Genomic Analysis of Human Aging and Cognitive Decline

大脑老化是老年人认知能力下降的原因之一，也是阿尔茨海默氏症的主要危险因素 和帕金森氏症。一个令人兴奋的最新进展是阐明了一种DNA损伤模式 与调节突触可塑性的基因表达减少有关的老化的人脑， 囊泡运输和线粒体功能。我们发现大脑老化的“基因特征”可能是 解释说，至少部分是由于DNA氧化损伤对脆弱的基因启动子提供了潜在的 了解大脑如何衰老的新概念框架。此外，初步的成绩单分析 对人类血淋巴细胞的研究表明，一些年龄调节基因在血液和大脑中是共同的， 这表明这一过程可能总体上与人类衰老有关。初步研究也提高了 阿尔茨海默病中与年龄相关的基因表达变化可能会加速。这些 这些发现为我们的假设提供了基础，即DNA损伤有助于减少 在人类衰老中具有重要功能的基因，这一过程可能导致认知能力下降和 易患阿尔茨海默氏症。这项提案中的研究将建立一个全基因组数据库 人血淋巴细胞增龄期的基因表达和DNA损伤及其比较 通过大脑和肾脏的图谱来确定人类是否存在保守的基因组计划 衰老。年龄调节基因和DNA损伤的变化将与详细的 通过参与宗教教团的受试者的寿命获得的神经心理指数 学习。将对基因表达或DNA损伤的特定模式进行评估，以预测 整体和特定的认知能力，以及对轻度认知障碍和阿尔茨海默病的易感性， 有长达15年的年度随访的受试者。这些研究可能为深入了解其发病机制提供帮助。 与年龄相关的认知功能减退，具有潜在的重要诊断和治疗意义。

The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's and Parkinson's disease. An exciting recent development is the elucidation of a pattern of DNA damage in the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity, vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be explained, at least in part, by oxidative DNA damage to vulnerable gene promoters provides a potentially novel conceptual framework for understanding how the brain ages. Moreover,preliminary transcript profiling of human blood lymphocytes shows that some age-regulated genes are common to blood and brain, suggesting that this process may be generally relevant to human aging. Preliminary studies also raise the possibility that age-related gene expression changes may be accelerated in Alzheimer's disease. These findings provide the basis for our hypothesis that DNA damage contributes to reduced expression of functionally important genes in human aging, and that this process may contribute to cognitive decline and vulnerability to Alzheimer's disease. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in aging human blood lymphocytesthrough the lifespan and compare it with the brain and kidney profiles to determine whether there is a conserved genomic program of human aging. Changes in age-regulated genes and DNA damage will be correlated with detailed neuropsychological indices obtained through the lifespan in subjects participating in the Religious Orders Study. Specific patterns of gene expression or DNA damage will be assessed that can predict change in global and specific cognitive abilities, and vulnerability to mild cognitive impairment and Alzheimer's disease, in subjects with up to 15 years of annual follow-up. These studies may provide insight into the pathogenesis of age-related cognitive decline, with potentially important diagnostic and therapeutic implications.