Cardiometabolic Aging Driven by Multi-Organ Crosstalk: Mechanisms and Therapeutic Strategies

Abstract

Cardiac senescence is not an isolated organ decline but a systemic consequence driven by pathological crosstalk between the heart and its peripheral metabolic organs. In this review, we discard the traditional organ–centric perspective and construct an integrated framework around multi-organ crosstalk axes, including the epicardial adipose tissue–heart axis, the skeletal muscle–heart axis, the gut–heart axis, and the kidney–heart axis. For each axis, we dissect the local molecular mediators—inflammatory cytokines, lipotoxic metabolites, microbiota-derived compounds such as trimethylamine N-oxide (TMAO), renin-angiotensin-aldosterone system (RAAS) effectors, and extracellular vesicle (EV) cargoes—and illustrate how they converge onto common pathways of oxidative stress, impaired autophagy, and cellular senescence. Importantly, we emphasize that these signals do not operate in isolation; they act synergistically through the circulation, converting local organ dysfunction into systemic cardiac aging via convergence onto shared senescence pathways. By redefining aging as a potentially modifiable multi-organ crosstalk, we propose emerging nodal points—senolytics, myokine mimetics, gut microbiota modulation, RAAS/sodium–glucose cotransporter 2 (SGLT2) inhibitors, and integrated lifestyle strategies—to block pathological crosstalk and delay cardiovascular aging. This framework shifts the research focus from isolated organs to systemic multi-organ crosstalk, providing new insights into cardiometabolic aging.