Endocannabinoid signaling and aging

描述（由申请人提供）：哺乳动物内源性大麻素系统（ECS）在营养摄入、能量平衡、免疫、炎症和神经退行性变中发挥作用，其中许多过程与衰老和年龄相关疾病有关。然而，内源性大麻素信号在衰老过程中的直接作用尚未得到证实。我在线虫秀丽隐杆线虫中发现了内源性大麻素系统，并观察到内源性大麻素代谢酶的一种基因操作可以延长寿命，这表明这种强大的模式生物可以用来确定内源性大麻素在寿命决定中的作用。使用气相色谱-质谱（GC-MS），我已经鉴定了秀丽隐杆线虫中的多种内源性大麻素（EC）分子，包括哺乳动物内源性大麻素配体的异构体。在蠕虫中，内源性大麻素似乎在生殖发育和幼虫形成中起作用。就像哺乳动物一样，它们也调节着幼虫和成虫的摄食率。在成年野生型动物中，EC水平随着年龄的增长而增加，但在长寿的胰岛素信号突变体中却没有，这表明EC缺乏可能与长寿有关。我还发现，对脂肪酸酰胺水解酶（FAAH）（负责EC水解和失活的酶）的蠕虫同源物进行化学或遗传操作，以与该酶功能守恒一致的方式改变EC水平。此外，转基因FAAH的过表达会降低内源性大麻素水平，从而延长成年动物的寿命，而这种长寿效应不需要FOXO转录因子DAF-16的活性。这些数据为线虫中存在功能性内源性大麻素系统提供了第一个证据，并表明现在可以利用这个强大的遗传模型系统来确定哪种ECS操作对健康、衰老和与年龄相关的疾病最有益。在本提案中，我将评估操纵内源性大麻素系统对寿命确定和功能衰老（健康寿命）测量的影响。由于衰老是许多疾病的主要危险因素，我还将在已建立的与年龄相关的疾病的蠕虫模型中检查这些操作的影响。最后，我将进行有针对性的筛选，以确定内源性大麻素生物合成中的限速酶，因为这可能为干预提供新的靶点。总之，这些研究将提供一个机会来确定内源性大麻素系统可以被操纵的方式，以促进健康衰老，以及确定人类衰老和疾病的新治疗策略。

DESCRIPTION (provided by applicant): The mammalian endocannabinoid system (ECS) plays a role in nutrient intake, energy balance, immunity, inflammation and neurodegeneration, and many of these processes have been implicated in aging and age- related disease. However, a direct role for endocannabinoid signaling in the aging process has yet to be demonstrated. My discovery of an endocannabinoid system in the nematode C. elegans, combined with the observation that genetic manipulation of one of the endocannabinoid metabolizing enzymes extends lifespan, now suggests that this powerful model organism can be used to define the role of endocannabinoids in lifespan determination. Using gas chromatography-mass spectrometry (GC-MS) I have identified multiple endocannabinoid (EC) molecules in C. elegans, including isoforms of the mammalian endocannabinoid ligands. In worms endocannabinoids appear to have a role in reproductive development and formation of the dauer larva. As is the case in mammals, they also regulate feeding rates in both larvae and adults. EC levels increase with age in adult wild type animals but not in a long-lived insulin signaling mutant, suggesting that EC deficiency may associate with longevity. I have also found that chemical or genetic manipulation of the worm ortholog of fatty acid amide hydrolase (FAAH), the enzyme responsible for EC hydrolysis and inactivation, alters EC levels in a manner consistent with a conservation of function of this enzyme. Furthermore, transgenic over-expression of FAAH, which reduces endocannabinoid levels, leads to lifespan extension in adult animals and this longevity effect does not require the activity of the FOXO transcription factor DAF-16. These data provide the first evidence for the existence of a functional endocannabinoid system in the nematode and suggest that this powerful genetic model system can now be exploited to define which manipulations of the ECS are most beneficial in terms of healthspan, aging and age-related disease. In this proposal I will assess the effects of manipulating the endocannabinoid system on lifespan determination and measures of functional aging (healthspan). Since aging is a major risk factor for a number of diseases I will also examine the impact of these manipulations in established worm models of age-related disease. Finally I will undertake a targeted screen to identify the rate-limiting enzyme in endocannabinoid biosynthesis as this may provide a novel target for intervention. Together these studies will provide an opportunity to define the ways in which the endocannabinoid system can be manipulated to promote healthy aging as well as identifying novel therapeutic strategies for human aging and disease. PUBLIC HEALTH RELEVANCE: The mammalian endocannabinoid system plays a role in nutrient intake, energy balance, immunity, inflammation and neurodegeneration, and many of these processes have been implicated in aging and age- related disease. The discovery that genetic manipulation of a novel endocannabinoid system in the nematode C. elegans extends lifespan suggests that this invertebrate model system may be useful for defining a role of the endocannabinoid signaling in the aging process.