# Epigenetic Signaling in the Aging Hypothalamus

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $262,500

## Abstract

PROJECT SUMMARY
In women, aging is characterized by a marked decrease in circulating estrogen (E) levels, which negatively
impacts many physiological systems including sleep-wake cycles and cognitive performance. Consequently,
many postmenopausal women chose to undergo E hormone replacement therapy (HRT), with the hope of
reversing or alleviating these negative symptoms. Unfortunately, the underlying neuroendocrine mechanisms
associated with HRT are poorly understood and the long-term efficacy of these hormonal manipulations on the
central nervous system are unclear, especially in women who are overweight. Using the rhesus macaque as a
translational animal model, we previously demonstrated an age-associated increase in perturbed sleep-wake
cycles, and found that individuals with the most perturbed cycles showed inferior cognitive performance in a
spatial memory task, as well as compromised immune responses. We also demonstrated cognitive benefits
resulting from long-term administration of E to old ovariectomized females; importantly, however, the beneficial
effects of E on various physiological functions were not sustained in animals maintained on a high-fat, high-
sugar Western-style diet (WSD). The goal of this R21 exploratory study is to test the hypothesis that age-
related molecular changes within the suprachiasmatic nucleus (SCN) contribute to disrupted sleep-wake cycles
and that these are exacerbated by the marked postmenopausal attenuation of circulating E concentrations,
especially when concomitantly exposed to a WSD. Therefore, our study will examine DNA methylation
developments within the SCN (Aim 1), and use RNA-seq to profile gene expression changes (Aim 2), using
archived brain tissue from the following pair-groups of previously-characterized rhesus macaques:
 1. Young adult ovary-intact females (on a standard diet)
 2. Old ovary-intact females (on a standard diet)
 3. Old ovariectomized females (on a standard diet)
 4. Old ovariectomized females (on a standard diet + treated with HRT for ~3 years)
 5. Old ovariectomized females (on a WSD for ~3 years)
 6. Old ovariectomized females (on a WSD for ~3 years + treated with HRT for ~3 years)
Using a previously-validated MethylSeq approach to provide single-base resolution DNA methylation data, we
will examine differential methylation CpG (DMC) and region (DMR) in the SCN – i.e., the well-established site
of the master circadian clock that plays a key role in sleep maintenance and synchronizing daily physiological
functions. We predict that aging, maintenance on a WSD, and insufficient E in the circulation produce
functional epigenetic modifications within the core clock mechanism of the SCN that result in perturbed
circadian activity-rest pattern, and in turn predispose individuals to development of Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10056001
- **Project number:** 1R21AG061141-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alejandro Lomniczi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,500
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056001

## Citation

> US National Institutes of Health, RePORTER application 10056001, Epigenetic Signaling in the Aging Hypothalamus (1R21AG061141-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10056001. Licensed CC0.

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