PROJECT 3 focuses on the idea that diminished exposure to GH and/or IGF-1 signals in early life leads both to lifespan extension and to a spectrum of cellular abnormalities that we have documented in fibroblasts from long-lived Snell dwarf mutant mice, including sensitivity to inducers of ER stress, resistance to a broad range of lethal agents, and resistance to inhibition of the plasma membrane redox system (PMRS). Eight varieties of mice will be compared in the project, including: (a) Snell dwarf mice;(b) LID mice that lack IGF-1 expression in liver;(c) IGF-1 midi mice, with abnormally low levels of IGF-1 and high GH levels;(d) IGF-1 R het mice, with abnormally low response to IGF-1, (e) GHRKO mice, which lack GH receptors in all tissues; and (f) three new varieties of tissue-specific GHR mutants, which lack GH receptors, respectively, in liver, adipose tissue, or skeletal muscle.
Aim 1 will test skin-derived fibroblast cell lines from these mice, evaluating resistance to lethal oxidative and non-oxidative stresses (peroxide, paraquat, cadmium, and UV), to which Snell dwarf cells are resistant, and inducers of the unfolded protein response (tunicamycin, thapsigargin), to which Snell cells are sensitive. PMRS reactivity will be tested using non-lethal doses of rotenone. Fibroblasts from week-old mice will be tested to see if stress patterns require post-natal maturation, and from middle-aged mice to see if the stress-resistance profile lasts into midlife. Pre- adipocytes will be tested to see if they, too, show stress resistance when taken from long-lived donor stocks.
Aim 2, using biochemical approaches, will test in vitro fibrobtasts, and tissues from intact and UV-exposed mice, for four pathways involved in stress resistance: Erk-family MAP kinase signals, activation of mTOR, repair and apoptotic pathways of the unfolded protein response, and mRNA levels for heat shock proteins and HSFs.
Aim 3 will measure lifespan in the three tissue-specific GHRKO models, and will measure three age-sensitive traits (immune status, cataracts, and activity) as indices of delayed aging. Project 3 will provide resources to other parts of the program: tissues from terminal necropsies to Core B, fibroblast lysates for gene expression analyses to Project 1, and adipose tissue depots to Project 4. Project 3 will provide tests of the hypothesis that endocrine manipulations that modulate stress resistance lead to extended longevity, and in collaboration with the program as a whole will shed new light on the connections linking cellular stress resistance to genetic and pharmacologic modulators of endocrine and adipose tissues.
This project is intended to suggest clues about the biology of aging and late-life illness, provide models for investigation of the aging process, and confirm or refute ideas about proposed anti-aging drugs. Positive findings could, potentially, suggest new strategies in preventive medicine.
| Fang, Yimin; Hill, Cristal M; Darcy, Justin et al. (2018) Effects of rapamycin on growth hormone receptor knockout mice. Proc Natl Acad Sci U S A 115:E1495-E1503 |
| Householder, Lara A; Comisford, Ross; Duran-Ortiz, Silvana et al. (2018) Increased fibrosis: A novel means by which GH influences white adipose tissue function. Growth Horm IGF Res 39:45-53 |
| Nelson, Caroline N; List, Edward O; Ieremia, Makerita et al. (2018) Growth hormone activated STAT5 is required for induction of beige fat in vivo. Growth Horm IGF Res 42-43:40-51 |
| Duran-Ortiz, Silvana; Noboa, Vanessa; Kopchick, John J (2018) Disruption of the GH receptor gene in adult mice and in insulin sensitive tissues. Growth Horm IGF Res 38:3-7 |
| 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 |
| 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 |
| 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 |
| Bartke, Andrzej; Darcy, Justin (2017) GH and ageing: Pitfalls and new insights. Best Pract Res Clin Endocrinol Metab 31:113-125 |
| Bennis, Mohammed T; Schneider, Augusto; Victoria, Berta et al. (2017) The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience 39:51-59 |
| 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 |
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