Metabolically Active but Dysfunctional: The Impact of Senescent Cells and SASP

The accumulation of senescent cells in metabolic tissues, including adipose tissue, liver, pancreas, and skeletal muscle - along with the senescence-associated secretory phenotype (SASP) has emerged as a significant factor in developing chronic inflammation and metabolic dysfunction. Senescent cells, which have stopped dividing but remain metabolically active, secrete a complex mix of pro-inflammatory cytokines, chemokines, proteases, and growth factors. This secretory profile disrupts tissue homeostasis and creates a persistent inflammatory environment, impairing metabolic processes. These disruptions contribute to insulin resistance, type 2 diabetes, and obesity-related complications. Importantly, the relationship between senescence and metabolic dysfunction is bidirectional - metabolic stress can itself drive senescence, while persistent SASP amplifies tissue dysfunction in a context-dependent manner. This review delves into the molecular mechanisms that initiate cellular senescence within metabolic tissues and examines how the ensuing SASP fosters an inflammatory microenvironment, linking senescence to disorders such as insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD), and type 2 diabetes. Additionally, we explore the interplay between environmental stressors, metabolic stress, and the onset of cellular aging, emphasizing how these factors collectively exacerbate the deleterious impact of SASP. Emerging therapeutic strategies are critically evaluated, including senolytics, which preferentially target senescent cells, and SASP modulators to dampen the harmful secretory milieu. These interventions have shown promise in preclinical and early clinical studies for improving metabolic parameters and may help slow the progression of age-associated metabolic disease, though evidence in humans remains limited. This review examines the molecular mechanisms linking senescence and SASP to metabolic disease and evaluates emerging senolytic and senomorphic strategies.