You're only as old as your arteries: translational strategies for preserving vascular endothelial function with aging

Abstract

Endothelial dysfunction develops with age and increases the risk of age-associated vascular disorders. Nitric oxide insufficiency, oxidative stress, and chronic low-grade inflammation, induced by upregulation of adverse cellular signaling processes and imbalances in stress resistance pathways, mediate endothelial dysfunction with aging. Healthy lifestyle behaviors preserve endothelial function with aging by inhibiting these mechanisms, and novel nutraceutical compounds that favorably modulate these pathways hold promise as a complementary approach for preserving endothelial health.

FIGURE 1.

Vascular endothelial dysfunction and CVD risk with aging Age-related vascular endothelial dysfunction is characterized by reductions in anti-coagulative, anti-proliferative, anti-inflammatory, and vasodilatory processes, all of which increase CVD risk. Nitric oxide (NO)-mediated endothelium-dependent dilation (EDD) in response to blood flow or pharmacological stimuli such as acetylcholine (ACh) is an important physiological indicator of endothelial function. EDD is impaired in older rodents and humans as a result of reduced NO bioavailability.

FIGURE 2.

Mechanisms of age-related endothelial dysfunction A: the primary mechanisms of endothelial dysfunction with aging are reduced NO bioavailability and increased oxidative stress/inflammation characterized by increased superoxide (O₂⁻) and inflammatory mediators. B: various adverse cellular aging processes contribute to the development of age-associated oxidative stress and inflammation. C: cellular homeostasis and stress resistance systems protect endothelial function with aging by preventing adverse events and directly reducing oxidative stress/inflammation. Age-related impairments in these protective processes contribute to oxidative stress-/inflammation-mediated NO insufficiency and endothelial dysfunction with aging.

FIGURE 3.

Example of translational assessment of endothelial function Age-related differences in endothelial function can be examined in cell and animal models, and in human subjects. A: acetylcholine (ACh)-mediated NO production can be assessed in isolated and/or cultured endothelial cells (EC) using NO-specific fluorescent probes and microscopy. B: endothelium-dependent dilation (EDD) can be examined in arteries isolated from young and old rodents (or humans) by measuring increases in arterial diameter to cumulative addition of ACh. C: differences in EDD with aging can also be assessed in human subjects by monitoring changes in forearm blood flow in response to brachial artery infusions of ACh and/or other pharmacological agents. Another example would be flow/shear shear-stress stimulation of endothelial cells in culture, flow-mediated dilation (FMD) of arteries studied ex vivo, and in vivo assessments of FMD in humans (e.g., brachial artery FMD) (see text).

FIGURE 4.

Translational strategies for preventing and treating age-related endothelial dysfunction A: aerobic exercise and energy restriction are powerful lifestyle strategies for preserving endothelial function with aging by reducing adverse aging processes and enhancing homeostasis/stress resistance systems. B: poor dietary/lifestyle choices exert a negative influence on endothelial function by stimulating unfavorable signaling. C: healthy diets may exert some of their beneficial effects on endothelial function by enhancing the activity of homeostasis/stress resistance systems. D: certain pharmacological agents and/or nutraceuticals may preserve endothelial function with aging by directly suppressing adverse processes, and other novel compounds (E) may improve function by stimulating upstream protective pathways. Evidence for efficacy of these strategies comes from translational studies conducted in both preclinical models and human subjects.