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

Nature Reviews Cardiology volume 18, pages 58–68 (2021)Cite this article

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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.

Key points

  • 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.

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Fig. 1: Ageing-related processes that promote atherogenesis: IL-6 as a potential shared pathway.
Fig. 2: IL-6 as a potential therapeutic target in age-related atherosclerosis.

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Acknowledgements

D.J.T. is supported by NIH award F32-HL1400728, and D.R.G. is supported by NIH awards R01-HL127687, R01-AI138347 and K07-AG050096.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Daniel J. Tyrrell & Daniel R. Goldstein

  2. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA

    Daniel J. Tyrrell & Daniel R. Goldstein

  3. Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA

    Daniel R. Goldstein

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Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

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Correspondence to Daniel R. Goldstein.

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Nature Reviews Cardiology thanks C. Leeuwenburgh, H. Oliveira, A. Tedgui and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Clonal haematopoiesis of indeterminate potential

(CHIP). Clonal expansion of haematopoietic stem cells that carry certain somatic mutations that confer a cell proliferation advantage.

Mitophagy

Type of macroautophagy for the removal of damaged or dysfunctional mitochondria.

Senescence

A state of permanent replicative arrest in normally proliferative cells.

Senescence-associated secretory phenotype

(SASP). Secretion of cytokines, chemokines, growth factors and proteases by senescent cells.

Variant allele frequency

(VAF). The proportion of sequences that match a gene mutation divided by the overall coverage at that gene locus.

Efferocytosis

Phagocytosis of apoptotic cells by phagocytic cells.

Mitochondrial damage-associated molecular patterns

(mtDAMPs). Pro-inflammatory components of mitochondria that are released as a result of mitochondrial dysfunction or damage.

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Tyrrell, D.J., Goldstein, D.R. Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6. Nat Rev Cardiol 18, 58–68 (2021). https://doi.org/10.1038/s41569-020-0431-7

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