# Inclusive Transcriptomics to Uncover Molecular Mechanisms Underlying Healthspan

> **NIH NIH R21** · COLORADO STATE UNIVERSITY · 2020 · $158,623

## Abstract

PROJECT SUMMARY
A major goal of current geroscience is to increase healthspan by preserving physiological function into older
age, and as emphasized in NIA PA-17-089, there is considerable potential in using secondary analyses of
existing biospecimens and data to test new hypotheses in this area. Next-generation sequencing approaches
such as transcriptomics hold great promise in this context, but most sequencing data on aging are based on
known proteins/genes, while the role of non-coding genetic material (the majority of the genome) is often
overlooked. To address this, we used existing samples from human subjects to perform a preliminary study of
total transcriptome changes with aging and exercise—one of the few proven strategies for preserving
physiological function with age. We found age-related increases in gene transcription related to inflammation,
a central hallmark of aging that reduces healthspan, and major changes in non-coding RNA (ncRNA). In
particular, we observed: 1) an age-related increase in repetitive element (RE) transcripts, commonly
overlooked ncRNA derived from repeat sequences that make up > 50% of the genome; 2) strong correlations
between RE transcript levels and both inflammation and physiological function; and 3) a marked reversal of
these events with exercise. These novel observations suggest that dysregulation of RE transcripts may reflect
a previously unrecognized, clinically relevant mechanism of aging. Therefore, we propose to extend this
preliminary study to a larger set of existing samples and data, and we hypothesize that:
 · Aging will be associated with an increase in RE/other ncRNAs and gene expression changes consistent
 with hallmarks of aging (e.g., inflammation), which will be reversed with exercise. To test this, we will isolate
 RNA from peripheral blood cells that we have already collected from carefully matched groups (10 subjects
 per group) of young, older, and older exercising adults, as well as older adults who participated in an
 exercise intervention, and we will characterize the transcriptome by total RNA-seq.
 · RE/other ncRNAs will be related to differences in inflammation and physiological function with aging, and
 may, therefore, provide insight into novel mechanisms of healthspan. We will relate RE/ncRNA and gene
 expression to circulating markers of inflammation and a battery of physiological function measurements
 (vascular, motor/physical, cognitive and metabolic) in a larger group of older adults (n = 110).
 · Changes in RE/ncRNA/gene expression with aging and exercise may be explained by differences in
 chromatin structure, which could provide insight into novel targets for future studies and interventions. To
 test this, we will profile global chromatin accessibility in samples described above using ATAC-seq.
This will be the first research of its kind to profile total transcriptome changes with aging and exercise and to
relate them to inflammation and multiple domains of physiologic...

## Key facts

- **NIH application ID:** 9974455
- **Project number:** 5R21AG060302-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Thomas LaRocca
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $158,623
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974455

## Citation

> US National Institutes of Health, RePORTER application 9974455, Inclusive Transcriptomics to Uncover Molecular Mechanisms Underlying Healthspan (5R21AG060302-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974455. Licensed CC0.

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