# Targeting Estrogen-Sensitive Hypothalamic Neurons to Reverse Frailty in Aging Females

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $444,541

## Abstract

PROJECT SUMMARY
Sex differences impact the prevalence and degree of frailty. Women have a higher prevalence of more severe
frailty compared to age-matched men. A key difference between the sexes is their exposure to distinct steroid
hormone profiles across the life course. In studying how E2 (17β-estradiol) regulates metabolism across
female reproductive stages we recently identified a small population of ERα (estrogen receptor alpha) neurons
in the hypothalamus that drive spontaneous physical activity in mice in response to E2. These neurons
coordinate energy expenditure to support changes in behavior and physiology across the female reproductive
cycle. We predict that disengagement of these neurons after menopause contributes to metabolic and
functional declines that predispose women to frailty. However, using CRISPRa (CRISPR-mediated gene
activation) we can bypass ERα-dependent regulation of these neurons and dramatically increase physical
activity levels in female and male mice. As sedentary behavior is a risk factor for chronic diseases, including
frailty, and interventions that promote a more active lifestyle improve health and longevity, the goal of this R21
is to determine if we can leverage CRISPRa gene engineering in these nominally estrogen-sensitive neurons
to restore and maintain physical activity levels and associated health benefits as females age. In aim 1 we will
determine if stimulation of these activity-promoting neurons in E2-depleted mice is sufficient to ameliorate sex
differences in frailty phenotype and hypothalamic neuroinflammation. Longitudinal assessments of frailty
phenotype along with terminal examination of histological markers of neuroinflammatory stress in these
hypothalamic neurons will be performed in CRISPRa stimulated female and male mice as well as sedentary
controls. In response to exercise the liver produces several secreted factors that act systemically to improve
neuronal and metabolic health. The liver also expresses ERα and exhibits distinct gene expression programs
in males and females. In aim 2 we will determine if there are sex differences in the hepatic response to
physical activity that ultimately contribute to female bias in frailty. To that end we will use proximity labeling and
mass spectrometry to specifically examine physical activity-dependent changes in the liver secretome of
female and male mice. Collectively, we anticipate that this integrative approach will rationalize sex differences
in frailty and may identify new translational opportunities.

## Key facts

- **NIH application ID:** 10872941
- **Project number:** 1R21AG086774-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HOLLY A. INGRAHAM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,541
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872941

## Citation

> US National Institutes of Health, RePORTER application 10872941, Targeting Estrogen-Sensitive Hypothalamic Neurons to Reverse Frailty in Aging Females (1R21AG086774-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10872941. Licensed CC0.

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