Mechanisms of Vascular Aging, A Geroscience Perspective: JACC Focus Seminar

Abstract

Age-related pathological alterations of the vasculature have a critical role in morbidity and mortality of older adults. In epidemiological studies, age is the single most important cardiovascular risk factor that dwarfs the impact of traditional risk factors. To develop novel therapeutic interventions for prevention of age-related vascular pathologies, it is crucial to understand the cellular and molecular mechanisms of vascular aging. In this review, shared molecular mechanisms of aging are considered in terms of their contribution to the pathogenesis of macrovascular and microvascular diseases associated with old age. The role of cellular senescence in development of vascular aging phenotypes is highlighted, and potential interventions to prevent senescence and to eliminate senescent cells for prevention of vascular pathologies are presented. The evidence supporting a role for interorgan communication and circulating progeronic and antigeronic factors in vascular aging is discussed.

Keywords: atherosclerosis; endothelial dysfunction; geroscience; microcirculation; senescence.

Figure 1.. Conceptual model for the causes and pathological consequences of cellular senescence in vascular aging.

The model predicts that increased presence of senescent cells in the aged vasculature and their proinflammatory secretome (SASP: senescence-associated secretory phenotype) contributes to impaired angiogenesis and microvascular rarefaction, impaired vasodilation, chronic inflammation, pathological remodeling of the extracellular matrix (ECM), barrier disruption, and/or atherogenesis, all of which contribute to age-related tissue dysfunction. It is predicted that signals that induce senescence may be transmitted between cells (vis gap junctions). Secretion of SASP factors may also induce paracrine senescence and/or impair the function of neighboring cells. The model predicts that in aging increased ROS, DNA damage and/or mitochondrial dysfunction promote cellular senescence in the vasculature (MiDAS: mitochondrial dysfunction-associated senescence). Exogenous stressors/risk factors (blue) exacerbate vascular aging by induction of senescence. Interventions for targeting senescence-related mechanisms include prevention of ROS-mediated DNA damage (by antioxidants and Nrf2 activators), mitochondria-targeted treatments and removal of senescent cells by senolytic treatment.

Figure 2.. Regulation of vascular aging by pro-geronic and anti-geronic circulating factors.

The model depicts the role of inter-organ communication in the hierarchical regulatory cascade for vascular aging. Cell-autonomous cellular and molecular aging processes in the vascular wall are modulated by circulating pro-geronic (e.g., inflammatory cytokines) and anti-geronic factors (e.g., IGF-1, mediators of caloric restriction, estrogen) derived from the central nervous system, endocrine organs, the adipose tissue and other organs. RAS: renin-angiotensin system; MMPs: matrix metalloproteinases; DAMPs: damage-associated molecular patterns; EPCs: endothelial progenitor cells; GH: growth hormone.

Central Illustration.. Multiple shared mechanisms of aging contribute to the pathogenesis of diverse age-related diseases in each organ system, including the vasculature, simultaneously.

Consequences of vascular aging lead to the genesis of micro- and macrovascular pathologies, ranging from atherosclerotic vascular diseases to Alzheimer’s disease. Conventional risk factors (purple) promote age-related cardiovascular and cerebrovascular pathologies by exacerbating one or more fundamental molecular and cellular (cell autonomous and non-cell autonomous) aging processes (roots). Clinical disciplines, biogerontology and public health research separately focus on the individual age-related diseases (leaves), the mechanisms of aging (roots) and the risk factors, respectively. Geroscience is an integrative scientific field that considers the interaction of all of these levels.