# PROJECT 3 - Kynurenine-AhR Signaling Effects on Mitophagy and Senescence with Age in Bone Marrow Stem Cells

> **NIH NIH P01** · AUGUSTA UNIVERSITY · 2023 · $361,769

## Abstract

Our group recently identified the tryptophan-kynurenine (Kyn) catabolic pathway as a novel causal
mechanism in age-associated musculoskeletal complications (stem cell dysfunction, muscle, and bone
loss). Our published studies reported that the Kyn pathway is activated with age and decreases bone
marrow-derived mesenchymal stem cells (BMSCs) differentiation, decreased autophagy flux, induces
premature senescence, and promotes bone loss. Furthermore, our pilot study demonstrated that inhibiting
AhR prevented bone deterioration and reduced systemic stress markers in aged mice. Based on our
published and preliminary data, our central hypothesis is that elevated levels of Kyn metabolites and AhR
activation with age in bone and BMSCs lead to altered autophagy/mitophagy flux, which underlies
mitochondrial dysfunction and BMSC’s vulnerability to premature senescence, leading to decreased
osteogenic differentiation, and consequently increased bone loss. This hypothesis will be tested with two
independent but related aims. Specific Aim 1: To test the hypothesis that the accumulation of Kyn
and its metabolites alters mitophagy and induces premature senescence with age in BMSCs
thereby affecting osteogenic pathways (in vitro and in vivo). We will define the roles of several Kyn
metabolites (e.g., Kyn, KynA) in the inhibition of mitophagy and senescence in vitro and in vivo. We will
assess autophagy and senescent biomarkers, senescence-associated secretory phenotype (SASP) gene
expression, and Kyn metabolite profiles to identify potential translational approaches. Specific Aim 2:
Test the hypothesis that inhibiting AhR signaling in response to Kyn pathway metabolites restores
mitophagy and inhibits premature senescence, rescuing osteogenesis, thereby reducing or
preventing bone loss with age. For this specific aim, we will use pharmacological inhibitors (e.g., CH-
223191) and genetic manipulation (stem cell and bone-specific AhR KO mice using, e.g., Prrx1-Cre, Osx1-
Cre) to examine the ability of AhR inhibition to restore autophagy and inhibit senescence in BMSCs. The
knowledge gained from our proposed studies will establish a conceptual framework to advance the
therapeutic potential of AhR inhibition in age-related musculoskeletal fragility.

## Key facts

- **NIH application ID:** 10691505
- **Project number:** 5P01AG036675-12
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Sadanand tukdoji Fulzele
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $361,769
- **Award type:** 5
- **Project period:** 2011-05-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691505

## Citation

> US National Institutes of Health, RePORTER application 10691505, PROJECT 3 - Kynurenine-AhR Signaling Effects on Mitophagy and Senescence with Age in Bone Marrow Stem Cells (5P01AG036675-12). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691505. Licensed CC0.

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