DESCRIPTION (provided by applicant): New fat cells develop from preadipocytes throughout life. Fat tissue function and distribution change dramatically with aging. After middle age, fat is redistributed from subcutaneous to metabolically deleterious visceral depots and lipid accumulates in muscle, marrow, and liver instead of fat depots, with increased predisposition to diabetes and atherosclerosis. Our hypothesis is that fat cell progenitor overutilization with aging generates senescent preadipocytes with a secretory phenotype that impairs adipogenesis. This occurs at different rates in different depots, is accelerated by repeated replication and metabolic stress, and occurs prematurely in obesity. We found preadipocyte differentiation is impaired with aging and inflammatory cytokine generation and susceptibility to metabolic stress increase. We demonstrated preadipocytes from different fat depots are inherently distinct. We found senescent preadipocytes accumulate with aging and after repeated replication in vitro and in vivo (in obesity) in a depot-dependent manner. These findings open an entirely new way of looking at fat tissue redistribution and dysfunction with aging. Aim 1 is to test the hypothesis that dysfunctional preadipocytes accumulate with aging and dissect responsible mechanisms, and test fat depot-dependence in humans. We will test cellular senescence mediators (DNA damage-associated foci/ 3-H2AX/ p53/p21 components; senescence associated foci/p16/Rb components) and distinguish between processes that potentially mediate senescent preadipocyte generation. We will perturb them by varying preadipocyte replicative history, with cytokines that increase with aging, and by eliciting metabolic stress. Aim 2 is to define the aging preadipocyte secretory phenotype, the impact of replicative history and depot origin upon it, and its effect on chemotaxis. Late passage human skin fibroblasts acquire an aberrant, pro-inflammatory secretory phenotype. We will define the secretory profile of preadipocytes from old vs. younger subjects, later vs. early passage preadipocytes in vitro, and in obesity. We will test if this aberrant secretory phenotype induces dysfunction in neighboring cells, magnifying impact. Aim 3 is to test the hypothesis that dysfunctional preadipocytes contribute to impaired adipogenesis with aging, define responsible mechanisms and, based on these, test molecular interventions. C/EBP1 and PPAR3 are essential for adipogenesis. C/EBP1 and PPAR3 expression are impaired with aging. We found exposure to preadipocytes from old animals, increased TNF1 release by preadipocytes with aging, and stress-responsive, anti-adipogenic regulators (CUGBP, CHOP) all impede adipogenesis in old rats. Co-culture and conditioned medium from preadipocytes of old subjects will be used to perturb these processes. We will define anti-adipogenic mechanisms in human aging and their relation to preadipocyte senescence. We will test if interventions that restore adipogenesis in preadipocytes from old rats do so in humans. These studies represent an entirely new way of thinking about mechanisms causing the fat redistribution and metabolic dysfunction common in old age. PUBLIC HEALTH RELEVANCE: Fat tissue function changes dramatically with aging. After middle age, fat is redistributed from regions under the skin to metabolically deleterious depots in the abdomen. Fat accumulates outside of fat tissue in muscle, marrow, the liver, and other sites. This change increases the predisposition to diabetes and atherosclerosis. The mounting evidence placing fat tissue function at the nexus of processes impacting maximum lifespan and timing of age-related disease onset in animal models has led us to ask if: 1) fat cell progenitor overutilization with aging results in dysfunctional cells that produce proteins that impede function of neighboring cells and 2) if this may underlie fat dysfunction in old age. This represents an entirely new way of thinking about mechanisms causing the fat redistribution, diabetes, and their complications so common in old age.
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