Effects of Ovariectomy on the Biology of Physical and Cognitive Aging in a Murine Model

Hypothesis

The Mayo Clinic SCORE on Sex Differences is testing the idea that ovariectomized mice (OVX) will have reduced periods of deficit-free lives (health spans), as measured at 12, 18 and 24 months of age. Health span is measured in the following domains:

  • Body weight and composition
  • Physical performance, measured through treadmill exercise capacity, physical activity and muscle strength
  • Cardiovascular performance, measured through echocardiography for left ventricular and vascular function
  • Metabolic performance, measured through glucose and insulin sensitivity and whole-body metabolism
  • Cognitive performance, measured through episodic learning and memory, executive function, and anxiety

In addition, the team hypothesizes that OVX will exhibit increased senescent cell burden in muscle, vasculature, adipose tissue and specific brain regions — such as the hypothalamus, hippocampus, cortex and cerebellum — at 12, 18 and 24 months of age, compared with sham-operated mice. Finally, the team is testing whether treatment with 17-β estradiol will mitigate the effects of ovariectomy on the aging processes of the OVX.

Background

Studies have shown that premenopausal women who had both ovaries removed (bilateral salpingo-oophorectomy, or BSO) and had abrupt endocrine disruption as a result, experienced an accelerated rate of accumulation of multiple chronic conditions, including:

  • Arthritis
  • Chronic obstructive pulmonary disease
  • Coronary artery disease
  • Osteoporosis

These manifestations of accelerated aging appeared to be partially mitigated by estrogen therapy. These data suggest that ovarian hormones may govern fundamental aging processes. However, this hypothesis has not been directly tested.

Cellular senescence, a state of stable growth arrest accompanied by a bioactive secretome, is a hallmark of aging. There is now convincing evidence that senescent cells amass in multiple organs with advancing age and through the release of bioactive proteins accelerate the development of age-related diseases.

The SCORE's murine model project is a mechanistic component to the projects with human participants. It aims to determine whether endocrine disruption in mice hastens and exacerbates senescent cell burden and, in turn, compromises clinically relevant measures of physical and cognitive function. Additionally, it investigates whether these processes are impacted by estrogen treatments.

Project aims

The specific goals of the SCORE's project on how ovary removal affects the biology of physical and cognitive aging in mice are to:

  • Determine the degree to which ovary removal and chronic estrogen treatment impact health span in mice
  • Determine the extent to which ovary removal and estrogen treatment affect the accumulation and abundance of senescent cells in multiple tissues

Project leader