# Project 3 - Effects of Ovariectomy on the Biology of Physical and Cognitive Aging in Mice

> **NIH NIH U54** · MAYO CLINIC ROCHESTER · 2020 · $370,225

## Abstract

PROJECT 3: SUMMARY/ABSTRACT Nathan K. LeBrasseur, M.S., Ph.D.
As a mechanistic complement to the human projects (Projects 1 and 2) in the Mayo Clinic Specialized Center
of Research Excellence (SCORE) on Sex Differences, this Project will test the central hypothesis that
ovariectomy (OVX)-induced endocrine disruption in female mice hastens and exacerbates the accumulation of
age-related senescent cells and, in turn, compromises clinically-relevant measures of physical and cognitive
performance. Our hypothesis is founded on our recent work demonstrating the causal role of cellular
senescence, a hallmark of aging, in the genesis of multiple age-related conditions. Our preliminary data
support our hypothesis and demonstrate that senescent cells mediate functional decline and, in specific tissues
relevant to physical and cognitive performance, are more abundant in female compared to male mice of
advanced age. We will test our central hypothesis through two specific aims, which will (1) determine the
degree to which OVX and long-term estrogen replacement impacts healthspan in mice; and (2) determine the
extent to which OVX and long-term estrogen replacement affects the accumulation and abundance of
senescent cells in multiple tissues. Our approach will leverage a novel transgenic reporter system in mice that
enables the unique ability to quantitatively, temporally, and inducibly visualize, track, and isolate p16Ink4a-
positive senescent cells. At six months of age, mice will undergo OVX or sham surgery and begin continuous
estrogen or placebo treatment [three experimental groups: 1) sham surgery + placebo, 2) OVX + estrogen, and
3) OVX + placebo]. We will then measure the trajectory of healthspan across five clinically-relevant domains:
body composition, physical performance, cardiovascular function, metabolic homeostasis, and cognitive
function at 12, 18, and 24 months of age. We will systematically quantify senescent cells at these timepoints
across tissues, and test their association with measures of healthspan. We anticipate that OVX mice will
exhibit accelerated and more severe deficits in the five healthspan domains compared to sham-operated mice,
and that estrogen replacement will both delay and mitigate functional consequences of OVX. We predict that
the deleterious effects of OVX and therapeutic effects of estrogen will be reflected, if not preceded, by
senescent cell burden in tissues responsible for synchronizing functional parameters. As in Project 1 for
women, we further anticipate that circulating markers of systemic senescent cell burden will correlate with the
clinically-relevant measures of physical and cognitive health in mice. This Project will enable systematic
exploration of the long-term effects of OVX and estrogen replacement on integrated measures of healthspan
and importantly, will reveal whether aging and endocrine disruption exert synergistically detrimental effects on
the fundamental biology of aging at a level of resolution...

## Key facts

- **NIH application ID:** 9936104
- **Project number:** 5U54AG044170-08
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Nathan K LeBrasseur
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,225
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936104

## Citation

> US National Institutes of Health, RePORTER application 9936104, Project 3 - Effects of Ovariectomy on the Biology of Physical and Cognitive Aging in Mice (5U54AG044170-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936104. Licensed CC0.

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