Reversing age-associated arterial dysfunction: insight from preclinical models

Abstract

Cardiovascular diseases (CVDs) remain the leading causes of death in the United States, and advancing age is a primary risk factor. Impaired endothelium-dependent dilation and increased stiffening of the arteries with aging are independent predictors of CVD. Increased tissue and systemic oxidative stress and inflammation underlie this age-associated arterial dysfunction. Calorie restriction (CR) is the most powerful intervention known to increase life span and improve age-related phenotypes, including arterial dysfunction. However, the translatability of long-term CR to clinical populations is limited, stimulating interest in the pursuit of pharmacological CR mimetics to reproduce the beneficial effects of CR. The energy-sensing pathways, mammalian target of rapamycin, AMPK, and sirtuin-1 have all been implicated in the beneficial effects of CR on longevity and/or physiological function and, as such, have emerged as potential targets for therapeutic intervention as CR mimetics. Although manipulation of each of these pathways has CR-like benefits on arterial function, the magnitude and/or mechanisms can be disparate from that of CR. Nevertheless, targeting these pathways in older individuals may provide some benefits against arterial dysfunction and CVD. The goal of this review is to provide a brief discussion of the mechanisms and pathways underlying age-associated dysfunction in large arteries, explain how these are impacted by CR, and to present the available evidence, suggesting that targets for energy-sensing pathways may act as vascular CR mimetics.

Keywords: AMPK; SIRT-1; aging; arterial stiffness; calorie restriction; endothelial function; inflammation; mTOR; oxidative stress; vasodilation.

Fig. 1.

Effects of aging and caloric restriction (CR) on arterial function. Age-associated increases in oxidative stress and inflammation lead to endothelial dysfunction and large artery stiffening that is prevented by lifelong CR. With aging, oxidative stress and inflammation are the consequence of increases in oxidant production, NF-κB activation, and proinflammatory cytokine/adhesion molecule expression in arteries that contribute to reduced vasodilation and nitric oxide bioavailability, as well as to alterations in the structural components of the artery, i.e., collagen and elastin, favoring increased arterial stiffness. Life-long CR prevents these age-associated arterial changes.

Fig. 2.

Targeting energy-sensing pathways as vascular caloric restriction mimetics. Although pharmacological inhibition of mammalian target of rapamycin (mTOR) or activation of AMPK or sirtuin-1 (SIRT-1) can lead to improvements in endothelial function and/or arterial stiffness in old mice, the mechanisms underlying these beneficial effects can be disparate from that of caloric restriction. Superscripts indicate the isoform/subunit of NADPH oxidase that was examined. Arrows indicate activation, while lines ending in a circle indicate inhibition. *Denotes a tendency for decrease.