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、炎症和神经变性中起作用，并且这些过程中的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C. elegans，结合内源性大麻素代谢酶之一的遗传操纵延长寿命的观察，现在表明这种强大的模式生物可用于定义内源性大麻素在寿命决定中的作用。利用气相色谱-质谱（GC-MS），我已经确定了多种内源性大麻素（EC）分子在C。包括哺乳动物内源性大麻素配体的同种型。在蠕虫中，内源性大麻素似乎在生殖发育和幼虫的形成中起作用。与哺乳动物一样，它们也调节幼虫和成虫的摄食率。在成年野生型动物中，EC水平随年龄增加，但在长寿的胰岛素信号转导突变体中则不然，这表明EC缺乏可能与长寿有关。我还发现，化学或遗传操作的蠕虫直向同源物的脂肪酸酰胺水解酶（FAAH），酶负责EC水解和失活，改变EC水平的方式与保守的功能，这种酶。此外，降低内源性大麻素水平的FAAH的转基因过表达导致成年动物的寿命延长，并且这种寿命效应不需要FOXO转录因子β-16的活性。这些数据提供了线虫中存在功能性内源性大麻素系统的第一个证据，并表明现在可以利用这种强大的遗传模型系统来定义ECS的哪些操作在健康寿命，衰老和年龄相关疾病方面最有益。在这个建议中，我将评估操纵内源性大麻素系统对寿命决定和功能性衰老（健康寿命）的影响。由于衰老是许多疾病的主要危险因素，我还将在已建立的年龄相关疾病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的限速酶，因为这可能提供一个新的干预目标。这些研究将共同提供一个机会，以确定内源性大麻素系统可以被操纵以促进健康衰老的方式，以及确定人类衰老和疾病的新治疗策略。 公共卫生相关性：哺乳动物内源性大麻素系统在营养摄入、能量平衡、免疫、炎症和神经退行性变中起作用，并且这些过程中的许多过程与衰老和年龄相关疾病有关。在线虫C. elegans延长寿命表明，这种无脊椎动物模型系统可能有助于确定内源性大麻素信号在衰老过程中的作用。

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.