CN116440142A - 甘油磷酰胆碱在抗衰老和/或延长寿命中的应用 - Google Patents
甘油磷酰胆碱在抗衰老和/或延长寿命中的应用 Download PDFInfo
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract
本发明公开了甘油磷酰胆碱在抗衰老和/或延长寿命中的应用。本发明提供了甘油磷酰胆碱在制备延缓衰老和/或延长线虫寿命的药物中的应用。所述甘油磷酰胆碱在制备具有下述任一种功能：延长寿命；提高运动机能和健康机能；延缓脂褐素的累积；增强生殖能力。本发明发现了甘油磷酰胆碱在延长寿命和延缓衰老中的应用，提供了甘油磷酰胆碱的新用途，扩展了甘油磷酰胆碱的应用范围，且具有重要的经济效益和社会效益。
Description
技术领域
本发明涉及甘油磷酰胆碱在抗衰老和/或延长寿命中的应用，属于抗衰老药物技术领域。
背景技术
衰老是机体在退化过程中细胞、组织以及器官的生理功能下降和紊乱的综合表现。衰老是导致心血管疾病、代谢疾病和神经退行性疾病发生的主要危险因素，而这些疾病对老年人的生活质量造成严重不良影响，给社会和家庭带来沉重经济负担。因此进行抗衰老研究，发现延长寿命抗衰老的药物对提高老年人的生活质量具有重要意义。
内源代谢产物参与机体重要的生理病理过程。近年来，因其天然、安全、成药性好等优势被越来越多的人关注。有研究报道，三羧酸循环的中间产物α-酮戊二酸、烟酰胺腺嘌呤二核苷酸(Nicotinamide adenine dinucleotide,NAD+)等能降低促炎因子水平、改善线粒体和干细胞的功能，从而发挥抗衰老作用。甘油磷酰胆碱(glycerophosphocholine，GPC)是人体内天然存在的磷脂代谢产物，是一种重要的神经递质和磷脂前体。甘油磷酸胆碱是一种胆碱衍生物，是细胞质中胆碱储存的主要形式之一。肾脏(特别是髓质细胞)在正常生理条件下暴露在广泛波动的细胞外溶质浓度下，通过积累有机渗透液甘油磷酸胆碱、甜菜碱、肌醇、山梨醇和游离氨基酸来对高渗应激作出反应。这些渗透液的细胞内含量的增加是通过增加摄取(肌醇和甜菜碱)和合成(山梨醇、GPC)、减少降解(GPC)和减少渗透液释放的组合来实现的。甘油磷酸胆碱是肾脏髓质细胞中四大有机渗透液之一，在细胞渗透适应过程中改变其细胞内渗透液浓度和细胞胞外渗力。甘油磷酸基胆碱作为一种渗透剂，可以抑制尿素对酶和其他大分子的影响。目前，没有有关甘油磷酰胆碱在抗衰老中的相关研究。
发明内容
本发明的目的是提供甘油磷酰胆碱在延缓衰老和/或延长寿命中的应用，扩展了甘油磷酰胆碱的应用范围。
本发明提供了甘油磷酰胆碱在制备延缓动物衰老和/或延长动物寿命的产品中的应用；
所述动物为哺乳动物，具体为人；
所述动物为无脊椎动物，具体为秀丽隐杆线虫。
本发明还提供了甘油磷酰胆碱在制备具有下述1)-3)中任一种功能的药物和保健品中的应用：
1)延长寿命；
2)提高运动机能和健康机能；
3)延缓脂褐素的累积。
本发明通过秀丽隐杆线虫生殖能力实验发现，甘油磷酰胆碱在延长线虫寿命的同时，对生殖能力并没有造成影响，说明延缓线虫衰老的同时其机体处于健康状态。
本发明还提供了一种培养秀丽隐杆线虫的方法，包括在培养基中添加甘油磷酰胆碱的步骤；
所述甘油磷酰胆碱的浓度优选为50mM。
本发明以秀丽隐杆线虫为模式生物，从线虫的寿命、身体活动度、脂褐素水平和生殖能力等方面研究了甘油磷酰胆碱的抗衰老功效，为进一步发展甘油磷酰胆碱相关的抗衰老药物和保健品提供基础。
本发明发现了甘油磷酰胆碱在延长寿命和延缓衰老中的应用，提供了甘油磷酰胆碱的新用途，扩展了甘油磷酰胆碱的应用范围，且具有重要的经济效益和社会效益。
附图说明
图1为不同浓度甘油磷酰胆碱对秀丽隐杆线虫生存曲线的影响。
图2为甘油磷酰胆碱对秀丽隐杆线虫身体活动度的影响。
图3为甘油磷酰胆碱对秀丽隐杆线虫脂褐素荧光强度的影响(左图为脂褐素积累的相对荧光强度，值为平均值±s.e.m.；n.s.，无显著性差异；**P≤0.01；***P≤0.0001；采用双向方差分析(ANOVA)及Bonferroni检验；右图为线虫生长第4、8天脂褐素聚集代表性图)。
图4为甘油磷酰胆碱对秀丽隐杆线虫产卵能力的影响。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中各材料的来源：
大肠埃希菌OP50和野生秀丽隐杆线虫品系N2均由中国科学院生物物理研究所张宏实验室惠赠(Gangming Zhang et al.,Cell 174,1492-1506,September 6,2018)。
甘油磷酰胆碱：安耐吉公司，蛋白胨、胆固醇和FUDR：sigma公司，磷酸二氢钾、氯化钙和硫酸镁等试剂均为分析纯。
一、培养方法和测定方法
1、秀丽隐杆线虫的培养与同期化
将L4线虫挑于含E.coli OP50的NGM板中，将培养皿置于20℃生化培养箱中培养，每3天转一次皿。线虫的同步化采用次氯酸钠裂解法，用M9溶液将线虫从NGM皿上冲洗下来，3000rpm离心3min。向管中加入5.5mL裂解液(注意避光)，用涡旋震荡仪震荡直至虫体全部消失。离心弃上清收集沉淀(虫卵沉淀呈白色)，16-20h后转L1线虫至含E.coli OP50的NGM板中，约48h线虫发育至L4时期，完成同期化。
2、秀丽隐杆线虫生命周期实验
挑取120只L4时期的线虫到各组NGM板中，置于20℃培养。在线虫生命的早期(第0～10天)使用含5μM FUDR的NGM板，第11天转至普通的NGM板中。每3天将线虫转至新的皿中。同时每天记录线虫的存活、死亡、丢失等数量，直至所有的线虫均死亡。
3、身体活动度的测定
在第5、10和15天的时候，测定实验组和对照组线虫的身体弯曲的次数。挑取一只线虫放置在不含OP50的NGM培养皿上，让其先***约1min，记录30s内身体弯曲的次数。一次弯曲定义为线虫相对于身体长轴方向上的一个波长的移动。每组实验测定的线虫数量不少于20条。
4、脂褐素水平的测定
每组挑取20只L4线虫于培养皿内，在第3、7和11天分别进行脂褐素荧光检测。吸取20μL M9 buffer滴于凝固的琼脂中央，用5mM左旋咪唑溶液麻醉线虫3min，将线虫挑取转移至M9 buffer液滴中，盖片。倒置荧光显微镜观察线虫肠道脂褐素水平。利用Image J软件分析脂褐素自发荧光强度。
5、生殖能力的测定
挑取10条L4线虫至各组NGM皿中，每个皿放置1条线虫。将线虫开始产卵的当天记为第1天，每天将线虫转至新的皿中，直至线虫产卵期结束。待虫卵孵化至L4时期，记录皿中线虫的数量即为产卵量。
6、数据统计分析
ˉ
采用GraphPad Prism 8软件进行统计学分析，所得结果采用x±s表示，组间比较采用单因素方差分析，两两比较采用t检验，以P＜0.05为差异有统计学意义。
二、实验结果
1、甘油磷酰胆碱对线虫寿命的影响
生存曲线是评价药物对寿命影响的首要方法，本发明测定了2个浓度条件下甘油磷酰胆碱对线虫寿命的影响，对其平均寿命、最长寿命以及寿命中位数进行分析，结果如图1和表1所示。
可以看出，与对照组相比，50mM甘油磷酰胆碱能显著延长线虫的平均寿命和最长寿命。但当浓度为10mM时，线虫平均寿命与最长寿命与对照组无显著差异，说明甘油磷酰胆碱对线虫寿命的影响是呈剂量依赖性的。
表1甘油磷酰胆碱对秀丽隐杆线虫寿命的影响
注：*最大寿命为群体最后生存10％的平均寿命。
2、甘油磷酰胆碱对线虫身体活动度的影响
衰老会引起肌肉功能退化，所以线虫的身体活动度会随着年龄的增长而下降。为了探究甘油磷酰胆碱是否通过增强线虫的身体活动度促机体健康，本发明观察了第3和7天线虫身体活动度的变化，结果如图2所示。
可以看出，无论在第3天还是第7天，50mM甘油磷酰胆碱均能显著提高线虫身体活动度，说明甘油磷酰胆碱可以改善线虫的健康状况。
3、甘油磷酰胆碱对线虫脂褐素水平的影响
脂褐素又称老年素，由溶酶体消化后的化合物和脂肪残基组成，可自发荧光。随着衰老的进程，脂褐素会沉积在神经、心肌、肝脏、皮肤等组织衰老细胞中不断地积累，是衰老的重要的标志。特别地，沉积于浅表皮肤的脂褐素又称“老年斑”。本发明研究了甘油磷酰胆碱对不同生命阶段肠道脂褐素自发荧光的影响，结果如图3所示。
可以看出，与对照组相比，50mM甘油磷酰胆碱处理延缓了年龄依赖性肠道脂褐素的积累。
4、甘油磷酰胆碱对线虫生殖能力的影响
根据现有研究，很多生物延长寿命的同时要以牺牲生殖为代价，也有报道指出白藜芦醇、淫羊藿总黄酮延长寿命的同时不影响生殖能力。本发明通过秀丽隐杆线虫生殖能力实验发现，甘油磷酰胆碱在延长线虫寿命的同时，对生殖能力并没有造成影响，说明延缓线虫衰老的同时其机体处于健康状态，如图4所示。
Claims (8)
1.甘油磷酰胆碱在制备延缓动物衰老和/或延长动物寿命的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述动物为哺乳动物。
3.根据权利要求2所述的应用，其特征在于：所述哺乳动物为人。
4.根据权利要求1所述的应用，其特征在于：所述动物为无脊椎动物。
5.根据权利要求4所述的应用，其特征在于：所述无脊椎动物为秀丽隐杆线虫。
6.根据权利要求4所述的应用，其特征在于：所述应用表现为下述1)-3)所示功能中任一种：
1)延长寿命；
2)提高运动机能和健康机能；
3)延缓脂褐素的累积。
7.甘油磷酰胆碱在制备具有下述1)-3)中任一种功能的药物中的应用：
1)延长寿命；
2)提高运动机能和健康机能；
3)延缓脂褐素的累积。
8.一种培养秀丽隐杆线虫的方法，包括在培养基中添加甘油磷酰胆碱的步骤。
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