills et al , 2016), decline in physical performance (Mills et al , 2016; Zhang et al , 2016) and muscle regeneration (Zhang et al , 2016), arterial dysfunction (de Picciotto et al , 2016), decline in vision (Lin et al ,…”
InfluentialSelf-citationAcute Sarcopenia Secondary to Hospitalisation - An Emerging Condition Affecting Older Adults
Welch, C., Hassan-Smith, Z. K., Greig, C. A., Lord, J. M., & Jackson, T. (2018) · Aging and Disease · doi:10.14336/ad.2017.0315 · Cited by 232
“Increased numbers of senescent satellite cells associated with reduced muscle mitochondrial function have been reported in aged mice [38].”
BackgroundNicotinamide Riboside—The Current State of Research and Therapeutic Uses
Mehmel, M., Jovanović, N. D., & Spitz, U. P. (2020) · Nutrients · doi:10.3390/nu12061616 · Cited by 231
“Oral supplementation with NR has been shown to increase NAD+ levels in multiple tissues, along with increased SIRT activity [10,11], improved mitochondrial function [37], and regenerative potential of stem cells [38].”
BackgroundInfluentialNeurogenesis in aging and age-related neurodegenerative diseases
Čulig, L., Chu, X., & Bohr, V. A. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101636 · Cited by 235
Key proteins and pathways that regulate lifespan
Pan, H., & Finkel, T. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.771915 · Cited by 228
NAD and the aging process: role in life, death and everything in between
Chini, C. C. S., Tarragó, M. G., & Chini, E. N. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.11.003 · Cited by 208
Metadata
- Authors
- Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., Schoonjans, K., Menzies, K. J., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- ETH Zurich (CH)
- Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Laboratory of Stem Cell Bioengineering, EPFL, 1015 Lausanne, Switzerland.
- University of Zurich (CH)
- University of Ottawa (CA)
- Corresponding author
- Menzies, Keir J.
- Auwerx, Johan
- ORCID
- Venue
- Science
- Published
- 2016-06-17
- Volume
- 352
- Issue
- 6292
- Pages
- 1436-1443
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2343193821
- Cited by
- 1,255
- References
- 54
- Citations by year
- 2026: 109 · 2025: 139 · 2024: 110 · 2023: 123 · 2022: 142 · 2021: 151 · 2020: 131 · 2019: 111 · 2018: 114 · 2017: 93 · 2016: 29
- FWCI
- 66.83
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- University of Ottawa
- Heart and Stroke Foundation of Canada
- NIH (R01AG043930)
- Krebsforschung Schweiz/SwissCancerLeague (KFS-3082-02-2013)
- Systems X (SySX.ch 2013/153)
- Swiss National Science Foundation (31003A-140780)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- nicotinamide riboside, muscle stem cells, mitochondrial unfolded protein response, prohibitin, mitochondrial function, aging, lifespan extension, neural stem cells, melanocyte stem cells, mdx mice, muscular dystrophy, cellular reprogramming
- MeSH terms
- Prohibitins, Animals, Disease Models, Animal, Longevity, Melanocytes, Mice, Inbred C57BL, Mitochondria, Muscular Dystrophies, NAD, Niacinamide, Pyridinium Compounds, Repressor Proteins, Cellular Senescence, Mice, Inbred mdx, Oxidative Stress, Myoblasts, Skeletal, Mice, Unfolded Protein Response, Neural Stem Cells, Cellular Reprogramming
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