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途径抑制对健康的影响， 小鼠的寿命和细胞变化与衰老相关 项目概要/ASTRACT（30行文本） 通过对老年和慢性炎症小鼠以及老年小鼠的转化研究发现， 和体弱的老年人，我们已经确定了犬尿氨酸途径（KP）的代谢产物作为潜在的介质， 由慢性炎症引起的系统性损害。我们最近发现，KP代谢物，包括 犬尿氨酸、犬尿烯酸、3-羟基犬尿氨酸和喹啉酸在 老年小鼠和强壮和虚弱的老年人，这与功能衰退有关， 神经变性被称为“犬尿氨酸”的分子家族来源于氨基酸 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，有些具有病理学潜力。例如喹啉酸（QA） 和3-羟基犬尿氨酸（3-HK）具有神经细胞毒性和诱导氧化应激，而犬尿氨酸（KYN） 和犬尿烯酸（KA）是芳香烃受体（AhR）的配体，其信号传导活性与 免疫抑制衰老和自噬受损相反，基因抑制KP延长 寿命在C.在线虫和果蝇中，药理学KP阻断增加果蝇的寿命。 减少饮食中的色氨酸可以延长啮齿类动物的寿命，但尚不清楚遗传或药理学上的KP 阻断可以改善健康状况或延长小鼠的寿命。在这项研究中，我们的目标是评估假设， KP代谢物的遗传和代谢抑制水平可以延迟功能衰退， 病理生理代谢变化、死亡率和与小鼠衰老相关的细胞变化。到 为了了解KP抑制对衰老的影响，我们将确定抑制氧化应激的效果。 使用犬尿氨酸3-单加氧酶敲除小鼠（KMO -/-，Aim 1）。我们还将确定抑制氧化应激诱导的犬尿氨酸，3-HK和QA， 以及AhR激动剂犬尿氨酸、KYN和KA，使用吲哚胺2，3双加氧酶敲除小鼠（Ido -/-，目标2）。然后，我们将确定毒性犬尿氨酸和AhR配体的药理学抑制是否可以 使用1-甲基色氨酸延缓小鼠衰老（目的3）。此外，我们将确定是否将所有这些KP配对 抑制策略与NAD+补充将协同有益于健康寿命，寿命和 小鼠衰老的特征。这些研究将告知KP在功能衰退和衰老中的作用 以及KP抑制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.