A NAD+/PARP1/SIRT1 axis in Aging.
Rejuvenation Res. 2017 May 24;:
Authors: Mendelsohn AR, Larrick J
NAD+ levels decline with age in diverse animals from C. elegans to mice. Raising NAD+ levels by dietary supplementation with NAD+ precursors NR or NMN improves mitochondrial function and muscle, neural and melanocyte stem cell function in mice as well as increasing murine lifespan. Decreased NAD+ levels with age reduces SIRT1 function and reduces the mitochondrial unfolded protein response, which can be overcome by NR supplementation. Decreased NAD+ levels cause NAD+-binding protein DCB1 to form a complex with PARP1, inhibiting PARP catalytic activity. Old mice have increased amounts of DCB1-PARP1 complexes. lower PARP activity, increased DNA damage and reduced non-homologous end joining (NHEJ) and homologous recombination (HR) repair. DCB1-PARP1 complexes in old mice can be broken by increasing NAD+ levels through treatment with NMN, reducing DNA damage and restoring PARP activity to youthful levels. The mechanism of declining NAD+ levels and its fundamental importance to aging are yet to be elucidated. There is a correlation of PARP activity with mammalian lifespan, that suggests that a NAD+/SIRT1/PARP1 may be more significant than the modest effects on lifespan observed for NR supplementation on old mice. A NAD+/PARP1/SIRT1 axis may link NAD+ levels and DNA damage with the apparent epigenomic DNA methylation "clocks" that have been described.
PMID: 28537485 [PubMed - as supplied by publisher]Read more...