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 hematopoietic stem cells, endothelial stem cells, muscle stem cells, and melanocyte stem cells.
“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 aged mice, nicotinamide riboside treatment increased proliferation and neurogenesis in both the subventricular zone and the dentate gyrus of the hippocampus.
“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 primary cell culture, nicotinamide riboside supplementation delays cellular senescence, and nicotinamide riboside treatment reduces the senescent state in neural stem cells and other stem cell types.
“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
Nicotinamide riboside supplementation delayed senescence of adult neural stem cells in 2-year-old mice, suggesting a role for a deficit in NAD+ or one or more of the enzymes it supports in neural-cell senescence.
“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
NR administration in old mice showed a small but significant increase in lifespan (5%).
“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]
NR treatment improved muscle stem cell functions by regulating mitochondrial metabolism in a mouse model of muscular dystrophy.
“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 mice, NR causes a wide range of beneficial effects, including a moderate lifespan extension.
“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]
Nicotinamide riboside treatment in aging mice increased skeletal muscle function by preventing stem cell senescence, improved mitochondrial function, and higher expression of genes involved in the TCA cycle and OXPHOS.
“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]
Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance.
“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]
Conversion of NAD+ precursors (NR or NMN) to NAD+ bypasses the rate-limited enzyme NAMPT.
“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]
New therapeutic strategies have emerged to restore NAD+ levels in muscle by administration of dietary NAD+ precursors such as NR or NMN.
“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]
Some old MuSCs become senescent, a state characterized by irreversible cell cycle arrest and secretion of cytokines and other proteins.
“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]
NAD precursors such as nicotinamide riboside can restore ageing defects in ISCs, as well as in MuSCs, NSCs and melanocyte stem cells.
“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]
Administration of NAD precursors, in particular nicotinamide riboside and nicotinamide mononucleotide, has shown benefits in terms of healthspan and lifespan.
“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]
Nicotinamide riboside has beneficial effects on old MuSCs, NSCs and melanocyte stem cells, in part by rescuing mitochondrial function.
“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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InfluentialMetabolic Control of Longevity
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“Recently, the lifespan-extending effects of nicotinamide riboside have been linked to the activation of the UPRmt in various stem cell compartments in mice (Zhang et al., 2016), suggesting that the UPRmt may be important for longevity in several organisms beyond worms.”
BackgroundMetabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease
Smith, R. L., Soeters, M. R., Wüst, R. C. I., & Houtkooper, R. H. (2018) · Endocrine Reviews · doi:10.1210/er.2017-00211 · Cited by 787 · see citing works
Nicotinamide riboside is uniquely and orally bioavailable in mice and humans
Trammell, S. A. J., Schmidt, M. S., Weidemann, B. J., Redpath, P., Jaksch, F., Dellinger, R. W., Li, Z., Abel, E. D., Migaud, M. E., & Brenner, C. (2016) · Nature Communications · doi:10.1038/ncomms12948 · Cited by 697 · see citing works
The mitochondrial UPR: mechanisms, physiological functions and implications in ageing
Shpilka, T., & Haynes, C. M. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.110 · Cited by 716 · see citing works
The metabolic roots of senescence: mechanisms and opportunities for intervention
Wiley, C. D., & Campisi, J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00483-8 · Cited by 691 · see citing works
Epigenetic regulation of aging: implications for interventions of aging and diseases
Kang, W., Liu, H., Hu, Q., Wang, L., Liu, J., Zheng, Z., Zhang, W., Ren, J., Zhu, F., & Liu, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01211-8 · Cited by 694 · see citing works
“In mammals, NR supplementation increases mitochondrial function, delays the senescence of NSCs, and increases mouse lifespan.(203) NR supplementation also increases mitochondrial function and reduces aging-associated amyloidosis in muscle.”
BackgroundEnhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity
Sorrentino, V., Romani, M., Mouchiroud, L., Beck, J. S., Zhang, H., D’Amico, D., Moullan, N., Potenza, F., Schmid, A. W., Rietsch, S., et al. (2017) · Nature · doi:10.1038/nature25143 · Cited by 630 · see citing works
“We have previously shown that NR exerts beneficial effects on health-and lifespan 34,36 , but whether it also improves mitochondrial function and proteostasis in vivo in a mouse model of A β proteotoxicity is so far unknown.”
Self-citationVitamin B <sub>3</sub> modulates mitochondrial vulnerability and prevents glaucoma in aged mice
Williams, P. A., Harder, J. M., Foxworth, N. E., Cochran, K. E., Philip, V. M., Porciatti, V., Smithies, O., & John, S. W. M. (2017) · Science · doi:10.1126/science.aal0092 · Cited by 617 · see citing works
NAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627 · see citing works
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“NAD+ is a key cellular factor linked to metabolism, MT health, stem cell rejuvenation, neuroprotection, and longevity in worms and mice (Igarashi and Guarente, 2016; Verdin, 2015; Zhang et al., 2016).”
T cells with dysfunctional mitochondria induce multimorbidity and premature senescence
Desdín-Micó, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabandé-Rodríguez, E., Blanco, E. M., Alfranca, A., Cussó, L., Desco, M., et al. (2020) · Science · doi:10.1126/science.aax0860 · Cited by 572 · see citing works
Ascorbate regulates haematopoietic stem cell function and leukaemogenesis
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“It is generally unknown whether dietary changes alter stem cell function due to changes in metabolite levels; however, muscle stem cell aging is regulated by changes in NAD + levels 4 .”
Hou, Y., Wei, Y. Q., Lautrup, S., Yang, B., Wang, Y., Cordonnier, S. A., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2011226118 · Cited by 545 · see citing works
Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510 · see citing works
“In mice, NR causes a wide range of beneficial effects, including a moderate lifespan extension [202].”
NAD+ metabolism, stemness, the immune response, and cancer
Navas, L. E., & Carnero, A. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00354-w · Cited by 529 · see citing works
“On the other hand, the recovery of NAD levels by supplementation with nicotinamide riboside, NR, precursor of the nucleoside pathway, enhances the function of mitochondria and stem cells in elderly mice.(84,106) Consistently, the overexpression of NNMT and NMNAT3 and subsequent restoration of the mitochondrial NAD poo…”
BackgroundImpairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging
Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., Kim, L.-J., Osborne, B., Joshi, S., Lu, Y., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.008 · Cited by 496 · see citing works
“Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016).”
NAD(+) in aging: molecular mechanisms and translational implications
Fang, E. F., Lautrup, S., Hou, Y., Demarest, T. G., Croteau, D. L., Mattson, M. P., & Bohr, V. A. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.08.001 · Cited by 501 · see citing works
Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
Bitto, A., Ito, T. K., Pineda, V. V., LeTexier, N. J., Huang, H. Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K., et al. (2016) · eLife · doi:10.7554/elife.16351 · Cited by 474 · see citing works
“Of particular note are two studies reporting improved healthspan from short-term treatments in older mice with a JAK pathway inhibitor ( Xu et al., 2015 ) and increased lifespan after transient treatment with the NAD + precursor nicotinamide riboside ( Zhang et al., 2016 ).”
The quest to slow ageing through drug discovery
Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0067-7 · Cited by 468 · see citing works
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The ageing epigenome and its rejuvenation
Zhang, W., Qu, J. T., Liu, G., & Belmonte, J. C. I. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0204-5 · Cited by 472 · see citing works
Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate
Chakrabarty, R. P., & Chandel, N. S. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.011 · Cited by 490 · see citing works
“NR treatment also protects NSCs and melanocyte stem cells from senescence (Zhang et al., 2016).”
BackgroundInfluentialControl of satellite cell function in muscle regeneration and its disruption in ageing
Sousa-Victor, P., García-Prat, L., & Muñoz-Cánoves, P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00421-2 · Cited by 476 · see citing works
Nutrition, inflammation and cancer
Zitvogel, L., Pietrocola, F., & Kroemer, G. (2017) · Nature Immunology · doi:10.1038/ni.3754 · Cited by 446 · see citing works
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“NR and nicotinamide mononucleotide (NMN) are reported to extend life spans (Zhang et al., 2016) and enhance metabolism in aged mice (Mills et al., 2016).”
BackgroundInfluentialA synopsis on aging—Theories, mechanisms and future prospects
da Costa, J. P., Vitorino, R. M. P., Silva, G. M., Vogel, C., Duarte, A. C., & Rocha‐Santos, T. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.06.005 · Cited by 486 · see citing works
The role of lipid metabolism in aging, lifespan regulation, and age‐related disease
Johnson, A. A., & Stolzing, A. (2019) · Aging Cell · doi:10.1111/acel.13048 · Cited by 452 · see citing works
“Moreover, NAD+ supplementation extends lifespan in mice (Zhang et al., 2016) as well as in yeast and worms (Verdin, 2015).”
BackgroundSirtuin signaling in cellular senescence and aging
Lee, S.-H., Lee, J.-H., Lee, H., & Min, K. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.1.290 · Cited by 438 · see citing works
“(130-132), which is mediated by Sirtuin activation (130).”
BackgroundPerez Ortiz, J. M., & Swerdlow, R. H. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14585 · Cited by 426 · see citing works
NAD+ metabolism governs the proinflammatory senescence-associated secretome
Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., Aird, K. M., Iwasaki, O., Kossenkov, A. V., Schultz, D., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0287-4 · Cited by 402 · see citing works
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Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
Mitochondria as central regulators of neural stem cell fate and cognitive function
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NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells
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Self-citationZhu, X., Chen, Z., Shen, W., Huang, G., Sedivy, J. M., Wang, H., & Ju, Z. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00646-9 · Cited by 410 · see citing works
Perspectives on skeletal muscle stem cells
Relaix, F., Bencze, M., Borok, M. J., Vartanian, A. D., Gattazzo, F., Mademtzoglou, D., Perez-Diaz, S., Prola, A., Fernandez, P. C. R., Rotini, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20760-6 · Cited by 389 · see citing works
It takes two to tango: NAD(+) and sirtuins in aging/longevity control
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“elegans) and HSP60 (mammals), in worms, mammalian cells, and skeletal muscle stem cells.(25,77) Interestingly, the activation of UPR is tightly associated with mitonuclear protein imbalance, as defined by the decreased ratio between the nuclear DNA-encoded ATP5A and the mitochondrial Figure 4.”
BackgroundTarragó, M. G., Chini, C. C. S., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., Rud, M., Samani, A., Hein, K. Z., Huang, R., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.016 · Cited by 384 · see citing works
“…integrity, DNA damage repair, metabolism, aging, health span, and longevity (Cantó and Auwerx, 2012; Escande et al., 2013; Imai and Guarente, 2014; Li et. al., 2017; López-Otin et al., 2016; Schultz and Sinclair, 2016; Verdin, 2015; Yoshino et al., 2011; Yoshini et al., 2017; Zhang et al., 2016).”
BackgroundInfluentialRole of NAD+ in regulating cellular and metabolic signaling pathways
Amjad, S., Nisar, S., Bhat, A. A., Shah, A. R., Frenneaux, M. P., Fakhro, K. A., Haris, M., Reddy, R. D., Patay, Z. J., Baur, J. A., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101195 · Cited by 394 · see citing works
“Another study found that treatment with NR rejuvenate muscle stem cells and delays senescence in neural and melanocyte stem cells in aged mice, thus increasing the mouse life span [41].”
BackgroundVitale, I., Manic, G., De Maria, R., Kroemer, G., & Galluzzi, L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.006 · Cited by 361 · see citing works
“Along similar lines, administration of the NAD precursor nicotinamide riboside to mice limits senescence in multiple non-hematopoietic ASCs pools, including MuSCs, NSCs, and McSCs, as it extends organismal lifespan (Zhang et al., 2016).”
BackgroundBao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
Self-citationBiological aging processes underlying cognitive decline and neurodegenerative disease
Gonzales, M. M., Garbarino, V. R., Pollet, E., Palavicini, J. P., Kellogg, D. L., Kraig, E., & Orr, M. E. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158453 · Cited by 394 · see citing works
“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 · see citing works
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
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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 · see citing works
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 359 · see citing works
“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 · see citing works
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 · see citing works
Tissue Stem Cells: Architects of Their Niches
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“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 309 · see citing works
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 · see citing works
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 297 · see citing works
“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 288 · see citing works
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 285 · see citing works
“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 282 · see citing works
“, 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 279 · see citing works
“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 · see citing works
Rottenberg, H., & Hoek, J. B. (2017) · Aging Cell · doi:10.1111/acel.12650 · Cited by 275 · see citing works
“…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 · see citing works
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 269 · see citing works
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 254 · see citing works
NAD + Metabolism in Cardiac Health, Aging, and Disease
Abdellatif, M., Sedej, S., & Kroemer, G. (2021) · Circulation · doi:10.1161/circulationaha.121.056589 · Cited by 262 · see citing works
Zhu, Y., Liu, X., Ding, X., Wang, F., & Geng, X. (2019) · Biogerontology · doi:10.1007/s10522-018-9769-1 · Cited by 255 · see citing works
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 257 · see citing works
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“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 · see citing works
“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 256 · see citing works
“…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 238 · see citing works
“…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 · see citing works
“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 · see citing works
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 242 · see citing works
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 232 · see citing works
“…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 · see citing works
“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 · see citing works
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 228 · see citing works
“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 · see citing works
“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 · see citing works
“…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 224 · see citing works
“…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 223 · see citing works
“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 225 · see citing works
“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 229 · see citing works
Key proteins and pathways that regulate lifespan
Pan, H., & Finkel, T. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.771915 · Cited by 218 · see citing works
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 · see citing works
- 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 · 2015: 1
- 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
- Health Sciences › Medicine › Physiology › 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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