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

TLDR

Adult stem cells are essential for tissue maintenance and regeneration but become senescent with age. The study demonstrates that the level of oxidized NAD+ and its influence on mitochondrial activity serve as a pivotal switch to modulate muscle stem cell senescence. Treatment of aged mice with the NAD+ precursor nicotinamide riboside activated the mitochondrial unfolded protein response and increased prohibitin synthesis, thereby rejuvenating muscle stem cells. NR prevented MuSC senescence in the mdx muscular dystrophy model, delayed senescence of neural and melanocyte stem cells, increased mouse lifespan, and suggests that conserving NAD+ can reprogram dysfunctional stem cells and extend lifespan.

Abstract

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-Dmd(mdx)/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.