Aging and vascular endothelial function in humans

Abstract

Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging.

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

“…Endothelial dysfunction is the major antecedent to atherosclerosis, a predictor of clinical CVD risk, and is linked to many common disorders of aging including cognitive impairments, Alzheimer's disease, motor dysfunction, insulin resistance, and sarcopenia (Heitzer et al ., 2001; Gokce et al ., 2002; Lakatta & Levy, 2003; Widlansky et al ., 2003; Seals et al ., 2011, 2014). We have previously demonstrated that arterial SIRT1 activity is reduced with aging and contributes to the age‐related impairment in endothelial function (Donato et al ., 2011; Gano et al ., 2014).…”

“…NMN supplementation completely restored EDD by restoring NO‐mediated dilation. The improvement in EDD with NMN treatment in old mice was not due to an increase in vascular smooth muscle sensitivity to NO because NMN did not influence dilation in response to administration of a NO donor (sodium nitroprusside), that is, a dilation that is not induced by endothelial NO production (Seals et al ., 2011). …”

“…A common mechanism that contributes to both vascular endothelial dysfunction and large elastic artery stiffness with aging is excessive superoxide‐associated vascular oxidative stress (Seals et al ., 2011; Fleenor et al ., 2012a; Bachschmid et al ., 2013). Increased vascular production of superoxide occurs with aging and reduces the bioavailability of the vasoprotective and vasodilatory molecule nitric oxide (NO), while also causing alterations in major structural proteins (collagen and elastin) in the large elastic arteries (i.e., the aorta and carotid arteries) (Deanfield et al ., 2007; Fleenor et al ., 2010; Seals et al ., 2014).…”

“…Increased vascular production of superoxide occurs with aging and reduces the bioavailability of the vasoprotective and vasodilatory molecule nitric oxide (NO), while also causing alterations in major structural proteins (collagen and elastin) in the large elastic arteries (i.e., the aorta and carotid arteries) (Deanfield et al ., 2007; Fleenor et al ., 2010; Seals et al ., 2014). These changes contribute directly to age‐related endothelial dysfunction and increased arterial stiffness (Lakatta & Levy, 2003; Seals et al ., 2011). As such, treatments that reduce the excessive superoxide production in aging arteries hold the potential for improving age‐associated vascular dysfunction.…”

K Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

“…Dysregulated redox signaling and increased ROS production with aging lead to endothelial dysfunction, thereby contributing to the pathogenesis of cardiovascular diseases, such as coronary artery diseases, hypertension, and atherosclerosis, in elderly patients (Ungvari et al ., 2010). An increase in ROS generation reduces NO bioavailability through several mechanisms including a direct interaction between NO and ROS, resulting in vascular dysfunction (Donato et al ., 2007; Ungvari et al ., 2008; Seals et al ., 2011). However, little is known about the mechanism by which ECs preserve their function of relaxing vascular smooth muscle during aging‐related oxidative stress.…”