衰老过程中行为和认知功能退化的调控机制研究

doi:10.16288/j.yczz.21-060

[an error occurred while processing this directive]

Hereditas(Beijing) ›› 2021, Vol. 43 ›› Issue (6): 545-570.doi: 10.16288/j.yczz.21-060

• Special Section: Excellent Doctoral Thesis • Previous Articles Next Articles

The regulatory mechanisms of behavioral and cognitive aging

Jie Yuan^1,²(), Shiqing Cai^1,²

1. Institute of Neuroscience and State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China
2. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China

Received:2021-02-08 Revised:2021-03-11 Online:2021-06-20 Published:2021-03-30
Contact: Yuan Jie E-mail:yuanjiejane@gmail.com
Supported by:
Supported by the National Natural Science Foundation of China No(91949206)

Abstract

Abstract:

With the increase of life expectancy, the world’s population is aging rapidly. Previous work in the field of aging greatly increases our understanding of biological mechanisms underlying longevity. Researchers have unraveled a number of longevity pathways conserved from yeast to mammals. However, recent evidence shows that mechanisms regulating the life span and those regulating age-related behavioral decline could be dissociated. The regulatory mechanisms underlying behavioral and cognitive aging is largely unknown. Previous work has described a significant age-related decline in cognitive behaviors including episodic memory, working memory, processing speed, as well as motor function deterioration and circadian dysfunction. With the advance of neuroscience and technology, more and more studies have focused on the age-related changes in structure and function of the brain. In this review, we briefly describe the deterioration of cognitive function and other behaviors in the aging process, and survey the role of age-related changes in brain structure and network, neuron morphology and function, transcriptome in brain and some conserved biological pathways on age-related cognitive and behavioral decline. Further studies on the mechanisms underpinning age-related cognitive and behavioral decline may provide clues not only for improving the quality of life for the ageing population, but also for developing intervention approaches for neurodegenerative diseases.

Key words: aging, cognitive function, behavioral deterioration, synapse, neurotransmitter, mitochondrion, oxidative stress, epigenetic

Jie Yuan, Shiqing Cai. The regulatory mechanisms of behavioral and cognitive aging[J]. Hereditas(Beijing), 2021, 43(6): 545-570.

Figures/Tables 3

References 293

[1]	Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline. Nature, 2010,464(7288):529-535.
[2]	Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med, 2013,29(4):737-752.
[3]	McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition, 1989, 5(3): 155-171; discussion 172.
[4]	Gavrilov LA, Gavrilova NS. Evolutionary theories of aging and longevity. Sci World J, 2002,2:339-356.
[5]	Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol, 2000,1(1):72-76.
[6]	Jiang H, Ju Z, Rudolph KL. Telomere shortening and ageing. Z Gerontol Geriatr, 2007,40(5):314-324.
[7]	Jin K. Modern biological theories of aging. Aging Dis, 2010,1(2):72-74.
[8]	Klass MR. A method for the isolation of longevity mutants in the nematode caenorhabditis elegans and initial results. Mech Ageing Dev, 1983,22(3-4):279-286.
[9]	Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A c. Elegans mutant that lives twice as long as wild type. Nature, 1993,366(6454):461-464.
[10]	Kenyon CJ. The genetics of ageing. Nature, 2010,464(7288):504-512.
[11]	Yin JA, Liu XJ, Yuan J, Jiang J, Cai SQ. Longevity manipulations differentially affect serotonin/dopamine level and behavioral deterioration in aging caenorhabditis elegans. J Neurosci, 2014,34(11):3947-3958.
[12]	Bansal A, Zhu LJ, Yen K, Tissenbaum HA. Uncoupling lifespan and healthspan in caenorhabditis elegans longevity mutants. Proc Natl Acad Sci USA, 2015,112(3):E277-286.
[13]	Hedden T, Gabrieli JD. Insights into the ageing mind: A view from cognitive neuroscience. Nat Rev Neurosci, 2004,5(2):87-96.
[14]	Riddle DR. Brain aging: Models, methods, and mechanisms. CRC Press, 2007.
[15]	Spencer WD, Raz N. Differential effects of aging on memory for content and context: A meta-analysis. Psychol Aging, 1995,10(4):527-539.
[16]	Nyberg L, Lövden M, Riklund K, Lindenberger U, Bäckman L. Memory aging and brain maintenance. Trends Cogn Sci, 2012,16(5):292-305.
[17]	Yeoman M, Scutt G, Faragher R. Insights into cns ageing from animal models of senescence. Nat Rev Neurosci, 2012,13(6):435-445.
[18]	Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D, Arnsten AF. Neuronal basis of age-related working memory decline. Nature, 2011,476(7359):210-213.
[19]	West RL. An application of prefrontal cortex function theory to cognitive aging. Psychol Bull, 1996,120(2):272-292.
[20]	Buckner RL. Memory and executive function in aging and ad: Multiple factors that cause decline and reserve factors that compensate. Neuron, 2004,44(1):195-208.
[21]	Kirova AM, Bays RB, Lagalwar S. Working memory and executive function decline across normal aging, mild cognitive impairment, and alzheimer's disease. Biomed Res Int, 2015,2015:748212.
[22]	Zelinski EM, Burnight KP. Sixteen-year longitudinal and time lag changes in memory and cognition in older adults. Psychol Aging, 1997,12(3):503-513.
[23]	Commodari E, Guarnera M. Attention and aging. Aging Clin Exp Res, 2008,20(6):578-584.
[24]	Rönnlund M, Nyberg L, Bäckman L, Nilsson LG. 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.
[25]	Carstensen LL, Lockenhoff CE. Aging, emotion, and evolution: The bigger picture. Ann N Y Acad Sci, 2003,1000:152-179.
[26]	Williams LM, Brown KJ, Palmer D, Liddell BJ, Kemp AH, Olivieri G, Peduto A, Gordon E. The mellow years?: Neural basis of improving emotional stability over age. J Neurosci, 2006,26(24):6422-6430.
[27]	Carstensen LL, Fung HH, Charles ST. Socioemotional selectivity theory and the regulation of emotion in the second half of life. Motiv Emotion, 2003,27(2):103-123.
[28]	Mattay VS, Fera F, Tessitore A, Hariri AR, Das S, Callicott JH, Weinberger DR. Neurophysiological correlates of age-related changes in human motor function. Neurology, 2002,58(4):630-635.
[29]	Seidler RD, Bernard JA, Burutolu TB, Fling BW, Gordon MT, Gwin JT, Kwak Y, Lipps DB. Motor control and aging: Links to age-related brain structural, functional, and biochemical effects. Neurosci Biobehav Rev, 2010,34(5):721-733.
[30]	Faulkner JA, Larkin LM, Claflin DR, Brooks SV. Age-related changes in the structure and function of skeletal muscles. Clin Exp Pharmacol Physiol, 2007,34(11):1091-1096.
[31]	Tsukahara S, Tanaka S, Ishida K, Hoshi N, Kitagawa H. Age-related change and its sex differences in histoarchitecture of the hypothalamic suprachiasmatic nucleus of f344/n rats. Exp Gerontol, 2005,40(3):147-155.
[32]	Roberts DE, Killiany RJ, Rosene DL. Neuron numbers in the hypothalamus of the normal aging rhesus monkey: Stability across the adult lifespan and between the sexes. J Comp Neurol, 2012,520(6):1181-1197.
[33]	Satoh A, Imai SI, Guarente L. The brain, sirtuins, and ageing. Nat Rev Neurosci, 2017,18(6):362-374.
[34]	Chang HC, Guarente L. Sirt1 mediates central circadian control in the scn by a mechanism that decays with aging. Cell, 2013,153(7):1448-1460.
[35]	Anderson ND, Craik FI. 50 years of cognitive aging theory. J Gerontol B Psychol Sci Soc Sci, 2017,72(1):1-6.
[36]	Persson J, Sylvester CY, Nelson JK, Welsh KM, Jonides J, Reuter-Lorenz PA. Selection requirements during verb generation: Differential recruitment in older and younger adults. Neuroimage, 2004,23(4):1382-1390.
[37]	Logan JM, Sanders AL, Snyder AZ, Morris JC, Buckner RL. Under-recruitment and nonselective recruitment: Dissociable neural mechanisms associated with aging. Neuron, 2002,33(5):827-840.
[38]	Rosen AC, Prull MW, O'Hara R, Race EA, Desmond JE, Glover GH, Yesavage JA, Gabrieli JDE. Variable effects of aging on frontal lobe contributions to memory. Neuroreport, 2002,13(18):2425-2428.
[39]	Andrews-Hanna JR, Snyder AZ, Vincent JL, Lustig C, Head D, Raichle ME, Buckner RL. Disruption of large-scale brain systems in advanced aging. Neuron, 2007,56(5):924-935.
[40]	Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C. Longitudinal magnetic resonance imaging studies of older adults: A shrinking brain. J Neurosci, 2003,23(8):3295-3301.
[41]	Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat Rev Neurosci, 2006,7(1):30-40.
[42]	Pakkenberg B, Gundersen HJ. Neocortical neuron number in humans: Effect of sex and age. J Comp Neurol, 1997,384(2):312-320.
[43]	West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and alzheimer's disease. Lancet, 1994,344(8925):769-772.
[44]	Merrill DA, Roberts JA, Tuszynski MH. Conservation of neuron number and size in entorhinal cortex layers ii, iii, and v/vi of aged primates. J Comp Neurol, 2000,422(3):396-401.
[45]	Keuker JI, Luiten PG, Fuchs E. Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol Aging, 2003,24(1):157-165.
[46]	Merrill DA, Chiba AA, Tuszynski MH. Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J Comp Neurol, 2001,438(4):445-456.
[47]	Rapp PR, Gallagher M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA, 1996,93(18):9926-9930.
[48]	Peters A, Morrison JH, Rosene DL, Hyman BT. Feature article: Are neurons lost from the primate cerebral cortex during normal aging? Cereb Cortex, 1998,8(4):295-300.
[49]	Smith DE, Rapp PR, McKay HM, Roberts JA, Tuszynski MH. Memory impairment in aged primates is associated with focal death of cortical neurons and atrophy of subcortical neurons. J Neurosci, 2004,24(18):4373-4381.
[50]	Scheibel ME, Lindsay RD, Tomiyasu U, Scheibel AB. Progressive dendritic changes in aging human cortex. Exp Neurol, 1975,47(3):392-403.
[51]	Nakamura S, Akiguchi I, Kameyama M, Mizuno N. Age-related changes of pyramidal cell basal dendrites in layers iii and v of human motor cortex: A quantitative golgi study. Acta Neuropathol, 1985,65(3-4):281-284.
[52]	de Brabander JM, Kramers RJ, Uylings HB. Layer- specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex. Eur J Neurosci, 1998,10(4):1261-1269.
[53]	Peters A, Sethares C, Moss MB. The effects of aging on layer 1 in area 46 of prefrontal cortex in the rhesus monkey. Cereb Cortex, 1998,8(8):671-684.
[54]	Markham JA, Juraska JM. Aging and sex influence the anatomy of the rat anterior cingulate cortex. Neurobiol Aging, 2002,23(4):579-588.
[55]	Hall TC, Miller AKH, Corsellis JAN. Variations in human purkinje-cell population according to age and sex. Neuropath Appl Neuro, 1975,1(3):267-292.
[56]	Andersen BB, Gundersen HJ, Pakkenberg B. Aging of the human cerebellum: A stereological study. J Comp Neurol, 2003,466(3):356-365.
[57]	Nandy K. Morphological changes in the cerebellar cortex of aging macaca nemestrina. Neurobiol Aging, 1981,2(1):61-64.
[58]	Rogers J, Zornetzer SF, Bloom FE, Mervis RE. Senescent microstructural changes in rat cerebellum. Brain Res, 1984,292(1):23-32.
[59]	Sturrock RR. Changes in neuron number in the cerebellar cortex of the ageing mouse. J Hirnforsch, 1989,30(4):499-503.
[60]	Woodruff-Pak DS, Foy MR, Akopian GG, Lee KH, Zach J, Nguyen KP, Comalli DM, Kennard JA, Agelan A, Thompson RF. Differential effects and rates of normal aging in cerebellum and hippocampus. Proc Natl Acad Sci USA, 2010,107(4):1624-1629.
[61]	Zhang C, Hua T, Zhu Z, Luo X. Age-related changes of structures in cerebellar cortex of cat. J Biosci, 2006,31(1):55-60.
[62]	Quackenbush LJ, Ngo H, Pentney RJ. Evidence for nonrandom regression of dendrites of purkinje neurons during aging. Neurobiol Aging, 1990,11(2):111-115.
[63]	Peters A, Sethares C, Luebke JI. Synapses are lost during aging in the primate prefrontal cortex. Neuroscience, 2008,152(4):970-981.
[64]	Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci, 2010,30(22):7507-7515.
[65]	Arnsten AF, Paspalas CD, Gamo NJ, Yang Y, Wang M. Dynamic network connectivity: A new form of neuroplasticity. Trends Cogn Sci, 2010,14(8):365-375.
[66]	Uemura E. Age-related changes in the subiculum of macaca mulatta: Synaptic density. Exp Neurol, 1985,87(3):403-411.
[67]	Adams MM, Donohue HS, Linville MC, Iversen EA, Newton IG, Brunso-Bechtold JK. Age-related synapse loss in hippocampal ca3 is not reversed by caloric restriction. Neuroscience, 2010,171(2):373-382.
[68]	Geinisman Y, Ganeshina O, Yoshida R, Berry RW, Disterhoft JF, Gallagher M. Aging, spatial learning, and total synapse number in the rat ca1 stratum radiatum. Neurobiol Aging, 2004,25(3):407-416.
[69]	Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J Neurosci, 2004,24(35):7648-7653.
[70]	Morrison JH, Baxter MG. The ageing cortical synapse: Hallmarks and implications for cognitive decline. Nat Rev Neurosci, 2012,13(4):240-250.
[71]	Bondareff W, Geinisman Y. Loss of synapses in the dentate gyrus of the senescent rat. Am J Anat, 1976,145(1):129-136.
[72]	Geinisman Y, Bondareff W, Dodge JT. Partial deafferentation of neurons in the dentate gyrus of the senescent rat. Brain Res, 1977,134(3):541-545.
[73]	Fan WJ, Yan MC, Wang L, Sun YZ, Deng JB, Deng JX. Synaptic aging disrupts synaptic morphology and function in cerebellar purkinje cells. Neural Regen Res, 2018,13(6):1019-1025.
[74]	Cruz-Sánchez FF, Cardozo A, Tolosa E. Neuronal changes in the substantia nigra with aging: A golgi study. J Neuropathol Exp Neurol, 1995,54(1):74-81.
[75]	Itzev D, Lolova I, Lolov S, Usunoff KG. Age-related changes in the synapses of the rat's neostriatum. Arch Physiol Biochem, 2001,109(1):80-89.
[76]	Levine MS, Adinolfi AM, Fisher RS, Hull CD, Buchwald NA, McAllister JP. Quantitative morphology of medium-sized caudate spiny neurons in aged cats. Neurobiol Aging, 1986,7(4):277-286.
[77]	Marcuzzo S, Dall'oglio A, Ribeiro MF, Achaval M, Rasia-Filho AA. Dendritic spines in the posterodorsal medial amygdala after restraint stress and ageing in rats. Neurosci Lett, 2007,424(1):16-21.
[78]	Rubinow MJ, Drogos LL, Juraska JM. Age-related dendritic hypertrophy and sexual dimorphism in rat basolateral amygdala. Neurobiol Aging, 2009,30(1):137-146.
[79]	Barnes CA. Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat. J Comp Physiol Psychol, 1979,93(1):74-104.
[80]	Barnes CA , McNaughton BL. Physiological compensation for loss of afferent synapses in rat hippocampal granule cells during senescence. J Physiol, 1980,309:473-485.
[81]	Luebke JI, Chang YM, Moore TL, Rosene DL. Normal aging results in decreased synaptic excitation and increased synaptic inhibition of layer 2/3 pyramidal cells in the monkey prefrontal cortex. Neuroscience, 2004,125(1):277-288.
[82]	Liu J, Zhang B, Lei H, Feng Z, Hsu AL, Xu XZ. Functional aging in the nervous system contributes to age-dependent motor activity decline in c. Elegans. Cell Metab, 2013,18(3):392-402.
[83]	Moore CI, Browning MD, Rose GM. Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area ca1 of aged fischer 344 rats. Hippocampus, 1993,3(1):57-66.
[84]	Norris CM, Korol DL, Foster TC. Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J Neurosci, 1996,16(17):5382-5392.
[85]	Lister JP, Barnes CA. Neurobiological changes in the hippocampus during normative aging. Arch Neurol, 2009,66(7):829-833.
[86]	Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A. Calcineurin links ca2+ dysregulation with brain aging. J Neurosci, 2001,21(11):4066-4073.
[87]	Ris L, Godaux E. Synapse specificity of long-term potentiation breaks down with aging. Learn Mem, 2007,14(3):185-189.
[88]	Backman L, Nyberg L, Lindenberger U, Li SC, Farde L. The correlative triad among aging, dopamine, and cognition: Current status and future prospects. Neurosci Biobehav Rev, 2006,30(6):791-807.
[89]	Chowdhury R, Guitart-Masip M, Lambert C, Dayan P, Huys Q, Düzel E, Dolan RJ. Dopamine restores reward prediction errors in old age. Nat Neurosci, 2013,16(5):648-653.
[90]	Karrer TM, Josef AK, Mata R, Morris ED, Samanez- Larkin GR. Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: A meta-analysis. Neurobiol Aging, 2017,57:36-46.
[91]	Reeves S, Bench C, Howard R. Ageing and the nigrostriatal dopaminergic system. Int J Geriatr Psychiatry, 2002,17(4):359-370.
[92]	Arnsten AF, Cai JX, Steere JC, Goldman-Rakic PS. Dopamine d2 receptor mechanisms contribute to age-related cognitive decline: The effects of quinpirole on memory and motor performance in monkeys. J Neurosci, 1995,15(5 Pt 1):3429-3439.
[93]	Melancon MO, Lorrain D, Dionne IJ. Exercise and sleep in aging: Emphasis on serotonin. Pathol Biol (Paris), 2014,62(5):276-283.
[94]	Meltzer CC, Smith G , DeKosky ST, Pollock BG, Mathis CA, Moore RY, Kupfer DJ, Reynolds CF, 3rd. Serotonin in aging, late-life depression, and alzheimer's disease: The emerging role of functional imaging. Neuropsychopharmacol, 1998,18(6):407-430.
[95]	Wester P, Hardy JA, Marcusson J, Nyberg P, Winblad B. Serotonin concentrations in normal aging human brains: Relation to serotonin receptors. Neurobiol Aging, 1984,5(3):199-203.
[96]	McEntee WJ, Crook TH. Serotonin, memory, and the aging brain. Psychopharmacology (Berl), 1991,103(2):143-149.
[97]	Miguez JM, Aldegunde M, Paz-Valinas L, Recio J, Sanchez-Barcelo E. Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging. J Neural Transm (Vienna), 1999,106(11-12):1089-1098.
[98]	Petkov VD, Stancheva SL, Petkov VV, Alova LG. Age-related changes in brain biogenic monoamines and monoamine oxidase. Gen Pharmacol, 1987,18(4):397-401.
[99]	Bhaskaran D, Radha E. Monoamine levels and monoamine oxidase activity in different regions of rat brain as a function of age. Mech Ageing Dev, 1983,23(2):151-160.
[100]	Herrera AJ, Machado A, Cano J. The influence of age on neurotransmitter turnover in the rat's superior colliculus. Neurobiol Aging, 1991,12(4):289-294.
[101]	Stemmelin J, Lazarus C, Cassel S, Kelche C, Cassel JC. Immunohistochemical and neurochemical correlates of learning deficits in aged rats. Neuroscience, 2000,96(2):275-289.
[102]	Rodriguez JJ, Noristani HN, Verkhratsky A. The serotonergic system in ageing and alzheimer's disease. Prog Neurobiol, 2012,99(1):15-41.
[103]	Karrer TM , McLaughlin CL, Guaglianone CP, Samanez-Larkin GR. Reduced serotonin receptors and transporters in normal aging adults: A meta-analysis of pet and spect imaging studies. Neurobiol Aging, 2019,80:1-10.
[104]	Fazio P, Schain M, Varnas K, Halldin C, Farde L, Varrone A. Mapping the distribution of serotonin transporter in the human brainstem with high-resolution pet: Validation using postmortem autoradiography data. Neuroimage, 2016,133:313-320.
[105]	Yamamoto M, Suhara T, Okubo Y, Ichimiya T, Sudo Y, Inoue M, Takano A, Yasuno F, Yoshikawa K, Tanada S. Age-related decline of serotonin transporters in living human brain of healthy males. Life Sci, 2002,71(7):751-757.
[106]	Wong DF, Wagner Jr HN, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH. Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science, 1984,226(4681):1393-1396.
[107]	Fonnum F. Glutamate: A neurotransmitter in mammalian brain. J Neurochem, 1984,42(1):1-11.
[108]	Orrego F, Villanueva S. The chemical nature of the main central excitatory transmitter: A critical appraisal based upon release studies and synaptic vesicle localization. Neuroscience, 1993,56(3):539-555.
[109]	Kaiser LG, Schuff N, Cashdollar N, Weiner MW. Age-related glutamate and glutamine concentration changes in normal human brain: 1h mr spectroscopy study at 4 t. Neurobiol Aging, 2005,26(5):665-672.
[110]	Zahr NM, Mayer D, Rohlfing T, Chanraud S, Gu M, Sullivan EV, Pfefferbaum A. In vivo glutamate measured with magnetic resonance spectroscopy: Behavioral correlates in aging. Neurobiol Aging, 2013,34(4):1265-1276.
[111]	Segovia G, Porras A, Del Arco A, Mora F. Glutamatergic neurotransmission in aging: A critical perspective. Mech Ageing Dev, 2001,122(1):1-29.
[112]	Saransaari P, Oja SS. Age-related changes in the uptake and release of glutamate and aspartate in the mouse brain. Mech Ageing Dev, 1995,81(2-3):61-71.
[113]	Najlerahim A, Francis PT, Bowen DM. Age-related alteration in excitatory amino acid neurotransmission in rat brain. Neurobiol Aging, 1990,11(2):155-158.
[114]	Clayton DA, Grosshans DR, Browning MD. Aging and surface expression of hippocampal nmda receptors. J Biol Chem, 2002,277(17):14367-14369.
[115]	Magnusson KR, Brim BL, Das SR. Selective vulnerabilities of n-methyl-d-aspartate (nmda) receptors during brain aging. Front Aging Neurosci, 2010,2:11.
[116]	Magnusson KR, Cotman CW. Age-related changes in excitatory amino acid receptors in two mouse strains. Neurobiol Aging, 1993,14(3):197-206.
[117]	Yang YJ, Chen HB, Wei B, Wang W, Zhou PL, Zhan JQ, Hu MR, Yan K, Hu B, Yu B. Cognitive decline is associated with reduced surface glur1 expression in the hippocampus of aged rats. Neurosci Lett, 2015,591:176-181.
[118]	Magnusson KR. Aging of glutamate receptors: Correlations between binding and spatial memory performance in mice. Mech Ageing Dev, 1998,104(3):227-248.
[119]	Paredes RG, Agmo A. Gaba and behavior: The role of receptor subtypes. Neurosci Biobehav Rev, 1992,16(2):145-170.
[120]	Cuypers K, Maes C, Swinnen SP. Aging and gaba. Aging (Albany NY), 2018,10(6):1186-1187.
[121]	Porges EC, Woods AJ, Edden RA, Puts NA, Harris AD, Chen H, Garcia AM, Seider TR, Lamb DG, Williamson JB, Cohen RA. Frontal gamma-aminobutyric acid concentrations are associated with cognitive performance in older adults. Biol Psychiatry Cogn Neurosci Neuroimaging, 2017,2(1):38-44.
[122]	Gao F, Edden RA, Li M, Puts NA, Wang G, Liu C, Zhao B, Wang H, Bai X, Zhao C, Wang X, Barker PB. Edited magnetic resonance spectroscopy detects an age-related decline in brain gaba levels. Neuroimage, 2013,78:75-82.
[123]	Peters A. Structural changes that occur during normal aging of primate cerebral hemispheres. Neurosci Biobehav Rev, 2002,26(7):733-741.
[124]	Petralia RS, Mattson MP, Yao PJ. Communication breakdown: The impact of ageing on synapse structure. Ageing Res Rev, 2014,14:31-42.
[125]	Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature, 2004,429(6994):883-891.
[126]	McCarroll SA, Murphy CT, Zou S, Pletcher SD, Chin CS, Jan YN, Kenyon C, Bargmann CI, Li H. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet, 2004,36(2):197-204.
[127]	Wruck W, Adjaye J. Meta-analysis of human prefrontal cortex reveals activation of gfap and decline of synaptic transmission in the aging brain. Acta Neuropathol Commun, 2020,8(1):26.
[128]	Ham S, Lee SV. Advances in transcriptome analysis of human brain aging. Exp Mol Med, 2020,52(11):1787-1797.
[129]	Fraser HB, Khaitovich P, Plotkin JB, Pääbo S, Eisen MB. Aging and gene expression in the primate brain. PLoS Biol, 2005,3(9):e274.
[130]	Blalock EM, Chen KC, Sharrow K, Herman JP, Porter NM, Foster TC, Landfield PW. Gene microarrays in hippocampal aging: Statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci, 2003,23(9):3807-3819.
[131]	Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice. Nat Genet, 2000,25(3):294-297.
[132]	Jiang CH, Tsien JZ, Schultz PG, Hu Y. The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc Natl Acad Sci USA, 2001,98(4):1930-1934.
[133]	Meng S, Xia WC, Pan M, Jia YJ, He ZL, Ge W. Proteomics profiling and pathway analysis of hippocampal aging in rhesus monkeys. BMC Neurosci, 2020,21(1):2.
[134]	Li YC, Yu HT, Chen CY, Li SP, Zhang ZJ, Xu H, Zhu FQ, Liu JJ, Spencer PS, Dai ZL, Yang XF. Proteomic profile of mouse brain aging contributions to mitochondrial dysfunction, DNA oxidative damage, loss of neurotrophic factor, and synaptic and ribosomal proteins. Oxid Med Cell Longev, 2020,2020:5408452.
[135]	Vanguilder HD, Freeman WM. The hippocampal neuroproteome with aging and cognitive decline: Past progress and future directions. Front Aging Neurosci, 2011,3:8.
[136]	Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: A microarray study. J Neuroinflammation, 2012,9:179.
[137]	Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA. Alzheimer's disease is associated with reduced expression of energy metabolism genes neurons. Proc Natl Acad Sci USA, 2008,105(11):4441-4446.
[138]	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):1410-1420.
[139]	Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron, 2008,60(5):748-766.
[140]	López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell, 2013,153(6):1194-1217.
[141]	Hara Y, Yuk F, Puri R, Janssen WGM, Rapp PR, Morrison JH. Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proc Natl Acad Sci USA, 2014,111(1):486-491.
[142]	Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol, 2007,292(2):C670-686.
[143]	Navarro A, Boveris A. Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging. Am J Physiol Regul Integr Comp Physiol, 2004,287(5):R1244-1249.
[144]	Swerdlow RH. Brain aging, alzheimer's disease, and mitochondria. Bba-Mol Basis Dis, 2011,1812(12):1630-1639.
[145]	Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA, 1994,91(23):10771-10778.
[146]	Venkateshappa C, Harish G, Mahadevan A, Srinivas Bharath MM, Shankar SK. Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: Implications for neurodegeneration in alzheimer's disease. Neurochem Res, 2012,37(8):1601-1614.
[147]	Paradies G, Petrosillo G, Pistolese M, Ruggiero FM. The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett, 2000,466(2-3):323-326.
[148]	Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell, 2016,61(5):654-666.
[149]	Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D , CantóC, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J. The nad(+)/ sirtuin pathway modulates longevity through activation of mitochondrial upr and foxo signaling. Cell, 2013,154(2):430-441.
[150]	Zhao ZZ, Yu ZY, Hou YX, Zhang L, Fu AL. Improvement of cognitive and motor performance with mitotherapy in aged mice. Int J Biol Sci, 2020,16(5):849-858.
[151]	Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 2006,443(7113):787-795.
[152]	Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science, 2005,309(5733):481-484.
[153]	Kauppila TES, Kauppila JHK, Larsson NG. Mammalian mitochondria and aging: An update. Cell Metab, 2017,25(1):57-71.
[154]	Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear-DNA is extensive. Proc Natl Acad Sci USA, 1988,85(17):6465-6467.
[155]	Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: Regional variability and increase with advanced age. Nat Genet, 1992,2(4):324-329.
[156]	Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF. High aggregate burden of somatic mtdna point mutations in aging and alzheimer's disease brain. Hum Mol Genet, 2002,11(2):133-145.
[157]	Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 2004,429(6990):417-423.
[158]	Yuan J, Chang SY, Yin SG, Liu ZY, Cheng X, Liu XJ, Jiang Q, Gao G, Lin DY, Kang XL, Ye SW, Chen Z, Yin JA, Hao P, Jiang L, Cai SQ. Two conserved epigenetic regulators prevent healthy ageing. Nature, 2020,579(7797):118-122.
[159]	Stefanatos R, Sanz A. The role of mitochondrial ros in the aging brain. FEBS Lett, 2018,592(5):743-758.
[160]	Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB. Mitochondrial dysfunction during brain aging: Role of oxidative stress and modulation by antioxidant supplementation. Aging Dis, 2011,2(3):242-256.
[161]	Foster TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell, 2007,6(3):319-325.
[162]	Bodhinathan K, Kumar A, Foster TC. Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: Role for ryanodine receptor mediated calcium signaling. J Neurophysiol, 2010,104(5):2586-2593.
[163]	Serrano F, Klann E. Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev, 2004,3(4):431-443.
[164]	Melov S, Schneider JA, Day BJ, Hinerfeld D, Coskun P, Mirra SS, Crapo JD, Wallace DC. A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nat Genet, 1998,18(2):159-163.
[165]	Paul A, Belton A, Nag S, Martin I, Grotewiel MS, Duttaroy A. Reduced mitochondrial sod displays mortality characteristics reminiscent of natural aging. Mech Ageing Dev, 2007,128(11-12):706-716.
[166]	Hu D, Serrano F, Oury TD, Klann E. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J Neurosci, 2006,26(15):3933-3941.
[167]	Lee WH, Kumar A, Rani A, Herrera J, Xu J, Someya S, Foster TC. Influence of viral vector-mediated delivery of superoxide dismutase and catalase to the hippocampus on spatial learning and memory during aging. Antioxid Redox Signal, 2012,16(4):339-350.
[168]	Schaar CE, Dues DJ, Spielbauer KK, Machiela E, Cooper JF, Senchuk M, Hekimi S, Van Raamsdonk JM. Mitochondrial and cytoplasmic ros have opposing effects on lifespan. PLoS Genet, 2015,11(2):e1004972.
[169]	Back P, Braeckman BP, Matthijssens F. Ros in aging caenorhabditis elegans: Damage or signaling? Oxid Med Cell Longev, 2012,2012:608478.
[170]	Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell, 2012,48(2):158-167.
[171]	Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell, 2011,146(5):682-695.
[172]	Tomaru U, Takahashi S, Ishizu A, Miyatake Y, Gohda A, Suzuki S, Ono A, Ohara J, Baba T, Murata S, Tanaka K, Kasahara M. Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. Am J Pathol, 2012,180(3):963-972.
[173]	Juhász G, Erdi B, Sass M, Neufeld TP. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in drosophila. Genes Dev, 2007,21(23):3061-3066.
[174]	Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 2006,441(7095):885-889.
[175]	Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 2006,441(7095):880-884.
[176]	Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult drosophila. Autophagy, 2008,4(2):176-184.
[177]	Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes are essential for dauer development and life-span extension in c. Elegans. Science, 2003,301(5638):1387-1391.
[178]	Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in c. Elegans. PLoS Genet, 2008,4(2):e24.
[179]	Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med, 2013,19(8):983-997.
[180]	Fischer DF, van Dijk R, van Tijn P, Hobo B, Verhage MC, van der Schors RC, Li KW, van Minnen J, Hol EM, van Leeuwen FW. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging, 2009,30(6):847-863.
[181]	Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease. J Cell Biol, 2018,217(1):51-63.
[182]	Mattson MP, Magnus T. Ageing and neuronal vulnerability. Nat Rev Neurosci, 2006,7(4):278-294.
[183]	Walsh JG, Muruve DA, Power C. Inflammasomes in the cns. Nat Rev Neurosci, 2014,15(2):84-97.
[184]	Conde JR, Streit WJ. Microglia in the aging brain. J Neuropathol Exp Neurol, 2006,65(3):199-203.
[185]	Goss JR, Finch CE, Morgan DG. Age-related changes in glial fibrillary acidic protein mrna in the mouse brain. Neurobiol Aging, 1991,12(2):165-170.
[186]	Hayakawa N, Kato H, Araki T. Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal ca1 sector. Mech Ageing Dev, 2007,128(4):311-316.
[187]	Cotrina ML, Nedergaard M. Astrocytes in the aging brain. J Neurosci Res, 2002,67(1):1-10.
[188]	McCall MA, Gregg RG, Behringer RR, Brenner M, Delaney CL, Galbreath EJ, Zhang CL, Pearce RA, Chiu SY, Messing A. Targeted deletion in astrocyte intermediate filament (gfap) alters neuronal physiology. Proc Natl Acad Sci USA, 1996,93(13):6361-6366.
[189]	Menet V, Gimenez YRM, Sandillon F, Privat A. Gfap null astrocytes are a favorable substrate for neuronal survival and neurite growth. Glia, 2000,31(3):267-272.
[190]	Satoh A, Imai S, Guarente L. The brain, sirtuins, and ageing. Nat Rev Neurosci, 2017,18(6):362-374.
[191]	Hefendehl JK, Neher JJ, Sühs RB, Kohsaka S, Skodras A, Jucker M. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell, 2014,13(1):60-69.
[192]	Wong WT. Microglial aging in the healthy cns: Phenotypes, drivers, and rejuvenation. Front Cell Neurosci, 2013,7:22.
[193]	Peters A, Josephson K, Vincent SL. Effects of aging on the neuroglial cells and pericytes within area 17 of the rhesusmonkey cerebral cortex. Anat Rec, 1991,229(3):384-398.
[194]	Loane DJ, Deighan BF, Clarke RM, Griffin RJ, Lynch AM, Lynch MA. Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain. Neurobiol Aging, 2009,30(6):920-931.
[195]	Downer EJ, Cowley TR, Lyons A, Mills KH, Berezin V, Bock E, Lynch MA. A novel anti-inflammatory role of ncam-derived mimetic peptide, fgl. Neurobiol Aging, 2010,31(1):118-128.
[196]	Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity: Challenges and insights. Nat Rev Genet, 2006,7(6):436-448.
[197]	Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet, 2013,132(12):1323-1338.
[198]	Goldberg TE, Weinberger DR. Genes and the parsing of cognitive processes. Trends Cogn Sci, 2004,8(7):325-335.
[199]	Harris SE, Deary IJ. The genetics of cognitive ability and cognitive ageing in healthy older people. Trends Cogn Sci, 2011,15(9):388-394.
[200]	Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. New insights into brain bdnf function in normal aging and alzheimer disease. Brain Res Rev, 2008,59(1):201-220.
[201]	Gooney M, Messaoudi E, Maher FO, Bramham CR, Lynch MA. Bdnf-induced ltp in dentate gyrus is impaired with age: Analysis of changes in cell signaling events. Neurobiol Aging, 2004,25(10):1323-1331.
[202]	Wisdom NM, Callahan JL, Hawkins KA. The effects of apolipoprotein e on non-impaired cognitive functioning: A meta-analysis. Neurobiol Aging, 2011,32(1):63-74.
[203]	Herskind AM , McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity: A population-based study of 2872 danish twin pairs born 1870-1900. Hum Genet, 1996,97(3):319-323.
[204]	v BHJ, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity. Hum Genet, 2006,119(3):312-321.
[205]	Shadyab AH , LaCroix AZ. Genetic factors associated with longevity: A review of recent findings. Ageing Res Rev, 2015,19:1-7.
[206]	Newman AB, Murabito JM. The epidemiology of longevity and exceptional survival. Epidemiol Rev, 2013,35:181-197.
[207]	Gurland BJ, Page WF, Plassman BL. A twin study of the genetic contribution to age-related functional impairment. J Gerontol A Biol Sci Med Sci, 2004,59(8):859-863.
[208]	Akbarian S, Beeri MS, Haroutunian V. Epigenetic determinants of healthy and diseased brain aging and cognition. JAMA Neurol, 2013,70(6):711-718.
[209]	Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet, 2018,19(6):371-384.
[210]	Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging Cell, 2015,14(6):924-932.
[211]	Hernandez DG, Nalls MA, Gibbs JR , Arepalli S, van der Brug M, Chong S, Moore M, Longo DL, Cookson MR, Traynor BJ, Singleton AB. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet, 2011,20(6):1164-1172.
[212]	Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet, 2012,90(2):260-272.
[213]	Tang B, Dean B, Thomas EA. Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. Transl Psychiatry, 2011,1:e64.
[214]	Akbarian S, Beeri MS, Haroutunian V. Epigenetic determinants of healthy and diseased brain aging and cognition. JAMA Neurol, 2013,70(6):711-718.
[215]	Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science, 2010,328(5979):753-756.
[216]	Haettig J, Stefanko DP, Multani ML, Figueroa DX , McQuown SC, Wood MA. Hdac inhibition modulates hippocampus-dependent long-term memory for object location in a cbp-dependent manner. Learn Mem, 2011,18(2):71-79.
[217]	Reolon GK, Maurmann N, Werenicz A, Garcia VA, Schroder N, Wood MA, Roesler R. Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats. Behav Brain Res, 2011,221(1):329-332.
[218]	Fischer A, Sananbenesi F, Mungenast A, Tsai LH. Targeting the correct hdac(s) to treat cognitive disorders. Trends Pharmacol Sci, 2010,31(12):605-617.
[219]	Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT. Multiple roles of hdac inhibition in neurodegenerative conditions. Trends Neurosci, 2009,32(11):591-601.
[220]	Baltan S, Murphy SP, Danilov CA, Bachleda A, Morrison RS. Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving atp and reducing excitotoxicity. J Neurosci, 2011,31(11):3990-3999.
[221]	Tsou AY, Friedman LS, Wilson RB, Lynch DR. Pharmacotherapy for friedreich ataxia. CNS Drugs, 2009,23(3):213-223.
[222]	Covington HE , 3rd, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, Fass DM, Renthal W, Rush AJ, 3rd, Wu EY, Ghose S, Krishnan V, Russo SJ, Tamminga C, Haggarty SJ, Nestler EJ. Antidepressant actions of histone deacetylase inhibitors. J Neurosci, 2009,29(37):11451-11460.
[223]	Wang CM, Tsai SN, Yew TW, Kwan YW, Ngai SM. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology, 2010,11(1):87-102.
[224]	Wood JG, Hillenmeyer S, Lawrence C, Chang CY, Hosier S, Lightfoot W, Mukherjee E, Jiang N, Schorl C, Brodsky AS, Neretti N, Helfand SL. Chromatin remodeling in the aging genome of drosophila. Aging Cell, 2010,9(6):971-978.
[225]	Lin L, Liu A, Li HQ, Feng J, Yan Z. Inhibition of histone methyltransferases ehmt1/2 reverses amyloid- beta-induced loss of ampar currents in human stem cell-derived cortical neurons. J Alzheimers Dis, 2019,70(4):1175-1185.
[226]	Zheng Y, Liu AY, Wang ZJ, Cao Q, Wang W, Lin L, Ma KJ, Zhang F, Wei J, Matas E, Cheng J, Chen GJ, Wang X, Yan Z. Inhibition of ehmt1/2 rescues synaptic and cognitive functions for alzheimer's disease. Brain, 2019,142(3):787-807.
[227]	Anderson RM, Weindruch R. The caloric restriction paradigm: Implications for healthy human aging. Am J Hum Biol, 2012,24(2):101-106.
[228]	Leclerc E, Trevizol AP, Grigolon RB, Subramaniapillai M , McIntyre RS, Brietzke E, Mansur RB. The effect of caloric restriction on working memory in healthy non-obese adults. CNS Spectr, 2020,25(1):2-8.
[229]	Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci USA, 2009,106(4):1255-1260.
[230]	Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 2009,325(5937):201-204.
[231]	Dal-Pan A, Pifferi F, Marchal J, Picq JL, Aujard F. Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS One, 2011,6(1):e16581.
[232]	Goodrick CL. Effects of lifelong restricted feeding on complex maze performance in rats. Age, 1984,7(1):1-2.
[233]	Fontán-Lozano A, Sáez-Cassanelli JL , Inda MC, de los Santos-Arteaga M, Sierra-Domínguez SA, López-Lluch G, Delgado-García JM, Carrión AM. Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on nr2b subunits of the nmda receptor. J Neurosci, 2007,27(38):10185-10195.
[234]	Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE. Caloric restriction attenuates abeta-deposition in alzheimer transgenic models. Neurobiol Aging, 2005,26(7):995-1000.
[235]	Yu Q, Zou LY, Kong ZW, Yang L. Cognitive impact of calorie restriction: A narrative review. J Am Med Dir Assoc, 2020,21(10):1394-1401.
[236]	Yanai S, Okaichi Y, Okaichi H. Long-term dietary restriction causes negative effects on cognitive functions in rats. Neurobiol Aging, 2004,25(3):325-332.
[237]	Dias IR, Santos CS , Magalhaes C, de Oliveira LRS, Peixoto MFD, De Sousa RAL, Cassilhas RC. Does calorie restriction improve cognition? IBRO Rep, 2020,9:37-45.
[238]	Guarente L. Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell, 2008,132(2):171-176.
[239]	Zid BM, Rogers AN, Katewa SD, Vargas MA, Kolipinski MC, Lu TA, Benzer S, Kapahi P. 4e-bp extends lifespan upon dietary restriction by enhancing mitochondrial activity in drosophila. Cell, 2009,139(1):149-160.
[240]	Lanza IR, Zabielski P, Klaus KA, Morse DM, Heppelmann CJ, Bergen HR, Dasari S, Walrand S, Short KR, Johnson ML, Robinson MM, Schimke JM, Jakaitis DR, Asmann YW, Sun ZF, Nair KS. Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis. Cell Metab, 2012,16(6):777-788.
[241]	Hyun DH, Emerson SS, Jo DG , Mattson MP, de Cabo R. Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc Natl Acad Sci USA, 2006,103(52):19908-19912.
[242]	Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK. Caloric restriction and age affect synaptic proteins in hippocampal ca3 and spatial learning ability. Exp Neurol, 2008,211(1):141-149.
[243]	Mattson MP. The impact of dietary energy intake on cognitive aging. Front Aging Neurosci, 2010,2:5.
[244]	Prolla TA, Mattson MP. Molecular mechanisms of brain aging and neurodegenerative disorders: Lessons from dietary restriction. Trends Neurosci, 2001,24(11 Suppl):S21-31.
[245]	Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med, 1998,4(11):1313-1317.
[246]	Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem, 2002,82(6):1367-1375.
[247]	Longo VD, Kennedy BK. Sirtuins in aging and age-related disease. Cell, 2006,126(2):257-268.
[248]	Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT , Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the sirt1 deacetylase. Science, 2004,305(5682):390-392.
[249]	Michán S, Li Y, Chou MM, Parrella E, Ge H, Long JM, Allard JS, Lewis K, Miller M, Xu W, Mervis RF, Chen J, Guerin KI, Smith LE , McBurney MW, Sinclair DA, Baudry M, de Cabo R, Longo VD. Sirt1 is essential for normal cognitive function and synaptic plasticity. J Neurosci, 2010,30(29):9695-9707.
[250]	Gao J, Wang WY, Mao YW, Gräff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH. A novel pathway regulates memory and plasticity via sirt1 and mir-134. Nature, 2010,466(7310):1105-1109.
[251]	Herranz D, Muñoz-Martin M, Cañamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun, 2010,1:3.
[252]	Ng F, Wijaya L, Tang BL. Sirt1 in the brain-connections with aging-associated disorders and lifespan. Front Cell Neurosci, 2015,9:64.
[253]	Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM , Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. Declining nad(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 2013,155(7):1624-1638.
[254]	Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key nad(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab, 2011,14(4):528-536.
[255]	Johnson S, Wozniak DF, Imai S. Ca1 nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. NPJ Aging Mech Dis, 2018,4:10.
[256]	Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai S. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab, 2016,24(6):795-806.
[257]	Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in alzheimer's mouse models. Neurobiol Aging, 2013,34(6):1581-1588.
[258]	Busse AL, Gil G, Santarem JM, Jacob Filho W. Physical activity and cognition in the elderly: A review. Dement Neuropsychol, 2009,3(3):204-208.
[259]	Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol (1985), 2006,101(4):1237-1242.
[260]	Chakravarty EF, Hubert HB, Lingala VB, Fries JF. Reduced disability and mortality among aging runners: A 21-year longitudinal study. Arch Intern Med, 2008,168(15):1638-1646.
[261]	He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced bcl2-regulated autophagy is required for muscle glucose homeostasis. Nature, 2012,481(7382):511-515.
[262]	Nascimento CM , Pereira JR, de Andrade LP, Garuffi M, Talib LL, Forlenza OV, Cancela JM, Cominetti MR, Stella F. Physical exercise in mci elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and bdnf peripheral levels. Curr Alzheimer Res, 2014,11(8):799-805.
[263]	Stranahan AM, Mattson MP. Recruiting adaptive cellular stress responses for successful brain ageing. Nat Rev Neurosci, 2012,13(3):209-216.
[264]	Ferris LT, Williams JS, Shen CL. The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc, 2007,39(4):728-734.
[265]	Cotman CW, Berchtold NC. Exercise: A behavioral intervention to enhance brain health and plasticity. Trends Neurosci, 2002,25(6):295-301.
[266]	Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a bdnf-mediated mechanism that promotes neuroplasticity. J Neurophysiol, 2002,88(5):2187-2195.
[267]	Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal bdnf mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci, 2004,20(10):2580-2590.
[268]	Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA , Duzel E, van Praag H. Running-induced systemic cathepsin b secretion is associated with memory function. Cell Metab, 2016,24(2):332-340.
[269]	Gross AL, Mungas DM, Crane PK, Gibbons LE , MacKay-Brandt A, Manly JJ, Mukherjee S, Romero H, Sachs B, Thomas M, Potter GG, Jones RN. Effects of education and race on cognitive decline: An integrative study of generalizability versus study-specific results. Psychol Aging, 2015,30(4):863-880.
[270]	Valenzuela MJ, Sachdev P. Brain reserve and dementia: A systematic review. Psychol Med, 2006,36(4):441-454.
[271]	Farmer ME, Kittner SJ, Rae DS, Bartko JJ, Regier DA. Education and change in cognitive function. The epidemiologic catchment area study. Ann Epidemiol, 1995,5(1):1-7.
[272]	Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol, 2004,3(6):343-353.
[273]	Small BJ, Dixon RA , McArdle JJ, Grimm KJ. Do changes in lifestyle engagement moderate cognitive decline in normal aging? Evidence from the victoria longitudinal study. Neuropsychology, 2012,26(2):144-155.
[274]	Lövdén M, Bäckman L, Lindenberger U, Schaefer S, Schmiedek F. A theoretical framework for the study of adult cognitive plasticity. Psychol Bull, 2010,136(4):659-676.
[275]	May A. Experience-dependent structural plasticity in the adult human brain. Trends Cogn Sci, 2011,15(10):475-482.
[276]	Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A. Neuroplasticity: Changes in grey matter induced by training. Nature, 2004,427(6972):311-312.
[277]	Kempermann G, Kuhn HG, Gage FH. Experience- induced neurogenesis in the senescent dentate gyrus. J Neurosci, 1998,18(9):3206-3212.
[278]	Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mtor inhibitors as anti-aging therapeutics. J Clin Invest, 2013,123(3):980-989.
[279]	Bitto A, Ito TK, Pineda VV , LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, Meza D, Yajima M, Beyer RP, Kerr KF, Davis DJ, Gillespie CH, Snyder JM, Treuting PM, Kaeberlein M. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife, 2016,5:e16351.
[280]	Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 2009,460(7253):392-395.
[281]	Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV. Rapamycin suppresses brain aging in senescence-accelerated oxys rats. Aging (Albany NY), 2013,5(6):474-484.
[282]	Majumder S, Caccamo A, Medina DX, Benavides AD, Javors MA, Kraig E, Strong R, Richardson A, Oddo S. Lifelong rapamycin administration ameliorates age- dependent cognitive deficits by reducing il-1beta and enhancing nmda signaling. Aging Cell, 2012,11(2):326-335.
[283]	Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience, 2012,223:102-113.
[284]	Van Skike CE, Lin AL, Roberts Burbank R, Halloran JJ, Hernandez SF, Cuvillier J, Soto VY, Hussong SA, Jahrling JB, Javors MA, Hart MJ, Fischer KE, Austad SN, Galvan V. Mtor drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging. Aging Cell, 2020,19(1):e13057.
[285]	Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mtor), amyloid-beta, and tau: Effects on cognitive impairments. J Biol Chem, 2010,285(17):13107-13120.
[286]	Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mtor by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of alzheimer's disease. PLoS One, 2010,5(4):e9979.
[287]	Talboom JS, Velazquez R, Oddo S. The mammalian target of rapamycin at the crossroad between cognitive aging and alzheimer's disease. NPJ Aging Mech Dis, 2015,1:15008.
[288]	Castellano JM, Kirby ED, Wyss-Coray T. Blood-borne revitalization of the aged brain. JAMA Neurol, 2015,72(10):1191-1194.
[289]	Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature, 2016,539(7628):180-186.
[290]	Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding ZQ, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 2011,477(7362):90-94.
[291]	Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science, 2014,344(6184):630-634.
[292]	Castellano JM, Mosher KI, Abbey RJ , McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature, 2017,544(7651):488-492.
[293]	Yin JA, Gao G, Liu XJ, Hao ZQ, Li K, Kang XL, Li H, Shan YH, Hu WL, Li HP, Cai SQ. Genetic variation in glia-neuron signalling modulates ageing rate. Nature, 2017,551(7679):198-203.

Metrics

Comments

www.chinagene.cn
备案号：京ICP备09063187号

基因类别	人	非人灵长类	啮齿类	果蝇或线虫
突触功能	下调	下调	下调	不变
线粒体功能	下调	下调	下调	下调
压力应答	上调	上调	上调(小鼠某些脑区中下调)	上调
免疫和炎症	上调	不变	上调	果蝇中上调

The regulatory mechanisms of behavioral and cognitive aging

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 3

References 293

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Shan He, Jian Zhao, Xiaofeng Song. Effects of N⁶-methyladenosine modification on the function of the female reproductive system [J]. Hereditas(Beijing), 2023, 45(6): 472-487.
[2]	Xiaokang Shang, Simeng Zhang, Junjun Ni. Research progress of cathepsin B in brain aging and Alzheimer’s diseases [J]. Hereditas(Beijing), 2023, 45(3): 212-220.
[3]	Qian Zhang, Zihao Wang, Ye Tian. Inter-tissue communication of mitochondrial stress in aging [J]. Hereditas(Beijing), 2023, 45(3): 187-197.
[4]	Jiali Li, Jin Li, Hu Wang. Age-associated proteostasis collapse [J]. Hereditas(Beijing), 2022, 44(9): 733-744.
[5]	Yan Zhao, Chenxin Wang, Tianming Yang, Chunshuang Li, Lihong Zhang, Dongni Du, Ruoxi Wang, Jing Wang, Min Wei, Xueqing Ba. Linking oxidative DNA lesion 8-OxoG to tumor development and progression [J]. Hereditas(Beijing), 2022, 44(6): 466-477.
[6]	Hui Qu, Yi Liu, Yawen Chen, Hui Wang. Alteration of imprinted genes and offspring organ development caused by environmental factors [J]. Hereditas(Beijing), 2022, 44(2): 107-116.
[7]	Yangjinghui Zhang, Peiyao Chang, Zishu Yang, Yuhang Xue, Xueqi Li, Yang Zhang. Advances in epigenetic modification affecting anthocyanin synthesis [J]. Hereditas(Beijing), 2022, 44(12): 1117-1127.
[8]	Qingwen Zhao, Dongning Pan. Progress on the epigenetic regulation of adipose tissue thermogenesis [J]. Hereditas(Beijing), 2022, 44(10): 867-880.
[9]	Jiangping He, Jiekai Chen. Epigenetic control of transposable elements and cell fate decision [J]. Hereditas(Beijing), 2021, 43(9): 822-834.
[10]	Wang Ya'nan, Tao Xu, Wanpeng Wang, Qingzhu Zhang, Xie Li'nan. Role of epigenetic modifications in the development of crops essential traits [J]. Hereditas(Beijing), 2021, 43(9): 858-879.
[11]	Tianyi Wang, Yingxiang Wang, Chenjiang You. Structural and functional characteristics of plant PHD domain-containing proteins [J]. Hereditas(Beijing), 2021, 43(4): 323-339.
[12]	Xiangqian Zhang, Nan Li, Xinming Xie. Design and exploration of epigenetic comprehensive experiments [J]. Hereditas(Beijing), 2021, 43(12): 1179-1187.
[13]	Ziyan Liu, Ai Gao. Progress on inflamm-aging in hematologic diseases [J]. Hereditas(Beijing), 2021, 43(12): 1132-1141.
[14]	Xuewen Liu, Hongmei Wu, Ying Bai, Qun Zeng, Zemin Cao, Xiushan Wu, Min Tang. Potassium channel Shaker play a protective role against cardiac aging in Drosophila [J]. Hereditas(Beijing), 2021, 43(1): 94-99.
[15]	Yingchu Hu, Haochang Hu, Shaoyi Lin, Xiaomin Chen. The role of DNA hydroxymethylation in the regulation of atherosclerosis [J]. Hereditas(Beijing), 2020, 42(7): 632-640.