# The Impact of Biological Mechanisms of Aging on Response Variability to Resistance Training in Older Adults (BRIO)

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $1,294,013

## Abstract

SUMMARY
 In most individuals, exercise counters the onset and progression of chronic diseases (e.g., type 2 diabetes,
cardiovascular disease, cognitive decline, and cancers), geriatric syndromes (e.g., frailty), and disability, even
when introduced in later-life. However, the physiological effects conveyed by exercise are highly variable across
individuals. In line with RFA-AG-24-045, this application builds on a robust scientific foundation and will use
innovative, multidisciplinary approaches to critically test the central hypothesis that biological mechanisms of
aging are modulators of exercise response heterogeneity (ERH) in older adults. Our proposal centers on cellular
senescence and epigenetics as causes of ERH in two distinct, clinically meaningful co-primary outcomes:
physical function and insulin sensitivity. Senescence is a cell fate that contributes to age-related tissue pathology
and impairs regeneration. Recently, we characterized hallmarks of cellular senescence in human skeletal muscle
and observed negative associations with measures of physical function and insulin sensitivity. We have also
demonstrated that circulating biomarkers of cellular senescence are associated with deficits in physical function
and are responsive to exercise training. Epigenetic modifications effectively govern transcriptional programs that
regulate cellular homeostasis and adaptations to stimuli. DNA methylation (DNAm) at CpG sites is a key
epigenetic modification that changes radically with advancing age. In skeletal muscle, age-associated alterations
in DNAm affect the expression of genes central to functional and metabolic adaptations to exercise. Based on
these observations, we will conduct a randomized, two-site clinical trial of a 6-month structured progressive
resistance training intervention (n = 200) and a health education intervention (HE) (n = 100) to define the ERH
in physical function (Specific Aim 1) and insulin sensitivity (Specific Aim 2) in community dwelling older (³ 65
years) women and men with evidence of mobility limitations. We will use state-of-the-art molecular profiling to
rigorously examine cellular senescence and DNAm in skeletal muscle in parallel with their blood-based
biomarkers. Through predictive approaches to treatment effect heterogeneity, we will examine how these
biological mechanisms, key clinical variables (sex, BMI, comorbid conditions, medications, depression, and
fatigue), and behavioral factors (nutrition, habitual physical activity, sleep, fatigue, and depressive symptoms),
and their interactions, mediate ERH.

## Key facts

- **NIH application ID:** 10979394
- **Project number:** 1R01AG089150-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Roger A. Fielding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,294,013
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979394

## Citation

> US National Institutes of Health, RePORTER application 10979394, The Impact of Biological Mechanisms of Aging on Response Variability to Resistance Training in Older Adults (BRIO) (1R01AG089150-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979394. Licensed CC0.

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