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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031736-04
Application #
8377763
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$413,648
Indirect Cost
$34,649
Name
Southern Illinois University School of Medicine
Department
Type
DUNS #
038415006
City
Springfield
State
IL
Country
United States
Zip Code
62794
Xu, Ming; Tchkonia, Tamar; Kirkland, James L (2016) Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol Res 111:152-4
Bartke, A; Sun, L; Fang, Y et al. (2016) Growth hormone actions during development influence adult phenotype and longevity. Exp Gerontol 86:22-27
Saccon, Tatiana D; Moreira, Fabiana; Cruz, Luis A et al. (2016) 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 :
Hascup, Kevin N; Lynn, Mary K; Fitzgerald, Patrick J et al. (2016) Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging. J Gerontol A Biol Sci Med Sci :
Palmer, Allyson K; Kirkland, James L (2016) Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol 86:97-105
Liu, Yang; Knop, Erich; Knop, Nadja et al. (2016) Growth Hormone Influence on the Morphology and Size of the Mouse Meibomian Gland. J Ophthalmol 2016:5728071
Bartke, Andrzej; List, Edward O; Kopchick, John J (2016) The somatotropic axis and aging: Benefits of endocrine defects. Growth Horm IGF Res 27:41-5
Bartke, Andrzej (2016) Healthspan and longevity can be extended by suppression of growth hormone signaling. Mamm Genome 27:289-99
Dominick, Graham; Bowman, Jacqueline; Li, Xinna et al. (2016) mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell :
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

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