Linking kynurenine accumulation and the AHR pathway to exacerbated aging

点击翻译按钮获取中文摘要

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.