# The Role of Cellular Senescence in Mediating Age-Related Bone Loss

> **NIH NIH K01** · MAYO CLINIC ROCHESTER · 2020 · $128,034

## Abstract

PROJECT SUMMARY/ABSTRACT
Advanced age is the key risk factor for most chronic diseases, including osteoporosis, contributing to
enormous costs that will only worsen with our growing elderly population. Thus, there is a critical need to
develop interventions that can prevent or reverse age-related diseases as a group and thereby maximize
healthspan in humans. This may be feasible by targeting a fundamental aging mechanism – cellular
senescence. Emerging evidence suggests that senescent cells and their senescence-associated secretory
phenotype (SASP) are promising therapeutic targets to prevent age-related diseases as a group. Indeed,
because with advancing age senescent cells accumulate in multiple tissues in temporal and spatial synchrony
with age-associated functional decline in both animals and humans, they have been hypothesized to disrupt
tissue function and to promote degenerative pathologies. The causal link between senescence and age-related
tissue dysfunction has been demonstrated in genetically modified progeroid mice (an accelerated aging model)
expressing a “suicide” transgene, which permits inducible elimination of senescent cells upon administration of
a synthetic drug. This approach had a profound effect on enhancing healthspan by delaying the onset of aging
pathologies in multiple tissues, including adipose, eye, and skeletal muscle. However, how senescent cells
impact age-related bone loss and whether their removal can delay or prevent this loss remains unclear.
The goal of the proposed studies is to test the hypothesis, for the first time, that the adverse effects of
increased cellular senescence play a central role in age-related bone loss. This hypothesis is supported by
preliminary data indicating that senescent cells, particularly senescent osteocytes, accumulate in bone with
aging. As previous studies have used progeroid mice, there is a critical need to demonstrate a similar benefit of
eliminating senescent cells in normal aged mice. Thus, in normal chronologically aged mice, the proposed
studies will determine the extent to which systemic elimination of senescent cells through genetic and
pharmacological approaches prevents age-related bone loss, and whether local elimination of senescent
osteocytes is sufficient to prevent skeletal aging. Further, embedded in these studies will be analyses of highly
enriched populations of osteocytes as well as other cell types in the bone microenvironment hypothesized to
be of importance in mediating tissue damage in response to the SASP, thereby providing important
mechanistic insights. These innovative approaches should lead to new hypotheses regarding the mechanisms
by which senescent cells contribute to tissue dysfunction and the onset of age-related degenerative diseases.
The significance of these studies is the provocative possibility that targeted elimination of senescent cells may
prevent age-related diseases as group, potentially reducing polypharmacy and adverse drug interactio...

## Key facts

- **NIH application ID:** 9977929
- **Project number:** 5K01AR070241-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Joshua Nicholas Farr
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $128,034
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977929

## Citation

> US National Institutes of Health, RePORTER application 9977929, The Role of Cellular Senescence in Mediating Age-Related Bone Loss (5K01AR070241-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977929. Licensed CC0.

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