Cellular senescence is a hallmark of aging and a contributing factor to many age-related morbidity and decline. A key characteristic of senescent cells is a pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP). When tracked in circulation, SASP factors associate with age-related clinical traits and diseases, raising the captivating possibility that the senescence burden, and concomitant susceptibility to age-related morbidity, can be noninvasively assessed in clinical settings. This review consolidates human-focused evidence identifying these biomarkers of senescence in circulation, and emerging drug and lifestyle-based senotherapeutic interventions that modulate senescence burden and associated clinical parameters. Clinical parameters associated with the circulating senescence burden generally fall into four interrelated health domains: neurodegeneration, pulmonary disease, cardiometabolic disease, and musculoskeletal disorders. For each domain, the biological basis for the negative impact of senescence is explored in clinical and preclinical models, revealing that the accumulation of senescence often suppresses stemness throughout the body, suggesting that senescence plays a causal role in age-related decline and highlighting potential novel therapeutic avenues. Importantly, some circulating biomarkers of senescence, such as GDF15 and Activin A, demonstrate cross-study clinical relevance and are implicated in morbidities across multiple health domains. Collectively, these insights provide a framework for understanding the role that senescence plays in aging and the development of diagnostic biomarker panels that could better inform future clinical care.
