# Physical resilience is a predictor of healthy aging

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $659,148

## Abstract

Abstract Physical resilience is a predictor of healthy aging (Competitive renewal)
The ability to respond to and recover from a physically stressful event is defined as physical resilience. The
inherent individual variation in response to a physical stressor suggests that different stressors trigger different
stress response patterns. A deeper understanding as to why some individuals maintain or regain function
following an insult, while others do not, may help to characterize protective factors that can be engaged to
promote resilience and healthy aging. We have developed and partially characterized three translationally
relevant physical stressors in mice: acute sleep disruption (ASD), the chemotherapeutic drug
cyclophosphamide (CYP), and acute cutaneous trauma (ACT), that trigger responses showing a correlation
with physiological and pathological features associated with increasing age. We have shown in the first grant
period that ASD, CYP, and ACT administered to middle-aged mice results in a range of responsiveness from
low to high, such that mice can be categorized as resistant or susceptible and aligned with phenotypic and
geropathologic parameters of aging. The hypothesis of the competitive renewal is that resilience to aging
is characterized by heterogeneous response patterns unique to defined physical stressors in an age-
dependent manner. Aim 1 is designed to validate physiological targets of ASD, CYP, and ACT.
Responsiveness will be determined by readout assays (escape times in a learning task for ASD, neutrophil to
lymphocyte ratio for CYP, and biopsy healing area for ACT) in middle aged mice as resistant or susceptible to
each physical stressor. Each group of mice will then be followed to older age and aligned with phenotypic
aging endpoints including assessments for memory, strength and agility. Aim 2 is designed to confirm organ-
based targets of ASD, CYP, and ACT in tissues from Aim 1 mice using endpoints based on differences in
geropathology lesion scores in specific organs from the two groups. Digital imaging and biostatistical
paradigms for mouse PathoClock analyses will be used for evaluation of organ-specific and organ-common
geropathology data. Aim 3 is designed to identify and characterize molecular pathways of ASD, CYP, and ACT
in tissues from Aim 1 mice and employ RNA seq for transcriptomic pathway analysis followed by verification
with nanoscale protein analytical platforms and immunohistochemistry imaging for molecular analysis of
relevant pathways in stress resistant and stress susceptible mice. The data can then be aligned with data from
Aims 1 and 2. Investigations into the molecular pathways utilized by cells in a particular tissue and organ in
response to a physical stressor would be of merit in individuals predicted to be less resilient to aging and would
have impactful significance for designing clinical studies to enhance healthy aging.

## Key facts

- **NIH application ID:** 10901916
- **Project number:** 5R01AG057381-07
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Warren C LADIGES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,148
- **Award type:** 5
- **Project period:** 2017-09-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901916

## Citation

> US National Institutes of Health, RePORTER application 10901916, Physical resilience is a predictor of healthy aging (5R01AG057381-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901916. Licensed CC0.

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