NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice

• Published in: Science (American Association for the Advancement of Science) Vol. 352; no. 6292; pp. 1436 - 1443
• Main Authors: Zhang, Hongbo, Ryu, Dongryeol, Wu, Yibo, Gariani, Karim, Wang, Xu, Luan, Peiling, D'Amico, Davide, Ropelle, Eduardo R., Lutolf, Matthias P., Aebersold, Ruedi, Schoonjans, Kristina, Menzies, Keir J., Auwerx, Johan
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 17.06.2016; The American Association for the Advancement of Science
• Subjects: Aging; Animals; Cellular; Cellular Reprogramming; Cellular Senescence - drug effects; Cellular Senescence - physiology; Disease Models, Animal; Dystrophy; Enzymes; Life cycles; Life span; Longevity - drug effects; Longevity - physiology; Mathematical models; Melanocytes - cytology; Melanocytes - drug effects; Melanocytes - physiology; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Muscles; Muscular Dystrophies - therapy; Myoblasts, Skeletal - cytology; Myoblasts, Skeletal - drug effects; Myoblasts, Skeletal - physiology; NAD - metabolism; NAD - pharmacology; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - physiology; Niacinamide - analogs & derivatives; Niacinamide - metabolism; Nicotinamide adenine dinucleotide; Oxidative Stress; Precursors; Repressor Proteins - biosynthesis; Rodents; Stem cells; Unfolded Protein Response - drug effects
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aaf2693

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD⁺) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmdmdx/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD⁺ may reprogram dysfunctional SCs and improve life span in mammals.