Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease

Abstract

The ongoing worldwide increase in life expectancy portends a rising prevalence of age-related cardiovascular (CV) diseases in the coming decades that demands a deeper understanding of their molecular mechanisms. Inflammation has recently emerged as an important contributor for CV disease development. Indeed, a state of chronic sterile low-grade inflammation characterizes older organisms (also known as inflamm-ageing) and participates pivotally in the development of frailty, disability, and most chronic degenerative diseases including age-related CV and cerebrovascular afflictions. Due to chronic activation of inflammasomes and to reduced endogenous anti-inflammatory mechanisms, inflamm-ageing contributes to the activation of leucocytes, endothelial, and vascular smooth muscle cells, thus accelerating vascular ageing and atherosclerosis. Furthermore, inflamm-ageing promotes the development of catastrophic athero-thrombotic complications by enhancing platelet reactivity and predisposing to plaque rupture and erosion. Thus, inflamm-ageing and its contributors or molecular mediators might furnish targets for novel therapeutic strategies that could promote healthy ageing and conserve resources for health care systems worldwide. Here, we discuss recent findings in the pathophysiology of inflamm-ageing, the impact of these processes on the development of age-related CV diseases, results from clinical trials targeting its components and the potential implementation of these advances into daily clinical practice.

Keywords: Cardiovascular disease; Endothelial dysfunction; Inflamm-ageing; Inflammation; Vascular ageing.

Figure 1

The deep interactions between ageing, inflamm-ageing, and age-related conditions/disease. With ageing, several cellular and molecular mechanisms contribute to the chronic inappropriate activation of the inflammatory system (orange arrows). The resulting complex interaction between genetic predisposition and chronic exposure to a broad spectrum of exogenous and endogenous danger stimuli causes the continuous activation of a limited range of promiscuous sensors triggering different cellular stress-response pathways (upper half of the box). The resulting synthesis and release of different inflammatory mediators (lower half of the box) can drive a progressive increase of the inflammatory burden and lead to inflamm-ageing. Inflamm-ageing is the common pathophysiological mechanisms of frailty and several age-related diseases (included in the lowest circle), which in turn increase the rate of ageing and thus feed a vicious circle (red arrows).

Figure 2

Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. With ageing several endogenous and exogenous changes (included in the upper boxes), foster a less healthy oral and gut microbiota (left and right boxes, respectively). These alterations impair the homoeostatic symbiosis between the intestinal flora and the host. Total bacterial load increases, while microbiota diversity falls allowing pathobionts to establish a condition of chronic local inflammation known as dysbiosis (central box). Together with local consequences, dysbiosis also causes systemic effects (lower box) including increased circulating bacteria, danger-associated molecular pathways as well as trimethylamine N-oxide and other microbiota-derived metabolites eventually causing the systemic activation of inflammatory pathways, promoting age-related cardiovascular and cerebrovascular disease (bottom of the figure).