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Molecular damage associated with ageing drives inflammation in cardiovascular disease

Nature Reviews Cardiology (2026)Cite this article

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Abstract

Chronic inflammation has long been recognized as a major risk factor for and a causal contributor to cardiovascular disease (CVD). However, advances in omics technologies and deepening insights into CVD pathogenesis have expanded our understanding of the underlying mechanisms. Inflammation is now seen not as an isolated cause, but as one of several biological responses to cumulative tissue damage over time. In this Review, we propose that inflammation initially functions as a resilience mechanism, acting to resolve molecular and cellular damage driven by environmental stressors and intrinsic age-related entropy. With ageing, however, this protective response can become dysregulated and maladaptive, promoting collateral pathological changes. We illustrate this theory through two examples, atherosclerosis and age-related impairment of tissue perfusion, and support these conceptual models using proteomic data from large population studies with cardiovascular outcomes. Our findings reaffirm the central role of inflammation in CVD pathophysiology, but also indicate that the upstream biological driver of inflammation is molecular damage that is either not readily prevented or repaired by inadequate resilience mechanisms. Understanding the coordination of these responses offers new opportunities for targeted prevention and treatment of CVD.

Key points

  • Ageing, endothelial dysfunction and impaired perfusion lead to molecular damage and trigger resilience mechanisms to maintain tissue integrity.

  • Persistent, unrepaired molecular damage activates inflammatory responses that, over time, contribute to atherosclerosis.

  • In ageing, impaired vascular regulation and tissue fibrosis can cause recurrent hypoperfusion, leading to energy deficits and progressive molecular damage.

  • Chronic inflammation acts as a component of stress response pathways that, ultimately, lead to the onset and progression of cardiovascular disease.

  • Biomarkers of cardiovascular disease, such as fibroblast growth factor 23 and growth/differentiation factor 15, reflect not only inflammation, but also changes in the extracellular matrix, cellular senescence and proteostasis.

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Fig. 1: Resilience mechanisms that counter ageing-related cellular insults.
Fig. 2: Coordinated stress and inflammatory signalling network during atherosclerosis.
Fig. 3: Factors and mechanisms that modulate vascular regulation of tissue perfusion.
Fig. 4: Protein biomarkers of cardiovascular disease.

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Data availability

Datasets and the custom R source code used in the proteomic meta-analysis are available on the Open Science Framework repository117.

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Acknowledgements

The authors acknowledge the support of the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.

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Authors and Affiliations

  1. Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    Allison B. Herman, Julián Candia, Stefano Donega & Luigi Ferrucci

  2. Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium

    David M. Wilson III

  3. Columbia Aging Center, Columbia University Medical Center, New York, NY, USA

    Martin Picard

Authors
  1. Allison B. Herman
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  2. Julián Candia
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  3. David M. Wilson III
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  4. Stefano Donega
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Contributions

All the authors contributed substantially to all aspects of the article.

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Correspondence to Luigi Ferrucci.

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Nature Reviews Cardiology thanks Mika Kivimaki, Esther Lutgens, Andrew Steptoe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Biomarkers

Measurable indicators of biological and pathogenic processes or therapeutic efficacy.

Cellular senescence

A state of stable cell cycle arrest caused by sublethal DNA damage and stress.

Entropy

The measure of a system’s thermal energy per unit temperature that is unavailable for doing useful work.

Immunosenescence

Innate and adaptive immune dysregulation that occurs with ageing.

Integrated stress response

The signalling pathway activated in response to various forms of stress, including nutrient and oxygen deprivation, oxidative stress and viral infections.

Macromolecular damage

The accumulation of structural and chemical alterations in DNA, proteins, lipids and polysaccharides within cells.

Perfusion

The passing of a fluid through spaces.

Proteostasis or proteostatic

Protein homeostasis or homeostatic state.

Resilience response

The capacity of an organism to adapt or recover from stress. The response involves molecular pathways that detect stress, promote survival and enable repair.

Senescence-associated secretory phenotype

The secretion of bioactive molecules associated with damage-induced cellular senescence.

Stochastic

Occurring by chance or random variables.

Thermodynamics

The relationships between heat, work, temperature and energy.

Unfolded protein response

The signalling pathway responsible for the fidelity of protein folding in the lumen of the endoplasmic reticulum.

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Herman, A.B., Candia, J., Wilson, D.M. et al. Molecular damage associated with ageing drives inflammation in cardiovascular disease. Nat Rev Cardiol (2026). https://doi.org/10.1038/s41569-026-01253-3

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