Aging Immune Systems Fuel Artery Inflammation While Failing to Fight Viruses

Aging is the strongest risk factor for cardiovascular disease (CVD) and for severe viral illness. In the US, CVD prevalence rises from about 40% in people aged 40–59 to about 80% in those 80 and older, and roughly 80% of CVD deaths occur at age 65 or older. Older adults also have worse outcomes with influenza and SARS-CoV-2, and they are more prone to reactivating herpesviruses such as CMV and varicella zoster. The authors ask whether one process, immune aging, helps explain both problems. They focus on atherosclerosis.

This narrative review draws on human and animal studies of how innate and adaptive immunity change with age. In T cells, the thymus contributes under 1% of T cells in older adults, so the naïve pool shrinks, especially CD8+ cells. End-differentiated, clonally expanded TEMRA cells accumulate, often driven by chronic CMV, and TCR diversity contracts. Aged T cells also show mitochondrial and lysosomal failure, less efficient signaling, and exhaustion. In mice, losing mitochondrial function in CD4+ T cells alone is enough to produce age-related inflammatory disease, including CVD. B cells decline in number and lose repertoire diversity and class switching. Age-associated B cells, which respond to TLR7 and TLR9 rather than to antigen, accumulate and favor autoantibody production. Aged antigen-presenting cells may convert T cell responses from protective to disease-promoting.

Macrophages are short-lived, so their aging is largely the aging of their hematopoietic stem cell precursors. Somatic mutations in DNMT3A, TET2, ASXL1, and JAK2 cause clonal hematopoiesis of indeterminate potential (CHIP). About 10% of adults 70 and older and 18% of those 90 and older carry CHIP mutations. Carriers have nearly double the coronary artery disease risk and a 4-fold higher myocardial infarction risk, and TET2 loss worsens atherosclerosis in mice. A cited meta-analysis reported a 428% higher risk of hematologic malignancy and 146% higher risk of severe COVID-19 in CHIP carriers. Chronic CMV infection is linked to a 3.7-year shorter life expectancy after age 65 and a 2-fold increase in CVD death.

The central proposal, stated in the abstract, is bidirectional. Mounting an antiviral response may cause off-target bystander activation and exhaust immune cells, which would feed vascular inflammation. Conversely, atherosclerosis may epigenetically modify hematopoietic precursors and metabolically condition immune cells. That would produce a dysfunctional innate system that accelerates plaque inflammation and weakens host defense. The implication is that immune aging could be a shared therapeutic target, and that preventing or controlling viral infection may help protect the vasculature.

Caveats: this is a narrative review, so the bidirectional model is a hypothesis built largely on associations and mouse data rather than on direct human interventional evidence. The provided text was cut off partway through the macrophage section, so the sections on mechanisms of bystander activation, epigenetic reprogramming, and therapeutic implications are summarized only from the abstract.