Deceleration of Brain Senescence by Dietary Melatonin

描述（由申请人提供）：衰老是指数增加许多疾病发病率的一个因素。褪黑素是一种神经内分泌剂，已被发现可以预防或逆转与大脑衰老相关的一些生化变化。这些变化包括氧化和炎症事件的增加，这两者都与衰老有关。这种应用背后的假设是，膳食褪黑素可能在延缓大脑衰老的一些不良方面有用。将通过比较褪黑激素治疗小鼠与年轻小鼠的mRNA和蛋白质模式来评估与年龄相关的趋势的抑制或逆转。使用行为终点的平行研究将揭示检测到的分子变化是否反映在认知或运动强度的改变上。生理变化和行为变化之间的一致程度可能暗示着一种因果关系。用褪黑激素治疗老年小鼠后，基因表达的变化将使用阵列技术结合Northern blotting进行评估。研究那些与炎症或促氧化事件相关的基因将被强调。将寻求导致基因组调节的细胞质途径。这也将涉及到使用表达褪黑激素受体的细胞系。免疫组织化学鉴定特定肽从固定组织切片将允许更精确的定位信号通路的任何变化进行观察。可能受mRNA水平改变影响的蛋白质水平将使用ELISA和Western测定法进行定量分析。褪黑素恢复线粒体功能完整性和延缓与年龄相关的线粒体DNA缺失的能力也将被评估。本研究的主要目的是促进合理的营养策略的发展，以延缓大脑衰老的进程。

DESCRIPTION (provided by applicant): Aging is a factor that exponentially increases the incidence of many diseases. Melatonin, a neuroendocrine agent, has been found to prevent the development or reverse some biochemical changes associated with brain aging. These changes include increases in oxidative and inflammatory events both of which are associated with senescence. The hypothesis underlying this application is that dietary melatonin may be of utility in retarding some of the undesirable aspects of brain aging. Arrest or reversal of trends associated with age will be evaluated by comparing patterns of mRNA and proteins from melatonin-treated mice with those from younger animals. Parallel studies using behavioral endpoints will reveal whether molecular changes detected, are reflected by altered cognition or motor strength. The degree of consonance between biological and behavioral changes may imply a causal relation. Changes in gene expression following treatment of aged mice with melatonin will be evaluated using array technology in combination with Northern blotting. Investigation of those genes associated with inflammatory or pro-oxidant events will be emphasized. The cytosolic pathways leading to genomic modulation will be sought. This will also involve the use of a cell line expressing melatonin receptors. Immunohistochemical identification of specific peptides from fixed tissue sections will allow a more precise localization of any changes in signaling pathways to be observed. Levels of proteins potentially affected by altered mRNA levels will be quantitated using ELISA and Western assays. The ability of melatonin to restore integrity of mitochondrial functioning and retard age-related mitochondrial DNA deletion will also be evaluated. The principal goal of this study is to contribute to the development of a rational nutritional strategy for delaying progression of brain aging.