PROJECT SUMMARY/ABSTRACT
Physical frailty (hereafter simplified to “frailty”) refers to a clinical state associated with an
individual’s increased risk of dependence or mortality when exposed to a stressor and has
emerged as a major predictor of poor health outcomes in the elderly. Unfortunately, the
mechanisms contributing to the exacerbation of normal aging that precipitates frailty are largely
unknown. In this regard, recent epidemiological studies find that elevated circulating levels of
kynurenine, a product of tryptophan metabolism that accumulates in blood with aging, strongly
associate with poor physical function and elevated risk of frailty. However, a causal relationship
between elevated kynurenine and poor physical function/frailty has not been tested. Our
preliminary data show that kynurenine causes atrophy and impaired mitochondrial function in
skeletal muscle cells that can be rescued by increasing the capacity for kynurenine
biotransformation into the neuroprotective metabolite, kynurenic acid. Since kynurenine is also an
agonist of the ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR),
it is noteworthy that we find that transcripts regulated by the AHR are upregulated in aging muscle,
and that AHR knockdown blunts kynurenine-induced mitochondrial dysfunction. Finally, we also
show that chronic AHR activity alone is sufficient to induce atrophy, mitochondrial dysfunction and
neuromuscular junction degeneration in young mice, which are hallmarks of aging that are
exacerbated in frailty. On this basis, the first goal of this project is to determine if elevated
kynurenine levels accelerate the physical function decline and frailty with aging in mice. Secondly,
we will determine if enhancing kynurenine metabolism attenuates the decline of physical function
and frailty with aging in mice, with or without elevated kynurenine. Thirdly, we will test if knockout
of the AHR attenuates the decline of physical function and frailty with aging in mice, with or without
elevated kynurenine. Finally, we will test if chronic AHR activity in muscle alone is sufficient to
accelerate physical function decline and frailty with aging in mice. By doing so, our studies will lay
the foundation for future testing of therapies that augment kynurenine metabolism and/or inhibit
the AHR as a means of attenuating frailty with aging.