Is Adipose Tissue the Fountain of Youth? The Impact of Adipose Stem Cell Aging on Metabolic Homeostasis, Longevity, and Cell-Based Therapies

Aging is driven by four interlinked processes: (1) low-grade sterile inflammation; (2) macromolecular and organelle dysfunction, including DNA damage, telomere erosion, and mitochondrial dysfunction; (3) stem cell dysfunction; and (4) an accumulation of senescent cells in tissues. Adipose tissue is not immune to the effects of time, and all four of these processes contribute to a decline of adipose tissue function with advanced age. This decline is associated with an increase in metabolic disorders. Conversely, optimally functioning adipose tissue generates signals that promote longevity. As tissue-resident progenitor cells that actively participate in adipose tissue homeostasis and dysregulation, adipose stem cells (ASCs) have emerged as a key feature in the relationship between age and adipose tissue function. This review will give a mechanistic overview of the myriad ways in which age affects ASC function and, conversely, how ASC function contribute to healthspan and lifespan. A central mediator in this relationship is the degree of resilience of ASCs to maintain stemness into advanced age and the consequent preservation of adipose tissue function, in particular subcutaneous fat. The last sections of this review will discuss therapeutic options that target senescent ASCs to extend healthspan and lifespan, as well as ASC-based therapies that can be used to treat age-related pathologies, and collectively, these therapeutic applications may transform the way we age.