Orthotopic Ovarian Transplantation Procedures to Investigate the Life- and Health-span Influence of Ovarian Senescence in Female Mice

Ovarian transplantation was first conducted at Utah State University in 1963. In more recent work, heterochronic transplantation of mammalian ovaries is ...

Utah State University

There is compelling evidence that oocytes from mares >18 years of age have a high incidence of inherent defects that result in early embryonic loss. In women, an age-related decrease in oocyte quality is associated with an increased incidence of aneuploidy and it has recently been determined that the gene expression profile of human oocytes is altered with advancing age. We hypothesised that similar age-related aberrations in gene expression occur in equine oocytes. Therefore, the aim of the present study was to compare gene expression profiles of individual oocytes and cumulus cells from young and aged mares, specifically evaluating genes that have been identified as being differentially expressed with advancing maternal age and/or aneuploidy in human oocytes. Expression of 48 genes was compared between 14 cumulus-oocyte complexes (COCs) from mares aged 3-12 years and 10 COCs from mares ≥18 years of age. Three genes (mitochondrial translational initiation factor 3 (IF3), heat shock transcription factor 5 (HSF5) and Y box binding protein 2 (YBX2)) were differentially expressed in oocytes, with all being more abundant in oocytes from young mares. Three genes (ADP-ribosylation factor-like 6 interacting protein 6 (ARL6IP6), BCL2-associated X protein (BAX) and hypoxia upregulated 1 (HYOU1)) were differentially expressed in cumulus cells, with all being more abundant in aged mares. The results of the present study confirm there are age-related differences in gene expression in equine COCs, which may be associated with the lower quality and decreased developmental competence of oocytes from aged mares.

Expression profiles of select genes in cumulus-oocyte complexes from young and aged mares.

Previously, transplantation of ovaries from young cycling mice into old postreproductive-age mice increased life span. We anticipated that the same factors that increased life span could also influence health span. Female CBA/J mice received new (60 d) ovaries at 12 and 17 months of age and were evaluated at 16 and 25 months of age, respectively. There were no significant differences in body weight among any age or treatment group. The percentage of fat mass was significantly increased at 13 and 16 months of age but was reduced by ovarian transplantation in 16-month-old mice. The percentages of lean body mass and total body water were significantly reduced in 13-month-old control mice but were restored in 16- and 25-month-old recipient mice by ovarian transplantation to the levels found in six-month-old control mice. In summary, we have shown that skeletal muscle mass, which is negatively influenced by aging, can be positively influenced or restored by reestablishment of active ovarian function in aged female mice. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females.

Manipulation of Ovarian Function Significantly Influenced Sarcopenia in Postreproductive-Age Mice.

Proper immune functioning is necessary to maximize reproductive success. In addition, age-associated uremia in women is often associated with hypothalamic--pituitary-gonadal dysfunction. In the present experiments, we tested immune and renal function to determine if exposure of postreproductive mice to young, reproductively cycling ovaries would influence non-reproductive physiological functions. Control female CBA/J mice were evaluated at 6, 13 and 16 months of age. Additional mice received new (60-day-old) ovaries at 12 months of age and were evaluated at 16 months of age. Consequently, 6-month-old control mice and 16-month-old recipient mice both possessed 6-month-old ovaries and were reproductively cycling. A significant age-related decline in immune function (T-cell subset analysis) was found in 16-month-old mice, but was improved 64% by ovarian transplantation. Renal function (blood urea nitrogen:creatinine ratio) was also decreased with aging, but ovarian transplantation restored function to levels found in 6-month-old mice. In summary, we have shown that immune and renal function, which are negatively influenced by aging, can be positively influenced or restored by re-establishment of active ovarian function in aged female mice. These findings provide a strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females.

Restoration of immune and renal function in aged females by re-establishment of active ovarian function.

In mammals, the relationship between reproductive function and health has been particularly difficult to define. Previously, in old, postreproductive-aged mice, replacement of senescent ovaries with new ovaries from young, actively cycling mice increased life span. We hypothesized that the same factors that increased life span would also influence health span. In the current experiments, we tested two of the seven domains of function/health, sensory function and cognition to determine if exposure of postreproductive female mice to young transplanted ovaries influenced health span. We evaluated control female CBA/J mice at six, 13 and 16months of age. Additional mice received new (60d) ovaries at 12 or 17months of age and were subsequently evaluated at 16 or 25months of age, respectively. Evaluation of sensory function included two measures of olfactory perception; olfactory identification (buried pellet test) and olfactory discrimination (novel recognition block test). We found a significant age-related decline in olfactory identification in 16-month old mice. This decline was avoided by ovarian transplantation at 12months of age. The olfactory discrimination block test revealed an age-associated increase in time spent on both the novel and familiar blocks. This trend was reversed in 16-month old new-ovary recipients. We evaluated cognitive behavior with a burrowing behavior test. We detected a significant age-related decrease in burrowing behavior at 16months of age. This age-related decrease in burrowing behavior was prevented by ovarian transplantation at 12months of age. In summary, we have shown that cognitive behavior and sensory function, which are negatively influenced by aging, can be positively influenced or restored by re-establishment of active ovarian function in aged female mice. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females.

Kate C. Parkinson

Department of Animal,
Dairy and Veterinary Sciences,
Center for Integrated BioSystems,
School of Veterinary Medicine,
Department of Animal, Dairy and Veterinary Sciences, Center for Integrated BioSystems, School of Veterinary Medicine

Utah State University

Orthotopic Ovarian Transplantation Procedures to Investigate the Life- and Health-span Influence of Ovarian Senescence in Female Mice