# Noncoding Elements Shaping Brain Aging

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

PROJECT SUMMARY
The costs associated with Alzheimer's disease are estimated at over $243 billion annually in the United States.
The factors involved are not fully understood, but metabolic processes play an important role. Indeed, obesity
and type II diabetes are major risk factors for Alzheimer's disease. Gaining a deeper understanding of the
mechanisms involved is urgent, because obesity affects 17% of children, ~30% of US adults and especially the
elderly. Gene regulatory mechanisms are emerging as major drivers of human disease, but their roles in
obesity and Alzheimer's disease are poorly understood. Here, we propose a study that will uncover new
and important noncoding elements and gene regulatory mechanisms in the genome that underlie
mammalian obesity and age-related neurodegeneration. Our study builds on our recent publication in Cell
Reports (Ferris et al., 2018), in which we performed a comparative genome-wide analysis of accelerated
regions (ARs) in species with highly distinctive traits to define mammalian noncoding elements that shape
clinically important phenotypes. ARs are conserved genomic elements with significantly increased nucleotide
substitutions in a specific lineage, typically due to selective effects. In an unpublished study, we built on our
approach to uncover regulatory elements shaping mammalian obesity and neurodegeneration by studying
hibernators. Hibernators evolved metabolic and behavioral adaptations that resulted in a reversible obesogenic
phenotype. They also evolved neuroprotective mechanisms that prevent brain damage. We identified 2370
50bp elements in the mammalian genome that underwent parallel accelerated evolution in multiple species
that independently evolved hibernation. We call these noncoding elements hibernator accelerated regions
(ARs) and found a subset associated with risk loci for human obesity and Alzheimer's disease. Our study
tests the hypothesis that the conserved elements impacted by hibernator ARs near obesity and Alzheimer's
disease risk genes are critical regulatory elements that control gene expression in different tissues and shape
obesogenic behaviors, metabolic activity and age-related neurodegeneration. Our study is significant
because the results will define important new noncoding mechanisms that regulate biological processes
contributing to Alzheimer's disease. In the long-term, our results are expected to help reveal improved genetic
and epigenetic biomarkers and therapeutic strategies to prevent age-related obesity and neurodegeneration.

## Key facts

- **NIH application ID:** 10153649
- **Project number:** 5R01AG064013-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Christopher Gregg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153649

## Citation

> US National Institutes of Health, RePORTER application 10153649, Noncoding Elements Shaping Brain Aging (5R01AG064013-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10153649. Licensed CC0.

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