Impairment of an Endothelial NAD⁺-H₂S Signaling Network Is a Reversible Cause of Vascular Aging

Highlights

• Reduced blood flow with age is due to loss of endothelial NAD⁺-SIRT1 activity

• NAD⁺ and H₂S control muscle angiogenesis and increase endurance in old mice

• The NAD precursor NMN mimics and augments exercise by inhibiting NICD-Notch

• Neovascularization is as important as mitochondria for rejuvenating muscle

Summary

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1–SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD⁺ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H₂S), a DR mimetic and regulator of endothelial NAD⁺ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.