人参皂苷Rg1延长C57BL/6J小鼠寿命及延缓脑老化的机制研究
摘要
【目的】正常脑老化是导致老年人认知功能下降的最主要原因，本文旨在研究人参皂苷Rg1长期给药是否能延长生存寿命，改善年龄相关认知功能下降，并且从整体、组织和分子水平深入探讨可能的机制。
【方法】SPF级12月龄C57BL/6J雌性小鼠随机分为Rg1干预组和溶媒对照组。生存分析中，各亚组34~38只，观测低剂量Rg1（6mg/kg/3day）终身饲喂对小鼠生存寿命的影响；机制研究中，小鼠同上剂量干预至24月龄，以4月龄及12月龄小鼠分别作为青年及中年对照，每组12～16只，应用Y迷宫、Morris水迷宫等行为学实验检测Rg1对衰老动物学习记忆改善的情况，通过超微结构观察、酶学染色等检测神经细胞衰老情况，ELISA、分光度分析等方法检测脑组织氧化应激情况，并采用Westernblot方法，检测海马部位突触相关蛋白的表达及其相关调控通路mTOR信号的活化程度。
【结果】
1.长期、低剂量人参皂苷Rg1的饲喂能够显著延长C57BL/6J雌性小鼠的寿命，包括平均寿命和最大寿命，且明显改善老年小鼠的认知能力，而对其肿瘤发生、以及体重、饮食量并不造成影响。
2.人参皂苷Rg1能够降低脑组织中H2O2、羰基化蛋白质的含量，提高了SOD活性，从而降低神经元细胞中脂褐素的累积，减少线粒体结构的衰老损伤，具有增强机体抗氧化能力、延缓神经细胞衰老的作用。衰老及人参皂苷Rg1并未显著影响基底前脑区的ChAT表达。
3.人参皂苷Rg1能够延缓老年小鼠海马CA1区突触的结构退化，并且通过促进海马区mTOR/p70-S6K/4E-BP信号通路的活化，上调突触相关蛋白SYN-38、PSD-95、NMDAR1、CaMKIIα的翻译合成，从而改善认知功能。
【结论】人参皂苷Rg1可通过增强机体抗氧化能力，减少神经细胞氧化损伤，并且促进海马区mTOR信号通路的活化从而上调突触相关蛋白的翻译合成，改善突触可塑性。人参皂苷Rg1能够延长哺乳动物生存寿命，改善脑老化的认知功能损害，对促进老年期机体健康具有显著作用。因此，人参皂苷Rg1有望成为多层面、多靶点抗衰老的安全、有效的临床保健药物。
Object Normal aging brain is the most common cause of cognitive decline inaging individuals, and significantly reduces the quality of life by diminishing healthspan. Here we testify whether long-term administration of ginsenoside Rg1wouldextend the lifespan and improve age-related cognitive decline. In addition，we explorethe potential mechanisms using in vivo studies through animal，tissue and molecularlevels.It is a helpful exploration for anti-aging and slow brain aging via aim atdifferent crucial factors during the Rg1comprehensively intervene senescenceprogress.
Methods we initiated supplementation of female C57BL/6J mice with a lowdose （6mg/kg/3day）ginsenoside Rg1or solvent at12months of age, and randomlydivided into longevity and sacrifice groups. In longevity group, mice in the longevitygroup (n=34-38in each subgroup) were allowed to die of natural causes and analyzedthe survivals. In sacrifice groups, the supplementation ended at24months.,Solvent-control mice, young (4-months-old) and middle-aged (12-momths-old) micewere used as control (n=12-16in each subgroup). The effect of brain aging and Rg1on the learning and memory of C57BL/6J mice was tested by different behavioraltests including Y maze and Morris. The aged neuron was examined by the enzymestaining and electron microscope scanning, oxidative stress in brain tissue was testedby ELISA or spectrophotometer, and the plasticity-related proteins and the mTORsignaling pathwany in hippocampus were tested by immunohistochemistry stainingand Western blot.
Results1. Long-term low dose oral supplementation of Rg1increased theaverage and maximum lifespan and improve aged-related cognitive decline, withoutsignificant effects on the cancer incidence, body weight and food consumption.
2. Rg1reduce the levels of H2O2, protein carbonylation and improve SODactivity on brain tissue, so that decrease the lipofuscin accumulation and mitochondriadamage. Consequently, Rg1could enhance antioxidant ability and delay neuronalaging in aging individuals. However, senescence or Rg1did not play role on theumber of ChAT-positive neurons in the basal forebrain.
3. Rg1could protect the synaptic structural degradation on aged hippocampusCA1area and significantly up-regulated synaptic plasticity associated proteins inhippocampus, including synaptophysin, NMDAR1, PSD-95and CaMKIIα, viapromoting mTOR pathway activation, then improve the cognitive function.
Conclusion Rg1reduce the oxidative damage on the aged neuron throughenhance the antioxidant capacity, and up-regulate synaptic plasticity associatedproteins in hippocampus via promoting mTOR pathway activation. Rg1, that couldextend the lifespan and improve aged-related cognitive decline, is benefic for healthyof aging individuals. Consequently, Rg1may be a effective and safe effective healthmedicine for anti-aging.
【方法】SPF级12月龄C57BL/6J雌性小鼠随机分为Rg1干预组和溶媒对照组。生存分析中，各亚组34~38只，观测低剂量Rg1（6mg/kg/3day）终身饲喂对小鼠生存寿命的影响；机制研究中，小鼠同上剂量干预至24月龄，以4月龄及12月龄小鼠分别作为青年及中年对照，每组12～16只，应用Y迷宫、Morris水迷宫等行为学实验检测Rg1对衰老动物学习记忆改善的情况，通过超微结构观察、酶学染色等检测神经细胞衰老情况，ELISA、分光度分析等方法检测脑组织氧化应激情况，并采用Westernblot方法，检测海马部位突触相关蛋白的表达及其相关调控通路mTOR信号的活化程度。
【结果】
1.长期、低剂量人参皂苷Rg1的饲喂能够显著延长C57BL/6J雌性小鼠的寿命，包括平均寿命和最大寿命，且明显改善老年小鼠的认知能力，而对其肿瘤发生、以及体重、饮食量并不造成影响。
2.人参皂苷Rg1能够降低脑组织中H2O2、羰基化蛋白质的含量，提高了SOD活性，从而降低神经元细胞中脂褐素的累积，减少线粒体结构的衰老损伤，具有增强机体抗氧化能力、延缓神经细胞衰老的作用。衰老及人参皂苷Rg1并未显著影响基底前脑区的ChAT表达。
3.人参皂苷Rg1能够延缓老年小鼠海马CA1区突触的结构退化，并且通过促进海马区mTOR/p70-S6K/4E-BP信号通路的活化，上调突触相关蛋白SYN-38、PSD-95、NMDAR1、CaMKIIα的翻译合成，从而改善认知功能。
【结论】人参皂苷Rg1可通过增强机体抗氧化能力，减少神经细胞氧化损伤，并且促进海马区mTOR信号通路的活化从而上调突触相关蛋白的翻译合成，改善突触可塑性。人参皂苷Rg1能够延长哺乳动物生存寿命，改善脑老化的认知功能损害，对促进老年期机体健康具有显著作用。因此，人参皂苷Rg1有望成为多层面、多靶点抗衰老的安全、有效的临床保健药物。
Object Normal aging brain is the most common cause of cognitive decline inaging individuals, and significantly reduces the quality of life by diminishing healthspan. Here we testify whether long-term administration of ginsenoside Rg1wouldextend the lifespan and improve age-related cognitive decline. In addition，we explorethe potential mechanisms using in vivo studies through animal，tissue and molecularlevels.It is a helpful exploration for anti-aging and slow brain aging via aim atdifferent crucial factors during the Rg1comprehensively intervene senescenceprogress.
Methods we initiated supplementation of female C57BL/6J mice with a lowdose （6mg/kg/3day）ginsenoside Rg1or solvent at12months of age, and randomlydivided into longevity and sacrifice groups. In longevity group, mice in the longevitygroup (n=34-38in each subgroup) were allowed to die of natural causes and analyzedthe survivals. In sacrifice groups, the supplementation ended at24months.,Solvent-control mice, young (4-months-old) and middle-aged (12-momths-old) micewere used as control (n=12-16in each subgroup). The effect of brain aging and Rg1on the learning and memory of C57BL/6J mice was tested by different behavioraltests including Y maze and Morris. The aged neuron was examined by the enzymestaining and electron microscope scanning, oxidative stress in brain tissue was testedby ELISA or spectrophotometer, and the plasticity-related proteins and the mTORsignaling pathwany in hippocampus were tested by immunohistochemistry stainingand Western blot.
Results1. Long-term low dose oral supplementation of Rg1increased theaverage and maximum lifespan and improve aged-related cognitive decline, withoutsignificant effects on the cancer incidence, body weight and food consumption.
2. Rg1reduce the levels of H2O2, protein carbonylation and improve SODactivity on brain tissue, so that decrease the lipofuscin accumulation and mitochondriadamage. Consequently, Rg1could enhance antioxidant ability and delay neuronalaging in aging individuals. However, senescence or Rg1did not play role on theumber of ChAT-positive neurons in the basal forebrain.
3. Rg1could protect the synaptic structural degradation on aged hippocampusCA1area and significantly up-regulated synaptic plasticity associated proteins inhippocampus, including synaptophysin, NMDAR1, PSD-95and CaMKIIα, viapromoting mTOR pathway activation, then improve the cognitive function.
Conclusion Rg1reduce the oxidative damage on the aged neuron throughenhance the antioxidant capacity, and up-regulate synaptic plasticity associatedproteins in hippocampus via promoting mTOR pathway activation. Rg1, that couldextend the lifespan and improve aged-related cognitive decline, is benefic for healthyof aging individuals. Consequently, Rg1may be a effective and safe effective healthmedicine for anti-aging.
引文
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