# Targeting cellular senescence with senolytics to improve skeletal health in older humans

> **NIH NIH R21** · MAYO CLINIC ROCHESTER · 2021 · $189,645

## Abstract

PROJECT SUMMARY
Mounting evidence suggests that it is feasible to alleviate chronic disorders of aging as a group by targeting the
biology of aging. Because interventions that enhance healthspan (i.e., the healthy period of life free of chronic
disease) and extend lifespan in mammals now exist, we hypothesize that clinical interventions targeting
fundamental mechanisms of aging will delay or alleviate age-related disabilities and diseases as a group,
rather than the current paradigm of treating each separately. This may be feasible by targeting one such
fundamental aging mechanism – cellular senescence. Here we focus on osteoporosis, a common late-life
disease that often co-exists with other chronic diseases and leads to ~2 million fractures and ~$17 billion in
healthcare costs annually, by examining the effects of targeting senescent cells, using “senolytics” – i.e., drugs
that selectively induce senescent cell apoptosis, on skeletal health in older humans.
Our compelling preliminary data implicate cellular senescence at the nexus of skeletal aging. They also provide
evidence for selectively eliminating senescent cells as an innovative and conceptually novel approach to
address the enormous problem of age-related bone loss that is now ready for human testing. Therefore, given
that senescent cells are present at the time and location of age-related bone loss in humans as in mice, we
hypothesize that clinical interventions targeting senescent cells will delay or alleviate age-related bone loss in
older humans. Thus, we will perform a crucial, “proof-of-concept” 20-week, placebo-controlled, randomized
controlled trial to rigorously test whether targeting senescent cells with senolytic therapy improves skeletal
health in older humans. To test this hypothesis, we propose the following Specific Aim: In a cohort of 120 older
postmenopausal women, aged 70-90 yrs, with a high senescent cell burden (as these individuals are most
likely to benefit from pharmacological interventions that eliminate senescent cells – i.e., senolytics), we will test
the efficacy of intermittent senolytic therapy as compared to placebo therapy on improving bone turnover
markers and skeletal parameters over the course of 20 weeks (Aim 1a). We will further assess the impact of
senolytics as compared to placebo on reducing systemic surrogate markers of senescent cell abundance and
circulating senescence-associated secretory phenotype (SASP) factors (Aim 1b).
Translating drugs targeting basic aging processes, such as cellular senescence, into interventions to alleviate
chronic diseases and age-related disabilities is novel from the perspective of basic/clinical research, clinical
care, and healthcare policy. Our goal is to test the efficacy of interventions that target senescent cells to
alleviate skeletal aging. Based on strong preclinical data demonstrating efficacy in mice, our group is now
primed to test senolytics for alleviating age-related bone loss in human trials. If our h...

## Key facts

- **NIH application ID:** 10101603
- **Project number:** 5R21AG065868-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Joshua Nicholas Farr
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $189,645
- **Award type:** 5
- **Project period:** 2020-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101603

## Citation

> US National Institutes of Health, RePORTER application 10101603, Targeting cellular senescence with senolytics to improve skeletal health in older humans (5R21AG065868-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10101603. Licensed CC0.

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