Aging is a primary risk factor for the development of obesity and diabetes mellitus and is accompanied by impaired brown adipocyte formation. Deprivation of thermogenic capacity may contribute to an obesity-prone phenotype of aged individuals. To determine whether the age-related decline of brown adipogenesis is due to a cell-autonomous dysfunction of brown adipogenic cells, we isolated stem cells from brown adipose tissue of mice aged 2.5 or 25 months for characterization. While lipid accumulation capacity was unchanged, expression of brown adipocyte markers, such as Uncoupling protein-1 (Ucp1), were significantly reduced in aged cells after differentiation, suggesting that a cell-intrinsic defect is responsible for impaired brown adipogenesis during aging. We subsequently generated immortalized single stem cell clones from both age groups, which displayed a similar age-related defect. Transcriptomes generated from a total of 126 clones show that brown fat-derived stem cells from old mice more closely resemble stem cells isolated from white adipose tissue. Among the genetic pathways significantly altered in aged stem cells are changes to extracellular matrix function as well as cell-intrinsic pathways. Importantly, aged stem cells are characterized by an age-dependent induction of cellular senescence with increased expression of cell cycle inhibitors p16, p21 and p53. To further test the link between senescence and reduced brown adipogenic potential, we isolated brown adipogenic stem cells from a mouse model with conditional inactivation of p53. Confirming our hypothesis, p53-deficient stem cells displayed a marked increase in Ucp1-expression upon differentiation when compared to wild type stem cells. These data taken together suggest that aging of brown adipogenic stem cells may contribute to loss of brown adipocytes and that inhibition of cell cycle blockage may restore their ability to undergo full brown adipogenic differentiation.
A. Graja: None. S. Gohlke: None. L. Saraiva: None. T.J. Schulz: None.
German Center for Diabetes Research; German Research Foundation