Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2017 Jan 10

PMID 28068222

Citations 370

Authors

Kathryn F Mills

Shohei Yoshida

Liana R Stein

Alessia Grozio

Shunsuke Kubota

Yo Sasaki

Philip Redpath

Marie E Migaud

Rajendra S Apte

Koji Uchida

Jun Yoshino

Shin-Ichiro Imai

Affiliations

Soon will be listed here.

Abstract

NAD availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD intermediate, has been shown to enhance NAD biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD intermediates as effective anti-aging interventions in humans.

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References

Brown K, Maqsood S, Huang J, Pan Y, Harkcom W, Li W . Activation of SIRT3 by the NAD⁺ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab. 2014; 20(6):1059-68. PMC: 4940130. DOI: 10.1016/j.cmet.2014.11.003. View

Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L . Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging. 2013; 34(6):1581-8. PMC: 3632303. DOI: 10.1016/j.neurobiolaging.2012.12.005. View

Imai S . The NAD World: a new systemic regulatory network for metabolism and aging--Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys. 2009; 53(2):65-74. PMC: 2734380. DOI: 10.1007/s12013-008-9041-4. View

Zoukhri D . Effect of inflammation on lacrimal gland function. Exp Eye Res. 2005; 82(5):885-98. PMC: 1361268. DOI: 10.1016/j.exer.2005.10.018. View

Anderson R, Bitterman K, Wood J, Medvedik O, Cohen H, Lin S . Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J Biol Chem. 2002; 277(21):18881-90. DOI: 10.1074/jbc.M111773200. View

Long A, Owens K, Schlappal A, Kristian T, Fishman P, Schuh R . Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol. 2015; 15:19. PMC: 4358858. DOI: 10.1186/s12883-015-0272-x. View

Belenky P, Racette F, Bogan K, McClure J, Smith J, Brenner C . Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007; 129(3):473-84. DOI: 10.1016/j.cell.2007.03.024. View

Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin G . Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012; 7(7):e42357. PMC: 3407129. DOI: 10.1371/journal.pone.0042357. View

Yoshino J, Mills K, Yoon M, Imai S . Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011; 14(4):528-36. PMC: 3204926. DOI: 10.1016/j.cmet.2011.08.014. View

10.

Revollo J, Korner A, Mills K, Satoh A, Wang T, Garten A . Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007; 6(5):363-75. PMC: 2098698. DOI: 10.1016/j.cmet.2007.09.003. View

11.

Houtkooper R, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G . Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013; 497(7450):451-7. PMC: 3663447. DOI: 10.1038/nature12188. View

12.

Canto C, Houtkooper R, Pirinen E, Youn D, Oosterveer M, Cen Y . The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012; 15(6):838-47. PMC: 3616313. DOI: 10.1016/j.cmet.2012.04.022. View

13.

Mouchiroud L, Houtkooper R, Moullan N, Katsyuba E, Ryu D, Canto C . The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell. 2013; 154(2):430-41. PMC: 3753670. DOI: 10.1016/j.cell.2013.06.016. View

14.

Yoon M, Yoshida M, Johnson S, Takikawa A, Usui I, Tobe K . SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. Cell Metab. 2015; 21(5):706-17. PMC: 4426056. DOI: 10.1016/j.cmet.2015.04.002. View

15.

Imai S . Dissecting systemic control of metabolism and aging in the NAD World: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis. FEBS Lett. 2011; 585(11):1657-62. PMC: 3104082. DOI: 10.1016/j.febslet.2011.04.060. View

16.

Lee H, Hong Y, Jun W, Yang S . Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a Rodent Model of Type 2 Diabetes. J Med Food. 2015; 18(11):1207-13. DOI: 10.1089/jmf.2015.3439. View

17.

Hubbard B, Sinclair D . Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014; 35(3):146-54. PMC: 3970218. DOI: 10.1016/j.tips.2013.12.004. View

18.

de Picciotto N, Gano L, Johnson L, Martens C, Sindler A, Mills K . Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016; 15(3):522-30. PMC: 4854911. DOI: 10.1111/acel.12461. View

19.

Aredo B, Zhang K, Chen X, Wang C, Li T, Ufret-Vincenty R . Differences in the distribution, phenotype and gene expression of subretinal microglia/macrophages in C57BL/6N (Crb1 rd8/rd8) versus C57BL6/J (Crb1 wt/wt) mice. J Neuroinflammation. 2015; 12:6. PMC: 4305240. DOI: 10.1186/s12974-014-0221-4. View

20.

Satoh A, Brace C, Rensing N, Cliften P, Wozniak D, Herzog E . Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 2013; 18(3):416-30. PMC: 3794712. DOI: 10.1016/j.cmet.2013.07.013. View