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。这表明需要创新的方法，而针对老龄化就是这样的方法之一。 衰老是阿尔茨海默病和痴呆症的一个主要风险因素；然而，它经常被忽视。研究生物机制 而延缓衰老的人群可能会导致识别出可以保护人们免受AD影响的分子因素。 我们小组和其他人的大量证据表明，通过促生长激素途径传递的信号减弱 这通过胰岛素样生长因子-I发出信号，延缓衰老，导致更长的寿命和无痴呆症的存活， 不仅在模型生物中，而且在人类中也是如此。事实上，百岁老人尽管有痴呆症的抵抗力 高龄，富含减弱促生长激素信号的突变。认知 促生长激素信号减弱所产生的韧性可能是通过自噬来实现的。减少 促生长信号已被证明上调自噬，这是一种维持细胞过程的过程 通过清除功能失调的蛋白质和细胞碎片来实现动态平衡。与年龄相关的自噬活动下降 在大多数组织中观察到，并与包括阿尔茨海默病在内的神经退行性疾病有关，但 百岁老人保持着自噬活动。这个项目汇集了一个多学科的专家团队。 世卫组织将检验这样一种假设，即减少促生长激素信号会导致认知弹性和保护 从AD，部分是通过增强的自噬活动。它将决定是否体感运动的轨迹 荷尔蒙可以预测认知韧性，并可用作生物标记物(目标1)。它也将适用于整个外显子组 DNA序列(WES)数据新的计算方法，将功能性遗传变异整合到 通过这些基因之间的生物相互作用调节促生长轴的基因在一个途径水平上 计算估计促生长功能的遗传途径分数，如测量的循环水平 促生长激素并不总是准确地反映通路的功能。这一遗传途径得分将 随后测试其与认知功能减退、阿尔茨海默病发病率、核磁共振脑成像的关系(AIM 2) 和自噬活动(目标3)。这些方法将应用于老年人的纵向队列 (n=1,400；平均年龄76岁，中位随访6.1年)，来自正在进行的LonGenity研究，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 独特的队列(1)富含保护性基因，因为其中一半是百岁老人的后代，IS(2) 在基因上相对相同，因为所有的受试者都来自德系犹太人创始人群体，这是一个特征 这增加了基因发现的力量。该项目有可能发现遗传和分子 认知韧性的生物标记物。此外，它将彻底描述促生长激素信号的作用。 并可能确定通过延缓衰老来增强认知韧性的机制， 它可以作为治疗的靶点。

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.