Longevity assurance interventions, metabolic health and Alzheimer's Disease

神经退行性变发病的年龄依赖性机制是 未知，这代表了神经科学和神经生物学的一个基本问题。 阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征在于 痴呆、β淀粉样蛋白（A β）斑块沉积和神经原纤维tau缠结。尽管 尽管在开发用于AD症状缓解的治疗方面取得了进展，但大多数药物仅表现出 边际效益和目前没有治愈。流行病学和临床前研究提供 有力的证据表明，代谢紊乱，包括肥胖，代谢综合征和2型 糖尿病是包括痴呆和AD在内的年龄相关疾病的主要危险因素， 所涉及的机制仍有待阐明。 GH信号作为代谢和能量利用的中心调节器发挥作用， 通过激素信号协调整个生物体的生理反应。 GH信号减少的突变动物不仅寿命长，而且可以防止 与年龄相关的记忆力和学习能力下降。甲硫氨酸限制已经显示 以前在大鼠和小鼠中延长寿命和延缓衰老， 体重和肥胖，并改善胰岛素敏感性和改善衰老相关的变化 在葡萄糖和脂质体内平衡中。因此，将延缓衰老模型与AD疾病相结合， 表现出各种表型效应的模型为开发新的 这些模型将使研究集中在衰老、新陈代谢和 神经变性 我们提出的研究将确定是否抑制生长激素信号和蛋氨酸 限制将阻止行为，电生理和组织病理学的发展 AD表型的异常可以作为研究衰老与AD相互作用的模型， 提供了一个新的水平的分析人类大脑的健康和疾病。

The mechanisms responsible for the age dependence of the onset of neurodegeneration are unknown, which represents a fundamental problem both in neuroscience and biogerontology. Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by dementia, deposition of beta amyloid (Aβ) plaques, and neurofibrillary tau tangles. Despite progress in developing treatments for the symptomatic relief of AD, most drugs only exhibit marginal benefits and no cure currently exists. Epidemiological and preclinical studies provide strong evidence that metabolic derangements including obesity, metabolic syndrome and type 2 diabetes constitute major risk factors for age-related diseases including dementia and AD but the mechanisms involved remain to be elucidated. The GH signaling functions as a central regulator of metabolism and energy use, and it coordinates the physiological responses of the entire organism through hormonal signaling. Mutant animals with reduced GH signaling are not only long-lived, but are protected against age-associated decline in memory and learning. Methionine restriction has been shown previously to extend lifespan and delay aging in both rats and mice, dramatically decrease body weight and adiposity, and improve insulin sensitivity and ameliorate aging-associated alterations in glucose and lipid homeostasis. Thus, combing delaying aging models with AD disease models exhibiting various phenotypic effects provides a novel opportunity to develop new models that will allow studies focused on the interaction between aging, metabolism, and neurodegeneration. Our proposed study will determine if suppression of the GH signaling and methionine restriction will prevent development of behavioral, electrophysiological and histopathologic abnormalities of AD phenotype can serve as a model to study the interaction of aging with AD, providing a new level of analysis of the human brain in health and disease.