Aging of the Nitric Oxide System: Are We as Old as Our NO ?

Background Impaired generation and signaling of nitric oxide ( NO) contribute substantially to cardiovascular ( CV ) risk ( CVR ) associated with hypertension, hyperlipidemia, and diabetes mellitus. In our rapidly aging society, advanced age is, in itself, a consistent and independent CVR factor. Many processes involved in aging are modulated by NO . We therefore postulated that aging might be independently associated with impaired NO signaling. Methods and Results In a prospective cohort study of 204 subjects (mean age 63±6 at study entry), we evaluated the effects of 4 years of aging on parameters of NO generation and effect, including platelet aggregability and responsiveness to NO , and plasma concentrations of the NO synthase inhibitor, asymmetric dimethylarginine ( ADMA ). Clinical history, lipid profile, high‐sensitivity C‐reactive protein, routine biochemistry, and 25‐hydroxyvitamin D levels were obtained at study entry and after 4 years of follow‐up. Aging was associated with marked deterioration of responsiveness of platelets to NO ( P <0.0001) and increases in plasma ADMA concentrations ( P <0.0001). There was a significant correlation between changes in these parameters over time ( r =0.2; P =0.013). On multivariable analyses, the independent correlates of deterioration of responsiveness of platelets to NO were female gender (β=0.17; P =0.034) and low vitamin D concentrations (β=0.16; P =0.04), whereas increases in ADMA were associated with presence of diabetes (β=0.16; P =0.03) and impaired renal function (β=0.2; P =0.004). Conclusions Aging is associated with marked impairment of determinants of NO generation and effect, to an extent which is commensurate with adverse impact on CV outcomes. This deterioration represents a potential target for therapeutic interventions.