Supplementing aging mice with the NAD+ precursor nicotinamide riboside (NR) has been shown to protect against muscle degeneration, enhance muscle function, and preserve muscle, neural, and melanocyte stem cells, contributing to extended lifespan. This treatment triggers mitochondrial responses and increases the production of proteins that rejuvenate muscle stem cells and delay senescence in various stem cell types, suggesting that maintaining cellular NAD+ levels can help reprogram aging cells and extend life in mammals.
In adults, stem cell (SC) function is critical for maintaining tissue homeostasis, particularly in tissues that need constant regeneration or can become quiescent until damage or disease triggers a need for regeneration. Aging leads to SC senescence, reducing tissue homeostasis and regenerative capacity. For skeletal muscle, this involves muscle stem cells (MuSCs) that, in young individuals, readily activate to repair damage but exhibit reduced function and number with age due to factors like altered extrinsic signals and intrinsic senescence pathways. Notably, cyclin-dependent kinase inhibitor 2A (CDKN2A or p16INK4A) expression increases in older MuSCs, significantly contributing to senescence.
Further, mitochondrial dysfunction emerges as a key indicator of MuSC senescence, influenced by the down-regulation of mitochondrial genes, particularly those involved in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). This decline in mitochondrial function is consistent across various studies and is marked by reduced mitochondrial gene expression and lower mitochondrial and cellular energy production in aged MuSCs. Despite some variations in related pathways like CDKN2A or MAPK14, there is an overarching increase in early senescence markers, including those regulated by cyclin-dependent kinase inhibitor 1 (CDKN1A). This comprehensive analysis underscores mitochondrial dysfunction as a pivotal factor in the aging-induced decline of MuSC function and the broader loss of tissue regenerative capacity.
