The Endothelium Abridges Insulin Resistance to Premature Aging

A lthough there are different mechanistic theories for aging, 1 endothelial dysfunction (ED) is a rather neglected player in the aging process.A maladaptive insulin/IGF-1-like signaling (IIS) has a remarkable importance in proaging mechanisms, and insulin has direct effects on ED. 2 Therefore, we assume that the endothelium plays a key role in mediating the aging process in the presence of maladaptive insulin signaling.This latter condition leads to insulin resistance and affects several aspects involved in premature aging, such as body composition, mitochondrial activity, and endocrine function.The present review highlights key mediators and mechanisms responsible for the link between endothelial dysfunction, insulin resistance and aging.In particular, we discuss the sirtuin-1 system, the p66Shc pathway, telomeres, and their interrelationships with endothelial damage and repair. Endothelial Dysfunction: Consequence and Predictor of Insulin Resistance and Metabolic DiseasesED is considered a common ground of type 2 diabetes (T2DM) and cardiovascular disease (CVD). 3The ability of insulin to recruit nutritive capillaries that receive little or no blood flow in fasting conditions is a component of insulin-mediated glucose uptake.Therefore, in the capillary and arteriolar beds, which are in intimate contact with metabolically active insulin-sensitive tissues, ED leads to insulin resistance and T2DM. 4 The relationship between ED and glucose tolerance is experimentally and clinically solid.][9] Stehouwer and colleagues proposed that insulin resistance syndrome (or metabolic syndrome) components can be viewed as diverse consequences of ED. 10 More specifically, these authors hypothesized that approximately 40% of insulin-mediated glucose uptake by skeletal muscle can be attributed to capillary recruitment; according to this hypothesis, microvascular dysfunction not only precedes and predicts the development of T2DM but also constitutes one of the links between insulin resistance and hypertension in metabolic syndrome. 11Consistent with this view, elevated levels of endothelial activation biomarkers such as ICAM-1 and other adhesion molecules predict incident diabetes. 12,13Based on these data, it is reasonable that ED predicts insulin resistance and diabetes that, in turn, anticipate and accelerate the aging process.Aging is also typically associated with impaired glucose tolerance, mainly because of a decline in insulin action. 14,15In contrast, high insulin sensitivity is linked to longevity, and parental longevity is inversely correlated with the risk of diabetes. 16,17A remarkable body of data in support of this mutual relationship is also available and detailed in other reviews. 18From these works, it emerges that (1) insulin resistance can lead to ED, (2) ED can contribute to insulin resistance, and (3) both insulin resistance and ED accelerate aging.