As populations age worldwide, understanding the biology of aging and its contribution to disease becomes increasingly important. Cellular senescence, a hallmark of aging, plays a pivotal role in shaping inter-organ communication and systemic health. Once viewed primarily as a local mechanism to prevent the proliferation of damaged cells, senescence is now recognized as a dynamic, multifaceted process that influences physiology across the lifespan. Through senescence-associated secretory phenotype (SASP) proteins and other signaling modalities, including metabolites, extracellular vesicles, immune cells, and neural circuits, senescent cells contribute to both homeostatic regulation and the propagation of chronic inflammation, fibrosis, and age-related disease. These effects are often context-dependent, and senescence in one organ can influence distant tissues, driving asynchronous aging and disease vulnerability. This review examines the mechanisms by which senescent cells facilitate inter-organ communication, including emerging roles for blood-borne factors, immune cell dynamics, and neuroendocrine signals. We highlight illustrative examples of organ crosstalk and emphasize the potential translational relevance of these pathways. We also examine therapeutic strategies aimed at modulating senescence, including senolytics, senomorphics, and interventions targeting specific SASP components, as well as the potential of lifestyle modifications to mitigate biological aging. Understanding senescence and the associated inter-organ communication offers new insights into aging biology and opens promising avenues for addressing age-related diseases in an integrated, organ-spanning framework.
