Effects of Genetic and Pharmacological Kynurenine Pathway Suppression on Healthspan, Lifespan, and Cellular Changes Associated with Aging in Mice

遗传和药理学犬尿氨酸途径抑制对小鼠健康寿命、寿命和与衰老相关的细胞变化的影响

• 批准号: 10617775
• 负责人: Reyhan M. Westbrook
• 金额: $ 13.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617775
• 关键词: Affect; Age; Aging; Agonist; Amino Acids; Aryl Hydrocarbon Receptor; Autophagocytosis; C57BL/6 Mouse; Caenorhabditis elegans; Cells; Characteristics; Chronic; Coenzymes; Data; Dioxygenases; Drosophila genus; Elderly; Electrons; Epidemiology; Family; Frail Elderly; Free Radicals; Genetic; Genetic Engineering; Goals; Human; Immune; Immunosuppression; Impairment; Inflammation; Inflammatory; Intervention; Knock-out; Knockout Mice; Kynurenic Acid; Kynurenine; Kynurenine 3-monooxygenase; Lead; Link; Longevity; Mammals; Measures; Mediator; Metabolic; Molecular; Mus; Nerve Degeneration; Niacinamide; Organism; Oxidative Stress Induction; Pathologic; Pathway interactions; Phenotype; Physical Function; Physiological; Play; Process; Production; Property; Publishing; Quinolinic Acid; Rodent; Role; Serum; Signal Transduction; Supplementation; Testing; Text; Therapeutic; Tissues; Tryptophan; Vertebrates; aged; anti aging; aryl hydrocarbon receptor ligand; cytokine; cytotoxic; dietary; enzyme pathway; frailty; functional decline; healthspan; improved; indolamine; methyl tryptophan; mortality; pharmacologic; preservation; quinolinate; sarcopenia; senescence; synergism; translational study

Title: Impact of Genetic and Pharmacological Kynurenine Pathway Suppression on Healthspan, Lifespan and Cellular Changes Associated With Aging in Mice PROJECT SUMMARY/ASTRACT (30 LINES OF TEXT) Through findings from translational studies on both aged and chronically inflamed mice, as well as on aged and frail older adults, we have identified metabolites of the kynurenine pathway (KP) as potential mediators of systemic damage caused by chronic inflammation. We recently identified that KP metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine and quinolinic acid were significantly elevated in the serum of older mice and robust and frail older adults, and that this was linked to functional decline and neurodegeneration. The family of molecules known as `kynurenines' are derived from the amino acid tryptophan and are precursors for the important electron carrier and coenzyme molecule NAD+. Kynurenines possess unique bioactive properties and some have pathological potential. For example quinolinic acid (QA) and 3-hydroxykynurenine (3-HK) are neuro- and cytotoxic and induce oxidative stress while kynurenine (KYN) and kynurenic acid (KA) are ligands for the aryl hydrocarbon receptor (AhR), whose signaling activity is linked to immunosuppression, senescence and impaired autophagy. Conversely, genetically inhibiting the KP extends lifespan in C. elegans and Drosophila, and pharmacological KP blockade increases lifespan in Drosophila. Reduced dietary tryptophan extends lifespan in rodents, but it is unknown if genetic or pharmacological KP blockade improves healthspan or extends lifespan in mice. In this study, we aim to evaluate the hypothesis that genetically and pharmacologically suppressing levels of KP metabolites can delay functional decline, pathophysiological metabolic changes, mortality and cellular changes associated with aging in mice. To understand the effects of KP suppression on aging, we will determine the effect of suppressing the oxidative stress inducing kynurenines, 3-HK and QA, using kynurenine 3-monooxygenase knock out mice (KMO -/-, Aim 1). We will also determine the effect of suppressing both oxidative stress inducing kynurenines, 3-HK and QA, as well as AhR agonist kynurenines, KYN and KA using the indolamine 2,3 dioxygenase knockout mouse (Ido -/-, Aim 2). We will then determine if pharmacological suppression of toxic kynurenines and AhR ligands can delay aging in mice using 1-methyltryptophan (Aim 3). Additionally, we will determine if pairing all of these KP suppression strategies with NAD+ supplementation will synergistically benefit healthspan, lifespan and characteristics of aging in mice. These studies will inform on the role of the KP in functional decline and aging and the therapeutic potential of KP suppression as an anti-aging intervention.

标题：遗传和药理学kynurenine途径抑制对健康范围的影响， 与小鼠衰老有关的寿命和细胞变化 项目摘要/Astract（文本30行） 通过对老年和长期发炎的翻译研究的发现以及老化的发现 和脆弱的老年人，我们已经确定Kynurenine途径（KP）的代谢物是 由慢性炎症造成的全身损害。我们最近确定KP代谢产物包括 Kynurenine，Kynurenic酸，3-羟基氰脲和喹啉酸在血清中显着升高 年长的老鼠，健壮的老年人，这与功能下降和 神经变性。称为“ kynurenines”的分子家族源自氨基酸 色氨酸，是重要的电子载体和辅酶分子NAD+的前体。 Kynurenines 具有独特的生物活性特性，有些具有病理潜力。例如喹啉酸（QA） 和3-羟基基硝酸（3-hk）是神经和细胞毒性的，诱导氧化应激，而Kynurenine（Kyn）（Kyn） Kynurenic Acid（Ka）是芳基烃受体（AHR）的配体，其信号活性是连接的 免疫抑制，衰老和自噬受损。相反，遗传抑制KP延伸 秀丽隐杆线虫和果蝇中的寿命以及药理学KP封锁会增加果蝇的寿命。 减少的饮食色氨酸延长了啮齿动物的寿命，但遗传学或药理学KP尚不清楚 封锁改善了健康范围或延长小鼠的寿命。在这项研究中，我们旨在评估以下假设 遗传和药理抑制KP代谢产物水平会延迟功能下降， 与小鼠衰老有关的病理生理代谢变化，死亡率和细胞变化。到 了解KP抑制对衰老的影响，我们将确定抑制氧化的作用 使用kynurenine 3-毫克氧酶敲除小鼠（kmo - / - ，aim，AIM 1）。我们还将确定抑制诱导kynurenine的氧化应激的影响，3-HK和QA， 以及AHR激动剂kynurenines，Kyn和Ka使用吲哚胺2,3二氧酶敲除鼠标（IDO） - / - ，目标2）。然后，我们将确定药理学抑制有毒kynurenines和ahr配体是否可以 使用1-甲基try体延迟衰老（AIM 3）。此外，我们将确定是否配对所有这些KP NAD+补充的抑制策略将协同使HealthSpan，Lifess和 小鼠衰老的特征。这些研究将告知KP在功能下降和衰老中的作用 以及KP抑制作用作为抗衰老干预措施的治疗潜力。