Linking kynurenine accumulation and the AHR pathway to exacerbated aging

将犬尿氨酸积累和 AHR 通路与加速衰老联系起来

• 批准号: 10416585
• 负责人: Russell T Hepple
• 金额: $ 51.08万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416585
• 关键词: Age; Aging; Agonist; Aryl Hydrocarbon Receptor; Atrophic; Attenuated; Binding; Blood; Body Weight; Catabolism; Cells; Chronic; Chronic Disease; Clinical; Clinical Research; Coupled; Cytochrome P450; Cytosol; Data; Denervation; Dependence; Deterioration; Diet; Disease; Drug Metabolic Detoxication; Elderly; Enzymes; Exposure to; FDA approved; Foundations; Frail Elderly; Functional disorder; Future; GOT2 gene; Genetic Models; Goals; Hand Strength; Health; Human; Impairment; In Situ; Individual; Knock-out; Knockout Mice; Kynurenic Acid; Kynurenine; Kynurenine-oxoglutarate aminotransferase; Life Expectancy; Ligands; Link; Longevity; Metabolic; Metabolic Biotransformation; Metabolism; Mitochondria; Modeling; Modernization; Morbidity - disease rate; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Neuromuscular Junction; Outcome; Oxidative Phosphorylation; Pathway interactions; Phenotype; Physical Function; Physiological; Predisposition; Protein Isoforms; Proteolysis; Quality of life; Reactive Oxygen Species; Receptor Activation; Reporting; Research; Resveratrol; Risk; Rodent; Role; Skeletal Muscle; Testing; Tissues; Transcript; Tryptophan; Tryptophan Metabolism Pathway; Work; age related; antagonist; aryl hydrocarbon receptor ligand; base; disorder risk; drug testing; epidemiology study; exercise training; frailty; healthy aging; indexing; inhibitor; knock-down; loss of function; mitochondrial dysfunction; mortality; muscle aging; muscle form; neuromuscular; neuron loss; normal aging; sarcopenia; skeletal muscle wasting; stressor; therapeutic target; transcription factor; walking speed

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.

项目总结/摘要 身体虚弱（下文简化为“虚弱”）是指与疾病相关的临床状态。 个人的依赖性或死亡的风险增加时，暴露于压力， 成为老年人健康状况不佳的主要预测因素。可惜 导致正常衰老加剧的机制主要是 未知在这方面，最近的流行病学研究发现， 犬尿氨酸是色氨酸代谢的产物，随着年龄的增长在血液中积累， 与身体机能差和虚弱风险增加有关。然而，因果关系 犬尿氨酸升高与身体功能差/虚弱之间的关系尚未得到检验。我们 初步数据显示，犬尿氨酸导致脑萎缩和线粒体功能受损， 可以通过增加犬尿氨酸的能力来拯救的骨骼肌细胞 生物转化为神经保护代谢物犬尿烯酸。由于犬尿氨酸也是一种 被称为芳烃受体（AHR）的配体激活的转录因子的激动剂， 值得注意的是，我们发现由AHR调节的转录物在衰老的肌肉中上调， 并且AHR敲低减弱犬尿氨酸诱导的线粒体功能障碍。最后还 表明慢性AHR活性单独足以诱导萎缩、线粒体功能障碍 神经肌肉接头退化的年轻小鼠，这是老化的标志， 在脆弱中恶化。在此基础上，本项目的第一个目标是确定是否高架 犬尿氨酸水平加速了小鼠身体功能的衰退和衰老。第二、 我们将确定增强犬尿氨酸代谢是否会减弱身体功能的下降， 以及随着小鼠衰老而虚弱，具有或不具有升高的犬尿氨酸。第三，我们将测试如果淘汰赛 无论有无，AHR的作用均可减弱小鼠随着衰老而出现的身体机能衰退和虚弱 犬尿氨酸升高。最后，我们将测试单独肌肉中的慢性AHR活动是否足以 加速小鼠身体机能衰退和衰老衰弱。通过这样做，我们的研究将奠定 为将来测试增强犬尿氨酸代谢和/或抑制犬尿氨酸代谢的疗法奠定了基础。 AHR作为一种随着年龄增长而减弱虚弱的手段。