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

Abstract

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 (SIRT1-7) 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+ precursor 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.

NAD+repletion rescues female fertility during reproductive ageing

“…While we measured NAD + levels in the ovary in this study, we do not exclude the possibility that NMN exerts benefits especially to folliculogenesis through direct interactions with tissues other than the ovary, as we delivered NMN through systemic dosing. NMN may exert primary effects directly in the ovary, or it may instead be possible that systemic improvements in vascular function (56), metabolic homeostasis (13, 16), mitochondrial function (10) and stem cell function (57) or signalling in the brain could lead to secondary improvements in ovarian function. These findings should especially be viewed in light of the well-studied role of NAD + raising molecules in maintaining late-life health (14) and the biology of ageing.…”

Nicotinamide Deficiency in Primary Open-Angle Glaucoma

“…Mitochondrial dysfunctions and decreased NAD content are hallmarks of aging in most organs 13,14 and many experimental studies, essentially performed on mouse models, have revealed that strategies based on NAD repletion effectively reverse age-related phenotypes and disorders 15,16 , such as those affecting the skeletal muscles 17 , the brain 18 , and the endothelium 19 . Recent studies on the DBA/2J mouse model of glaucoma, have further confirmed a dose-dependent protective effect of NAD repletion on the optic nerve, reaching a protection level of 93% at the highest nicotinamide dose tested (2000 mg/kg/day), despite a continuously elevated IOP 6,7,20 .…”

Endothelial mTOR maintains hematopoiesis during aging

“…Aging is associated with increased risk of negative outcomes/treatment failures because elderly patients respond poorly to myeloablative strategies that are necessary for the successful transplantation of hematopoietic stem and progenitor cells (HSPCs) and also develop prolonged cytopenias following myelosuppressive therapies that are often used to treat hematopoietic malignancies and other cancers (Balducci, 2003). One of the most significant changes observed during the aging process is a decline in the overall function of endothelial cells (ECs), including the EC niche of the hematopoietic system (Das et al, 2018; El Assar et al, 2012; Le Couteur and Lakatta, 2010). An increasing body of evidence demonstrating functional interactions between the HSPC and its niche suggests that both local and systemic factors regulate HSPC function (Bowers et al, 2018; Crane et al, 2017; Decker et al, 2018; Lazzari and Butler, 2018; Pinho and Frenette, 2019).…”