Aging is characterized by progressive loss of physiological resilience accompanied by increased susceptibility to chronic diseases. Among the interconnected hallmarks of aging, cellular senescence has emerged as a central driver of systemic inflammation through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate across multiple tissues with advancing age and secrete complex mixtures of cytokines, growth factors, and proteases that reshape tissue microenvironments and propagate inflammatory signaling locally and systemically. Increasing evidence indicates that SASP composition is highly heterogeneous and depends on cell lineage, metabolic state, and the nature of the senescence-inducing stressor. Recent discoveries further demonstrate that inflammatory signaling in senescent cells is sustained by multiple nucleic acid-sensing pathways, including both cGAS-STING-dependent DNA sensing and mitochondrial RNA-mediated activation of RIG-I-like receptors. Concurrently, senescent cells deploy immune-evasion mechanisms that limit clearance by cytotoxic lymphocytes and natural killer cells, facilitating their persistence within aging tissues. Accumulation of senescent cells therefore represents a critical mechanistic link between molecular damage and the systemic inflammatory state known as inflammaging. This review synthesizes current understanding of tissue-specific SASP programs across immune, vascular, metabolic, hepatic, and neural systems. Particular emphasis is placed on mechanisms that amplify local senescence into organism-wide inflammation, including endocrine signaling, extracellular vesicle trafficking, and sex-dependent modulation of senescence pathways.
