Advancing age promotes cardiovascular disease (CVD), the leading cause of death in the United States and many developed nations. Two major age-related arterial phenotypes, large elastic artery stiffening and endothelial dysfunction, are independent predictors of future CVD diagnosis and likely are responsible for the development of CVD in older adults. Not limited to traditional CVD, these age-related changes in the vasculature also contribute to other age-related diseases that influence mammalian healthspan and potential lifespan. This review explores mechanisms that influence age-related large elastic artery stiffening and endothelial dysfunction at the tissue level via inflammation and oxidative stress, and at the cellular level via Klotho and energy sensing pathways (AMPK, Sirtuins, mTOR). We also discuss how long-term calorie restriction, a healthspan and lifespan extending intervention, can prevent many of these age-related vascular phenotypes through the prevention of deleterious alterations in these mechanisms. Lastly, we discuss emerging novel mechanisms of vascular aging, including senescence and genomic instability within cells of the vasculature. As the population of older adults steadily expands, elucidating the cellular and molecular mechanisms of vascular dysfunction with age is critical to better direct appropriate and measured strategies that utilize pharmacological and lifestyle interventions to prevent against CVD risk within this population.
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