Geroscience and Ovarian Aging

The geroscience view of the treatment of aging isn't limited to the reuse of existing drugs that happen to upregulate stress responses in ways that modestly slow aging, but this is the near entirely the focus of those researchers who publish on the topic. Unfortunately the effect size of this approach to aging is small, and diminishes as species life span increases. We know the upper limits of what can be achieved with the beneficial stress response induced by calorie restriction in humans, and we know that it won't really add more than a couple of years to human life spans. Better strategies exist, based on the development of biotechnologies that repair the underlying cell and tissue damage that causes aging. Repair can in principle achieve rejuvenation, not just a modest slowing of aging, and that rejuvenation has already been demonstrated in animal models for the repair-based approach of removing senescent cells from old tissues.

In women 35 years and older the incidences of infertility, aneuploidy, and birth defects dramatically increase. These outcomes are a result of age-related declines in both ovarian reserve and oocyte quality. In addition to waning reproductive function, the decline in estrogen secretion at menopause contributes to multi-system aging and the initiation of frailty. Both reproductive and hormonal ovarian function are limited by the primordial follicle pool (PFP), which is established in utero and declines irreversibly until menopause. Because ovarian function is dependent on the PFP, an understanding of the mechanisms that regulate follicular growth and maintenance of the PFP is critical for the development of interventions to prolong the reproductive lifespan.

Manipulating the rate of aging and delaying the onset of aging-related diseases have been the makeup of medical, scientific, and pseudo-scientific pursuits throughout history. However, it is not until relatively recently, in the later part of the 20th and early 21st centuries, that the molecular targets and geroscience approaches needed to make this a reality have been elucidated. For example, improvements in reproductive function after rapamycin treatment are evident in studies of physiologic murine aging. A 2-week course of rapamycin in healthy mice improved primordial follicle count, oocyte morphology, and mitochondrial activity. In mating studies, after 12 months of age, when the control mice began to experience age-related infertility, the rapamycin-treated mice retained fertility and continued to have pups. Equally, a 12-month course of resveratrol in mice increased primordial follicle counts, litter size, and oocyte quality at advanced ages. Additionally, a specific SIRT1 activator SRT1720 administered to mice suppressed the activation of primordial follicles and increased the ovarian reserve by activating SIRT1 and inhibiting mTOR signaling.

Multiple pathways, many of them nutrient-sensing, converge in the mammalian ovary to regulate the quiescence and activation of primordial follicles. The PI3K/PTEN/AKT/FOXO3 and mTOR pathways appear to be central to the regulation of the primordial follicle pool; however, GH/IGF-1 and H2S may also play a role. A delicate balance of primordial follicle activators and suppressors must be maintained in order to allow for continued ovulation while preventing rapid depletion of the ovarian reserve. The behavioral and pharmacologic interventions that prevent primordial follicle activation, including DR and rapamycin, cause infertility for the duration of the intervention. In order for these interventions to be useful clinically, the resulting period of infertility must be reversible, and the treatments must confer long-term benefits after a relatively short duration of use.




September 17, 2020
University of Gothenburg
Women with a longer reproductive period had an elevated risk for dementia in old age, compared with those who were fertile for a shorter period, a population-based study.

Posted by: Jones at September 18th, 2020 8:48 AM
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