Somatotropic Signaling and Resilience to Aging and Alzheimer's Disease

摘要 尽管研究界做出了重大努力，但阿尔茨海默病（AD）的有效疗法仍然存在 难以捉摸。这表明，需要采取创新的办法，而针对老龄化就是这样一种办法。 衰老是AD和痴呆症的主要危险因素;然而，它往往被忽视。研究生物机制 而延缓衰老的人群可能会导致识别出可以预防AD的分子因子。 我们的研究小组和其他研究小组提供的大量证据表明， 通过胰岛素样生长因子-I传递的信号可以延缓衰老，从而延长寿命和无痴呆症生存， 不仅在模式生物中，而且在人类中。事实上，百岁老人，谁是恢复痴呆症，尽管 年龄大的人，富含减弱促生长信号的突变。认知 由减少的促生长素信号传导所赋予的恢复力可由自噬介导。减少 促生长信号已被证明上调自噬，这是一种细胞过程， 通过清除功能失调的蛋白质和细胞碎片来维持体内平衡。自噬活性下降 在大多数组织中观察到，并涉及神经退行性疾病，包括AD，但 百岁老人保持着自噬的活性。该项目汇集了一个多学科的专家团队 他将检验这一假说，即减少促生长信号导致认知恢复力和保护 从AD，部分，通过增强自噬活性。它将决定是否somototropic轨迹 激素预测认知弹性，并可用作生物标志物（目标1）。它也适用于整个外显子组 DNA序列（WES）数据整合功能遗传变异的新计算方法 调节生长激素轴的基因，这些基因之间在通路水平上具有生物学相互作用 计算估计促生长功能的遗传途径评分，作为测量的循环水平， 促生长激素并不总是准确地反映通路功能。这种遗传途径得分将 随后测试其与认知下降、AD发病率、MRI脑成像的相关性（目的2） 和自噬活性（Aim 3）。这些方法将应用于一个纵向队列的老年人 （n= 1，400;平均年龄76岁，中位随访时间6.1年），这些患者每年 通过神经认知测试进行评估，储存了纵向生物样本，并进行了WES。这 一个独特的群体是（1）富含保护基因，因为他们中的一半是百岁老人的后代，（2） 相对同质的基因，因为所有的科目都来自德系犹太创始人人口，一个特点， 这增加了基因发现的力量。该项目有可能发现遗传和分子 认知恢复力的生物标志物。此外，它将彻底描述促生长信号的作用， 并可能确定通过延缓衰老赋予认知弹性的机制， 其可以是治疗靶向的。

ABSTRACT Despite major efforts by the research community, effective therapies for Alzheimer's disease (AD) remain elusive. This indicates that innovative approaches are required and targeting aging is one such approach. Aging is a major risk factor for AD and dementia; yet, it is often overlooked. Studying biological mechanisms and populations that delay aging may lead to the identification of molecular factors that can protect from AD. Substantial evidence exists from our group and others that diminished signaling via the somatotropic pathway that signals via insulin-like growth factor-I delays aging, resulting in longer lifespan and dementia-free survival, not only in model organisms, but also in humans. In fact, centenarians, who are resilient to dementia despite advanced chronological age, are enriched with mutations that attenuate somatotropic signaling. Cognitive resilience conferred by reduced somatotropic signaling may be mediated by autophagy. Reduction in somatotropic signaling has been shown to up-regulate autophagy, a cellular process that maintains homeostasis by clearing dysfunctional proteins and cellular debris. Age-related decline in autophagic activity has been observed in most tissues and implicated in neurodegenerative diseases, including AD, but centenarians maintain their autophagic activity. This project brings together a multidisciplinary team of experts who will test the hypothesis that reduced somatotropic signaling results in cognitive resilience and protection from AD, in part, via enhanced autophagic activity. It will determine whether trajectories of somototropic hormones predict cognitive resilience and can be used as biomarkers (Aim 1). It will also apply to whole exome DNA sequence (WES) data novel computational methods that integrate functional genetic variants within genes that regulate the somatotropic axis with biological interactions between these genes on a pathway level to compute a genetic pathway score that estimates somatotropic function, as measured levels of circulating somatotropic hormones do not always reflect pathway function accurately. This genetic pathway score will subsequently be tested for its association with cognitive decline, AD incidence, brain imaging on MRI (Aim 2) and autophagic activity (Aim 3). These approaches will be applied to a longitudinal cohort of older adults (n=1,400; mean age 76, median follow-up 6.1 years) from the ongoing LonGenity study, who are annually evaluated with neurocognitive tests, have banked longitudinal biological samples, and have had WES. This unique cohort is (1) enriched with protective genes, as half of them are offspring of centenarians and is (2) relatively homogeneous genetically, as all subjects are from an Ashkenazi Jewish founder population, a feature that increases the power for genetic discovery. The project has the potential to discover genetic and molecular biomarkers for cognitive resilience. Moreover, it will thoroughly characterize the role of somatotropic signaling in the brain in aging humans and may identify mechanisms that confer cognitive resilience by delaying aging, which can be therapeutically targeted.