Deceleration of Brain Senescence by Dietary Melatonin

描述（由申请人提供）：老龄化是一个因素，指数增加许多疾病的发病率。褪黑激素是一种神经内分泌因子，它能阻止或逆转与脑老化有关的某些生化变化。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。这项申请的假设是，饮食褪黑激素可能是在延缓大脑老化的一些不可取的方面的效用。将通过比较褪黑激素处理小鼠与年轻动物的mRNA和蛋白质模式，评价与年龄相关的趋势的停滞或逆转。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。生物学和行为变化之间的一致程度可能意味着因果关系。将使用阵列技术结合北方印迹法评估用褪黑激素处理老年小鼠后基因表达的变化。将强调与炎症或促氧化事件相关的那些基因的调查。将寻求导致基因组调节的胞质途径。这也将涉及使用表达褪黑激素受体的细胞系。从固定的组织切片的特定肽的免疫组织化学鉴定将允许更精确地定位待观察的信号通路中的任何变化。将使用ELISA和Western试验定量可能受mRNA水平改变影响的蛋白质水平。还将评估褪黑激素恢复线粒体功能完整性和延缓年龄相关的线粒体DNA缺失的能力。本研究的主要目的是为延缓脑老化的发展提供合理的营养策略。

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.