Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies

Abstract

Ageing constitutes the biggest risk factor for poor health and adversely affects the integrity and function of all the cells, tissues, and organs in the human body. Vascular ageing, characterised by vascular stiffness, endothelial dysfunction, increased oxidative stress, chronic low-grade inflammation, and early-stage atherosclerosis, may trigger or exacerbate the development of age-related vascular diseases, which each year contribute to more than 3.8 million deaths in Europe alone and necessitate a better understanding of the mechanisms involved. To this end, a large number of recent preclinical and clinical studies have focused on the exponential accumulation of senescent cells in the vascular system and paid particular attention to the specific roles of senescence-associated secretory phenotype, proteostasis dysfunction, age-mediated modulation of certain microRNA (miRNAs), and the contribution of other major vascular risk factors, notably diabetes, hypertension, or smoking, to vascular ageing in the elderly. The data generated paved the way for the development of various senotherapeutic interventions, ranging from the application of synthetic or natural senolytics and senomorphics to attempt to modify lifestyle, control diet, and restrict calorie intake. However, specific guidelines, considering the severity and characteristics of vascular ageing, need to be established before widespread use of these agents. This review briefly discusses the molecular and cellular mechanisms of vascular ageing and summarises the efficacy of widely studied senotherapeutics in the context of vascular ageing.

Keywords: ageing; natural senotherapeutics; senolytics; senomorphics; vasculature.

Figure 1

Mechanisms of vascular ageing. The presence of young and functional endothelial cells, vascular smooth muscle cells (VSMCs), and endothelial progenitor cells (EPCs) ensures that angiogenesis, vascular tone, coagulation, oxidative stress, vascular repair, and permeability are closely monitored in young vasculature at all times. To this end, young endothelial cells express high levels of tight junction proteins and low levels of adhesion molecules and secrete various vasoactive compounds with anti-inflammatory and vascular relaxant capacity, including prostaglandin (PGI2), acetylcholine (Ach), endothelium-derived hyperpolarizing factor (EDHF), and notably the most prominent endogenous vasodilator, nitric oxide (NO), through endothelial-type NO synthase (eNOS) activity. Young VSMCs, on the other hand, secrete elastin and collagen in a stable ratio to help maintain normal vascular tenacity, pliability, and contractility. In contrast, decreases in NO bioavailability, tight junction protein expression, endothelial cell proliferation, and elastin-to-collagen ratio, as well as concurrent increases in reactive oxygen species (ROS) production and adhesion molecule expression in aged vessels, lead to impaired angiogenesis and vasodilation, oxidative stress, inflammation, thrombogenesis, and vascular stiffening. Diminished availability or function of senescent EPCs and the secretion of senescence-associated secretory phenotype (SASP) comprising matrix metalloproteinases (MMPs), extracellular matrix components, growth factors, cytokines, etc. also contribute to the dysfunction of aged vessels. VCAM: vascular cell adhesion molecule 1; ICAM: intracellular adhesion molecule 1; RNS: reactive nitrogen species; PAI-1: plasminogen activator inhibitor 1; IL: interleukin; MCP1: monocyte chemoattractant protein 1; TNF: tumour necrosis factor; TGF: transforming growth factor; VEGF: vascular endothelial growth factor; HGF: hepatocyte growth factor; DDR: DNA damage response; SAHF: senescence-associated heterochromatin foci.

Figure 2

Triggers and general signalling pathways of cellular senescence. Telomere attrition, telomeric DNA damage, shelterin protein downregulation, and damages accumulated on non-telomeric DNA from other stimuli collectively trigger the DNA damage response (DDR) and p16/pRb pathway, resulting in either temporary cell cycle arrest for the DNA repair process or permanent cell cycle arrest, known as cellular senescence. DDR involves a series of processes. While the MRN (MRE11-RAD50-NBS1) complex, accompanied by activation of ataxia telangiectasia mutated (ATM)/Cell Cycle Checkpoint kinase-2 (CHK2), is implicated in DNA double-strand breaks, the 9-1-1 (RAD9-RAD1-HUS1) complex, leading to activation of ATM and rad3-related (ATR)/CHK1, is implicated in DNA single-strand breaks. Once activated, checkpoint kinases CHK1 and CHK2 trigger cell cycle arrest by inhibiting cyclin-dependent kinase 2 (CDK2) activation through the p53/p21 and CDC25 pathways. The accumulation of telomeric and non-telomeric DNA damage induces the expression of p16INK4A. The P16 protein inhibits CDK 4/6, thereby suppressing Rb phosphorylation and the release of E2F translation factor, which is crucial for cell cycle progression. RNF: ring finger containing nuclear factor; 53BP1: P53-binding protein 1; BRCA1: breast cancer type 1; RPA: replication protein A; ATRIP: ATR-interacting protein; TopBP1: DNA Topoisomerase II Binding protein 1; CDC: cell division cycle; TIN: telomeric repeat binding factor 1/2-interacting nuclear factor 2; TRF: telomeric repeat binding factor; RAP1: repressor/activator protein 1; POT1: protection of telomeres 1; TPP1: POT1-interacting protein 1.

Figure 3

MiRNAs modulate vascular ageing. MiRNAs regulate the process of senescence by modulating gene expression. Some miRNAs promote vascular ageing (pink rectangles), while others antagonise it (blue rectangles) through their specific effects on mRNAs of SRC kinase signalling inhibitor 1 (SRCIN1), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), transcription factor nuclear factor-kappa B (NF-κB), p53, and p21, which regulate inflammation, oxidative stress, vascular tone, and vascular cell senescence. The accumulation of senescent cells in aged arteries leads to the acquisition of the senescence-associated secretory phenotype (SASP).

Figure 4

Types of currently known senolytics and senomorphics and their mechanisms of action. Several signal transduction pathways and senescence-associated secretory phenotypes are involved in the actions of senolytics and senomorphics. Currently known senolytics are categorised into seven groups: tyrosine kinase inhibitors, heat shock protein 90 (HSP 90) inhibitors, B-cell lymphoma-2 (BCL-2) family inhibitors, mouse double minute 2 (MDM2) inhibitors, Forkhead Box O4 (FOXO4) inhibitors, glutaminase inhibitors, and histone deacetylase (HDAC) inhibitors. Currently known senomorphics are categorised into nine groups: telomerase activators, sirtuin (SIRT) activators, mammalian target of rapamycin (mTOR) inhibitors, antioxidants, nuclear factor-kappa B (NF-κB) inhibitors, ataxia telangiectasia mutated (ATM) inhibitors, Janus kinase (JAK) inhibitors, signal transducer and activator of transcription proteins (STAT) inhibitors, and p38 mitogen-activated protein kinase (MAPK) inhibitors. A series of downstream signalling pathways, enzymes, and environmental changes such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), senescence-associated secretory phenotype (SASP), endothelial nitric oxide synthase (eNOS), ATM and RAD3-related protein (ATR), and oxidative stress accompanied by excessive release of reactive oxygen species (ROS) play pivotal roles in the activity of senotherapeutics.