Caloric restriction (CR) extends the life span, slows aging and retards age-related disease processes in short-lived mammalian species. Reproductive aging encompasses a life-long continuum of follicle depletion in the ovary that leads to decreased fecundity in older women and culminates in menopause, the cessation of ovarian/menstrual cyclicity, and its associated health-related risks. Caloric restriction delays the onset of ovarian follicular loss in rodents. Whether ovarian senescence is likewise suspended during CR in primates is not well understood. Using young and old female rhesus monkeys undergoing acute and long-term CR and their age-matched controls (CON), we propose to assess whether CR alters ovarian aging by determining: 1 ) the patterns and levels of gonadotropin and steroid hormones as well as inhibin-related proteins during spontaneous menstrual cycles and the peri-menopausal period; 2) the responsiveness of somatic cells of the ovarian follicle, i.e. granulosa cells, to exogenous gonadotropin or """"""""fertility"""""""" treatment, and resultant follicular growth and maturation; and 3) gene expression in luteinizing granulosa cells and localization of protein factors involved in the pro- or anti-apoptotic (cell death) pathways in the ovarian follicle. Hormonal profiles will be measured in daily samples during 3 consecutive menstrual cycles in all animals, and frequent sampling will be done over a 6-hour period during the early follicular phase of 21 cycles to determine gonadotropin pulsatility in acute CON and CR animals. AII animals will receive recombinant human gonadotropins to stimulate the growth of multiple pre-ovulatory follicles followed by a bolus of hCG to induce peri-ovulatory events. Progesterone production by luteinizing granulosa cells in the presence or absence of hCG in vitro will be measured, and global gene expression will be assessed by microarray technology. Ovarian morphology and protein localization will be examined with histochemical and immunocytochemical analyses in acute CON and CR animals. These studies will provide valuable insight into the potential impact of CR on the mechanisms of ovarian aging in primates.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AG021382-01
Application #
6552683
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M4))
Program Officer
Bellino, Francis
Project Start
2002-09-30
Project End
2005-08-31
Budget Start
2002-09-30
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$378,531
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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
Wu, Julie M; Takahashi, Diana L; Ingram, Donald K et al. (2010) Ovarian reserve tests and their utility in predicting response to controlled ovarian stimulation in rhesus monkeys. Am J Primatol 72:672-80