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.

Fig. 1. Ageing-related processes that promote atherogenesis: IL-6 as a potential shared pathway.

Ageing promotes the development and progression of atherosclerosis through different mechanisms, which might be related to age-induced elevations in circulating and intracellular IL-6 levels. During ageing, IL-6 signalling in bone marrow adipocytes increases. This increased IL-6 signalling might skew haematopoietic stem cells towards myeloid cell differentiation and increase the risk of mutations in genes encoding transcriptional regulators, such as TET2, that can result in the positive selection and expansion of clones of haematopoietic cells without clear development of malignancy or other known clonal disorder, a phenomenon known as clonal haematopoiesis of indeterminate potential (CHIP). Ageing can also have direct effects on haematopoietic stem cells (HSCs) that lead to CHIP. Clones of myeloid cells with a TET2 mutation show an increased production of IL-6 and IL-1β, which can contribute to accelerated atherosclerosis. Ageing can also have pro-atherogenic effects directly on the vasculature. Ageing is associated with an increase in the levels of IL-6, possibly mediated by increased production by vascular smooth muscle cells (VSMCs), and mitochondrial genomic instability and with a decline in mitochondrial function in the vasculature. The reduced mitochondrial function alters mitophagy and increases IL-6 levels, creating a positive feedback loop that accelerates atherogenesis. Vascular ageing also leads to the production of chemoattractants that increase myeloid cell recruitment into the arterial wall, further promoting atherosclerosis. Impaired mitochondrial function combined with reduced mitophagy might lead to increased levels of reactive oxygen species (ROS).

Fig. 2. IL-6 as a potential therapeutic target in age-related atherosclerosis.

IL-6 is upregulated in multiple tissues that have important roles in the increase in atherogenesis with ageing. Therefore, blockade of IL-6 might be an effective therapeutic strategy to reduce atherosclerosis development and progression during ageing. Blocking IL-6 might interfere with the increased IL-6 signalling in bone marrow adipocytes that occurs with ageing (which promotes a skewing towards myeloid cell differentiation), thereby reducing the risk of clonal haematopoiesis of indeterminate potential (CHIP). IL-6 blockade might also reduce the inflammatory potential of clones of myeloid cells associated with CHIP. IL-6 blockade might reduce atherosclerosis burden, although direct comparisons of efficacy and safety with IL-1β inhibition requires future investigation. IL-6 blockade might increase mitochondrial function and reduce the expression of Parkin, a mitochondrial stress protein, which might also contribute to reducing atherogenesis during ageing. HSC, haematopoietic stem cell; VSMC, vascular smooth muscle cell.