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

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.