Genomic Analysis of Human Aging and Cognitive Decline

大脑老化是老年人认知能力下降的一个原因，也是老年痴呆症的主要危险因素 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， 衰老的人脑与介导突触可塑性的基因表达减少有关， 囊泡运输和线粒体功能。我们发现了大脑衰老的“基因特征”， 至少部分地解释了氧化DNA损伤脆弱的基因启动子提供了一个潜在的 一个新的概念框架来理解大脑如何衰老。此外，初步的转录本分析 人类血液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与人类衰老有关。初步研究还提出， 老年痴呆症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 在人类衰老过程中具有重要功能的基因，这一过程可能导致认知能力下降， 易患老年痴呆症该提案中的研究将建立一个全基因组数据库， 人血淋巴细胞衰老过程中基因表达和DNA损伤的比较 与脑和肾的概况，以确定是否有一个保守的人类基因组程序， 衰老年龄调节基因的变化和DNA损伤将与详细的 参与修会的受试者一生中获得的神经心理学指标 Study.将评估基因表达或DNA损伤的特定模式，这些模式可以预测 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脆弱性， 每年随访长达15年的受试者。这些研究可能提供深入了解发病机制 与年龄相关的认知能力下降，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.