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.
|Gesing, Adam; Wang, Feiya; List, Edward O et al. (2015) Expression of apoptosis-related genes in liver-specific growth hormone receptor gene-disrupted mice is sex dependent. J Gerontol A Biol Sci Med Sci 70:44-52|
|Li, Weiquan; Miller, Richard A (2015) Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J Gerontol A Biol Sci Med Sci 70:263-72|
|Lee, Changhan; Wan, Junxiang; Miyazaki, Brian et al. (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958-61|
|Tran, Duc; Bergholz, Johann; Zhang, Haibo et al. (2014) Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell 13:669-78|
|Kopchick, John J; List, Edward O; Kelder, Bruce et al. (2014) Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications. Mol Cell Endocrinol 386:34-45|
|Jara, Adam; Benner, Chance M; Sim, Don et al. (2014) Elevated systolic blood pressure in male GH transgenic mice is age dependent. Endocrinology 155:975-86|
|Schneider, Augusto; Zhi, Xu; Bartke, Andrzej et al. (2014) Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries. Age (Dordr) 36:9701|
|Wiesenborn, Denise S; Ayala, Julio E; King, Emily et al. (2014) Insulin sensitivity in long-living Ames dwarf mice. Age (Dordr) 36:9709|
|Berryman, Darlene E; Lubbers, Ellen R; Magon, Vishakha et al. (2014) A dwarf mouse model with decreased GH/IGF-1 activity that does not experience life-span extension: potential impact of increased adiposity, leptin, and insulin with advancing age. J Gerontol A Biol Sci Med Sci 69:131-41|
|Hong, S Lee; Longo, Kenneth A; Gosney, Elahu et al. (2014) Increased metabolic flexibility and complexity in a long-lived growth hormone insensitive mouse model. J Gerontol A Biol Sci Med Sci 69:274-81|
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