Topic: Targeting Metabolic Dysfunction to Promote Cardiovascular Healthspan

Although advances in medicine have extended life expectancy, healthspan, the years lived free of chronic disease and disability, has not kept pace. Cardiovascular disease (CVD) is the leading contributor to age-related morbidity and mortality. Several hallmarks of aging converge on metabolism: deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, and chronic low-grade inflammation. Insulin resistance, altered substrate utilization, and ectopic lipid accumulation can amplify these processes in the aging heart and vasculature and accelerate cardiovascular disease progression.

This Special Topic of “Targeting Metabolic Dysfunction to Promote Cardiovascular Healthspan,” will bring together original research and critical reviews examining how metabolic alterations contribute to cardiovascular aging and whether these mechanisms can be targeted to extend cardiovascular healthspan. We define cardiovascular healthspan by measurable outcomes, including preserved diastolic function, exercise capacity, arterial compliance, and endothelial function, as well as reduced incidence of heart failure and frailty.

The Special Topic will welcome original research and review articles addressing the following interconnected themes:

1. Metabolic Signaling, Mitochondrial Function, and Cellular Homeostasis

This theme will explore how nutrient sensing and metabolic regulation influence cardiovascular aging, including the roles of AMPK, mTOR, NAD⁺ metabolism, and sirtuins. Topics will include mitochondrial dysfunction and quality control, altered cardiac substrate utilization (fatty acid, glucose, ketone, and branched-chain amino acid oxidation), metabolic inflexibility, lipid accumulation, and the consequences of impaired cellular energy homeostasis in the aging heart and vasculature.

2. Immunometabolism, Inflammation, and Inter-Organ Communication

This theme will examine how metabolic reprogramming influences immune and inflammatory responses in cardiovascular aging. Areas of interest include macrophage immunometabolism, metabolic inflammation, epicardial and perivascular adipose tissue signaling, and the gut–heart axis. Emphasis will be placed on mechanistic studies linking metabolic changes to vascular dysfunction, myocardial remodeling, HFpEF, and cardiovascular disease progression.

3. Cellular Senescence and Mechanisms of Cardiovascular Aging

This theme will address the relationships between metabolic dysfunction, cellular senescence, and age-associated cardiovascular decline. Topics may include senescence-associated secretory phenotypes, mitochondrial stress and inflammatory signaling (including cytosolic mitochondrial DNA sensing through cGAS–STING), and emerging senolytic or senomorphic strategies. Contributions should critically evaluate the strength of the evidence and the translational potential of interventions targeting senescence in cardiovascular disease.

4. Therapeutic Strategies to Preserve Cardiovascular Healthspan

This theme will focus on therapeutic approaches that target metabolic dysfunction and its consequences in the aging cardiovascular system. Areas of interest include established cardiometabolic therapies, such as SGLT2 inhibitors and GLP-1 receptor agonists, as well as emerging interventions targeting mitochondrial function, metabolic signaling, inflammation, and cellular senescence, including NAD⁺ precursors, rapamycin and rapalogs, mitochondria-targeted agents, and lifestyle interventions such as caloric restriction and exercise. Studies addressing mechanisms of action, therapeutic targets, clinical translation, and opportunities for preserving cardiovascular function with aging are particularly encouraged.

We particularly welcome contributions that establish mechanistic links between metabolic alterations and cardiovascular phenotypes in aged animal models or older human cohorts (studies in young models should justify that choice), critically distinguish findings from experimental models from evidence in humans, account for sex as a biological variable, and identify opportunities for translating fundamental discoveries into clinically meaningful interventions. We invite Original Research Articles, Review, Perspectives and Commentaries are also welcome.