A bstract The study finds that NAD precursors can reverse certain aspects of aging by activating sirtuin deacylases (SIRT1-SIRT7), which also mediate the benefits of exercise and dietary restriction. Specifically, SIRT1 in endothelial cells is crucial for mediating pro-angiogenic signals from myocytes. Treating mice with the NAD+ booster nicotinamide mononucleotide (NMN) enhances blood flow and endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect that is enhanced by exercise or increased levels of hydrogen sulfide (H2S), a dietary restriction mimetic.
Tissue perfusion declines from age 40, leading to organ dysfunction and increased frailty. Although exercise delays this decline, aging reduces the levels of endothelial NAD+ and SIRT1, which are critical for vascular remodeling in response to VEGF-stimulated angiogenesis. This study shows that NMN treatment restores angiogenesis in aged mice through a SIRT1-regulated Notch signaling pathway, suggesting potential to reverse aging effects on microvasculature. NMN’s effectiveness increases with exercise or following ischemia, and does not increase capillary density beyond youthful levels, indicating a possible intrinsic capillary limit that exercise can overcome.
No changes were observed in muscle oxidative capacity with NMN treatment, challenging assumptions that NAD+ boosters primarily enhance exercise endurance by improving mitochondrial function. The risk of NMN stimulating tumor growth appears low, with extended studies showing no increased tumor burden.
The study also discusses the potential of the endothelial NAD+-H2S pathway to protect against oxidative stress and apoptosis, especially in response to exercise, and suggests testing whether enhancing this pathway can improve blood flow and treat common age-related diseases, highlighting NAD+ precursors and H2S as potential therapies for aging-related vascular issues.
