Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6

Abstract

The number of old people is rising worldwide, and advancing age is a major risk factor for atherosclerotic cardiovascular disease. However, the mechanisms underlying this phenomenon remain unclear. In this Review, we discuss vascular intrinsic and extrinsic mechanisms of how ageing influences the pathology of atherosclerosis. First, we focus on factors that are extrinsic to the vasculature. We discuss how ageing affects the development of myeloid cells leading to the expansion of certain myeloid cell clones and induces changes in myeloid cell functions that promote atherosclerosis via inflammation, including a potential role for IL-6. Next, we describe vascular intrinsic factors by which ageing promotes atherogenesis — in particular, the effects on mitochondrial function. Studies in mice and humans have shown that ageing leads to a decline in vascular mitochondrial function and impaired mitophagy. In mice, ageing is associated with an elevation in the levels of the inflammatory cytokine IL-6 in the aorta, which participates in a positive feedback loop with the impaired vascular mitochondrial function to accelerate atherogenesis. We speculate that vascular and myeloid cell ageing synergize, via IL-6 signalling, to accelerate atherosclerosis. Finally, we propose future avenues of clinical investigation and potential therapeutic approaches to reduce the burden of atherosclerosis in old people. In this Review, Tyrrell and Goldstein discuss vascular intrinsic and extrinsic mechanisms of how ageing promotes atherosclerosis, including changes in myeloid cells, mitochondrial dysfunction, impaired mitophagy and elevated IL-6 levels. They propose future steps for research and potential therapeutic approaches for age-related atherosclerosis. Ageing-related alterations in the bone marrow increase the phenomenon of clonal haematopoiesis of indeterminate potential (CHIP) and promote a skewing towards myeloid cell differentiation, both of which can accelerate atherosclerosis. The increased risk of atherosclerotic cardiovascular diseases associated with the presence of CHIP might be mediated by IL-6 signalling and/or inflammasome activation. Ageing is associated with a decline in mitochondrial function and an increase in IL-6 levels in the vasculature, and both effects probably accelerate atherosclerosis independently of chronic hyperlipidaemia. The role of the vasculature and myeloid cells of the immune system in promoting age-related atherosclerosis might be mediated by shared inflammatory pathways, in particular IL-6 signalling.