Fat tissue is at the nexus of mechanisms impacting maximum lifespan, timing of age-related disease onset, and metabolic consequences of manipulating the somatotrophic axis. Clinical morbidity, altered secretory profiles, insulin resistance, fat redistribution among depots, and ectopic fat deposition with aging are strikingly delayed by reducing somatotrophic drive. New fat cells develop from their progenitors, preadipocytes, throughout life. Preadipocyte differentiation is impaired and inflammatory cytokine generation, stress responses, and preadipocyte senescence increase with aging. IGF-1 promotes preadipocyte utilization by enhancing replication and differentiation. We propose that lifelong preadipocyte utilization and metabolic stress contribute to age-related fat tissue dysfunction, particularly in subcutaneous fat. Visceral preadipocytes are resistant to IGF-1, potentially contributing to delayed age-related accumulation of visceral fat in animal models with low IGF-1. Our hypothesis is that decreasing somatotrophic drive will reduce subcutaneous preadipocyte utilization with aging, delaying loss and dysfunction, while preventing visceral preadipocyte development into fat, delaying redistribution. We predict interventions that decrease IGF-1 exposure will delay declines in adipogenesis, increases in stress responses, preadipocyte inflammatory cytokine generation, and senescent cell accumulation. Using the unique animal models in this Project, we will dissect contributions of IGF-1 vs. GH and local fat tissue vs. systemic IGF-1.
In Aim 1, we will test if decreasing IGF-1 will: 1) reduce subcutaneous preadipocyte utilization with aging, preserving adipogenic capacity and delaying stress-responsive anti-adipogenic factor expression, and 2) impair visceral preadipocyte development into fat.
Aim 2 is to test if reducing IGF-1 exposure will delay age-related development of a metabolically unfavorable preadipocyte secretory profile with increased inflammatory cytokine, chemokine, and matrix remodeling protein production.
Aim 3 is to test if generation of senescent preadipocytes, which we found accumulate with aging, particularly in subcutaneous fat, and which may reflect progenitor overutilization and metabolic stress, is delayed by reducing life-long IGF-1 exposure. These studies will address critical knowledge gaps in aging and fat tissue function, pave the way for further analysis, and suggest potential mechanism-based interventions.
Fat tissue is at the nexus of mechanisms impacting maximum lifespan and timing of age-related disease onset. Age-related disease, insulin resistance, and fat redistribution are delayed by reducing growth hormone or insulin-like growth factor-1. Our hypothesis is that decreasing these hormones delays loss and dysfunction of skin fat with aging due to reduced fat cell progenitor dysfunction, while preventing development of progenitors into fat within the abdomen, delaying redistribution. These studies will address critical knowledge gaps in aging and fat tissue function and suggest potential mechanism-based treatments.
|Dominick, Graham; Bowman, Jacqueline; Li, Xinna et al. (2017) mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell 16:52-60|
|Saccon, Tatiana D; Moreira, Fabiana; Cruz, Luis A et al. (2017) Ovarian aging and the activation of the primordial follicle reserve in the long-lived Ames dwarf and the short-lived bGH transgenic mice. Mol Cell Endocrinol 455:23-32|
|Hascup, Kevin N; Lynn, Mary K; Fitzgerald, Patrick J et al. (2017) Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging. J Gerontol A Biol Sci Med Sci 72:329-337|
|Schneider, Augusto; Matkovich, Scot J; Saccon, Tatiana et al. (2017) Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice. Mol Cell Endocrinol 439:328-336|
|Fang, Yimin; McFadden, Samuel; Darcy, Justin et al. (2017) Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice. Geroscience 39:347-356|
|Bartke, Andrzej; Darcy, Justin (2017) GH and ageing: Pitfalls and new insights. Best Pract Res Clin Endocrinol Metab 31:113-125|
|Xu, Ming; Tchkonia, Tamar; Kirkland, James L (2016) Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol Res 111:152-154|
|Hascup, Erin R; Wang, Feiya; Kopchick, John J et al. (2016) Inflammatory and Glutamatergic Homeostasis Are Involved in Successful Aging. J Gerontol A Biol Sci Med Sci 71:281-9|
|Bartke, A; Sun, L; Fang, Y et al. (2016) Growth hormone actions during development influence adult phenotype and longevity. Exp Gerontol 86:22-27|
|Matzkin, María Eugenia; Miquet, Johanna Gabriela; Fang, Yimin et al. (2016) Alterations in oxidative, inflammatory and apoptotic events in short-lived and long-lived mice testes. Aging (Albany NY) 8:95-110|
Showing the most recent 10 out of 138 publications