Immunometabolism in the Aging Heart

Abstract

Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.

Keywords: cardiac aging; immunometabolism; inflammaging; oxidative phosphorylation.

Figure 1. Landscape of the aging heart.

Various facets of cardiac aging include structural, functional, inflammaging, apoptosis/necrosis, epigenetic modification, and metabolic changes. CAVD indicates calcified aortic valve disease; FFA, free fatty acid; LV, left ventricular; OXPHOS, oxidative phosphorylation; and ROS, reactive oxygen species.

Figure 2. Structural, metabolic, and functional impairments in the aging heart.

Mitochondrial dysfunction manifests collectively as impairments in mitophagy, mitochondrial dynamics, and bioenergetics (ATP production) concomitantly with increased ROS levels, contributing to oxidative damage. Thus, the redox imbalance causes alterations in substrate utilization, including decreased fatty acid oxidation, increased glucose metabolism, and insulin resistance leading to metabolic inflexibility, lipid accumulation, and inflammation. Increased mitochondrial ROS also causes cardiac lipid accumulation^109,110 leading to cardiomyopathy in the aging heart. ROS indicates reactive oxygen species.