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

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.