Human physiology shows strong rhythmic components with peaks and nadirs occurring regularly at specific times of the day. Accumulating evidence suggests that perturbation of the circadian neuroendocrine circuitry may play an important role in several aging-related disorders and may have a major influence on life span. Furthermore, there is growing support for the view that neuroendocrine aging may be caused by oxidative injury, stemming from a progressive overload of a cell's antioxidant capacity. The proposed research will use male rhesus monkeys to examine the mechanism by which caloric restriction can prevent aging-related deterioration of key neuroendocrine circadian rhythms, including DHEAS, cortisol, melatonin and testosterone. We will perform experiments to examine the aging-related progression of circadian dysfunction in ad libitum-fed and age-matched calorie-restricted animals in vivo. This will involve repeated serial blood collections via a catheter-swivel-tether set up, together with concomitant body temperature recordings and actography. In addition, changes in body composition and brain morphology will be assessed non-invasively using DEXA and MRI respectively. Ultimately, the brains of these animals will be examined postmortem to test the hypothesis that caloric restriction protects the aging primate hypothalamus from oxidative injury. Using electron microscopy, we will examine the synaptology of key hypothalamic nuclei involved in mediating circadian neuroendocrine function and use in situ hybridization histochemistry to assess changes in gene expression. We will also use immunohistochemistry to examine loss of specific axonal projections and the associated increase in gliosis. We expect to show that caloric restriction helps to protect hypothalamic nuclei from oxidative injury and, more importantly, that it helps to maintain the integrity of the neural pathway that links the suprachiasmatic nucleus (the central biological clock) to the paraventricular nucleus (the hypothalamic regulator of the adrenal axis). A deeper understanding of aging-related changes in central neuroendocrine circadian circuits of primates and the protective influence of caloric restriction should help to elucidate the mechanism of human aging and help with the development of effective therapies for a wide range of disorders in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG019914-04S1
Application #
7014333
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Monjan, Andrew A
Project Start
2001-09-01
Project End
2005-08-31
Budget Start
2005-02-15
Budget End
2005-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$52,470
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
Sitzmann, Brandon D; Brown, Donald I; Garyfallou, Vasilios T et al. (2014) Impact of moderate calorie restriction on testicular morphology and endocrine function in adult rhesus macaques (Macaca mulatta). Age (Dordr) 36:183-97
Urbanski, Henryk F; Mattison, Julie A; Roth, George S et al. (2013) Dehydroepiandrosterone sulfate (DHEAS) as an endocrine marker of aging in calorie restriction studies. Exp Gerontol 48:1136-9
Sorwell, Krystina G; Urbanski, Henryk F (2010) Dehydroepiandrosterone and age-related cognitive decline. Age (Dordr) 32:61-7
Sitzmann, Brandon D; Mattison, Julie A; Ingram, Donald K et al. (2010) Impact of Moderate Calorie Restriction on the Reproductive Neuroendocrine Axis of Male Rhesus Macaques. Open Longev Sci 3:38-47
Sitzmann, Brandon D; Leone, Erin H; Mattison, Julie A et al. (2010) Effects of moderate calorie restriction on testosterone production and semen characteristics in young rhesus macaques (Macaca mulatta). Biol Reprod 83:635-40
Downs, Jodi L; Mattison, Julie A; Ingram, Donald K et al. (2008) Effect of age and caloric restriction on circadian adrenal steroid rhythms in rhesus macaques. Neurobiol Aging 29:1412-22
Downs, Jodi L; Dunn, Michael R; Borok, Erzsebet et al. (2007) Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. Neurobiol Aging 28:1286-95
Downs, Jodi L; Urbanski, Henryk F (2006) Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macaca mulatta). Biol Reprod 75:539-46
Lemos, Dario R; Downs, Jodi L; Urbanski, Henryk F (2006) Twenty-four-hour rhythmic gene expression in the rhesus macaque adrenal gland. Mol Endocrinol 20:1164-76

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