Optimizing endothelial nitric oxide activity may slow endothelial aging

The capacity of vascular endothelium to generate bioactive nitric oxide (NO) decreases with advancing age, even in healthy subjects with a relatively benign risk factor profile; this phenomenon may reflect decreased expression of NO synthase, as well as increased production of superoxide, and evidently contributes importantly to the increased vascular risk associated with aging. Studies with cultured endothelial cells suggest that the rate of endothelial aging is determined primarily by the rate of cell turnover and the associated progressive shortening of telomeres; endothelial cells transfected with the catalytic subunit of telomerase--which preserves a youthful telomere length--do not show a reduction in NO synthase expression after numerous doublings, in contrast to the marked reduction observed in control cells. Also consistent with this view is the fact that, following balloon denudation of arteries, the regenerated endothelium makes less NO. In the vasculature of adults, the rate of endothelial cell mitosis is evidently a reflection of the rate of endothelial cell apoptosis. Numerous cell culture studies demonstrate that physiological levels of NO protect endothelial cells from apoptosis induced by a wide range of noxious stimuli--including vascular risk factors such as oxidized LDL, angiotensin II, and hyperglycemia. In the human vasculature, endothelial cells with disproportionately short telomeres are found capping atheromatous lesions and in atheroma-prone areas where blood flow is turbulent; these findings evidently reflect increased endothelial cell turnover in regions where NO bioactivity is relatively weak. It can be deduced that lifelong adherence to an "endotheliophilic lifestyle" that optimizes vascular NO production, while minimizing that of superoxide, will literally slow the rate of aging of vascular endothelium, such that, at any given advanced age, the optimal functional capacity of the vascular endothelium will be superior to that of age-matched controls. These considerations underline the desirability of actively promoting vascular health in younger and middle-aged individuals in whom risk for vascular events may still be quite low. The impact of lifelong caloric restriction on endothelial aging requires further study, preferably in primates.