Mechanisms of cellular senescence-induced vascular aging: evidence of senotherapeutic strategies

Abstract

Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with advancing age being the primary, nonmodifiable risk factor. Vascular dysfunction, namely arterial stiffening and endothelial dysfunction, is the key antecedent to the development of clinical CVD with aging. Fundamental aging macro-mechanistic processes that drive vascular aging include excess oxidative stress, chronic inflammation, and declines in the vasodilatory molecule nitric oxide. An important hallmark of aging that contributes to the vascular aging processes is cellular senescence - a stress response characterized by cell cycle arrest and accompanied by the production and secretion of proinflammatory molecules (i.e., the senescence-associated secretory phenotype [SASP]). Excess senescent cells and the SASP have deleterious effects on vascular function and in states of CVD, making it a putative therapeutic target for improving vascular function and preventing or reversing CVD. This review will focus on the role of cellular senescence in age-related vascular dysfunction and CVD. We will examine established and emerging mechanisms underlying cellular senescence-induced vascular dysfunction. We will then discuss groups with impaired vascular function and high cellular senescence burden and examine strategies to reduce or remove excess senescent cells and the SASP in the groups who are likely to benefit most from these therapies. Finally, we will highlight the systemic effects of vascular senescent cell suppression on other tissues and organs, given the integrative role of the vasculature in physiology. Together, this review will underscore the imperative role of cellular senescence in vascular dysfunction and the need for a deeper understanding of the translational use of cellular senescence and SASP targeting therapies in groups with high senescent cell burden.

Keywords

Vascular dysfunction / cellular senescence / senotherapeutics / vascular aging

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