Fat tissue, the largest organ in humans, plays a crucial role in longevity and age-related metabolic dysfunction. Its distribution and function change significantly throughout life, with obesity accelerating the onset of age-related diseases and fat ablation or certain mutations affecting fat increasing lifespan. Fat cells turnover throughout life, and preadipocytes, which are closely related to macrophages, dysdifferentiate into a pro-inflammatory, tissue-remodeling, senescent-like state in old age. Other mesenchymal progenitors also acquire an adipocyte-like, pro-inflammatory phenotype with aging. We propose a model where cellular stress and overutilization of preadipocytes with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, and activation of innate and adaptive immune responses. These pro-inflammatory processes may amplify each other and have systemic consequences. This model aligns with recent concepts of cellular senescence as a stress-responsive, adaptive phenotype that can occur in both dividing and nondividing cells. Senescent, pro-inflammatory cells in fat could have profound clinical implications due to the large size and central metabolic role of fat tissue.Fat tissue, the largest organ in humans, plays a crucial role in longevity and age-related metabolic dysfunction. Its distribution and function change significantly throughout life, with obesity accelerating the onset of age-related diseases and fat ablation or certain mutations affecting fat increasing lifespan. Fat cells turnover throughout life, and preadipocytes, which are closely related to macrophages, dysdifferentiate into a pro-inflammatory, tissue-remodeling, senescent-like state in old age. Other mesenchymal progenitors also acquire an adipocyte-like, pro-inflammatory phenotype with aging. We propose a model where cellular stress and overutilization of preadipocytes with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, and activation of innate and adaptive immune responses. These pro-inflammatory processes may amplify each other and have systemic consequences. This model aligns with recent concepts of cellular senescence as a stress-responsive, adaptive phenotype that can occur in both dividing and nondividing cells. Senescent, pro-inflammatory cells in fat could have profound clinical implications due to the large size and central metabolic role of fat tissue.