In men and male rhesus macaques testosterone (T) and dehydroepiandrosterone (DHEA, an adrenal androgen precursor) show characteristic 24-hour patterns in the circulation, and both show significant age-related decreases. Although the exact physiological consequence of these hormonal changes is unclear, both T and DHEA are thought to act as intracrine substrates for estradiol (E2) synthesis in the brain. Therefore, it is plausible that their age-related decline negatively impacts brain function, either directly through androgen receptors and/or indirectly through estrogen receptors. Using the rhesus macaque as a translational animal model, we propose to test the hypothesis that age-related attenuation of circulating T and DHEA levels negatively impacts centrally-mediated physiological processes, including the circadian sleep-wake cycle and cognition. Moreover, we predict that physiological testosterone supplementation, designed to mimic the circulating 24-hour T pattern of young animals, will ameliorate these age-associated disorders.
Specific Aim 1 will use a battery of cognitive tests to assess differences between young and old male rhesus macaques, and between old animals receiving extended treatment with """"""""young"""""""" physiological levels of T or placebo. Cognitive assessments will include: 1) the delayed response test of spatial working memory, which is particularly sensitive to aging and prefrontal cortex dysfunction;2) delayed non-matching-to-sample, a task probing primarily temporal lobe-based memory;3) a visuospatial cueing test of visual attention that is estrogen-sensitive, and 4) performance in a novel maze to assess spatial learning and memory. In addition, sleep-wake cycles will be continuously monitored using Actiwatches, while morphological and biochemical differences will be examined in targeted brain areas by magnetic resonance imaging (MRI).
Specific Aim 2 will use a series of biochemical and histochemical methodologies to elucidate the plasticity that occurs within the central nervous system (CNS) during male aging and after supplementation with T. Rhesus-specific gene microarrays and quantitative real-time PCR will be used to identify genes that are differentially expressed in the CNS among young males, untreated old and the T-treated old males. This integrative systems approach should help to identify plasticity in neurotransmitter systems and synapses and shed light on potential regulatory mechanisms. In situ hybridization, immunohistochemistry, enzymology, and hormone measurements will be used to further corroborate the results. Our current NIH grant (AG-029612) similarly examines the interacting impact of ovarian-adrenal interactions in perimenopausal female rhesus macaques. Consequently, data from the ongoing female study, combined with data from the proposed male study, will disclose important gender-based differences and help to elucidate their underlying mechanisms.

Public Health Relevance

The overall aim of this research is to examine the impact of aging-related endocrine changes on the central nervous system of male primates. Using the rhesus macaque as a pragmatic animal model, we propose to test the hypothesis that aging-related attenuation of testosterone levels in the brain negatively impacts centrally-mediated physiological processes, including the circadian sleep-wake cycle and cognition. Moreover, we predict that a physiological testosterone replacement paradigm will ameliorate many of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG036670-01A1
Application #
8106930
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Mackiewicz, Miroslaw
Project Start
2011-04-15
Project End
2016-03-31
Budget Start
2011-04-15
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$689,255
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Other Domestic Higher Education
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Urbanski, Henryk F (2017) Effect of androgen supplementation on 24-hour activity-rest patterns of aged male rhesus macaques. Neurobiol Aging 54:100-102
Luna, Selva L; Brown, Donald I; Eghlidi, Dominique H et al. (2017) Locomotor activity and the expression of orexin A and orexin B in aged female rhesus macaques. Neurobiol Aging 50:1-4
Urbanski, Henryk F; Sorwell, Krystina G; Prokai, Laszlo et al. (2017) Effect of short-term DHEA supplementation on serum and hippocampal estrogen concentrations in perimenopausal female rhesus macaques. Neurobiol Aging 55:172-174
Eghlidi, Dominique H; Garyfallou, Vasilios T; Kohama, Steven G et al. (2017) Age-associated gene expression changes in the arcuate nucleus of male rhesus macaques. J Mol Endocrinol 59:141-149
Aghazadeh-Sanai, Nona; Downs, Jodi L; Mattison, Julie A et al. (2017) Effect of caloric restriction on plasma melatonin levels in aged rhesus macaques. Neurobiol Aging 55:213-216
Urbanski, Henryk F; Mueller, Kevin; Bethea, Cynthia L (2017) Effect of an obesogenic diet on circadian activity and serum hormones in old monkeys. Endocr Connect 6:380-383
Rais, Maham; Wilson, Randall M; Urbanski, Henryk F et al. (2017) Androgen supplementation improves some but not all aspects of immune senescence in aged male macaques. Geroscience :
Sorwell, K G; Renner, L; Weiss, A R et al. (2017) Cognition in aged rhesus monkeys: effect of DHEA and correlation with steroidogenic gene expression. Genes Brain Behav 16:361-368
Burton, Katherine J; Li, Xiaohan; Li, Baoan et al. (2016) Expression of prokineticin 2 and its receptor in the macaque monkey brain. Chronobiol Int 33:191-9
Kohama, Steven G; Renner, Lauren; Landauer, Noelle et al. (2016) Effect of Ovarian Hormone Therapy on Cognition in the Aged Female Rhesus Macaque. J Neurosci 36:10416-10424

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