Skip to main content Accessibility help
Hostname: page-component-7f7b94f6bd-8mfwn Total loading time: 0.669 Render date: 2022-06-30T08:38:47.311Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true } hasContentIssue true

Brain aging research

Published online by Cambridge University Press:  01 November 2007

David R Riddle*
Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC, USA Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA J. Paul Sticht Center on Aging, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Matthew K Schindler
Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Address for correspondence: DR Riddle, Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1010, USA.


The last three decades produced a striking increase in investigations of the neurobiological basis of brain aging and aging-related changes in neural and cognitive function. Experimental and clinical studies of aging have become more valuable as the population, at least in industrialized countries, has become ‘greyer’. The increase in adult life expectancy that occurred in the twentieth century produced the motivation and necessity to invest resources in increasing ‘health span’ as well as lifespan, in order to maximize quality of life and minimize the financial and social burdens associated with disability in the later years of life. Specific interest in the aging nervous system is driven by recognition that increased longevity has little appeal for most people unless it is accompanied by maintenance of cognitive abilities. Indeed, surveys of older individuals routinely show that loss of mental capacity is among their greatest fear. In recent years, neuroscientists and gerontologists, with a variety of training and experimental approaches, have applied increasingly powerful quantitative methods to investigate why neural function declines with age. New animal model systems have been developed and old ones have become better characterized and standardized. The necessary and important descriptive studies that dominated the field in earlier years are increasingly supplemented by more hypothesis-driven research, resulting in sophisticated investigations and models of the mechanisms of brain aging. This review provides a selective overview of recent and current research on brain aging. The focus throughout will be on normal brain aging and the moderate cognitive changes that often accompany it, not on aging-related neurodegenerative diseases that result in dementia. To provide a context for studies of neurobiological changes in the aging brain, a brief overview of the types of cognitive changes that are commonly seen in aging humans is first provided. The remainder of the review focuses on animal studies that are progressively overcoming the unique challenges of aging research to reveal the neurobiological mechanisms of aging-related cognitive dysfunction, and suggest new targets for therapies to prevent or ameliorate cognitive decline.

Biological gerontology
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


1Gliskey, EL. Changes in cognitive function in human aging. In: Riddle, DR ed. Brain aging: models, methods and mechanisms. Boca Raton: CRC Press, 2007: 320.CrossRefGoogle Scholar
2Verhaeghen, P, Cerella, J. Aging, executive control, and attention: a review of meta-analyses. Neurosci Biobehav Rev 2002; 26: 849–57.CrossRefGoogle ScholarPubMed
3Thornton, WJ, Raz, N. Aging and the role of working memory resources in visuospatial attention. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2006; 13: 3661.CrossRefGoogle ScholarPubMed
4McDowd, JM, Shaw, RJ. Human memory. In: Craik, FIM, Salthouse, TA eds. The handbook of aging and cognition, second edition. Mahwah, NJ: Erlbaum, 2000: 221–92.Google Scholar
5Verhaeghen, P, Basak, C. Ageing and switching of the focus of attention in working memory: results from a modified N-back task. Q J Exp Psychol A 2005; 58: 134–54.CrossRefGoogle ScholarPubMed
6Hogan, MJ, Kelly, CA, Craik, FI. The effects of attention-switching on encoding and retrieval of words in younger and older adults. Exp Aging Res 2006; 32: 153–83.CrossRefGoogle ScholarPubMed
7Hillman, CH, Erickson, KI, Kramer, AF. Be smart, exercise your heart. Exercise effects on brain cognition. Nature Rev Neurosci 2008; 9: 5865CrossRefGoogle Scholar
8Kester, JD, Benjamin, AS, Castel, AD, Craik, FIM. Memory in elderly people. In: Baddeley, AD, Kopelman, MD, Wilson, BA eds. The handbook of memory disorders. West Sussex: Wiley, 2002: 543–68.Google Scholar
9Luszcz, MA, Bryan, J. Toward understanding age-related memory-loss in late adulthood. Gerontology 1999; 45: 29.CrossRefGoogle ScholarPubMed
10Grady, CL, Craik, FI. Changes in memory processing with age. Curr Opin Neurobiol 2000; 10: 224–31.CrossRefGoogle ScholarPubMed
11de Fockert, JW. Keeping priorities: the role of working memory and selective attention in cognitive aging. Sci Aging Knowledge Environ 2005; 44: 34.Google Scholar
12Buckner, RL.Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 2004; 44: 195208.CrossRefGoogle Scholar
13Burke, SN, Barnes, CA. Neural plasticity in the ageing brain. Nat Rev Neurosci 2006; 7: 3040.CrossRefGoogle ScholarPubMed
14Tanji, J, Hoshi, E. Role of the lateral prefrontal cortex in executive behavioral control. Physiol Rev 2008; 88: 3757.CrossRefGoogle ScholarPubMed
15West, RL. An application of prefrontal cortex function theory to cognitive aging. Psychol Bull 1996; 120: 272–92.CrossRefGoogle ScholarPubMed
16Resnick, SM, Pham, DL, Kraut, MA, Zonderman, AB, Davatzikos, C. Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J Neurosci 2003; 23: 3295–301.CrossRefGoogle ScholarPubMed
17Hedden, T. Imaging cognition in the aging human brain. In: Riddle, DR ed. Brain aging: models, methods and mechanisms. Boca Raton: CRC Press, 2007: 251–78.CrossRefGoogle ScholarPubMed
18Raz, N, Rodrigue, KM, Haacke, EM. Brain aging and its modifiers: insights from in vivo neuromorphometry and susceptibility weighted imaging. Ann N Y Acad Sci 2007; 1097: 8493.CrossRefGoogle ScholarPubMed
19Prvulovic, D, Van de Ven, V, Sack, AT, Maurer, K, Linden, DE. Functional activation imaging in aging and dementia. Psychiatry Res 2005 Nov 30; 140: 97113.CrossRefGoogle ScholarPubMed
20Rajah, MN, D'Esposito, M. Region-specific changes in prefrontal function with age: a review of PET and fMRI studies on working and episodic memory. Brain 2005; 128 (Pt 9): 1964–83.CrossRefGoogle ScholarPubMed
21Kessler, RM. Imaging methods for evaluating brain function in man. Neurobiol Aging 2003; 24 (suppl 1): 2135; discussion S3739.CrossRefGoogle ScholarPubMed
22Meltzer, CC, Becker, JT, Price, JC, Moses-Kolko, E. Positron emission tomography imaging of the aging brain. Neuroimaging Clin N Am 2003; 13: 759–67.CrossRefGoogle ScholarPubMed
23Charlton, RA, McIntyre, DJ, Howe, FA, Morris, RG, Markus, HS. The relationship between white matter brain metabolites and cognition in normal aging: the GENIE study. Brain Res 2007; 1164: 108–16.CrossRefGoogle ScholarPubMed
24McIntyre, DJ, Charlton, RA, Markus, HS, Howe, FA. Long and short echo-time proton magnetic resonance spectroscopic imaging of the healthy aging brain. J Magn Reson Imaging 2007; 26: 1596–606.CrossRefGoogle ScholarPubMed
25Petrella, JR, Mattay, VS, Doraiswamy, PM. Imaging genetics of brain longevity and mental wellness: the next frontier? Radiology 2008; 246: 2032.CrossRefGoogle ScholarPubMed
26Zahr, NM, Mayer, D, Pfefferbaum, A, Sullivan, EV. Low Striatal glutamate levels underlie cognitive decline in the elderly: Evidence from in vivo molecular spectroscopy. Cereb Cortex 2008 Jan 29; [Epub ahead of print].Google Scholar
27Nadon, 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: 813–15.CrossRefGoogle ScholarPubMed
28Dias, R, Robbins, TW, Roberts, AC. Primate analogue of the Wisconsin Card Sorting Test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav Neurosci 1996; 110: 872–86.CrossRefGoogle ScholarPubMed
29Dias, R, Robbins, TW, Roberts, AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature 1996; 380 (6569): 6972.CrossRefGoogle ScholarPubMed
30Herndon, JG, Lacreuse, A. The Rhesus Monkey Model as a heuristic resource in cognitive aging research. In: Erwin, JM, Hof, PR ed. Aging in nonhuman primates. Interdiscipl Top Gerontol Basel. Karger, 2002; 31: 178195.Google Scholar
31Moss, MB, Moore, TL, Schettler, SP, Killiany, R, Rosene, D. Successful vs. unsuccessful aging in the rhesus monkey. In: Riddle, DR ed. Brain aging: models, methods and mechanisms. Boca Raton: CRC Press, 2007: 2138.Google ScholarPubMed
32Geinisman, 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: 407–16.CrossRefGoogle ScholarPubMed
33Nicholson, 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: 7648–53.CrossRefGoogle ScholarPubMed
34Driscoll, I, Sutherland, RJ. The aging hippocampus: navigating between rat and human experiments. Rev Neurosci 2005; 16: 87121.CrossRefGoogle ScholarPubMed
35Lee, HK, Min, SS, Gallagher, M, Kirkwood, A. NMDA receptor-independent long-term depression correlates with successful aging in rats. Nat Neurosci 2005; 8: 1657–59.CrossRefGoogle ScholarPubMed
36McGaughy, J, Ross, RS, Eichenbaum, H. Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 2008 Feb 19; [Epub ahead of print].Google Scholar
37Barense, MD, Fox, MT, Baxter, MG. Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn Mem 2002; 9: 191201.CrossRefGoogle ScholarPubMed
38Brown, VJ, Bowman, EM. Rodent models of prefrontal cortical function. Trends Neurosci 2002; 25: 340–43.CrossRefGoogle ScholarPubMed
39Andersen, JK. Genetically engineered mice and their use in aging research. Mol Biotechnol 2001; 19: 4557.CrossRefGoogle ScholarPubMed
40Martin, GM. Genetic engineering of mice to test the oxidative damage theory of aging. Ann N Y Acad Sci. 2005; 1055: 2634.CrossRefGoogle Scholar
41Bartke, A. New findings in gene knockout, mutant and transgenic mice. Exp Gerontol 2008; 43: 1114.CrossRefGoogle ScholarPubMed
42Peters, A, Morrison, JH, Rosene, DL, Hyman, BT. Feature article: are neurons lost from the primate cerebral cortex during normal aging? Cereb Cortex 1998; 8: 295–00.CrossRefGoogle ScholarPubMed
43Jernigan, TL, Archibald, SL, Fennema-Notestine, C et al. Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging 2001; 22: 581–94.CrossRefGoogle ScholarPubMed
44Van Petten, C, Plante, E, Davidson, PS, Kuo, TY, Bajuscak, L, Glisky, EL. Memory and executive function in older adults: relationships with temporal and prefrontal gray matter volumes and white matter hyperintensities. Neuropsychologia 2004; 42: 1313–35.CrossRefGoogle ScholarPubMed
45Allen, JS, Bruss, J, Brown, CK, Damasio, H. Normal neuroanatomical variation due to age: the major lobes and a parcellation of the temporal region. Neurobiol Aging 2005; 26: 1245–60.CrossRefGoogle Scholar
46West, MJ. Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging 1993; 14: 287–93.CrossRefGoogle ScholarPubMed
47Rapp, PR, Gallagher, M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA 1996; 93 : 9926–30.CrossRefGoogle ScholarPubMed
48Rasmussen, T, Schliemann, T, Sorensen, JC, Zimmer, J, West, MJ. Memory-impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Aging 1996; 17: 143–47.CrossRefGoogle ScholarPubMed
49Hof, PR, Morrison, JH. The aging brain: morphomolecular senescence of cortical circuits. Trends Neurosci 2004; 27: 607–13.CrossRefGoogle ScholarPubMed
50Dickstein, DL, Kabaso, D, Rocher, AB, Luebke, JI, Wearne, SL, Hof, PR. Changes in the structural complexity of the aged brain. Aging Cell 2007; 6: 275–84.CrossRefGoogle ScholarPubMed
51Morrison, JH, Hof, PR. Life and death of neurons in the aging cerebral cortex. Int Rev Neurobiol 2007; 81: 4157.CrossRefGoogle ScholarPubMed
52Tang, Y, Nyengaard, JR, Pakkenberg, B, Gundersen, HJ. Age-induced white-matter changes in the human brain: a stereological investigation. Neurobiol Aging 1997; 18: 609–15.CrossRefGoogle ScholarPubMed
53Marner, L, Nyengaard, JR, Tang, Y, Pakkenberg, B. Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol 2003; 462: 144–52.CrossRefGoogle ScholarPubMed
54Hinman, JD, Abraham, CR. What's behind the decline? The role of white matter in brain aging. Neurochem Res 2007; 32: 2023–31.CrossRefGoogle ScholarPubMed
55Peters, A. The effects of normal aging on myelin and nerve fibers: a review. J Neurocytol 2002; 31: 581–93.CrossRefGoogle ScholarPubMed
56Nimchinsky, EA, Sabatini, BL, Svoboda, K. Structure and function of dendritic spines. Annu Rev Physiol 2002; 64: 313–53.CrossRefGoogle ScholarPubMed
57Halpain, S, Spencer, K, Graber, S. Dynamics and pathology of dendritic spines. Prog Brain Res 2005; 147: 2937.CrossRefGoogle ScholarPubMed
58von Bohlen und Halbach, O, Zacher, C, Gass, P, Unsicker, K. Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 2006; 83: 525–31.CrossRefGoogle ScholarPubMed
59Morrison, JH, Hof, PR. Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease. Prog Brain Res 2002; 136: 467–86.CrossRefGoogle ScholarPubMed
60Wallace, M, Frankfurt, M, Arellanos, A, Inagaki, T, Luine, V. Impaired recognition memory and decreased prefrontal cortex spine density in aged female rats. Ann N Y Acad Sci 2007; 1097: 5457CrossRefGoogle ScholarPubMed
61Coleman, PD, Flood, DG. Net dendritic stability of layer II pyramidal neurons in F344 rat entorhinal cortex from 12 to 37 months. Neurobiol Aging 1991; 12: 535–41.CrossRefGoogle ScholarPubMed
62Hanks, SD, Flood, DG. Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. I. CA1 of hippocampus. Brain Res 1991; 540: 6382.CrossRefGoogle ScholarPubMed
63Grill, JD, Riddle, DR. Age-related and laminar-specific dendritic changes in the medial frontal cortex of the rat. Brain Res 2002; 937: 821.CrossRefGoogle ScholarPubMed
64Alvarez, VA, Sabatini, BL. Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci 2007; 30: 7997.CrossRefGoogle ScholarPubMed
65Geinisman, Y, de Toledo-Morrell, L, Morrell, F, Persina, IS, Rossi, M. Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus 1992; 2: 437–44.CrossRefGoogle ScholarPubMed
66Rutten, BP, Van Der Kolk, NM, Schafer, S et al. Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L transgenic mice. Am J Pathol 2005; 167: 161–73.CrossRefGoogle ScholarPubMed
67Tigges, J, Herndon, JG, Rosene, DL. Mild age-related changes in the dentate gyrus of adult rhesus monkeys. Acta Anat (Basel) 1995; 153: 3948.CrossRefGoogle ScholarPubMed
68Tigges, J, Herndon, JG, Rosene, DL. Preservation into old age of synaptic number and size in the supragranular layer of the dentate gyrus in rhesus monkeys. Acta Anat (Basel) 1996; 157: 6372.CrossRefGoogle ScholarPubMed
69Newton, IG, Forbes, ME, Linville, MC et al. Effects of aging and caloric restriction on dentate gyrus synapses and glutamate receptor subunits. Neurobiol Aging 2007 Apr 10; [Epub ahead of print]Google Scholar
70Shi, L, Linville, MC, Tucker, EW, Sonntag, WE, Brunso-Bechtold, JK. Differential effects of aging and insulin-like growth factor-1 on synapses in CA1 of rat hippocampus. Cereb Cortex 2005; 15: 571–77.CrossRefGoogle ScholarPubMed
71Scheff, SW, Price, DA, Sparks, DL. Quantitative assessment of possible age-related change in synaptic numbers in the human frontal cortex. Neurobiol Aging 2001; 22: 355–65.CrossRefGoogle ScholarPubMed
72Shi, L, Pang, H, Linville, MC, Bartley, AN, Argenta, AE, Brunso-Bechtold, JK. Maintenance of inhibitory interneurons and boutons in sensorimotor cortex between middle and old age in Fischer 344 X Brown Norway rats. J Chem Neuroanat 2006; 32: 4653.CrossRefGoogle ScholarPubMed
73Peters, A, Sethares, C, Luebke, JI. Synapses are lost during aging in the primate prefrontal cortex. Neuroscience 2007 Jul 17; [Epub ahead of print]Google Scholar
74Barnes, CA. Long-term potentiation and the ageing brain. Philos Trans R Soc Lond B Biol Sci 2003; 358 (1432): 765–72.CrossRefGoogle ScholarPubMed
75Gallagher, M. Aging and hippocampal/cortical circuits in rodents. Alzheimer Dis Assoc Disord 2003; 17 (suppl 2): S457.CrossRefGoogle ScholarPubMed
76Rosenzweig, ES, Barnes, CA. Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog Neurobiol 2003; 69: 143–79.CrossRefGoogle ScholarPubMed
77Wilson, IA, Gallagher, M, Eichenbaum, H, Tanila, H. Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci 2006; 29: 662–70.CrossRefGoogle ScholarPubMed
78Zhang, HY, Watson, ML, Gallagher, M, Nicolle, MM. Muscarinic receptor-mediated GTP-Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats. Neurobiol Aging 2007; 28: 619–26.CrossRefGoogle ScholarPubMed
79Schoenbaum, G, Setlow, B, Saddoris, MP, Gallagher, M. Encoding changes in orbitofrontal cortex in reversal-impaired aged rats. J Neurophysiol 2006; 95 1509–17.CrossRefGoogle ScholarPubMed
80LaSarge, CL, Montgomery, KS, Tucker, C et al. Deficits across multiple cognitive domains in a subset of aged Fischer 344 rats. Neurobiol Aging 2007; 28: 928–36.CrossRefGoogle Scholar
81Segovia, G, Porras, A, Del Arco, A, Mora, F. Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev 2001; 122: 129.CrossRefGoogle ScholarPubMed
82Michaelis, EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 1998; 54: 369415.CrossRefGoogle ScholarPubMed
83Dingledine, R, Borges, K, Bowie, D, Traynelis, SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51: 761.Google ScholarPubMed
84Magnusson, KR. The aging of the NMDA receptor complexs. Front Biosci 1998; 3: 7080.CrossRefGoogle Scholar
85Yamada, K, Nabeshima, T. Changes in NMDA receptor/nitric oxide signaling pathway in the brain with aging. Microsc Res Tech 1998; 43: 6X74.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
86Adams, MM, Morrison, JH. Estrogen and the aging hippocampal synapse. Cereb Cortex 2003;13: 1271–75.CrossRefGoogle ScholarPubMed
87Foster, TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell. 2007; 6: 319–25.CrossRefGoogle ScholarPubMed
88Shi, L, Adams, M, Brunso-Bechtold, JK. Subtle alterations in glutamatergic receptors underlie the aging-related decline in hippocampal function. In: Riddle, DR ed. Brain aging: models, methods and mechanisms. Boca Raton: CRC Press, 2007: 189212.Google ScholarPubMed
89Simonyi, A, Miller, LA, Sun, GY. Region-specific decline in the expression of metabotropic glutamate receptor 7 mRNA in rat brain during aging. Brain Res Mol Brain Res 2000; 82: 101–06.CrossRefGoogle ScholarPubMed
90Simonyi, A, Ngomba, RT, Storto, M et al. Expression of groups I and II metabotropic glutamate receptors in the rat brain during aging. Brain Res 2005; 1043: 95106.CrossRefGoogle ScholarPubMed
91Hedberg, TG, Velísková, J, Sperber, EF, Nunes, ML, Moshé, SL. Age-related differences in NMDA/metabotropic glutamate receptor-binding in rat substantia nigra. Int J Dev Neurosci 2003; 21: 95103.CrossRefGoogle ScholarPubMed
92Nicolle, MM, Colombo, PJ, Gallagher, M, McKinney, M. Metabotropic glutamate receptor-mediated hippocampal phosphoinositide turnover is blunted in spatial learning-impaired aged rats. J Neurosci 1999; 19: 9604–10.CrossRefGoogle ScholarPubMed
93Domenici, MR, Pintor, A, Potenza, RL et al. Metabotropic glutamate receptor 5 (mGluR5)-mediated phosphoinositide hydrolysis and NMDA-potentiating effects are blunted in the striatum of aged rats: a possible additional mechanism in striatal senescence. Eur J Neurosci 2003; 17: 2047–55.CrossRefGoogle ScholarPubMed
94Sohal, RS, Agarwal, S, Sohal, BH. Oxidative stress and aging in the Mongolian gerbil (Meriones unguiculatus). Mech Ageing Dev 1995; 81: 1525.CrossRefGoogle Scholar
95Forster, MJ, Dubey, A, Dawson, KM, Stutts, WA, Lal, H, Sohal, RS. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci U S A 1996; 93: 4765–69.CrossRefGoogle Scholar
96Sohal, RS, Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 1996; 273: 5963.CrossRefGoogle ScholarPubMed
97Hamilton, ML, Van Remmen, H, Drake, JA et al. Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 2001; 98: 10469–74.CrossRefGoogle ScholarPubMed
98Agarwal, S, Sohal, RS. Relationship between susceptibility to protein oxidation, aging, and maximum lifespan potential of different species. Exp Gerontol 1996; 31: 365–72.CrossRefGoogle Scholar
99Chen, TS, Richie, JP Jr., Lang, CA. The effect of aging on glutathione and cysteine levels in different regions of the mouse brain. Proc Soc Exp Biol Med 1989; 190: 399402.CrossRefGoogle ScholarPubMed
100Rao, G, Xia, E, Richardson, A. Effect of age on the expression of antioxidant enzymes in male Fischer F344 rats. Mech Ageing Dev 1990; 53: 4960.CrossRefGoogle ScholarPubMed
101Semsei, I, Rao, G, Richardson, A. Expression of superoxide dismutase and catalase in rat brain as a function of age. Mech Ageing Dev 1991; 58: 1319.CrossRefGoogle ScholarPubMed
102LeBel, CP, Bondy, SC. Oxidative damage and cerebral aging. Prog Neurobiol 1992; 38: 601–09.CrossRefGoogle ScholarPubMed
103Butterfield, DA, Howard, B, Yatin, S et al. Elevated oxidative stress in models of normal brain aging and Alzheimer's disease. Life Sci 1999; 65: 1883–92.CrossRefGoogle ScholarPubMed
104Liu, J, Mori, A. Stress, aging, and brain oxidative damage. Neurochem Res 1999; 24: 1479–97.CrossRefGoogle ScholarPubMed
105Sohal, RS, Agarwal, S, Candas, M, Forster, MJ, Lal, H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev 1994; 76: 215–24.CrossRefGoogle ScholarPubMed
106Sohal, RS, Ku, HH, Agarwal, S, Forster, MJ, Lal, H. Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev 1994; 74: 121–33.CrossRefGoogle ScholarPubMed
107Nicolle, MM, Gonzalez, J, Sugaya, K et al. Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 2001; 107: 415–31.CrossRefGoogle ScholarPubMed
108Carney, JM, Starke-Reed, PE, Oliver, CN et al. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc Natl Acad Sci USA 1991; 88: 3633–36.CrossRefGoogle ScholarPubMed
109Wang, Y, Chang, CF, Chou, J et al. Dietary supplementation with blueberries, spinach, or spirulina reduces ischemic brain damage. Exp Neurol 2005; 193: 7584.CrossRefGoogle ScholarPubMed
110Joseph, JA, Shukitt-Hale, B, Lau, FC. Fruit polyphenols and their effects on neuronal signaling and behavior in senescence. Ann N Y Acad Sci 2007; 100: 470–85.CrossRefGoogle Scholar
111Calabrese, V, Guagliano, E, Sapienza, M et al. Redox regulation of cellular stress response in aging and neurodegenerative disorders: role of vitagenes. Neurochem Res 2007; 32: 757–73.CrossRefGoogle ScholarPubMed
112Dröge, W, Schipper, HM. Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 2007; 6: 361–70.CrossRefGoogle ScholarPubMed
113Taguchi, A, White, MF. Insulin-like signalling, nutrient homeostasis, and life span. Annu Rev Physiol 2008; 70: 191212.CrossRefGoogle Scholar
114Prolla, TA, Mattson, MP. Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction. Trends Neurosci 2001; 24: S21S31.CrossRefGoogle ScholarPubMed
115Ye, SM, Johnson, RW. An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 2001; 9: 183–92.CrossRefGoogle ScholarPubMed
116Sharman, KG, Sharman, EH, Yang, E, Bondy, SC. Dietary melatonin selectively reverses age-related changes in cortical cytokine mRNA levels, and their responses to an inflammatory stimulus. Neurobiol Aging 2002; 23: 633–38.CrossRefGoogle Scholar
117Weaver, JD, Huang, MH, Albert, M, Harris, T, Rowe, JW, Seeman, TE. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002; 59: 371–78.CrossRefGoogle ScholarPubMed
118Bodles, AM, Barger, SW. Cytokines and the aging brain – what we don't know might help us. Trends Neurosci 2004; 27: 621–26.CrossRefGoogle ScholarPubMed
119Weindruch, R, Kayo, T, Lee, CK, Prolla, TA. Gene-expression profiling of aging using DNA microarrays. Mech Ageing Dev 2002;123: 177–93.CrossRefGoogle ScholarPubMed
120Galvin, JE, Ginsberg, SD. Expression profiling in the aging brain: a perspective. Ageing Res Rev 2005; 4: 529–47.CrossRefGoogle ScholarPubMed
121Terao, A, Apte-Deshpande, A, Dousman, L et al. Immune response gene expression increases in the aging murine hippocampus. J Neuroimmunol 2002; 132: 99112.CrossRefGoogle ScholarPubMed
122Lynch, AM, Lynch, MA. The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur J Neurosci 2002; 15: 1779–88.CrossRefGoogle ScholarPubMed
123Lynch, MA. What is the biological significance of an age-related increase in IL-1beta in hippocampus? Mol Psychiatry 1999; 4: 1518.CrossRefGoogle ScholarPubMed
124Murray, CA, Lynch, MA. Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 1998; 18: 2974–81.CrossRefGoogle ScholarPubMed
125Nimmerjahn, A, Kirchhoff, F, Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314–18.CrossRefGoogle ScholarPubMed
126Raivich, G. Like cops on the beat: the active role of resting microglia. Trends Neurosci 2005; 28: 571–73CrossRefGoogle ScholarPubMed
127Hanisch, UK, Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007; 10: 1387–94.CrossRefGoogle ScholarPubMed
128Ferrari, D, Villalba, M, Chiozzi, P, Ricciardi-Castagnoli, P, Di Virgilio, F. Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J Immunol 1996; 156: 1531–39.Google ScholarPubMed
129Boddeke, EW, Meigel, I, Frentzel, S, Biber, K, Renn, LQ, Gebicke-Härter, P. Functional expression of the fractalkine (CX3C) receptor and its regulation by lipopolysaccharide in rat microglia. Eur J Pharmacol 1999;374: 309–13.CrossRefGoogle ScholarPubMed
130Hanisch, UK. Microglia as a source and target of cytokines. Glia 2002; 40: 140–55.CrossRefGoogle ScholarPubMed
131Davalos, D, Grutzendler, J, Yang, G et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005; 8: 752–58.CrossRefGoogle ScholarPubMed
132Becher, B, Prat, A, Antel, JP. Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia 2000; 29: 293304.3.0.CO;2-A>CrossRefGoogle ScholarPubMed
133Ekdahl, CT, Claasen, JH, Bonde, S, Kokaia, Z, Lindvall, O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 2003; 100: 13632–637.CrossRefGoogle ScholarPubMed
134Monje, ML, Toda, H, Palmer, TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 1760–65.CrossRefGoogle ScholarPubMed
135Gemma, C, Bachstetter, AD, Cole, MJ, Fister, M, Hudson, C, Bickford, PC. Blockade of caspase-1 increases neurogenesis in the aged hippocampus. Eur J Neurosci 2007; 26: 2795–803.CrossRefGoogle ScholarPubMed
136Griffin, R, Nally, R, Nolan, Y, McCartney, Y, Linden, J, Lynch, MA. The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 2006; 99: 1263–72.CrossRefGoogle ScholarPubMed
137Casolini, P, Catalani, A, Zuena, AR, Angelucci, L. Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res 2002; 68: 337–43.CrossRefGoogle ScholarPubMed
138Wilson, CJ, Finch, CE, Cohen, HJ. Cytokines and cognition–the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002; 50: 2041–56.CrossRefGoogle ScholarPubMed
139Lynch, MA. Analysis of the mechanisms underlying the age-related impairment in long-term potentiation in the rat. Rev Neurosci 1998; 9: 169201.CrossRefGoogle ScholarPubMed
140Maher, FO, Martin, DS, Lynch, MA. Increased IL-1beta in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase. Neurobiol Aging 2004; 25: 795806.CrossRefGoogle ScholarPubMed
141Nolan, Y, Maher, FO, Martin, DS et al. Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus. J Biol Chem 2005; 280: 9354–62.CrossRefGoogle ScholarPubMed
142Perry, VH, Matyszak, MK, Fearn, S. Altered antigen expression of microglia in the aged rodent CNS. Glia 1993; 7: 6067.CrossRefGoogle ScholarPubMed
143Kullberg, S, Aldskogius, H, Ulfhake, B. Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord. Brain Res 2001; 899: 169–86.CrossRefGoogle ScholarPubMed
144Stichel, CC, Luebbert, H. Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging 2007; 28: 1507–21.CrossRefGoogle ScholarPubMed
145Schindler, MK, Forbes, ME, Robbins, ME et al. Aging-dependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys 2008; 70: 826–34.CrossRefGoogle ScholarPubMed
146Sloane, JA, Hollander, W, Moss, MB, Rosene, DL, Abraham, CR. Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol Aging 1999; 20: 395405.CrossRefGoogle ScholarPubMed
147Conde, JR, Streit, WJ. Microglia in the aging brain. J Neuropathol Exp Neurol 2006; 65: 199203.CrossRefGoogle ScholarPubMed
148Simpson, JE, Ince, PG, Higham, CE et al. Microglial activation in white-matter lesions and nonlesional white matter of ageing brains. Neuropathol Appl Neurobiol 2007; 33: 670–83.CrossRefGoogle ScholarPubMed
149Long, JM, Kalehua, AN, Muth, NJ et al. Stereological analysis of astrocyte and microglia in aging mouse hippocampus. Neurobiol Aging 1998; 19: 497503.CrossRefGoogle ScholarPubMed
150Streit, WJ. Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev 2005; 48: 234–39.CrossRefGoogle ScholarPubMed
151Ziv, Y, Ron, N, Butovsky, O et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 2006; 9: 268–75.CrossRefGoogle ScholarPubMed
152Glezer, I, Simard, AR, Rivest, S. Neuroprotective role of the innate immune system by microglia. Neuroscience 2007; 147: 867–83.CrossRefGoogle ScholarPubMed
153Nakajima, K, Tohyama, Y, Maeda, S, Kohsaka, S, Kurihara, T. Neuronal regulation by which microglia enhance the production of neurotrophic factors for GABAergic, catecholaminergic, and cholinergic neurons. Neurochem Int 2007; 50: 807820.CrossRefGoogle ScholarPubMed
154Lai, AY, Todd, KG. Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury. Glia 2008; 56: 259–70.CrossRefGoogle ScholarPubMed
155Sierra, A, Gottfried-Blackmore, AC, McEwen, BS, Bulloch, K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 2007; 55: 412–24.CrossRefGoogle ScholarPubMed
156Joseph, JA, Shukitt-Hale, B, Casadesus, G, Fisher, D. Oxidative stress and inflammation in brain aging: nutritional considerations. Neurochem Res 2005; 30: 927–35.CrossRefGoogle ScholarPubMed
157Roth, GS, Ingram, DK, Joseph, JA. Nutritional interventions in aging and age-associated diseases. Ann N Y Acad Sci 2007; 1114: 369–71.CrossRefGoogle ScholarPubMed
158Bickford, PC, Gould, T, Briederick, L et al. Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Brain Res 2000; 866: 211–17.CrossRefGoogle ScholarPubMed
159Cartford, MC, Gemma, C, Bickford, PC. Eighteen-month-old Fischer 344 rats fed a spinach-enriched diet show improved delay classical eyeblink conditioning and reduced expression of tumor necrosis factor alpha (TNFalpha) and TNFbeta in the cerebellum. J Neurosci 2002; 22: 5813–16.CrossRefGoogle ScholarPubMed
160Goyarzu, P, Malin, DH, Lau, FC et al. Blueberry-supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci 2004 Apr; 7: 7583.CrossRefGoogle ScholarPubMed
161Shukitt-Hale, B, Carey, A, Simon, L, Mark, DA, Joseph, JA. Effects of Concord grape juice on cognitive and motor deficits in aging. Nutrition 2006; 22: 295302.CrossRefGoogle Scholar
162Kamel, NS, Gammack, J, Cepeda, O, Flaherty, JH. Antioxidants and hormones as anti-aging therapies: high hopes, disappointing results. Cleve Clin J Med 2006; 73: 1049–56.CrossRefGoogle Scholar
163Grodstein, F, Kang, JH, Glynn, RJ, Cook, NR, Gaziano, JM. A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II. Arch Intern Med 2007; 167: 2184–80.CrossRefGoogle ScholarPubMed
164McNeill, G, Avenell, A, Campbell, MK et al. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutr J 2007; 6: 10.CrossRefGoogle ScholarPubMed
165Rondanelli, M, Trotti, R, Opizzi, A, Solerte, SB. Relationship among nutritional status, pro/antioxidant balance and cognitive performance in a group of free-living healthy elderly. Minerva Med 2007; 98: 639–45.Google Scholar
166Wengreen, HJ, Munger, RG, Corcoran, CD et al. Antioxidant intake and cognitive function of elderly men and women: the Cache County Study. J Nutr Health Aging 2007; 11: 230–37.Google ScholarPubMed
167Duffy, KB, Spangler, EL, Devan, BD et al. A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats. Neurobiol Aging. 2007 May 22; [Epub ahead of print]Google Scholar
168Shukitt-Hale, B, Carey, AN, Jenkins, D, Rabin, BM, Joseph, JA. Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging. Neurobiol Aging 2007; 28: 1187–94.CrossRefGoogle Scholar
169Bekker, AY, Weeks, EJ. Cognitive function after anaesthesia in the elderly. Best Pract Res Clin Anaesthesiol 2003; 17: 259–72.CrossRefGoogle ScholarPubMed
170Cohendy, R, Brougere, A, Cuvillon, P. Anaesthesia in the older patient. Curr Opin Clin Nutr Metab Care 2005; 8: 17–1.CrossRefGoogle ScholarPubMed
171Levine, WC, Mehta, V, Landesberg, G. Anesthesia for the elderly: selected topics. Curr Opin Anaesthesiol 2006; 19: 320–24.CrossRefGoogle ScholarPubMed
172Culley, DJ, Xie, Z, Crosby, G. General anesthetic-induced neurotoxicity: an emerging problem for the young and old? Curr Opin Anaesthesiol 2007; 20: 408–13.CrossRefGoogle Scholar
173Perouansky, M. General anesthetics and long-term neurotoxicity. Handb Exp Pharmacol 2008; 182: 143–57.CrossRefGoogle Scholar
174Kyrkanides, S, O'Banion, MK, Whiteley, PE, Daeschner, JC, Olschowka, JA. Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury. J Neuroimmunol 2001; 119: 269–77.CrossRefGoogle ScholarPubMed
175Popa-Wagner, A, Badan, I, Walker, L, Groppa, S, Patrana, N, Kessler, C. Accelerated infarct development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats. Acta Neuropathol (Berl) 2007; 113: 277–93.CrossRefGoogle ScholarPubMed
176Lamproglou, I, Chen, QM, Boisserie, G et al. Radiation-induced cognitive dysfunction: an experimental model in the old rat. Int J Radiat Oncol Biol Phys 1995; 31: 6570.CrossRefGoogle ScholarPubMed
177Lamproglou, I, Baillet, F, Boisserie, G, Mazeron, JJ, Delattre, JY. The influence of age on radiation-induced cognitive deficit: experimental studies on brain irradiation of 30 Gy in 10 sessions and 12 hours in the Wistar rat at 1 1/2, 4 and 18 months age. Can J Physiol Pharmacol 2002; 80: 679–85.CrossRefGoogle ScholarPubMed
178Abrey, LE, Deangelis, LM, Yahalom, J. Long-term survival in primary CNS lymphoma. J Clin Oncol 1998; 16: 859–63.CrossRefGoogle ScholarPubMed
179Deangelis, LM. Primary CNS lymphoma: treatment with combined chemotherapy and radiotherapy. J Neurooncol 1999; 43: 249–57.CrossRefGoogle ScholarPubMed
180Swennen, MH, Bromberg, JE, Witkamp, TD, Terhaard, CH, Postma, TJ, Taphoorn, MJ. Delayed radiation toxicity after focal or whole brain radiotherapy for low-grade glioma. J Neurooncol 2004; 66: 333–39.CrossRefGoogle ScholarPubMed
181Omuro, AM, Ben-Porat, LS, Panageas, KS, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 2005; 62: 15951600.CrossRefGoogle ScholarPubMed
182Barrientos, RM, Higgins, EA, Biedenkapp, JC et al. Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 2006; 27: 723–32.CrossRefGoogle ScholarPubMed
183Frank, MG, Baratta, MV, Sprunger, DB, Watkins, LR, Maier, SF. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 2007; 21: 4759.CrossRefGoogle ScholarPubMed
184Perry, VH, Cunningham, C, Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007; 7: –67.CrossRefGoogle ScholarPubMed
185Chen, J, Buchanan, JB, Sparkman, NL, Godbout, JP, Freund, GG, Johnson, RW. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 3: 301–11.CrossRefGoogle Scholar
186Mangano, EN, Hayley, S. Inflammatory priming of the substantia nigra influences the impact of later paraquat exposure: neuroimmune sensitization of neurodegeneration. Neurobiol Aging 2008 (in press).Google Scholar
187Viviani, B, Gardoni, F, Marinovich, M. Cytokines and neuronal ion channels in health and disease. Int Rev Neurobiol 2007; 82: 247–63.CrossRefGoogle ScholarPubMed
188Pickering, M, Cumiskey, D, O'Connor, JJ. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol 2005; 90: 663–70.CrossRefGoogle ScholarPubMed
189Pickering, M, O'Connor, JJ. Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res 2007; 163: 339–54.CrossRefGoogle ScholarPubMed
190Neumann, H, Schweigreiter, R, Yamashita, T, Rosenkranz, K, Wekerle, H, Barde, YA. Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci 2002; 22: 854–62.CrossRefGoogle ScholarPubMed
191Katafuchi, T, Take, S, Hori, T. Roles of cytokines in the neural-immune interactions: modulation of NMDA responses by IFN-alpha. Neurobiology 1995; 3: 319–27.Google ScholarPubMed
192Vereyken, EJ, Bajova, H, Chow, S, de Graan, PN, Gruol, DL. Chronic interleukin-6 alters the level of synaptic proteins in hippocampus in culture and in vivo. Eur J Neurosci 2007; 25: 3605–16.CrossRefGoogle ScholarPubMed
193Bessis, A, Béchade, C, Bernard, D et al. Microglial control of neuronal death and synaptic properties. Glia 2007; 55: 233–38.CrossRefGoogle ScholarPubMed
194Trapp, BD, Wujek, JR, Criste, GA et al. Evidence for synaptic stripping by cortical microglia. Glia 2007; 55: 360–68.CrossRefGoogle ScholarPubMed
Cited by