# Frailty:  Prediction of Onset and Progression

> **NIH NIH R56** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2020 · $759,461

## Abstract

ABSTRACT
A poorly understood characteristic in the progression of frailty is the earliest time point within the lifespan at
which frailty is first observed (i.e., onset of frailty). The significance of recognizing this critical time point lies in its
potential to discover the biological mechanisms associated with the pre-frail status and to initiate timely
interventions to prevent frailty. Recently, our work with the mouse frailty phenotype, reverse-translated from
human frailty assessment tools (Fried’s frailty phenotype), demonstrate that C57Bl/6 mice model frailty that is
observed in humans. Hence, we have a mouse assessment tool that has potential to capture the onset of frailty
and the associated biological signatures such as physical function, and cellular and molecular biomarkers. Low-
grade inflammation is postulated to be an underlying mechanism of frailty; yet, it is unknown if the onset of frailty
is associated with an enhanced inflammatory state. If inflammation is at the root of the genesis of frailty,
modulating inflammation is likely to be most effective at the early stage of health decline, at a time when the
compensatory capacity of the organism is not completely exhausted. Driven by our robust preliminary data, we
will test the overarching hypothesis that systemic inflammation is the primary trigger regulating the
genesis of frailty through activation of protein degradation pathways in skeletal muscle, resulting in
decreased muscle function and performance. Aim 1 will determine the onset of frailty and the mortality risk
in male and female mice in experiments designed to gain a better understanding of how the mouse frailty
phenotype provides for rigorous testing of frailty across the lifespan and whether changes in neuromuscular
behavioral performance identify the earliest time points at which frailty markers manifest, using two preclinical
animal models, the C57Bl/6 and the Ames dwarf mice. At the same time, we will integrate the assessment of
memory and the inflammatory profile that likely contribute to health decline with age. Experiments in Aim 2 will
delineate the extent to which skeletal muscle health contributes to the development of frailty in C57Bl/6 mice.
Our preliminary data suggest that the muscles of frail mice at the age of frailty onset are in a catabolic state, with
increased inflammatory stress, impaired muscle contractility, and altered gene expression (RNA-seq profile). To
extend our initial evidence on the role of muscle at the onset of frailty, we will examine muscle function, muscle
protein degradation, transcriptome and inflammatory profiles in age-matched frail and robust, nonfrail mice. At
the completion of this project we will: 1) have confirmed and extended the mouse frailty phenotype as a reliable
tool to determine frailty onset; 2) know in detail whether systemic inflammation is a trigger for the initiation of
frailty; 3) know in cellular and molecular detail whether skeletal muscle is a primary driv...

## Key facts

- **NIH application ID:** 10253486
- **Project number:** 1R56AG067724-01
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** HOLLY M. BROWN-BORG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $759,461
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253486

## Citation

> US National Institutes of Health, RePORTER application 10253486, Frailty:  Prediction of Onset and Progression (1R56AG067724-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10253486. Licensed CC0.

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