Resveratrol for Enriching Neurogenesis & Memory in the Aged

描述(申请人提供)：海马区神经发生功能在老年时下降。由于新增加的神经元参与海马体依赖的学习和记忆功能，与年龄相关的神经发生减少被认为是老年人认知功能障碍的原因之一。虽然衰老不会减少可能的海马神经干细胞(NSCs)的数量，也不会损害新生细胞的神经元分化和存活，但在衰老的海马区，静止的NSCs比例会增加。在这种背景下，寻找能够刺激静止的神经干细胞在衰老的海马区产生新神经元的安全膳食补充剂，对于促进老年人认知功能的改善具有巨大的价值。白藜芦醇是一种在红葡萄皮肤中发现的植物保健素，具有强大的抗氧化和抗炎特性，是一种潜在的膳食补充剂，可以改善老化的海马体的神经发生，因为人们认为NSC可塑性的降低与衰老过程中活性氧物种的增加和炎症之间存在联系。此外，在人们意识到白藜芦醇红酒消费者降低了心脏风险后，白藜芦醇正被推广为一种改善心血管健康的膳食补充剂。然而，它对神经干细胞和神经发生的影响尚不清楚。我们假设，老年时给予白藜芦醇可促进海马神经干细胞的增殖和神经发生，进而改善认知功能。我们建议通过以下两个具体目标通过高度量化的实验来解决这一假设。在具体目标1中，我们将量化长期(28天)给予不同剂量的白藜芦醇对老年大鼠刺激神经干细胞增殖和增加海马神经发生程度的效果。在具体目标2中，我们将确定长期服用白藜芦醇是否会改善认知功能障碍的老年大鼠的学习和记忆功能。我们还将确定白藜芦醇治疗后这些受损大鼠的认知功能增强是否与新生神经元加入海马体记忆回路的增加以及神经发生相关基因的表达增加有关。这些研究与开发饮食补充策略高度相关，这些策略可以缓解老年人或阿尔茨海默病早期老年患者与海马体相关的认知障碍。 公共卫生相关性：该项目将测试长期给予白藜芦醇对认知受损老年大鼠刺激神经干细胞增殖、改善海马神经发生和认知功能的效果。这些研究与开发膳食补充剂疗法有关，可以缓解老年人或阿尔茨海默病早期老年患者的认知障碍。

DESCRIPTION (provided by applicant): Hippocampal neurogenesis declines in old age. As newly added neurons participate in hippocampal- dependent learning and memory functions, age-related decrease in neurogenesis is believed to contribute to cognitive dysfunction observed in the elderly. While aging does not reduce the numbers of putative hippocampal neural stem/progenitor cells (NSCs) or impair neuronal differentiation and survival of newly born cells, the percentage of quiescent NSCs increases in the aged hippocampus. In this context, identification of safe dietary supplements that have the ability to stimulate the quiescent NSCs to produce new neurons in the aged hippocampus has immense value for promoting improved cognitive function in the elderly. Resveratrol, a phytoalexin found in the skin of red grapes with potent antioxidant and anti- inflammatory properties, strikes as a potential dietary supplement for improving neurogenesis in the aged hippocampus because of the perceived link between reductions in NSC plasticity and increases in reactive oxygen species and inflammation during aging. Moreover, after the awareness of reduced cardiac risk in the consumers of Resveratrol-containing red wine, Resveratrol is being promoted as a dietary supplement for improving cardiovascular health. However, its effects on NSCs and neurogenesis are unknown. We hypothesize that Resveratrol administration in old age promotes hippocampal NSC proliferation and neurogenesis, which in turn leads to improved cognitive function. We propose to address this hypothesis through highly quantitative experiments in the following two specific aims. In Specific Aim 1, we will quantify the efficacy of long-term (28 days) administration of different doses of Resveratrol in aged rats for stimulating the proliferation of NSCs and increasing the extent of hippocampal neurogenesis. In Specific Aim 2, we will ascertain whether long-term administration of Resveratrol would improve learning and memory function in aged rats displaying cognitive dysfunction. We will also determine whether the enhanced cognitive function after Resveratrol treatment in these impaired rats is associated with increased incorporation of newly born neurons into the hippocampal memory circuitry and increased expression of neurogenesis-related genes. These studies are highly relevant towards developing dietary supplement strategies that ease hippocampal-related cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This project will test the efficacy of long-term administration of Resveratrol in cognitively impaired aged rats for stimulating neural stem cell proliferation and improving hippocampal neurogenesis and cognitive function. These studies are relevant towards developing dietary supplement therapies that alleviate cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease.