Aging-associated changes in motor function are ovarian somatic tissue-dependent, but germ cell and estradiol independent in post-reproductive female mice exposed to young ovarian tissue

Authors: HABERMEHL, TRACY - Utah State University; UNDERWOOD, KADEN - Utah State University; Welch, Kevin; GAWRYS, STEVEN - Rocky Vista University; PARKINSON, KATE - Utah State University; SCHNEIDER, AUGUSTO - Universidade Federal De Pelotas; MASTERNAK, MICHAL - University Of Central Florida; MASON, JEFFREY - Utah State University

Submitted to: GeroScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/17/2022
Publication Date: 3/29/2022
Citation: Habermehl, T., Underwood, K., Welch, K.D., Gawrys, S., Parkinson, K., Schneider, A., Masternak, M., Mason, J. 2022. Aging-associated changes in motor function are ovarian somatic tissue-dependent, but germ cell and estradiol independent in post-reproductive female mice exposed to young ovarian tissue. GeroScience. https://doi.org/10.1007/s11357-022-00549-9.
DOI: https://doi.org/10.1007/s11357-022-00549-9

Interpretive Summary: Chronological life span in humans has been extended dramatically over the last century. However, the timing of menopause or the end of the reproductive life span in women has remained relatively constant over this same time period. Reproduction is often thought to negatively influence health and survival. Opposition to this concept comes from manipulation of reproduction to increase or decrease exposure to reproductive function and observations of the influence of these manipulations on health and longevity. Results from these types of experiments suggest that there are still large gaps in our knowledge about the effects of reproduction on health and survival. Reproductive function can significantly influence non-reproductive biological functions and is exquisitely sensitive to aging-related changes. Evidence over the past decade indicate that a decline in an individual's reproductive status is commonly associated with an increased risk of developing chronic health conditions. The association is particularly striking in women. Prior to reproductive decline, females hold a significant health advantage over males of the same age. However, at the time of reproductive decline, the increase in disease risks for women significantly outpace those of men. This dependence on reproductive function for the maintenance of health is exemplified in surgically menopausal women and in women with premature ovarian failure, who suffer from a decline in health at a much younger age than in women with traditional menopausal timing. In the current experiments, we evaluated aging-associated and reproduction-influenced changes in motor function, utilizing two measures of health span, tremor amplitude and grip strength. The well-established supportive role of ovarian hormones in many aspects of female health implicates the loss of hormone production from actively cycling germ cells, as the principal cause of increased disease risks at menopause. While the value of ovarian hormones in female health is unquestionable, efforts to replace the hormonal milieu of actively cycling ovaries in peri- and post-menopausal women have struggled to reliably restore the health benefits enjoyed by young, reproductively cycling women with young ovaries. Preliminary data suggest that estrogen levels are not changed in post-reproductive recipients of new ovaries, compared with age-matched controls, further suggesting a non-estrogenic influence of young ovarian tissue. Here we specifically examined the influence of young ovarian tissue on tremor amplitude and grip strength in the presence or absence of ovarian germ cell influence. The findings from this study demonstrated that in female CBA/J mice, tremors increased, and grip strength and estradiol levels decreased with chronological and ovarian aging. Increased exposure of post-reproductive females to young ovarian tissue improved/restored tremor amplitude and grip strength parameters to reflect measures found in much younger mice and did so independent of ovarian germ cells and circulating estradiol. In addition, while grip strength is well established as a measure of aging-related health span change, the current results suggest that tremor amplitude, which is independent of subject collaboration may serve as an additional measure to determine biological age/aging and health span.

Technical Abstract: Chronological life span in humans has been extended dramatically over the last century. However, the timing of menopause has remained relatively constant over this same time period. Prior to reproductive decline, females hold a significant health advantage over males of the same age. However, at menopause, the increase in disease risks for women significantly outpace those of men. Tremors are a common movement disorder phenomenon, are associated with many disease states and are often correlated with increasing age. Muscle quality is also diminished with age and these declines are different between men and women. In the current experiments, we evaluated aging-associated and reproduction-influenced changes in motor function, utilizing changes in tremor amplitude and grip strength. In control mice, tremor amplitude increased with aging, but decreased in mice that received young ovarian tissue transplants to levels found in young mice, and far below levels in age-matched control mice, both in mice that received germ cell-containing and germ cell-depleted tissue transplants. Forelimb grip strength decreased significantly with age and was restored in recipients of young ovarian tissue to levels found in 8mo control mice in germ cell-containing, germ cell-depleted recipients and in recipients of isolated ovarian somatic cells. Estradiol levels decreased with age and were not changed with exposure to young ovarian tissues/cells. We have shown tremor amplitude and grip strength, which are negatively influenced by aging, can be positively influenced or restored by exposure to young ovarian tissues/cells in aged female mice and that this influence is independent of ovarian germ cells and estradiol levels. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in post-reproductive females and suggest that changes in tremor amplitude, which is independent of subject collaboration may serve as an additional measure to determine biological age/aging and health span. These results also suggest that there are still large gaps in our knowledge about the influence of reproduction on health and survival.