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

标题：遗传和药理学犬尿氨酸通路抑制对健康寿命的影响， 小鼠寿命和细胞随增龄的变化 项目摘要/摘要(30行文本) 通过对老年和慢性炎症小鼠以及老年小鼠的翻译研究发现 和虚弱的老年人，我们已经确定犬尿氨酸途径(KP)的代谢物是潜在的 慢性炎症引起的全身性损伤。我们最近发现KP代谢物包括 犬尿氨酸、犬尿酸、3-羟基尿氨酸和喹啉酸均显著升高。 年长的小鼠和强壮和虚弱的老年人，这与功能衰退和 神经退行性变。被称为犬尿氨酸的分子家族由氨基酸衍生而来。 色氨酸是重要的电子载体和辅酶分子NAD的前体。犬尿氨酸 具有独特的生物活性，有些具有病理潜力。例如，喹啉酸(QA) 和3-羟基犬尿氨酸(3-HK)具有神经和细胞毒性，并诱导氧化应激，而犬尿氨酸(KYN) 和犬尿酸(KA)是芳香烃受体(AhR)的配体，其信号活性与 免疫抑制、衰老和自噬受损。相反，从基因上抑制Kp延长了 线虫和果蝇的寿命，以及药理上的KP阻滞剂延长果蝇的寿命。 减少饮食中的色氨酸可以延长啮齿动物的寿命，但尚不清楚是否存在遗传或药理学上的KP 封锁可改善小鼠的健康寿命或延长其寿命。在这项研究中，我们的目标是评估假设 从基因和药物上抑制KP代谢物的水平可以延缓功能衰退， 与衰老相关的小鼠病理生理代谢变化、死亡率和细胞变化。至 了解KP抑制对衰老的影响，我们将确定抑制氧化的效果 应激诱导犬尿氨酸、3-HK和QA，使用犬尿氨酸3-单加氧酶基因敲除小鼠(KMO-/-，目的 1)。我们还将确定抑制氧化应激诱导的犬尿氨酸、3-HK和QA的效果。 以及使用吲哚胺2，3双加氧酶基因敲除小鼠(IDO)的AhR激动剂Kynine、Kyn和Ka -/-，目标2)。然后我们将确定药物抑制有毒的犬尿氨酸和AhR配体是否可以 使用1-甲基色氨酸延缓小鼠衰老(目标3)。此外，我们将确定是否将所有这些KP配对 补充NAD的抑制策略将协同有益于健康寿命、寿命和 小鼠的衰老特点。这些研究将揭示KP在功能衰退和衰老中的作用。 以及抑制KP作为抗衰老干预的治疗潜力。

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.