基于端粒叶酸对神经细胞凋亡及延缓老年人认知减退的作用及机制研究

With the aging of population, improving cognitive function in older people has been becoming one of the major research interests recently. Folate may affect the length and stability of telomere through modulates nucleotide synthesis and DNA methylation, which is associated with cell apoptosis and neurodegenerative diseases. Our previous studies showed that folic acid supplementation could improve cognitive function in older people, which was associated with significant reducing the levels of plasma homocysteine and serum inflammatory cytokines. However, whether folate delays neurodegenerative changes through mediate neurocyte apoptosis and telomere stability remains unclear. In this study, a cohort will be established to investigate the effects of folic acid on cognitive function in older people and its underlying mechanism. And health effects of folate on improving cognitive function in older people via mediating telomere stability will be verified by the randomized control trial of folic acid intervention. Then the relationship among folate and telomere stability and neurocytes apoptosis and cognitive function will be confirmed in vivo and in vitro at molecular level. The effects of folate modulate neurocytes apoptosis and cognitive function by mediating telomere stability through three pathways including telomere stability, neurocytes apoptosis and methionine cycle metabolites will study by epidemiology study, in vivo and in vitro studies. The research will explore the molecular mechanisms of folate modulate neurocytes apoptosis and cognitive function by mediating telomere stability. This study will can provide new approach of delaying cognitive decline in older people.

随着人口老龄化，改善老年认知功能已成为研究的热点。叶酸通过参与核苷酸合成和DNA甲基化反应等作用影响端粒长度和稳定性，端粒长度和稳定性又与细胞凋亡、神经退行性疾病相关；我们前期研究结果显示补充叶酸可降低血中同型半胱氨酸和炎性因子水平改善老年人的认知功能，但是叶酸是否通过调节端粒影响神经细胞凋亡进而减缓认知功能减退尚不清楚。我们拟通过老年人队列研究，探讨不同叶酸水平对老年人认知功能的影响及其作用机制；采用随机对照叶酸干预研究，确定叶酸通过调节端粒的稳定性改善老年人认知功能的健康效应；通过动物实验和体外细胞实验，确定叶酸-端粒稳定性-神经细胞凋亡-认知功能四者之间关联，探讨其分子作用机制。通过人群研究、动物实验及体外细胞实验三个层次，端粒稳定性、神经细胞凋亡、蛋氨酸循环代谢产物三条途径，确定叶酸通过调节端粒稳定性对神经细胞凋亡影响进而对认知功能产生作用，为叶酸防治老年人认知功能减退提供新的途径。

轻度认知障碍（mild cognitive impairment, MCI）是介于正常衰老和痴呆之间的一种认知功能损害状态，MCI作为阿尔茨海默病(Alzheimer’s disease, AD)前期可进一步发展为AD。对MCI的干预可以促进认知好转、延缓认知减退、降低痴呆发生的风险。端粒随年龄的增长而缩短，是衰老的标志之一。叶酸参与核苷酸合成、DNA甲基化反应等作用，与中枢神经系统功能密切相关。本研究通过人群队列和干预研究、动物实验及体外细胞实验三个层次，探讨叶酸-端粒稳定性-神经细胞凋亡-认知功能之间的关联。人群研究结果提示：60岁以上老年人MCI患病率是10.7%，女性（13.1%）高于男性（8.2%），随年龄的增长患病率逐渐增加。队列研究显示，较低的叶酸水平增加MCI的发生风险，白细胞端粒长度与MCI发病风险呈负相关；白细胞端粒长度和线粒体DNA拷贝数在膳食炎症指数和MCI风险之间起着中介作用。人群干预研究，补充叶酸（800μg/d）能够改善MCI老年人认知功能，DHA及叶酸联合DHA干预也可以改善MCI老年人认知功能，叶酸和DHA联合干预效果更好，其作用机制可通过减轻氧化损伤、降低炎症水平和延缓端粒缩短发挥作用。动物实验研究结果提示：叶酸补充能够减缓衰老相关的认知功能减退和神经细胞凋亡，减轻海马萎缩，其机制为叶酸减缓端粒磨损、抑制氧化应激及增加脑组织胸苷酸合成酶的表达，保护端粒完整性。体外细胞实验研究结果提示，叶酸补充能够抑制原代神经干细胞、星形胶质细胞及神经元细胞的凋亡，其机制为叶酸降低细胞端粒磨损。综上，我们建议老年人应合理补充叶酸，以减缓端粒磨损介导的神经细胞凋亡，进而延缓老年人认知功能减退。此外，人群队列研究显示，适当增加膳食蛋白摄入量、握力、适当午睡能够改善认知功能；每天吃好早餐、适量饮水、清淡饮食、减少加工食品摄入能够改善认知功能。