Aging, Adipose Tissue and Cellular Senescence - James Kirkland
Author: J.L. Kirkland - Mayo Clinic
Adipose tissue is at the nexus of processes involved in healthspan and metabolic dysfunction. Progression of age-related fat tissue dysfunction follows different trajectories across different fat depots, with fat becoming redistributed from subcutaneous to intra-peritoneal depots and ultimately ectopic sites, such as liver, muscle, and bone marrow. This is associated with insulin resistance, hypertension, atherosclerosis, strokes, myocardial infarction, cancer, and cognitive dysfunction. The preadipocytes from which new fat cells develop throughout the lifespan switch into a pro-inflammatory, tissue-remodeling state in old age, instead of differentiating into fat cells. In cellular senescence, proliferation becomes arrested and cells acquire a pro-inflammatory senescent secretory phenotype (SASP), with release of chemokines, cytokines, and extracellular matrix proteases. We found that chronological aging, obesity, progeroid states, and serial subculturing result in accumulation of senescent preadipocytes with impaired adipogenesis and a pro-inflammatory phenotype. Senescent cells accumulate to a greater extent in subcutaneous than intraperitoneal fat. TNF alpha and IL-6, which increase in fat tissue with aging and obesity, can induce preadipocyte cellular senescence and pro-inflammatory cytokine and chemokine secretion, potentially spreading senescence from cell to cell. We found that growth hormone/IGF-1 pathway mutations that extend lifespan and delay onset of age-related dysfunction in mice also delay fat redistribution, preadipocyte dysfunction, and cellular senescence, particularly in more IGF-1-responsive subcutaneous fat. We propose a model in which metabolic stress or repeated preadipocyte replication with aging cause cellular senescence in a fat depot-dependent manner, with inflammatory cytokine and chemokine generation, immune response activation, and failure to sequester lipotoxic fatty acids. This model is consistent with recent concepts about cellular senescence as being a stress-responsive, adaptive phenotype that entails metabolic and secretory readjustments. Senescent cells in adipose tissue could have profound clinical consequences because of their pro-inflammatory secretory phenotype, the large amount of adipose tissue in humans, and its central metabolic role.