The short term objectives of this K02 proposal are: 1) to increase the time devoted to conduct and complete experiments of a recently awarded R01;and 2) to complete exercises designed to enhance and enrich the applicants focus and expertise in the areas of aging and epigenetics. The long-term objective of the K02 is to effectively utilize both 1) and 2) to enhance the training of graduate students, post docs, faculty (not currently practicing in the field of aging) and undergraduates, in particular, in aging research and to obtain additional support in future years. The research environment at the University of North Dakota School of Medicine &Health Sciences is active and growing. Two major NIH grants (INBRE, COBRE) over the last 8 years have increased the resources available to the basic scientists. The Proteomics/Mass Spectrometry core, a core in Bioinformatics that is under development and the Center for Biomedical Research (animal facilities) will be utilized by the applicant. The applicant has developed an active research program at UND with the current tools available and plans to increase those activities during the period of the award and beyond. The objective of the science integral to this proposal is to delineate mechanisms of the beneficial effects of growth hormone deficiency on mitochondrial function, stress resistance and health span. Our research has been focused on understanding the hypothesis that in long living animals, an upregulation of thiol metabolism leads to greater protection from cellular stress. The applicant's work has established that reduced growth hormone (GH) signaling is a major player in longevity assurance. The global hypothesis to be tested is that thiol metabolism plays a key role in aging and that GH modulates key components of this pathway ultimately leading to changes in health span (via stress resistance/protection) and lifespan. Thus, reduced GH signaling confers a biologic advantage to dwarf mice leading to better scavenging of toxic metabolic byproducts, altered mitochondrial function and enhanced longevity. To further address and define this global hypothesis the applicant plans to elucidate the relationship between GH, thiol metabolism and cellular protection by: 1) directly linking the enhanced respiratory and antioxidative activities in dwarf mice to increased mitochondrial GSH and glutathionylation of these proteins;2) providing direct evidence that the lack of GH is responsible for substrate-specific enhancement of the GST system;3) defining the changes in thiol metabolism linked to stress resistance and longevity following altered dietary MET;and 4) establishing the first epigenomic profile of a long-living mouse. Determining GH-dependent pathways and mechanisms may suggest therapeutic interventions to enhance stress resistance, delay aging, treat aging-related disorders and extend health span in humans.

Public Health Relevance

This K02 proposal is designed to provide protected time for research and training and to enrich the applicants'science in the areas of aging and epigenetics. This protected time will be used towards the successful completion of experiments designed to determine the influence of growth hormone on processes related to stress resistance and longevity using two long-living mouse strains, Ames dwarf and growth hormone receptor knockout mice. Determining GH-dependent pathways and mechanisms may suggest potential therapeutic interventions to delay aging, treat aging-related disorders and extend life span in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AG038509-02
Application #
8149871
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Finkelstein, David B
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$114,912
Indirect Cost
Name
University of North Dakota
Department
Pharmacology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Cole, John J; Robertson, Neil A; Rather, Mohammed Iqbal et al. (2017) Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol 18:58
Wang, Tina; Tsui, Brian; Kreisberg, Jason F et al. (2017) Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol 18:57
Brown-Borg, Holly M; Buffenstein, Rochelle (2017) Cutting back on the essentials: Can manipulating intake of specific amino acids modulate health and lifespan? Ageing Res Rev 39:87-95
Brown-Borg, Holly M (2016) Reduced growth hormone signaling and methionine restriction: interventions that improve metabolic health and extend life span. Ann N Y Acad Sci 1363:40-9
Brown-Borg, H M (2015) The somatotropic axis and longevity in mice. Am J Physiol Endocrinol Metab 309:E503-10
Derenne, Adam; Brown-Borg, Holly M; Martner, Sarah et al. (2014) Spatial delayed nonmatching-to-sample performances in long-living Ames dwarf mice. Physiol Behav 123:100-4
Rojanathammanee, Lalida; Rakoczy, Sharlene; Brown-Borg, Holly M (2014) Growth hormone alters the glutathione S-transferase and mitochondrial thioredoxin systems in long-living Ames dwarf mice. J Gerontol A Biol Sci Med Sci 69:1199-211
Rojanathammanee, Lalida; Rakoczy, Sharlene; Kopchick, John et al. (2014) Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice. Age (Dordr) 36:9687
Armstrong, Vanessa L; Rakoczy, Sharlene; Rojanathammanee, Lalida et al. (2014) Expression of DNA methyltransferases is influenced by growth hormone in the long-living Ames dwarf mouse in vivo and in vitro. J Gerontol A Biol Sci Med Sci 69:923-33
Brown-Borg, Holly M; Rakoczy, Sharlene G; Wonderlich, Joseph A et al. (2014) Growth hormone signaling is necessary for lifespan extension by dietary methionine. Aging Cell 13:1019-27

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