摘要
背景
随着人类社会的老龄化，衰老相关性研究日益成为国内外研究的热点。虽然大量的资料证明衰老总是伴随着行为学的改变（尤其是认知功能减退），且许多因素（如心理社会环境、生活方式）会对衰老相关性行为产生影响，但是这些研究主要集中在学习记忆方面，且得出的结论不完全一致，同时涉及其它行为的研究很少或缺如。啮齿类动物对于衰老的研究至关重要，其中小鼠衰老模型日益受到关注。因此，探讨小鼠衰老过程中所发生的各种行为改变及其影响因素对于提出防治衰老的策略将非常有益。
目的
①探讨我国实验室常用的远交系CD-1小鼠中年行为学改变；②探索不同时期接受心理社会因素（应激和丰富环境）对中年CD-1小鼠行为改变的影响；③探讨桑叶活性成分1-脱氧野尻霉素（DNJ）对快速老化易感小鼠8（senescence-acceleratedpronestrains8，SAMP8）衰老相关行为改变的影响。
方法
根据上述目的，设计3个试验
试验一：CD-1小鼠分为5月龄（青年）和12月龄（中年）组。评估小鼠衰老相关性行为改变，包括种属行为（储藏、挖掘和筑巢）、感觉运动能力（平衡木和紧绳任务）、自发性探索和焦虑行为（旷场实验、十字迷宫和黑白巷任务）、空间性学习记忆能力（六臂辐射状水迷宫和Morris水迷宫）和非空间性学习记忆能力（新物体再认）。
试验二：CD-1小鼠分别于1、6和10月龄时随机分成不同处理组和空白组。不同处理组小鼠又分为应激、丰富环境和应激+丰富环境亚组。应激的小鼠每天随机接受束缚、悬吊和夜间光照方式之一，三天一循环，共四个循环。接受丰富环境的小鼠，其饲养笼内每周放置1个不同玩具，直至行为学实验结束。小鼠13月龄时评估行为学：种属行为、感觉运动能力、自发性探索和焦虑行为评估任务同试验一，空间性学习记忆能力检测用Morris水迷宫，再认记忆能力检测用新物体再认、位置再认和情景记忆任务。另设6月龄作青年组。
试验三：SAMP8小鼠随机分成空白组、10mg/kg·dDNJ（低剂量）组和20mg/kg·dDNJ（高剂量）组。处理组于3月龄时开始经饮水给予不同剂量DNJ，空白组小鼠饮普通水。记录小鼠每月体重，小鼠9月龄（老年期）时行为学检测（评估内容同试验二）。另以3月龄小鼠作青年组。
结果
试验一：中年CD-1小鼠行为学改变
中年鼠的挖掘行为和作窝能力低于青年鼠（主要是雌鼠）；平衡木成绩好于青年鼠，紧绳成绩仅中年雄鼠好。中年小鼠在旷场、十字迷宫和黑白巷试验中自发性探索活性降低和焦虑性升高（雌鼠为主）。在六臂辐射状水迷宫中，中年鼠学习期和记忆期的潜伏期和错误数均长（多）于青年鼠（雌鼠更明显）。在Morris水迷宫中，中年鼠定位航行的潜伏期显著长于青年鼠，探索原平台象限的停留时间和路程百分比显著少于青年鼠。在新物体再认任务中，中年鼠探索新物体的优先指数与青年鼠无统计学差异。
试验二：应激和丰富环境对中年CD-1小鼠行为改变的影响
不同时期接受应激和丰富环境对中年CD-1鼠弱化的种属行为和增强的感觉运动能力无显著影响。1月龄应激加剧中年鼠自发性探索活性的降低和焦虑性的增高，1、6月龄丰富环境可降低中年鼠的焦虑性。年龄和处理因素均未对小鼠的新物体再认和位置再认产生影响，然而，中年鼠在情景记忆任务中探索物体优先指数显著低于青年鼠，即中年鼠存在情景样记忆能力降低，不同时期应激可恶化中年鼠降低的情景样记忆，而1、6月龄应激+丰富环境和丰富环境则起到相反的作用。在Morris水迷宫中，中年鼠表现空间学习和记忆能力的下降（结果与实验一相似）。空白组小鼠的游泳路程和潜伏期显著短于1月龄应激小鼠，但长于1月龄丰富环境小鼠，1、6月龄应激小鼠的游泳路程和潜伏期显著长于同龄丰富环境小鼠，且1月龄应激小鼠也长于同龄应激+丰富环境小鼠。同时，空白组小鼠在原平台象限内停留时间和路程的百分比显著少于1、10月龄应激+丰富环境小鼠和不同时期丰富环境小鼠，不同时期应激小鼠也显著少于同龄应激+丰富环境和丰富环境小鼠。
实验三：DNJ对SAMP8小鼠衰老相关行为改变的影响
2个DNJ处理组体重曲线与空白组类似。老年空白组的挖掘和筑巢能力、在平衡木和紧绳上的平衡能力均显著差于青年鼠，但低剂量DNJ可改善筑巢能力，2个剂量DNJ均可减轻平衡能力下降。与青年鼠相比，空白组小鼠自发性探索活性、在旷场和高架十字迷宫中的焦虑性均显著降低，而在黑白巷中的焦虑性显著增高，低剂量DNJ可减轻这种探索活性和焦虑性的改变。空白组新物体再认（10min延迟）和位置再认（10min和24h延迟）的优先指数均显著少于青年鼠，但2个剂量的DNJ均可阻碍10min延迟新物体和位置再认成绩的下降。在情景记忆任务中，空白组优先指数显著低于青年鼠和不同剂量DNJ组。在Morris水迷宫中，空白组定位航行游泳距离和潜伏期显著长于青年鼠，在原平台象限探索时间和路程的百分比显著少于青年鼠。2个剂量的DNJ效应可纠正定位航行游泳距离的增加，低剂量DNJ可纠正探索时间和路程百分比的下降。
小结
1.中年CD-1小鼠存在一定的行为学改变，即种属行为、自发性探索活性和空间学习记忆能力弱化，而感觉运动能力和焦虑性增强。这些行为的改变以雌鼠为主，提示中年CD-1小鼠可能是研究衰老的良好模型。
2.中年CD-1鼠的种属行为、感觉运动、新物体再认和位置再认能力可能均不受应激和丰富环境的影响，但中年期前受到应激可加重自发性探索下降、焦虑性增强、情景样记忆和空间学习记忆能力减退，而长期丰富环境可延缓这些行为改变。这些加重或延缓效应呈年龄依赖性，即越早越明显。
3.长期DNJ处理不影响SAMP8小鼠生长发育，但可延缓其年龄相关性种属行为、感觉运动能力、焦虑性、空间性和非空间学习记忆能力的改变，提示DNJ具有抗脑衰老作用。
结论
中年期已发生了某些行为改变，但改变的方向不同，且受生活事件、社会环境的影响，时间越早效应越强。此外，生活方式或某些植物成分可延缓衰老相关性行为改变。
Background
With the aging of the population, there is increasing emphasis on aging-related research. Although abundant evidence indicates that aging accompanies with behavioral changes especially cognitive decline and many factors (such as psycho-social environment, lifestyles) can affect these behaviors, these studies mainly focus on learning and memory without evaluating other behaviors, moreover their conclusions are not always consistent. Rodents play a vital role in the studies of development of brain aging, and mice model has become a growing concern in age-related behavioral changes. Therefore, it is beneficial to explore the behavioral changes in the aging process and their influencing factors for finding aging interventions.
Objective
①To investigate the behavioral changes in the middle-aged CD-I mice that is most frequently used in Chinese laboratories;②To further investigate the effects of chronic stress and environmental enrichment on age-related behavioral changes in CD-1mice;③To explore the effects of long-term orally administered the extract of mulberry leaves i.e.,1-deoxynojirimycin (DNJ), on age-related behavioral changes in SAMP8mice.
Methods
According to the above objective, three experiments were designed.
Experiment1:Two age groups of CD-1mice (young group aged5months and middle-aged group at age of12months) were used to assess behavioral changes, including species-typical behaviors (burrowing, nesting and hoarding), sensorimotor behaviors (beam walking and tightrope task), spontaneous exploration and anxiety (open field, elevated plus maze and black-white alley), spatial learning and memory (Morris water maze (MWM) and radial six arm water maze (RAWM)) and novel object recognition.
Experiment2:CD-I mice were were randomly divided into four groups as follows: normal old control,1,6and10-month-treatment. Normal old control mice did not undergo any treatment. The treatment groups were divided into stressed, stressed+enriched and enriched subgroups. The stressed mice were randomized to receive daily one way of stresses (restraint, illumination or tail suspension), three days a cycle and a totle of four cycles. The enriched mice had access to objects that stimulated their exploratory behavior and permitted social conditions until finishing the behavioral examination. The objects were rearranged every week and different objects were placed on alternate weeks for novelty. The stressed+enriched mice were exposed to stress followed by enriched environment housing. At age of13months old, all mice were conducted to behavioral evaluation, including species-typical behaviors, sensorimotor behaviors, spontaneous exploration and anxiety, spatial learning and memory (MWM) and recognition memory (novel object recognition(NOR), object recognition location (ORL) and episodic-like memory). In addition, normal6-month old mice were used as young control group.
Experiment3:SAMP8mice were randomly divided into three groups:blank control,10mg/kg·d DNJ (low-dose) and20mg/kg·d DNJ (high-dose) groups. DNJ-treated mice at3months old were orally administered DNJ mixed with drinking water for6months until the behavioral tests began, and the blank control mice were received normal drinking water. At age of9months, behavioral changes were assessed as previously described in experiment2. Moreover, another3-month-old mice was set as the young control.
Results
Experiment1:The behavioral changes in middle-aged CD-1mice
In the species-typical tasks, the weights hoarded and burrowed in the middle-aged mice were significantly lower than that in the young mice, which was attributable to the female mice. The middle-aged mice showed better performance than the young mice in the beam walking, and only the middle-aged male mice had better performance than the young male mice in tightrope task. During open-field, the elevated plus maze and black-white alley testing, the middle-aged mice exhibited low locomotor activity and high anxiety, which was attributable to the female mice. In the RAWM, the latency and number of errors of the middle-aged mice were significantly longer or more than those of the young mice in both the learning and memory phases, and the cognitive impairment was mainly found in the females. In the MWM, the middle-aged mice had longer latency than the young mice but no difference in the swimming distance in the place learning test, and they showed shorter percentage of distance and time in the target quadrant than the young mice. Meawhile, the middle-aged mice showed the similar performance to the younger mice in the novel object recognition task.
Experiment2:The effects of stress and enriched environment on behavioral changes in the middle-aged CD-1mice
During the species-typical behaviors and sensorimotor testing, age effect, rather than different treatment effect, was found. In the open-field, the elevated plus maze and black-white alley tasks, the middle-aged mice showed low locomotor activity and high anxiety, and pubertal stress could aggravate the age effects but long-term enriched environment could postphone these age-related behavioral changes. In the recognition testing, there were no significant effects of age and treatment in the NOR and ORL. But, the middle-aged mice exhibited lower preferential index of exploring object than the young mice in the episodic-like memory task, indicating that the middle-aged mice had impaired episodic-like memory. And, stress experienced in different periods (in particular1and6months old) could accelerate episodic-like memory decline and enriched environment could delay this decline. In the MWM, the middle-aged mice had longer latency and swimming distance than the young mice and1-month-stressed mice, but shorter than1-month-enriched mice. The stressed mice showed longer latency and swimming distance than the enriched mice, especially in the1-and6-months stressed mice. The middle-aged mice spent less time and distance in the target quadrant than the young,1-and10-month-stresed+enriched mice, andl,6,10-month enriched mice.1,6, and10-month-stressed mice also spent more time and distance than the same age experienced stresed+enriched and enriched mice.
Experiment3:The effects of DNJ on the age-related behavioral changes in SAMP8mice
There was insignificant difference of body weight between DNJ-treated group and control group. In the species-typical behaviors, the older control mice exhibited lower performance than the young mice in the nesting and burrowing, and low dose DNJ treated mice had better performance than the control mice in the nesting. In the tightrope and beam walking, the older control mice had worse performance in these tasks than the young mice, and DNJ treated mice had better performance than the control mice. During spontaneous exploration and anxiety testing, the older control mice showed low exploration activity and anxiety, and DNJ treatment could delay these behavioral changes. In the NOR task, the older control mice had lower preferential index of exploring the novel object than the young mice in the10min delay choice, and DNJ treated mice exhibited higher preferential index than the control mice. In the ORL task, the older control mice showed lower preferential index of exploring object than the young mice in the10min-and24h-delay choices, and DNJ treated mice had higher preferential index than the control mice only in the10min-delay choice. During the episodic-like memory task, the older control mice had lower preferential indexes than the young and DNJ treated mice. In the MWM, the older control mice showed longer swimming distance and latency than the young mice and shorter than DNJ treated mice in the place learning test, and they spent shorter swimming distance and time in the target quadrant than the young and low dose DNJ treated mice.
Summary
1. Middle-aged CD-1mouse have exhibited some behavioral changes, including low species-typical behaviors, spontaneous exploratory and spatial learning and memory, and high anxiety and sensorimotor. These behavioral changes are attributable to the females, suggesting that CD-1may be an excellent aging model.
2. Stress and enrichment experienced in different period do not affect species-typical behaviors, sensorimotor, NOR and ORL in the middle-aged CD-1mice. Chronic stress experienced before middle age can aggravate some behavioral changes in middle-aged mice, including spontaneous exploratory, anxiety, episodic-like memory and spatial learning and memory. But, long-term enrichment can delay these behavioral changes. Moreover, these effects depend on onset time.
3. Long-term administrated DNJ do not affect growth development in SAMP8mice, but it can delay age-related behavioral changes, including species-typical behaviors sensorimotor, anxiety, non-spatial and spatial learning and memory. Therefore, DNJ may have the property of anti-brain aging.
Conclusion
Some behavioral changes have occurred in middle age, but their changeable patterns are different. Moreover, life event and social environment can affect these behavioral changes. The earlier it is, the stronger the effect is. In addition, lifestyles or some food additives can delay aging-related behavioral changes.
引文
[1]Kowald A. Lifespan does not measure ageing. Biogerontology,2002;3(3):187-90.
[2]Lapane KL, Gambassi G, Landi F, et al. Gender differences in predictors of mortality in nursing home residents with AD. Neurology,2001;56(5):650-4.
[3]Fillit HM, Butler RN, O'Connell AW, et al. Achieving and maintaining cognitive vitality with aging. Mayo Clin Proc,2002;77(7):681-96.
[4]马永兴,俞卓伟,谢素珍,等.老年记忆及认知功能生理增龄性及整体增龄性减退与老年各认知障碍的相对患病率.北京：科学技术文献出版社,2008:145-62.
[5]Ricciarelli R, d'Abramo C, Massone S, et al. Microarray analysis in Alzheimer's disease and normal aging. IUBMB Life,2004;56(6):349-54.
[6]Reuter-Lorenz PA, Lustig C. Brain aging:reorganizing discoveries about the aging mind. Curr Opin Neurobiol,2005;15(2):245-51.
[7]Maylor EA, Logie RH. A large-scale comparison of prospective and retrospective memory development from childhood to middle age. Q J Exp Psychol (Hove),2010;63(3):442-51.
[8]Maylor EA, Vousden JI, Brown GD. Adult age differences in short-term memory for serial order:data and a model. Psychol Aging,1999;14(4):572-94.
[9]Frick KM. Building a better hormone therapy? How understanding the rapid effects of sex steroid hormones could lead to new therapeutics for age-related memory decline. Behav Neurosci,2012;126(1):29-53.
[10]Beier ME, Ackerman PL. Age, ability, and the role of prior knowledge on the acquisition of new domain knowledge:promising results in a real-world learning environment. Psychol Aging,2005;20(2):341-55.
[11]Strough J, Karns TE, Schlosnagle L. Decision-making heuristics and biases across the life span. Ann N Y Acad Sci,2011;1235:57-74.
[12]Dommes A, Cavallo V. The role of perceptual, cognitive, and motor abilities in street-crossing decisions of young and older pedestrians. Ophthalmic Physiol Opt,2011;31(3):292-301.
[13]Kalisch T, Kattenstroth JC, Kowalewski R, et al. Cognitive and tactile factors affecting human haptic performance in later life. PLoS One,2012;7(1):e30420.
[14]Morris MC, Scherr PA, Hebert LE, et al. Association between blood pressure and cognitive function in a biracial community population of older persons. Neuroepidemiology,2002;21(3):123-30.
[15]Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline. Nature,2010;464(7288):529-35.
[16]Gorelick PB, William M. Feinberg Lecture:Cognitive vitality and the role of stroke and cardiovascular disease risk factors. Stroke,2005;36(4):875-9.
[17]Fillit H, Nash DT, Rundek T, et al. Cardiovascular risk factors and dementia. Am J Geriatr Pharmacother,2008;6(2):100-18.
[18]Panza F, Frisardi V, Seripa D, et al. Metabolic syndrome, mild cognitive impairment, and dementia. Curr Alzheimer Res,2011;8(5):492-509.
[19]Cherubini A, Lowenthal DT, Paran E, et al. Hypertension and cognitive function in the elderly. Dis Mon,2010;56(3):106-47.
[20]Duthie SJ, Whalley LJ, Collins AR, et al. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr,2002;75(5):908-13.
[21]Reyes Del Paso GA, Pulgar A, Duschek S, et al. Cognitive impairment in fibromyalgia syndrome:The impact of cardiovascular regulation, pain, emotional disorders and medication. Eur J Pain,2011.
[22]Rostrup E, Gouw AA, Vrenken H, et al. The spatial distribution of age-related white matter changes as a function of vascular risk factors-Results from the LADIS study. Neuroimage,2012.
[23]Sahathevan R, Brodtmann A, Donnan GA. Dementia, stroke, and vascular risk factors; a review. Int J Stroke,2012;7(1):61-73.
[24]Yan CM, Deng QN, Zhong WZ.[Correlations among metabolic syndrome and mild cognitive impairment]. Zhonghua Yi Xue Za Zhi,2011;91(45):3193-6.
[25]Hildreth KL, Van Pelt RE, Schwartz RS. Obesity, Insulin resistance and Alzheimer's Disease. Obesity (Silver Spring),2012.
[26]Moore AR, O'Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging,1999;15(1):15-28.
[27]Balsters JH, O'Connell RG, Martin MP, et al. Donepezil impairs memory in healthy older subjects:behavioural, EEG and simultaneous EEG/fMRI biomarkers. PLoS One,2011;6(9):e24126.
[28]俞马.防治认知障碍必须关注老年整体人群.老年医学与保健,2006;12(4)：193-4.
[29]YX, YZM. The total population of aged should be considered as the cognitive function health care object. Abstract book of the8th Asia/Oceania Regional congress of Gerontology and Geriatrics. Beijing,2007:276.
[30]Ahlskog JE, Geda YE, Graff-Radford NR, et al. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc,2011;86(9):876-84.
[31]吴振云,许淑莲,孙长华,等.高龄老人的认知功能和心理健康.中国人口科学,2001(增刊)：57-60.
[32]管新丽.抑郁症病人的社会支持状况及护理干预.护理研究,2003;17(8):902-3.
[33]Valls-Pedret C, Lamuela-Raventos RM, Medina-Remon A, et al. Polyphenol-Rich Foods in the Mediterranean Diet are Associated with Better Cognitive Function in Elderly Subjects at High Cardiovascular Risk. J Alzheimers Dis,2012.
[34]Ku PW, Stevinson C, Chen LJ. Prospective Associations Between Leisure-Time Physical Activity and Cognitive Performance Among Older Adults Across an11-Year Period. J Epidemiol,2012.
[35]Stranahan AM, Martin B, Maudsley S. Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer's disease. Curr Alzheimer Res,2012;9(1):86-92.
[36]Morrison JH. Which synapses are affected in aging and what is the nature of their vulnerability? A commentary on "life span and synapses:will there be a primary senile dementia?". Neurobiol Aging,2001;22(3):349-50.
[37]Gallagher M, Rapp PR. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol,1997;48:339-70.
[38]Chidgey AP, Boyd RL. Stemming the tide of thymic aging. Nat Immunol,2006;7(10):1013-6.
[39]Chan YC, Hosoda K, Tsai CJ, et al. Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. J Nutr Sci Vitaminol (Tokyo),2006;52(4):266-73.
[40]杜小燕,杨慧,王钜.长爪沙鼠脑缺血模型的建寺及脑组织中超氧歧化酶和丙二醛含量的测定.中国比较医学杂志,2006;16(11)：664-7.
[41]丁贤明,钱宝珍.实验动物长爪沙鼠的研究进展.浙江省医学科学院学报,2006;62(6)：34-8.
[42]Brignull HR, Morley JF, Morimoto RI. The stress of misfolded proteins:C. elegans models for neurodegenerative disease and aging. Adv Exp Med Biol,2007;594: 167-89.
[43]Nadon NL. Of mice and monkeys:National Institute on Aging resources supporting the use of animal models in biogerontology research. J Gerontol A Biol Sci Med Sci,2006;61(8):813-5.
[44]丁远望,于莉莉,张淑珍.中医药科研实验动物的选择原则.陕西中医学院学报,2002;7(4)：50-2.
[45]Assuncao M, Santos-Marques MJ, Carvalho F, et al. Chronic green tea consumption prevents age-related changes in rat hippocampal formation. Neurobiol Aging,2011;32(4):707-17.
[46]Hauser E, Tolentino JC, Pirogovsky E, et al. The effects of aging on memory for sequentially presented objects in rats. Behav Neurosci,2009;123(6):1339-45.
[47]Liu P, Smith PF, Appleton I, et al. Hippocampal nitric oxide synthase and arginase and age-associated behavioral deficits. Hippocampus,2005;15(5):642-55.
[48]Luu TT, Pirogovsky E, Gilbert PE. Age-related changes in contextual associative learning. Neurobiol Learn Mem,2008;89(1):81-5.
[49]Platano D, Fattoretti P, Balietti M, et al. Long-term visual object recognition memory in aged rats. Rejuvenation Res,2008;11(2):333-9.
[50]Prediger RD, De-Mello N, Takahashi RN. Pilocarpine improves olfactory discrimination and social recognition memory deficits in24month-old rats. Eur J Pharmacol,2006;531(1-3):176-82.
[51]Fischer W, Chen KS, Gage FH, et al. Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiol Aging,1992;13(1):9-23.
[52]Meyza KZ, Boguszewski PM, Nikolaev E, et al. Age increases anxiety and reactivity of the fear/anxiety circuit in Lewis rats. Behav Brain Res,2011;225(1):192-200.
[53]Gagliese L,Melzack R. Age differences in nociception and pain behaviours in the rat. Neurosci Biobehav Rev,2000;24(8):843-54.
[54]Ingram DK, Jucker M. Developing mouse models of aging:a consideration of strain differences in age-related behavioral and neural parameters. Neurobiol Aging,1999;20(2):137-45.
[55]Higuchi K, Hosokawa M, Takeda T. Senescence-accelerated mouse. Methods Enzymol,1999;309:674-86.
[56]Takeda T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8and SAMP10mice. Neurochem Res,2009;34(4):639-59.
[1]Terry AV, Jr., Callahan PM, Hall B, et al. Alzheimer's disease and age-related memory decline (preclinical). Pharmacol Biochem Behav,2011;99(2):190-210.
[2]Grady CL,Craik FI. Changes in memory processing with age. Curr Opin Neurobiol,2000;10(2):224-31.
[3]Aartsen MJ, Smits CH, van Tilburg T, et al. Activity in older adults:cause or consequence of cognitive functioning? A longitudinal study on everyday activities and cognitive performance in older adults. J Gerontol B Psychol Sci Soc Sci,2002;57(2):P153-62.
[4]Plassman BL, Welsh KA, Helms M, et al. Intelligence and education as predictors of cognitive state in late life:a50-year follow-up. Neurology,1995;45(8):1446-50.
[5]Ronnlund M, Nyberg L, Backman L, et al. Stability, growth, and decline in adult life span development of declarative memory:cross-sectional and longitudinal data from a population-based study. Psychol Aging,2005;20(1):3-18.
[6]Salthouse TA. When does age-related cognitive decline begin? Neurobiol Aging,2009;30(4):507-14.
[7]Nilsson LG, Sternang O, Ronnlund M, et al. Challenging the notion of an early-onset of cognitive decline. Neurobiol Aging,2009;30(4):521-4; discussion530-3.
[8]Li KZ, Lindenberger U, Freund AM, et al. Walking while memorizing:age-related differences in compensatory behavior. Psychol Sci,2001;12(3):230-7.
[9]Ricciarelli R, d'Abramo C, Massone S, et al. Microarray analysis in Alzheimer's disease and normal aging. IUBMB Life,2004;56(6):349-54.
[10]Ingram DK, Jucker M. Developing mouse models of aging:a consideration of strain differences in age-related behavioral and neural parameters. Neurobiol Aging,1999;20(2):137-45.
[11]Francia N, Cirulli F, Chiarotti F, et al. Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status:role of hippocampal neurotrophins. Eur J Neurosci,2006;23(3):711-28.
[12]Jucker M, Bondolfi L, Calhoun ME, et al. Structural brain aging in inbred mice: potential for genetic linkage. Exp Gerontol,2000;35(9-10):1383-8.
[13]Guidi M, Foster TC. Behavioral model for assessing cognitive decline. Methods Mol Biol,2012;829:145-53.
[14]Frick KM, Burlingame LA, Alters JA, et al. Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex. Neuroscience,2000;95(1):293-307.
[15]Benice TS, Rizk A, Kohama S, et al. Sex-differences in age-related cognitive decline in C57BL/6J mice associated with increased brain microtubule-associated protein2and synaptophysin immunoreactivity. Neuroscience,2006;137(2):413-23.
[16]Hebda-Bauer EK, Luo J, Watson SJ, et al. Female CREBalphadelta-deficient mice show earlier age-related cognitive deficits than males. Neuroscience,2007;150(2):260-72.
[17]Benice TS, Raber J. Testosterone and dihydrotestosterone differentially improve cognition in aged female mice. Learn Mem,2009;16(8):479-85.
[18]Chen GH, Wang YJ, Zhang LQ, et al. Age-and sex-related disturbance in a battery of sensorimotor and cognitive tasks in Kunming mice. Physiol Behav,2004;83(3):531-41.
[19]Bimonte HA, Hyde LA, Hoplight BJ, et al. In two species, females exhibit superior working memory and inferior reference memory on the water radial-arm maze. Physiol Behav,2000;70(3-4):311-7.
[20]King DL AG. Behavioral characterization of the Tg2576transgenic model of Alzheimer's disease through19months. Physiol Behav,2002;75(5):627-642.
[21]Aitken DH, Meaney MJ. Temporally graded, age-related impairments in spatial memory in the rat. Neurobiol Aging,1989;10(3):273-6.
[22]Pitsikas N, Carli M, Fidecka S, et al. Effect of life-long hypocaloric diet on age-related changes in motor and cognitive behavior in a rat population. Neurobiol Aging,1990;11(4):417-23.
[23]Wyss JM, Chambless BD, Kadish I, et al. Age-related decline in water maze learning and memory in rats:strain differences. Neurobiol Aging,2000;21(5):671-81.
[24]Shukitt-Hale B, Mouzakis G, Joseph JA. Psychomotor and spatial memory performance in aging male Fischer344rats. Exp Gerontol,1998;33(6):615-24.
[25]Brandeis R, Dachir S, Sapir M, et al. Reversal of age-related cognitive impairments by an M1cholinergic agonist, AF102B. Pharmacol Biochem Behav,1990;36(1):89-95.
[26]Fouquet C, Petit GH, Auffret A, et al. Early detection of age-related memory deficits in individual mice. Neurobiol Aging,2011;32(10):1881-95.
[27]Ennaceur A, Michalikova S, van Rensburg R, et al. Detailed analysis of the behavior and memory performance of middle-aged male and female CD-1mice in a3D maze. Behav Brain Res,2008;187(2):312-26.
[28]Jucker M, Ingram DK. Murine models of brain aging and age-related neurodegenerative diseases. Behav Brain Res,1997;85(1):1-26.
[29]Adams B, Fitch T, Chaney S, et al. Altered performance characteristics in cognitive tasks:comparison of the albino ICR and CD1mouse strains. Behav Brain Res,2002;133(2):351-61.
[30]Chen GH, Wang H, Yang QG, et al. Acceleration of age-related learning and memory decline in middle-aged CD-1mice due to maternal exposure to lipopolysaccharide during late pregnancy. Behav Brain Res,2011;218(2):267-79.
[31]Chen GH, Wang YJ, Wang XM, et al. Effect of aging on species-typical behaviors in senescence-accelerated mouse. Physiol Behav,2005;85(5):536-45.
[32]熊向东,徐文锐,陈贵海.C57BL/6小鼠年龄和性别对种属型行为的影响.安徽农业大学学报,2006;33(3)：310-3.
[33]Charron I, Cabanac M. Influence of pellet size on rat's hoarding behavior. Physiol Behav,2004;82(2-3):447-51.
[34]Hengemihle JM, Long JM, Betkey J, et al. Age-related psychomotor and spatial learning deficits in129/SvJ mice. Neurobiol Aging,1999;20(1):9-18.
[35]Markowska AL, Spangler EL, Ingram DK. Behavioral assessment of the senescence-accelerated mouse (SAM P8and R1). Physiol Behav,1998;64(1):15-26.
[36]Arendash GW, King DL, Gordon MN, et al. Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1transgenes. Brain Res,2001;891(1-2):42-53.
[37]Barreto G, Huang TT, Giffard RG. Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL/6mice. J Neurosurg Anesthesiol,2010;22(3):214-9.
[38]吴旭,王月菊,陈贵海.钢质平衡木直径对SAM小鼠感觉运动能力检测的影响.安徽农业大学学报,2005;32(4)：460-2.
[39]Chen GH, Wang C, Yangcheng HY, et al. Age-related changes in anxiety are task-specific in the senescence-accelerated prone mouse8. Physiol Behav,2007;91(5):644-51.
[40]Bergado JA, Almaguer W, Rojas Y, et al. Spatial and emotional memory in aged rats:a behavioral-statistical analysis. Neuroscience,2011;172:256-69.
[41]Michalikova S, Ennaceur A, van Rensburg R, et al. Emotional responses and memory performance of middle-aged CD1mice in a3D maze:effects of low infrared light. Neurobiol Learn Mem,2008;89(4):480-8.
[42]Dere E, Huston JP, De Souza Silva MA. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev,2007;31(5):673-704.
[43]Ennaceur A. One-trial object recognition in rats and mice:methodological and theoretical issues. Behav Brain Res,2010;215(2):244-54.
[1]Aguilera G. HPA axis responsiveness to stress:implications for healthy aging. Exp Gerontol,2011;46(2-3):90-5.
[2]程少容,王仁法,李勇刚,等.慢性复合应激对大鼠学习记忆及海马N-甲基D-天冬氨酸受体亚基表达的影响.中国康复医学杂志,2005;9(28)：123-5.
[3]Conrad CD, Bimonte-Nelson HA. Impact of the hypothalamic-pituitary-adrenal/gonadal axes on trajectory of age-related cognitive decline. Prog Brain Res,2010;182:31-76.
[4]Volkers KM, Scherder EJ. Impoverished environment, cognition, aging and dementia. Rev Neurosci,2011;22(3):259-66.
[5]张国庆.丰富环境对于中枢神经系统可塑性的影响.中国康复医学杂志,2006;21(3)：280-3.
[6]Laviola G, Rea M, Morley-Fletcher S, et al. Beneficial effects of enriched environment on adolescent rats from stressed pregnancies. Eur J Neurosci,2004;20(6):1655-64.
[7]魏勇,刘宇.衰老与感觉运动功能、下肢刚度研究进展.中国运动医学杂志,2008;27(5)：667-9.
[8]Gambarian LS.[Disorders in motor functions in lesions of the cerebellum and posterior columns of the spinal cord]. Fiziol Zh SSSR Im I M Sechenova,1960;46:516-25.
[9]Baev KV, Shimanskii Iu P. A new concept of the role of the cerebellum in operative motor control and the shaping of motor automatism. Neirofiziologiia,1990;22(3):415-21.
[10]Shaffer SW, Harrison AL. Aging of the somatosensory system:a translational perspective. Phys Ther,2007;87(2):193-207.
[11]Deschenes MR, Britt AA, Chandler WC. A comparison of the effects of unloading in young adult and aged skeletal muscle. Med Sci Sports Exerc,2001;33(9):1477-83.
[12]Derave W, Eijnde BO, Ramaekers M, et al. Soleus muscles of SAMP8mice provide an accelerated model of skeletal muscle senescence. Exp Gerontol,2005;40(7):562-72.
[13]Brzozka MM, Fischer A, Falkai P, et al. Acute treatment with cannabinoid receptor agonist WIN55212.2improves prepulse inhibition in psychosocially stressed mice. Behav Brain Res,2011;218(2):280-7.
[14]Liu YP, Tung CS, Chuang CH, et al. Tail-pinch stress and REM sleep deprivation differentially affect sensorimotor gating function in modafinil-treated rats. Behav Brain Res,2011;219(1):98-104.
[15]Sutherland JE, Conti LH. Restraint stress-induced reduction in prepulse inhibition in Brown Norway rats:role of the CRF2receptor. Neuropharmacology,2011;60(4):561-71.
[16]Mychasiuk R, Ilnytskyy S, Kovalchuk O, et al. Intensity matters:brain, behaviour and the epigenome of prenatally stressed rats. Neuroscience,2011;180:105-10.
[17]Markham JA, Koenig JI. Prenatal stress:role in psychotic and depressive diseases. Psychopharmacology (Berl),2011;214(1):89-106.
[18]Buga AM, Balseanu A, Popa-Wagner A, et al. Strategies to improve post-stroke behavioral recovery in aged subjects. Rom J Morphol Embryol,2009;50(4):559-82.
[19]Janssen H, Bernhardt J, Collier JM, et al. An enriched environment improves sensorimotor function post-ischemic stroke. Neurorehabil Neural Repair,2010;24(9):802-13.
[20]Chen GH, Wang C, Yangcheng HY, et al. Age-related changes in anxiety are task-specific in the senescence-accelerated prone mouse8. Physiol Behav,2007; 91(5):644-51.
[21]Estanislau C, Morato S. Prenatal stress produces more behavioral alterations than maternal separation in the elevated plus-maze and in the elevated T-maze. Behav Brain Res,2005;163(1):70-7.
[22]Pallares ME, Scacchi Bernasconi PA, Feleder C, et al. Effects of prenatal stress on motor performance and anxiety behavior in Swiss mice. Physiol Behav,2007;92(5):951-6.
[23]Kinn Rod AM, Milde AM, Gronli J, et al. Long-term effects of footshock and social defeat on anxiety-like behaviours in rats:Relationships to pre-stressor plasma corticosterone concentration. Stress,2012.
[24]Wang Q, Yu K, Wang J, et al. Predator stress-induced persistent emotional arousal is associated with alterations of plasma corticosterone and hippocampal steroid receptors in rat. Behav Brain Res,2012;230(1):167-74.
[25]Pena Y, Prunell M, Rotllant D, et al. Enduring effects of environmental enrichment from weaning to adulthood on pituitary-adrenal function, pre-pulse inhibition and learning in male and female rats. Psychoneuroendocrinology,2009;34(9):1390-404.
[26]Ilin Y, Richter-Levin G. Enriched environment experience overcomes learning deficits and depressive-like behavior induced by juvenile stress. PLoS One,2009;4(1):e4329.
[27]Grady CL. Cognitive neuroscience of aging. Ann N Y Acad Sci,2008;1124:127-44.
[28]Lee AC, Rahman S, Hodges JR, et al. Associative and recognition memory for novel objects in dementia:implications for diagnosis. Eur J Neurosci,2003;18(6):1660-70.
[29]Ennaceur A, Delacour J. Effect of combined or separate administration of piracetam and choline on learning and memory in the rat. Psychopharmacology (Berl),1987;92(1):58-67.
[30]Forwood SE, Winters BD, Bussey TJ. Hippocampal lesions that abolish spatial maze performance spare object recognition memory at delays of up to48hours. Hippocampus,2005;15(3):347-55.
[31]Winters BD, Forwood SE, Cowell RA, et al. Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory:heterogeneity of function within the temporal lobe. J Neurosci,2004;24(26):5901-8.
[32]Chen GH, Wang YJ, Wang XM, et al. Accelerated senescence prone mouse-8shows early onset of deficits in spatial learning and memory in the radial six-arm water maze. Physiol Behav,2004;82(5):883-90.
[33]Benice TS, Rizk A, Kohama S, et al. Sex-differences in age-related cognitive decline in C57BL/6J mice associated with increased brain microtubule-associated protein2and synaptophysin immunoreactivity. Neuroscience,2006;137(2):413-23.
[34]Dere E, Huston JP, De Souza Silva MA. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev,2007;31(5):673-704.
[35]Ennaceur A. One-trial object recognition in rats and mice:methodological and theoretical issues. Behav Brain Res,2010;215(2):244-54.
[36]王超,江伟,黄德武,等.装置影响昆明小鼠物体再认记忆.安徽农业大学学报,2009;36(2)：214-7.
[37]Ennaceur A, Neave N, Aggleton JP. Spontaneous object recognition and object location memory in rats:the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp Brain Res,1997;113(3):509-19.
[38]Dix SL, Aggleton JP. Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition. Behav Brain Res,1999;99(2):191-200.
[39]江伟,王超,陈贵海.昆明小鼠年龄相关性物体位置再认能力减退.安徽农业大学学报,2009;36(2)：218-21.
[40]Clayton NS, Griffiths DP, Emery NJ, et al. Elements of episodic-like memory in animals. Philos Trans R Soc Lond B Biol Sci,2001;356(1413):1483-91.
[41]Dere E, Silva MA, Huston JP. Higher order memories for objects encountered in different spatio-temporal contexts in mice:evidence for episodic memory. Rev Neurosci,2004;15(4):231-40.
[42]Crystal JD. Elements of episodic-like memory in animal models. Behav Processes,2009;80(3):269-77.
[43]Dere E, Huston JP, De Souza Silva MA. Episodic-like memory in mice: simultaneous assessment of object, place and temporal order memory. Brain Res Brain Res Protoc,2005;16(1-3):10-9.
[44]Good MA, Hale G, Staal V. Impaired "episodic-like" object memory in adult APPswe transgenic mice. Behav Neurosci,2007;121(2):443-8.
[45]Prediger RD, Franco JL, Pandolfo P, et al. Differential susceptibility following beta-amyloid peptide-(1-40) administration in C57BL/6and Swiss albino mice: Evidence for a dissociation between cognitive deficits and the glutathione system response. Behav Brain Res,2007;177(2):205-13.
[46]Kart-Teke E, De Souza Silva MA, Huston JP, et al. Wistar rats show episodic-like memory for unique experiences. Neurobiol Learn Mem,2006;85(2):173-82.
[47]Wang L, Jiao J, Dulawa SC. Infant maternal separation impairs adult cognitive performance in BALB/cJ mice. Psychopharmacology (Berl),2011;216(2):207-18.
[48]Llorente R, Miguel-Blanco C, Aisa B, et al. Long term sex-dependent psychoneuroendocrine effects of maternal deprivation and juvenile unpredictable stress in rats. J Neuroendocrinol,2011;23(4):329-44.
[49]Luine V. Sex differences in chronic stress effects on memory in rats. Stress,2002;5(3):205-16.
[50]Vedovelli K, Silveira E, Velho E, et al. Effects of increased opportunity for physical exercise and learning experiences on recognition memory and brain-derived neurotrophic factor levels in brain and serum of rats. Neuroscience,2011;199:284-91.
[51]Kazlauckas V, Pagnussat N, Mioranzza S, et al. Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice. Physiol Behav,2011;102(5):475-80.
[52]Da Silva Costa-Aze V, Dauphin F, Boulouard M. Serotonin5-HT6receptor blockade reverses the age-related deficits of recognition memory and working memory in mice. Behav Brain Res,2011;222(1):134-40.
[53]Diniz DG, Foro CA, Rego CM, et al. Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes. Eur J Neurosci,2010;32(3):509-19.
[54]Meyza KZ, Boguszewski PM, Nikolaev E, et al. Age increases anxiety and reactivity of the fear/anxiety circuit in Lewis rats. Behav Brain Res,2011;225(1):192-200.
[55]Moncek F, Duncko R, Johansson BB, et al. Effect of environmental enrichment on stress related systems in rats. J Neuroendocrinol,2004;16(5):423-31.
[56]Wilson RS, Arnold SE, Schneider JA, et al. Chronic distress, age-related neuropathology, and late-life dementia. Psychosom Med,2007;69(1):47-53.
[57]Yau JL, Noble J, Hibberd C, et al. Chronic treatment with the antidepressant amitriptyline prevents impairments in water maze learning in aging rats. J Neurosci,2002;22(4):1436-42.
[58]Wyss JM, Chambless BD, Kadish I, et al. Age-related decline in water maze learning and memory in rats:strain differences. Neurobiol Aging,2000;21(5):671-81.
[59]Wang F, Xu WH, Wang C, et al. Can outbred mice be used as a mouse model of mild cognitive impairment?. Neural Regen Res,2010;5(21):1650-56.
[60]Michalikova S, Ennaceur A, van Rensburg R, et al. Emotional responses and memory performance of middle-aged CD1mice in a3D maze:effects of low infrared light. Neurobiol Learn Mem,2008;89(4):480-8.
[61]McCormick CM, Mathews IZ. HPA function in adolescence:role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol Biochem Behav,2007;86(2):220-33.
[62]Sterlemann V, Rammes G, Wolf M, et al. Chronic social stress during adolescence induces cognitive impairment in aged mice. Hippocampus,2010;20(4):540-9.
[63]Isgor C, Kabbaj M, Akil H, et al. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus,2004;14(5):636-48.
[64]Lupien SJ, McEwen BS, Gunnar MR, et al. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci,2009;10(6):434-45.
[65]Segovia G, del Arco A, Mora F. Environmental enrichment, prefrontal cortex, stress, and aging of the brain. J Neural Transm,2009;116(8):1007-16.
[66]Redolat R, Mesa-Gresa P. Potential Benefits and Limitations of Enriched Environments and Cognitive Activity on Age-Related Behavioural Decline. Curr Top Behav Neurosci,2011.
[67]Cui M, Yang Y, Yang J, et al. Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress. Neurosci Lett,2006;404(1-2):208-12.
[1]Hayflick L. Biological aging is no longer an unsolved problem. Ann N Y Acad Sci,2007;1100:1-13.
[2]Chung HY, Lee EK, Choi YJ, et al. Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res,2011;90(7):830-40.
[3]Liu D, Xu Y. p53, oxidative stress, and aging. Antioxid Redox Signal,2011;15(6):1669-78.
[4]Seo AY, Joseph AM, Dutta D, et al. New insights into the role of mitochondria in aging:mitochondrial dynamics and more. J Cell Sci,2010;123(Pt15):2533-42.
[5]Ostojic S, Pereza N, Kapovic M. A current genetic and epigenetic view on human aging mechanisms. Coll Antropol,2009;33(2):687-99.
[6]Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline. Nature,2010;464(7288):529-35.
[7]Haigis MC, Guarente LP. Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev,2006;20(21):2913-21.
[8]Mercken EM, Carboneau BA, Krzysik-Walker SM, et al. Of mice and men:The benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev,2011.
[9]Corbi G, Conti V, Scapagnini G, et al. Role of sirtuins, calorie restriction and physical activity in aging. Front Biosci (Elite Ed),2012;4:768-78.
[10]Ford D, Ions LJ, Alatawi F, et al. The potential role of epigenetic responses to diet in ageing. Proc Nutr Soc,2011;70(3):374-84.
[11]Jak AJ. The Impact of Physical and Mental Activity on Cognitive Aging. Curr Top Behav Neurosci,2011.
[12]Archer T. Physical exercise alleviates debilities of normal aging and Alzheimer's disease. Acta Neurol Scand,2011;123(4):221-38.
[13]Hipkiss AR. Aging, Proteotoxicity, Mitochondria, Glycation, NAD and Carnosine: Possible Inter-Relationships and Resolution of the Oxygen Paradox. Front Aging Neurosci,2010;2:10.
[14]Grossman T. Latest advances in antiaging medicine. Keio J Med,2005;54(2):85-94.
[15]Liu H, Bravata DM, Olkin I, et al. Systematic review:the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med,2007;146(2):104-15.
[16]Giordano R, Bonelli L, Marinazzo E, et al. Growth hormone treatment in human ageing:benefits and risks. Hormones (Athens),2008;7(2):133-9.
[17]Mathew B, Biju R. Neuroprotective effects of garlic a review. Libyan J Med,2008;3(1):23-33.
[18]Andrade JP, Assuncao M. Protective effects of chronic green tea consumption on age-related neurodegeneration. Curr Pharm Des,2012;18(1):4-14.
[19]Doi K, Kojima T, Makino M, et al. Studies on the constituents of the leaves of Morus alba L. Chem Pharm Bull (Tokyo),2001;49(2):151-3.
[20]Asano N, Yamashita T, Yasuda K, et al. Polyhydroxylated alkaloids isolated from mulberry trees (Morusalba L.) and silkworms (Bombyx mori L.). J Agric Food Chem,2001;49(9):4208-13.
[21]Kimura T, Nakagawa K, Kubota H, et al. Food-grade mulberry powder enriched with1-deoxynojirimycin suppresses the elevation of postprandial blood glucose in humans. J Agric Food Chem,2007;55(14):5869-74.
[22]Kong WH, Oh SH, Ahn YR, et al. Antiobesity effects and improvement of insulin sensitivity by1-deoxynojirimycin in animal models. J Agric Food Chem,2008;56(8):2613-9.
[23]Islam B, Khan SN, Haque I, et al. Novel anti-adherence activity of mulberry leaves:inhibition of Streptococcus mutans biofilm by1-deoxynojirimycin isolated from Morus alba. J Antimicrob Chemother,2008;62(4):151-1.
[24]Fenouillet E, Papandreou MJ, Jones IM. Recombinant HIV envelope expressed in an alpha-glucosidase I-deficient CHO cell line and its parental cell line in the presence of1-deoxynojirimycin is functional. Virology,1997;231(1):89-95.
[25]Balzarini J. The alpha(1,2)-mannosidase Ⅰ inhibitor1-deoxymannojirimycin potentiates the antiviral activity of carbohydrate-binding agents against wild-type and mutant HIV-1strains containing glycan deletions in gp120. FEBS Lett,2007;581(10):2060-4.
[26]Kojima Y, Kimura T, Nakagawa K, et al. Effects of mulberry leaf extract rich in1-deoxynojirimycin on blood lipid profiles in humans. J Clin Biochem Nutr,2010;47(2):155-61.
[27]Roggero P, Gianni ML, Amato O, et al. Influence of protein and energy intakes on body composition of formula-fed preterm infants after term. J Pediatr Gastroenterol Nutr,2008;47(3):375-8.
[28]Fouquet C, Petit GH, Auffret A, et al. Early detection of age-related memory deficits in individual mice. Neurobiol Aging,2011;32(10):1881-95.
[29]Chen GH, Wang YJ, Wang XM, et al. Effect of aging on species-typical behaviors in senescence-accelerated mouse. Physiol Behav,2005;85(5):536-45.
[30]熊向东,徐文锐,陈贵海.C57BL/6小鼠年龄和性别对种属型行为的影响.安徽农业大学学报,2006;33(3)：310-3.
[31]吴旭,王月菊,陈贵海.钢质平衡木直径对SAM小鼠感觉运动能力检测的影响.安徽农业大学学报,2005;32(4)：460-2.
[32]Barreto G, Huang TT, Giffard RG. Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL/6mice. J Neurosurg Anesthesiol,2010;22(3):214-9.
[33]曹磊,王芳,陈贵海.中年C57BL/6和ICR小鼠感觉运动能力的改变.安徽农业大学学报,2009;36：120-3.
[34]Chen GH, Wang YJ, Zhang LQ, et al. Age-and sex-related disturbance in a battery of sensorimotor and cognitive tasks in Kunming mice. Physiol Behav,2004;83(3):531-41.
[35]Boguszewski P, Zagrodzka J. Emotional changes related to age in rats--a behavioral analysis. Behav Brain Res,2002;133(2):323-32.
[36]Comijs HC, Deeg DJ, Dik MG, et al. Memory complaints; the association with psycho-affective and health problems and the role of personality characteristics. A6-year follow-up study. J Affect Disord,2002;72(2):157-65.
[37]Chen GH, Wang C, Yangcheng HY, et al. Age-related changes in anxiety are task-specific in the senescence-accelerated prone mouse8. Physiol Behav,2007;91(5):644-51.
[38]Takeda T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8and SAMP10mice. Neurochem Res,2009;34(4):639-59.
[39]Zhao Q, Yokozawa T, Yamabe N, et al. Kangen-karyu improves memory deficit caused by aging through normalization of neuro-plasticity-related signaling system and VEGF system in the brain. J Ethnopharmacol,2010;131(2):377-85.
[40]Tomobe K, Nomura Y. Neurochemistry, neuropathology, and heredity in SAMP8: a mouse model of senescence. Neurochem Res,2009;34(4):660-9.
[41]Rugg MD, Yonelinas AP. Human recognition memory:a cognitive neuroscience perspective. Trends Cogn Sci,2003;7(7):313-9.
[42]Da Silva Costa V, Duchatelle P, Boulouard M, et al. Selective5-HT6receptor blockade improves spatial recognition memory and reverses age-related deficits in spatial recognition memory in the mouse. Neuropsychopharmacology,2009;34(2):488-500.
[43]Da Silva Costa-Aze V, Dauphin F, Boulouard M. Serotonin5-HT6receptor blockade reverses the age-related deficits of recognition memory and working memory in mice. Behav Brain Res,2011;222(1):134-40.
[44]Pallas M, Camins A, Smith MA, et al. From aging to Alzheimer's disease: unveiling "the switch" with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis,2008;15(4):615-24.
[45]Nomura Y, Okuma Y. Age-related defects in lifespan and learning ability in SAMP8mice. Neurobiol Aging,1999;20(2):111-5.
[46]Butterfield DA, Poon HF. The senescence-accelerated prone mouse (SAMP8):a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease. Exp Gerontol,2005;40(10):774-83.
[47]Chen GH, Wang YJ, Qin S, et al. Age-related spatial cognitive impairment is correlated with increase of synaptotagmin1in dorsal hippocampus in SAMP8mice. Neurobiol Aging,2007;28(4):611-8.
[48]Wang F, Chen H, Sun X. Age-related spatial cognitive impairment is correlated with a decrease in ChAT in the cerebral cortex, hippocampus and forebrain of SAMP8mice. Neurosci Lett,2009;454(3):212-7.
[49]Chen GH, Wang YJ, Wang XM, et al. Accelerated senescence prone mouse-8shows early onset of deficits in spatial learning and memory in the radial six-arm water maze. Physiol Behav,2004;82(5):883-90.
[1]Kowald A. Lifespan does not measure ageing. Biogerontology,2002;3(3):187-90.
[2]Andrews-Hanna JR, Snyder AZ, Vincent JL, et al. Disruption of large-scale brain systems in advanced aging. Neuron,2007;56(5):924-35.
[3]Cabeza R. Hemispheric asymmetry reduction in older adults:the HAROLD model. Psychol Aging,2002;17(1):85-100.
[4]Park DC,Reuter-Lorenz P. The adaptive brain:aging and neurocognitive scaffolding. Annu Rev Psychol,2009;60:173-96.
[5]Cabeza R, Anderson ND, Locantore JK, et al. Aging gracefully:compensatory brain activity in high-performing older adults. Neuroimage,2002;17(3):1394-402.
[6]Lu T, Pan Y, Kao SY, et al. Gene regulation and DNA damage in the ageing human brain. Nature,2004;429(6994):883-91.
[7]Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice. Nat Genet,2000;25(3):294-7.
[8]Jiang CH, Tsien JZ, Schultz PG, et al. The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc Natl Acad Sci U S A,2001;98(4):1930-4.
[9]Blalock EM, Chen KC, Sharrow K, et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci,2003;23(9):3807-19.
[10]Fraser HB, Khaitovich P, Plotkin JB, et al. Aging and gene expression in the primate brain. PLoS Biol,2005;3(9):e274.
[11]Erraji-Benchekroun L, Underwood MD, Arango V, et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol Psychiatry,2005;57(5):549-58.
[12]Loerch PM, Lu T, Dakin KA, et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS One,2008;3(10):e3329.
[13]Small SA, Tsai WY, DeLaPaz R, et al. Imaging hippocampal function across the human life span:is memory decline normal or not? Ann Neurol,2002;51(3):290-5.
[14]West MJ, Coleman PD, Flood DG, et al. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet,1994;344(8925):769-72.
[15]Price JL, Ko AI, Wade MJ, et al. Neuron number in the entorhinal cortex and CA1in preclinical Alzheimer disease. Arch Neurol,2001;58(9):1395-402.
[16]Gomez-Isla T, Price JL, McKeel DW, Jr., et al. Profound loss of layer Ⅱ entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci,1996;16(14):4491-500.
[17]Rodrigue KM, Raz N. Shrinkage of the entorhinal cortex over five years predicts memory performance in healthy adults. J Neurosci,2004;24(4):956-63.
[18]Yankner BA, Lu T, Loerch P. The aging brain. Annu Rev Pathol,2008;3:41-66.
[19]Zahn JM, Poosala S, Owen AB, et al. AGEMAP:a gene expression database for aging in mice. PLoS Genet,2007;3(11):e201.
[20]Blalock EM, Geddes JW, Chen KC, et al. Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci U S A,2004;101(7):2173-8.
[21]Liang WS, Reiman EM, Valla J, et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A,2008;105(11):4441-6.
[22]Miller JA, Oldham MC, Geschwind DH. A systems level analysis of transcriptional changes in Alzheimer's disease and normal aging. J Neurosci,2008;28(6):1410-20.
[23]Walker DW, Muffat J, Rundel C, et al. Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan. Curr Biol,2006;16(7):674-9.
[24]Sanchez D, Lopez-Arias B, Torroja L, et al. Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila. Curr Biol,2006;16(7):680-6.
[25]Kalman J, McConathy W, Araoz C, et al. Apolipoprotein D in the aging brain and in Alzheimer's dementia. Neurol Res,2000;22(4):330-6.
[26]Bishop NA, Guarente L. Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature,2007;447(7144):545-9.
[27]Flurkey K, Papaconstantinou J, Miller RA, et al. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A,2001;98(12):6736-41.
[28]Conti B, Sanchez-Alavez M, Winsky-Sommerer R, et al. Transgenic mice with a reduced core body temperature have an increased life span. Science,2006;314(5800):825-8.
[29]Jankord R, Herman JP. Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann N Y Acad Sci,2008;1148:64-73.
[30]Conrad CD. Chronic stress-induced hippocampal vulnerability:the glucocorticoid vulnerability hypothesis. Rev Neurosci,2008;19(6):395-411.
[31]Bao AM, Meynen G, Swaab DF. The stress system in depression and neurodegeneration:focus on the human hypothalamus. Brain Res Rev,2008;57(2):531-53.
[32]Sedensky MM, Morgan PG. Mitochondrial respiration and reactive oxygen species in mitochondrial aging mutants. Exp Gerontol,2006;41(3):237-45.
[33]Rea SL, Ventura N, Johnson TE. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol,2007;5(10):e259.
[34]Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature,2004;429(6990):417-23.
[35]Kujoth GC, Hiona A, Pugh TD, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science,2005;309(5733):481-4.
[36]Schriner SE, Linford NJ, Martin GM, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science,2005;308(5730): 1909-11.
[37]Sanchez-Blanco A, Fridell YW, Helfand SL. Involvement of Drosophila uncoupling protein5in metabolism and aging. Genetics,2006;172(3):1699-710.
[38]Lee SS, Lee RY, Fraser AG, et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet,2003;33(1):40-8.
[39]Dillin A, Hsu AL, Arantes-Oliveira N, et al. Rates of behavior and aging specified by mitochondrial function during development. Science,2002;298(5602):2398-401.
[40]Yang W, Hekimi S. Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell,2010;9(3):433-47.
[41]Copeland JM, Cho J, Lo T, Jr., et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr Biol,2009;19(19):1591-8.
[42]Liu X, Jiang N, Hughes B, et al. Evolutionary conservation of the clk-1-dependent mechanism of longevity:loss of mclkl increases cellular fitness and lifespan in mice. Genes Dev,2005;19(20):2424-34.
[43]Dell'agnello C, Leo S, Agostino A, et al. Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surfl knockout mice. Hum Mol Genet,2007;16(4):431-44.
[44]Muller FL, Lustgarten MS, Jang Y, et al. Trends in oxidative aging theories. Free Radic Biol Med,2007;43(4):477-503.
[45]Park SK, Kim K, Page GP, et al. Gene expression profiling of aging in multiple mouse strains:identification of aging biomarkers and impact of dietary antioxidants. Aging Cell,2009;8(4):484-95.
[46]Liu J, Head E, Gharib AM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation:partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci U S A,2002;99(4):2356-61.
[47]Oberdoerffer P, Michan S, McVay M, et al. SIRT1redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell,2008;135(5):907-18.
[48]O'Hagan HM, Mohammad HP, Baylin SB. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet,2008;4(8):e1000155.
[49]Guarente L. Sir2links chromatin silencing, metabolism, and aging. Genes Dev,2000;14(9):1021-6.
[50]Curran SP, Ruvkun G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet,2007;3(4):e56.
[51]Fischer A, Sananbenesi F, Wang X, et al. Recovery of learning and memory is associated with chromatin remodelling. Nature,2007;447(7141):178-82.
[52]Melendez A, Talloczy Z, Seaman M, et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science,2003;301(5638):1387-91.
[53]Hansen M, Chandra A, Mitic LL, et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet,2008;4(2):e24.
[54]Lapierre LR, Gelino S, Melendez A, et al. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr Biol,2011;21(18):1507-14.
[55]Simonsen A, Cumming RC, Brech A, et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy,2008;4(2):176-84.
[56]Juhasz G, Erdi B, Sass M, et al. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev,2007;21(23):3061-6.
[57]Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature,2006;441(7095):885-9.
[58]Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature,2006;441(7095):880-4.
[59]Shibata M, Lu T, Furuya T, et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin1. J Biol Chem,2006;281(20):14474-85.
[60]Schieke SM, Finkel T. Mitochondrial signaling, TOR, and life span. Biol Chem,2006;387(10-11):1357-61.
[61]Raffaello A, Rizzuto R. Mitochondrial longevity pathways. Biochim Biophys Acta,2011;1813(1):260-8.
[62]Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature,2009;460(7253):392-5.
[63]Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet,2004;36(6):585-95.
[64]Mendelsohn AR, Larrick JW. Rapamycin as an antiaging therapeutic?:targeting mammalian target of rapamycin to treat Hutchinson-Gilford progeria and neurodegenerative diseases. Rejuvenation Res,2011;14(4):437-41.
[65]Santos RX, Correia SC, Cardoso S, et al. Effects of rapamycin and TOR on aging and memory:implications for Alzheimer's disease. J Neurochem,2011;117(6):927-36.
[66]Broughton S, Partridge L. Insulin/IGF-like signalling, the central nervous system and aging. Biochem J,2009;418(1):1-12.
[67]Flachsbart F, Caliebe A, Kleindorp R, et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A,2009;106(8):2700-5.
[68]Suh Y, Atzmon G, Cho MO, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A,2008;105(9):3438-42.
[69]Willcox BJ, Donlon TA, He Q, et al. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A,2008;105(37):13987-92.
[70]Libina N, Berman JR, Kenyon C. Tissue-specific activities of C. elegans DAF-16in the regulation of lifespan. Cell,2003;115(4):489-502.
[71]Iser WB, Gami MS, Wolkow CA. Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs. Dev Biol,2007;303(2):434-47.
[72]Broughton SJ, Piper MD, Ikeya T, et al. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A,2005;102(8):3105-10.
[73]van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system:learning to survive. Prog Neurobiol,2006;79(4):205-21.
[74]Taguchi A, Wartschow LM, White MF. Brain IRS2signaling coordinates life span and nutrient homeostasis. Science,2007;317(5836):369-72.
[75]Cohen E, Bieschke J, Perciavalle RM, et al. Opposing activities protect against age-onset proteotoxicity. Science,2006;313(5793):1604-10.
[76]Freude S, Hettich MM, Schumann C, et al. Neuronal IGF-1resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer's disease. Faseb J,2009;23(10):3315-24.
[77]Cohen E, Paulsson JF, Blinder P, et al. Reduced IGF-1signaling delays age-associated proteotoxicity in mice. Cell,2009;139(6):1157-69.
[78]Moloney AM, Griffin RJ, Timmons S, et al. Defects in IGF-1receptor, insulin receptor and IRS-1/2in Alzheimer's disease indicate possible resistance to IGF-1and insulin signalling. Neurobiol Aging,2010;31(2):224-43.
[79]Haigis MC, Guarente LP. Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev,2006;20(21):2913-21.
[80]Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science,2009;325(5937):201-4.
[81]Ingram DK, Weindruch R, Spangler EL, et al. Dietary restriction benefits learning and motor performance of aged mice. J Gerontol,1987;42(1):78-81.
[82]Stewart J, Mitchell J, Kalant N. The effects of life-long food restriction on spatial memory in young and aged Fischer344rats measured in the eight-arm radial and the Morris water mazes. Neurobiol Aging,1989;10(6):669-75.
[83]Witte AV, Fobker M, Gellner R, et al. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A,2009;106(4):1255-60.
[84]Halagappa VK, Guo Z, Pearson M, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiol Dis,2007;26(1):212-20.
[85]Mair W, Dillin A. Aging and survival:the genetics of life span extension by dietary restriction. Annu Rev Biochem,2008;77:727-54.
[86]Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science,2000;289(5487):2126-8.
[87]Rogina B, Helfand SL. Sir2mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A,2004;101(45):15998-6003.
[88]Boily G, Seifert EL, Bevilacqua L, et al. SirTl regulates energy metabolism and response to caloric restriction in mice. PLoS One,2008;3(3):e1759.
[89]Chen D, Steele AD, Lindquist S, et al. Increase in activity during calorie restriction requires Sirtl. Science,2005;310(5754):1641.
[90]Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1activation prevent axonal degeneration. Science,2004;305(5686):1010-3.
[91]Kim D, Nguyen MD, Dobbin MM, et al. SIRT1deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. Embo J,2007;26(13):3169-79.
[92]Li Y, Xu W, McBurney MW, et al. SirT1inhibition reduces IGF-Ⅰ/IRS-2/Ras/ERK1/2signaling and protects neurons. Cell Metab,2008;8(1):38-48.