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.

项目摘要/摘要 身体虚弱（以下简化为“脆弱”）是指与 暴露于压力源时，个人的依赖或死亡风险增加，并且 成为对健康状况不佳的主要预测指标。不幸的是， 导致加剧正常衰老的机制在很大程度上是脆弱的 未知。在这方面，最近的流行病学研究发现循环水平升高 kynurenine，色氨酸代谢的产物，随着衰老而积累，强烈 与身体机能差，脆弱风险升高。但是，因果关系 尚未测试雌激素升高和身体功能/脆弱性之间。我们的 初步数据表明，kynurenine在 可以通过增加kynurenine的能力来挽救的骨骼肌细胞 生物转化为神经保护代谢产物，kynurenic酸。由于kynurenine也是 配体激活转录因子的激动剂，称为芳基烃受体（AHR）， 值得注意的是，我们发现由AHR调节的成绩单已在衰老的肌肉中更新， AHR敲低钝化kynurenine诱导的线粒体功能障碍。最后，我们也是 表明仅慢性AHR活性就足以诱导萎缩，线粒体功能障碍和 年轻小鼠的神经肌肉连接变性，这是衰老的标志 脆弱的恶化。在此基础上，该项目的第一个目标是确定是否提升 小鼠的身体机能下降和脆弱，kynurenine水平随着小鼠的衰老而加速。第二， 我们将确定增强Kynurenine代谢是否会减轻身体机能的下降 和衰老的小鼠，有或没有升高的雌激素。第三，我们将测试是否淘汰赛 AHR的衰老减弱了小鼠，有或没有的衰老 甲鲁尼升高。最后，我们将测试单独肌肉中的慢性AHR活性是否足以 随着小鼠的衰老而加速身体机能下降和脆弱。通过这样做，我们的研究将奠定 对疗法的未来测试基础，增强kynurenine代谢和/或抑制 AHR是一种衰老的减轻脆弱的手段。