Mechanisms of Vascular Aging

Abstract

Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.

Keywords: atherosclerosis; inflammation; phenotype; proteostasis; stem cells.

Figure 1:. Conceptual model for the role of cell-autonomous and non-cell-autonomous mechanisms in vascular aging.

The model predicts that circulating pro-geronic (e.g. inflammatory cytokines, RAS/renin-angiotensin system, aldosterone) and anti-geronic factors (e.g. IGF-1, mediators of caloric restriction, estrogen) derived from the brain, the endocrine system, cells of the immune system and/or the adipose tissue orchestrate aging processes simultaneously in the endothelial and smooth muscle cells within the large vessels and microcirculation. The hierarchical regulatory cascade for vascular aging involves modulation of cell-autonomous cellular and molecular aging processes. The resulting functional dysregulation of vascular cells (i.e. impaired vasomotor, barrier, secretory and transport functions of the vasculature as well as adverse structural remodeling) promote the development of a wide range of age-related vascular pathologies.

Figure 2:. Proposed scheme for mechanisms and pathological consequences of age-related oxidative stress in vascular endothelial cells.

The model predicts that in aged endothelial cells dysfunctional mitochondria and NAD(P)H oxidases are critical sources of increased ROS production. Increased levels of O₂^.- generated by the electron transport chain are dismutated to H₂O₂, which can penetrate the mitochondrial membrane increasing cytoplasmic H₂O₂ levels. Increased oxidative stress is exacerbated by age-related impairment of Nrf2-dependent homeostatic antioxidant defense mechanisms. H₂O₂ plays important signaling roles, including activation of NF-κB, which contribute to age-associated low grade chronic vascular inflammation. Increased levels of O₂^.- generated by NAD(P)H oxidases (stimulated by elevated TNFα levels and/or by the activated local renin-angiotensin system [RAS] in the vascular wall) decrease the bioavailability of NO by forming ONOO-. Increased nitrative stress lead to PARP-1 activation, which promotes vascular inflammation and contributes to cellular energetic dysfunction by consuming NAD+ , compromising sirtuin-mediated anti-aging pathways. Impaired bioavailability of NO promotes vasodilator dysfunction and compromises endothelial viability. In addition, increased vascular oxidative stress in aging also induces MMP activation, promoting the pathogenesis of intracerebral hemorrhages, aneurysm formation and blood brain barrier disruption.

Figure 3:. Mechanisms and consequences of age-related vascular inflammation.

The model predicts that multiple pathways converge on activation of inflammatory processes in the vascular tissue. During aging increased ROS production, exacerbated by Nrf2 dysfunction, enhances NF-κB activation, which promotes inflammatory cytokine and chemokine expression, microvascular endothelial activation, leukocyte adhesion and extravasation. Increased nitrative stress promotes PARP1 activation, which contributes to impaired activity of anti-inflammatory sirtuins. Sterile inflammation in the vascular wall is also exacerbated by increased secretion of inflammatory mediators from senescent cells and danger-associated molecular patterns (DAMPs), which activate innate immune system effectors, including toll-like receptors (TLRs) and the NLRP3 inflammasome complex. The aging vasculature in humans is also affected by the high prevalence of endothelium-trophic persistent cytomegalovirus (CMV) infection. Inflammatory processes contribute to a wide range of macro- and micro-vascular pathologies affecting older people.

Figure 4:. Conceptual model for the pathogenic role of cellular senescence in vascular aging.

The model predicts that increased presence of senescent endothelial and/or smooth muscle cell (SMC) in the aged vasculature and their proinflammatory secretome (SASP: senescence-associated secretory phenotype) contributes to impaired angiogenesis and microvascular rarefaction, pathological remodeling of the ECM, barrier disruption, chronic inflammation and atherogenesis.