Inflammaging and Its Contribution to the Development of Atherosclerosis

Inflammaging describes the raised, unresolved inflammation characteristic of old tissues, a dysfunction of the immune system that in turn produces failures of tissue maintenance and function. It arises from issues such as the inflammatory signaling of senescent cells and the reaction of the innate immune system to DNA debris from age-damaged cells. That senescent cells can be cleared, and that clearance will soon enough become a part of everyday medicine, means that the burden of inflammaging for future generations will be diminished. As a result, many age-related diseases will be reduced in incidence and severity, including atherosclerosis.

An increasing number of reports show that aging is a driving factor of atherosclerosis. Aging is closely related to endothelial dysfunction and arterial stiffness, which are considered to be early events leading to CVD. The aging process involves promotion of a series of risk factors (i.e., oxidative stress, endothelial dysfunction, and pro-inflammatory cytokines), leading to endothelial dysfunction and vascular system damage. In addition, cellular aging induces the release of microvesicles, further contributing to the development and calcification of atherosclerotic plaques. Therefore, the incidence of atherosclerosis increases with chronological age, and accelerated aging is the main risk factor for the development of atherosclerotic plaques. Furthermore, atherosclerotic plaques represent a key index of cellular aging, which is characterized by reduced cell proliferation, increased DNA damage, and telomere shortening. In summary, a growing body of evidence indicates that atherosclerosis is promoted by cellular aging.

Atherosclerosis is closely related to inflamm-aging, along with oxidative stress, endothelial dysfunction, and inflammation. Inflamm-aging is defined as a chronic inflammatory process during aging and mainly characterized by chronic progressive strengthening of the pro-inflammatory response. In other words, inflamm-aging promotes the body's pro-inflammatory status with advancing aging, which is closely related to many aging diseases. A series of studies have shown that aging can promote atherosclerosis by damaging the connection between mitochondrial function and the intravascular inflammatory pathway. For example, chronic inflammation is the main cause of age-related atherosclerosis, possibly exerting its effect through the IL-6 signaling pathway. Furthermore, inflammatory factors released by senescent cells result in a senescence-associated secretory phenotype and even atherosclerosis. Selective targeting and elimination of these senescent cells has been shown to slow the growth of atherosclerotic lesions by reducing the release of inflammatory and adhesion factors.

However, the potential mechanism by which inflamm-aging induces atherosclerosis needs to be studied more thoroughly, and there is currently a lack of powerful prediction models. Here, an improved inflamm-aging prediction model was constructed by integrating aging, inflammation, and disease markers with the help of machine learning methods; then, inflamm-aging scores were calculated. In addition, the causal relationship between aging and disease was identified using Mendelian randomization. A series of risk factors were also identified by causal analysis, sensitivity analysis, and network analysis. Our results revealed an accelerated inflamm-aging pattern in atherosclerosis and suggested a causal relationship between inflamm-aging and atherosclerosis. Mechanisms involving inflammation, nutritional balance, vascular homeostasis, and oxidative stress were found to be driving factors of atherosclerosis in the context of inflamm-aging.


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