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Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Abstract

Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

Key points

  • High levels of pro-inflammatory markers in the blood and other tissues are often detected in older individuals and predict the risk of cardiovascular diseases, frailty, multimorbidity, and decline of physical and cognitive function.

  • In individuals with obesity, visceral fat produces pro-inflammatory and chemotactic compounds and is infiltrated by macrophages, lymphocytes, and senescent cells with a senescence-associated secretory phenotype that contributes to inflammageing.

  • Mechanisms potentially underlying inflammageing include genomic instability, cell senescence, mitochondria dysfunction, microbiota composition changes, NLRP3 inflammasome activation, primary dysregulation of immune cells, and chronic infections.

  • Clinical trials suggest that modulating inflammation prevents cardiovascular diseases, but studies to explore the effects on other chronic diseases, frailty, and disability are scarce and controversial.

  • Inflammageing can complicate the clinical features of cardiovascular disease in older individuals by causing an energetic imbalance towards catabolism and interfering with homeostatic signalling, leading to frailty.

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Fig. 1: Potential causes of inflammageing.
Fig. 2: Inflammageing is a risk factor for multiple chronic diseases.
Fig. 3: Inflammageing induces a catabolic state.

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Acknowledgements

The authors received support from the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA. The authors thank A. Cornish (National Institute on Aging) for help in editing the manuscript and for the many suggestions that greatly improved the quality of this work, in particular the microbiota section.

Review criteria

The information in this Review is based on a search of the scientific literature published since 2008 using the Medline database and the search terms: “inflammaging”, “inflammation and cardiovascular disease and aging”, “inflammation and frailty”, or “cardiovascular disease and frailty”. The authors reviewed all 3,377 relevant abstracts and selected the manuscripts for which information is reported in this Review. Of note, some articles >10 years old were also cited because their content was considered critical for the topic addressed.

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Correspondence to Luigi Ferrucci.

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Ferrucci, L., Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 15, 505–522 (2018). https://doi.org/10.1038/s41569-018-0064-2

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