# Targeting muscle kynurenine aminotransferases and the AHR pathway to mitigate age-related physical decline

> **NIH NIH F32** · UNIVERSITY OF FLORIDA · 2024 · $79,756

## Abstract

ABSTRACT.
The aging process involves a gradual deterioration of physical and physiological
functions, ultimately leading to mortality. Frailty and muscle weakness are prevalent
conditions in the elderly and are strongly associated with negative health outcomes.
Unfortunately, there are no treatments available that can mitigate the potentially reversible
age-associate decline in physical function, although such interventions could have
tremendous impact on the health care system. Recent studies have revealed a strong
correlation between elevated levels of L-kynurenine (L-Kyn) and frailty, muscle weakness,
and neuromuscular junction degeneration in humans, however a causal relationship has
not been tested. L-Kyn is a product of tryptophan breakdown and has been linked to motor
neuron death, skeletal muscle atrophy, mitochondrial dysfunction, all characteristics of
aging. Skeletal muscle plays a critical role in detoxifying L-Kyn into neuroprotective
kynurenic acid via kynurenine aminotransferases (KATs). Interestingly, KAT4, a
mitochondrial isoform, declines with age and distinguishes healthy aging from sarcopenia.
L-Kyn also activates the aryl hydrocarbon receptor (AHR), a transcription factor involved
in regulating gene expression and functioning as an E3 ubiquitin ligase. Chronic AHR
activation has shown toxicity in various cells but has not been explored in the context of
frailty and age-related physical decline. Based on supporting data, I hypothesize that
elevated kynurenine levels and increased AHR activity play a causal role in the decline of
physical function during aging. In this fellowship, I will use novel genetic mouse models
to test if elevated L-Kyn, skeletal muscle L-Kyn degradation, and AHR activation in muscle
are mechanistic drivers of the decline in muscle and physical function with aging. In
addition to advanced training in aging biology, mitochondrial energetics, and muscle
physiology, a robust career development program including scientific communication and
training for leadership in academia have been developed. This training will prepare the
applicant to become an emerging leading in aging research and attain a tenure-track
position at a research-intensive academic institution.

## Key facts

- **NIH application ID:** 10902589
- **Project number:** 1F32AG087637-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Keon Wimberly
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $79,756
- **Award type:** 1
- **Project period:** 2024-08-23 → 2026-03-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902589

## Citation

> US National Institutes of Health, RePORTER application 10902589, Targeting muscle kynurenine aminotransferases and the AHR pathway to mitigate age-related physical decline (1F32AG087637-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10902589. Licensed CC0.

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