Metabolically Active but Dysfunctional: The Role of Senescence and SASP in Metabolic Diseases

As we age or become overweight, certain cells in our bodies stop dividing and enter a state called “senescence.” Although these senescent cells no longer grow, they remain active and release a mix of inflammatory signals (known as SASP) that can harm nearby tissues. In fat, liver, and other organs, this ongoing inflammation makes it harder for cells to use insulin properly, leading to conditions like type 2 diabetes and fatty liver disease. Researchers are exploring drugs that either remove these senescent cells or block their harmful signals, as well as lifestyle changes like exercise and healthy eating, to reduce inflammation and restore normal metabolism. By targeting the root causes of this “toxic” cell behavior, we hope to prevent or treat many age‐related metabolic problems. 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. Consequently, this leads to conditions such as insulin resistance, type 2 diabetes, and obesity-related complications. 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, non-alcoholic fatty liver disease, 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 selectively target and eliminate senescent cells, and SASP modulators to dampen the harmful secretory milieu. These interventions hold promise for restoring metabolic balance and preventing the progression of age-associated metabolic diseases. By synthesizing current research and highlighting potential clinical applications, this review provides a comprehensive framework for understanding the toxic legacy of cellular senescence and SASP in the metabolic arena, and it underscores the importance of targeting these pathways to mitigate chronic inflammation and metabolic dysfunction.