The aging brain.

Aging is accompanied by cognitive decline in a major segment of the population and is the primary risk factor for Alzheimer's disease and other prevalent neurodegenerative disorders. Despite this central role in disease pathogenesis and morbidity, the aging of the brain has not been well understood at a molecular level. This review seeks to integrate what is known about age-related cognitive and neuroanatomical changes with recent advances in understanding basic molecular mechanisms that underlie aging. An important issue is how normal brain aging transitions to pathological aging, giving rise to neurodegenerative disorders. Toxic protein aggregates have been identified as potential contributory factors, including amyloid beta-protein in Alzheimer's disease, tau in frontotemporal dementia, and alpha-synuclein in Parkinson's disease. However, current models of pathogenesis do not explain the origin of the common sporadic forms of these diseases or address the critical nexus between aging and disease. This review discusses potential approaches to unifying the systems biology of the aging brain with the pathogenesis of neurodegeneration.

[1]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[2]  Takashi Morihara,et al.  A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model , 2005, The Journal of Neuroscience.

[3]  C. Geula,et al.  Loss of calbindin‐D28k from aging human cholinergic basal forebrain: Relation to neuronal loss , 2003, The Journal of comparative neurology.

[4]  M Moscovitch,et al.  Contributions of surface and conceptual information to performance on implicit and explicit memory tasks. , 1994, Journal of experimental psychology. Learning, memory, and cognition.

[5]  W. Markesbery,et al.  Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Hoeijmakers,et al.  Aging and Genome Maintenance: Lessons from the Mouse? , 2003, Science.

[7]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[8]  H. Potter,et al.  Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  E. Tangalos,et al.  Memory function in normal aging , 1992, Neurology.

[10]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[11]  U. Brunk,et al.  The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. , 2002, European journal of biochemistry.

[12]  Cornelia I Bargmann,et al.  Comparing genomic expression patterns across species identifies shared transcriptional profile in aging , 2004, Nature Genetics.

[13]  Junying Yuan,et al.  Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β , 2000, Nature.

[14]  P. Rakić,et al.  Synaptogenesis in the Occipital Cortex of Macaque Monkey Devoid of Retinal Input From Early Embryonic Stages , 1996, The European journal of neuroscience.

[15]  James K. Nelson,et al.  Selection requirements during verb generation: differential recruitment in older and younger adults , 2004, NeuroImage.

[16]  B. Hyman,et al.  Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function , 2005, Science.

[17]  B. Sommer,et al.  Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease , 2000, Nature Neuroscience.

[18]  B. Hyman,et al.  Aβ Deposition Is Associated with Neuropil Changes, but not with Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F (PDAPP) Transgenic Mouse , 1997, The Journal of Neuroscience.

[19]  F. Morrell,et al.  Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Bruce A. Yankner,et al.  Aging renders the brain vulnerable to amyloid β-protein neurotoxicity , 1998, Nature Medicine.

[21]  P G Schultz,et al.  The effects of aging on gene expression in the hypothalamus and cortex of mice. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  F. LaFerla,et al.  Reduction of Soluble Aβ and Tau, but Not Soluble Aβ Alone, Ameliorates Cognitive Decline in Transgenic Mice with Plaques and Tangles* , 2006, Journal of Biological Chemistry.

[23]  G. Schellenberg,et al.  Apolipoprotein E genotypes and age of onset in early‐onset familial Alzheimer's disease , 1995, Annals of neurology.

[24]  J. Troncoso,et al.  Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease , 1994, The Lancet.

[25]  S. Helfand,et al.  Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila melanogaster Extends Life Span , 2005, Current Biology.

[26]  S. Christakos,et al.  Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Benzer,et al.  Extended life-span and stress resistance in the Drosophila mutant methuselah. , 1998, Science.

[28]  D. Bredesen,et al.  Correction for Galvan et al., Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664 , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Frederick W. Alt,et al.  DNA Repair, Genome Stability, and Aging , 2005, Cell.

[30]  D. Selkoe,et al.  Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity , 1999, Nature.

[31]  D. Bredesen,et al.  Aβ induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597–624) , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  R. S. Williams,et al.  A prospective study of Alzheimer disease in Down syndrome. , 1989, Archives of neurology.

[33]  C. Barnes,et al.  Neural plasticity in the ageing brain , 2006, Nature Reviews Neuroscience.

[34]  A. Brun,et al.  Cortical synaptic changes and gliosis in normal aging, Alzheimer's disease and frontal lobe degeneration. , 1996, Dementia.

[35]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[36]  G. Lynch,et al.  Impaired monosynaptic potentiation in in vitro hippocampal slices from aged, memory-deficient rats. , 1977, Journal of gerontology.

[37]  Maria Dusinska,et al.  Measurement of DNA oxidation in human cells by chromatographic and enzymic methods. , 2003, Free radical biology & medicine.

[38]  J. Cummings,et al.  Treatment of Alzheimer's disease: current and future therapeutic approaches. , 2004, Reviews in neurological diseases.

[39]  A. Fagan,et al.  Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  H. E. Stanley,et al.  Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  David B. Goldstein,et al.  Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster , 2002, Current Biology.

[42]  G. Schellenberg,et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus , 1995, Science.

[43]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[44]  Richard Weindruch,et al.  Gene-expression profile of the ageing brain in mice , 2000, Nature Genetics.

[45]  R. S. Sohal,et al.  Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. , 1994, Science.

[46]  A. Blankenship,et al.  Cognitive and Physical Activity Differently Modulate Disease Progression in the Amyloid Precursor Protein (APP)-23 Model of Alzheimer’s Disease , 2006, Biological Psychiatry.

[47]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[48]  Carol A Barnes,et al.  Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Brian J Cummings,et al.  Spatial learning and memory as a function of age in the dog. , 1995, Behavioral neuroscience.

[50]  V. Arango,et al.  Molecular aging in human prefrontal cortex is selective and continuous throughout adult life , 2005, Biological Psychiatry.

[51]  I. Kohane,et al.  Gene regulation and DNA damage in the ageing human brain , 2004, Nature.

[52]  L. Guarente,et al.  Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. , 2006, Genes & development.

[53]  P. Puigserver,et al.  Resveratrol improves health and survival of mice on a high-calorie diet , 2006, Nature.

[54]  R. Killiany,et al.  Executive system dysfunction in the aged monkey: Spatial and object reversal learning , 1995, Neurobiology of Aging.

[55]  P. Greengard,et al.  Regulation of NMDA receptor trafficking by amyloid-β , 2005, Nature Neuroscience.

[56]  B. Strooper,et al.  Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex , 2003, Neuron.

[57]  M. Mattson,et al.  Evidence for calcium-reducing and excitoprotective roles for the calcium-binding protein calbindin-1328k in cultured hippocampal neurons , 1991, Neuron.

[58]  L. Tsai,et al.  Neurotoxicity induces cleavage of p35 to p25 by calpain , 2000, Nature.

[59]  Alexei Degterev,et al.  Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1* , 2006, Journal of Biological Chemistry.

[60]  J. Trojanowski,et al.  Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. , 2006, Annual review of pathology.

[61]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[62]  Li-Huei Tsai,et al.  Recovery of learning and memory is associated with chromatin remodelling , 2007, Nature.

[63]  J. Hardy,et al.  Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). , 1990, Science.

[64]  Karl Herrup,et al.  Neuronal Cell Death Is Preceded by Cell Cycle Events at All Stages of Alzheimer's Disease , 2003, The Journal of Neuroscience.

[65]  S. Younkin,et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. , 1994, Science.

[66]  P. Coleman,et al.  Dendritic growth in the aged human brain and failure of growth in senile dementia. , 1979, Science.

[67]  M. Beal,et al.  High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. , 2002, Human molecular genetics.

[68]  Hugo Vanderstichele,et al.  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein , 1998, Nature.

[69]  G. Bartzokis,et al.  White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. , 2003, Archives of neurology.

[70]  M. Albert,et al.  Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain , 2004, Neurology.

[71]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[72]  J. Gabrieli,et al.  Insights into the ageing mind: a view from cognitive neuroscience , 2004, Nature Reviews Neuroscience.

[73]  S. Browne,et al.  Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[74]  M. Beal,et al.  Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[75]  C. Barnes.  Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. , 1979, Journal of comparative and physiological psychology.

[76]  S. Blair Hedges,et al.  The origin and evolution of model organisms , 2002, Nature Reviews Genetics.

[77]  S. Younkin,et al.  Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. , 1993, Science.

[78]  F H Duffy,et al.  Nonlinear changes in cognition with age and their neuropsychologic correlates. , 1987, Canadian journal of psychology.

[79]  Denis A. Evans,et al.  Vitamin E and cognitive decline in older persons. , 2002, Archives of neurology.

[80]  L. Honig,et al.  Model‐guided microarray implicates the retromer complex in Alzheimer's disease , 2005, Annals of neurology.

[81]  D. Praticò,et al.  Coxibs and Alzheimer's disease: Should they stay or should they go? , 2006, Annals of neurology.

[82]  Xiongwei Zhu,et al.  Ribosomal RNA in Alzheimer Disease Is Oxidized by Bound Redox-active Iron* , 2005, Journal of Biological Chemistry.

[83]  Arthur F Kramer,et al.  Achieving and maintaining cognitive vitality with aging. , 2002, Mayo Clinic proceedings.

[84]  Roland N. Emokpae,et al.  Cell Cycle Activation Linked to Neuronal Cell Death Initiated by DNA Damage , 2004, Neuron.

[85]  Arthur F Kramer,et al.  Exercise, cognition, and the aging brain. , 2006, Journal of applied physiology.

[86]  Wen-Lang Lin,et al.  Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein , 2000, Nature Genetics.

[87]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[88]  Joel S Perlmutter,et al.  Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. , 2002, Archives of neurology.

[89]  M. J. Wade,et al.  Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. , 2001, Archives of neurology.

[90]  I. Lieberburg,et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. , 1990, Science.

[91]  F. Alt,et al.  DNA double strand break repair and chromosomal translocation: Lessons from animal models , 2001, Oncogene.

[92]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[93]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[94]  C. Epstein,et al.  Familial mitochondrial encephalomyopathy (MERRF): Genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease , 1988, Cell.

[95]  Carl W. Cotman,et al.  Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[96]  J. Morris,et al.  Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease , 1996, The Journal of Neuroscience.

[97]  L. Villa-komaroff,et al.  Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. , 1989, Science.

[98]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[99]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[100]  Leanne M Williams,et al.  The Mellow Years?: Neural Basis of Improving Emotional Stability over Age , 2006, The Journal of Neuroscience.

[101]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[102]  G. Schellenberg,et al.  Aging-associated neuropathology in Werner syndrome , 1998, Acta Neuropathologica.

[103]  A. Roses,et al.  Apolipoprotein E and the CNS Response to Injury , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[104]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[105]  B. Ames,et al.  Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-l-carnitine and/or R-α-lipoic acid , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[106]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[107]  Philipp Khaitovich,et al.  Aging and Gene Expression in the Primate Brain , 2005, PLoS biology.

[108]  K. Jellinger,et al.  Synaptic Pathology of Alzheimer's Disease a , 1993, Annals of the New York Academy of Sciences.

[109]  E. Zelinski,et al.  Sixteen-year longitudinal and time lag changes in memory and cognition in older adults. , 1997, Psychology and aging.

[110]  J. Busciglio,et al.  Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons , 2006, The Journal of Neuroscience.

[111]  S. Rabacchi,et al.  Caspase-2 Mediates Neuronal Cell Death Induced by β-Amyloid , 2000, The Journal of Neuroscience.

[112]  E. Kandel,et al.  Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[113]  P. Lansbury,et al.  Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? , 1993, Cell.

[114]  C. Barnes,et al.  LTP induction threshold change in old rats at the perforant path–granule cell synapse , 2000, Neurobiology of Aging.

[115]  T. Foster,et al.  Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment , 2003, The Journal of Neuroscience.

[116]  J. Wood,et al.  Sirtuin activators mimic caloric restriction and delay ageing in metazoans , 2004, Nature.

[117]  B. Yankner.  Mechanisms of Neuronal Degeneration in Alzheimer's Disease , 1996, Neuron.

[118]  Faith M. Gunning-Dixon,et al.  The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. , 2000, Neuropsychology.

[119]  P Woodbury,et al.  A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. , 1997, The New England journal of medicine.

[120]  Florence Rémy,et al.  Mental calculation impairment in Alzheimer's disease: a functional magnetic resonance imaging study , 2004, Neuroscience Letters.

[121]  D. Selkoe,et al.  Natural oligomers of the amyloid-β protein specifically disrupt cognitive function , 2005, Nature Neuroscience.

[122]  A. Harding,et al.  Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies , 1988, Nature.

[123]  Pier Paolo Pandolfi,et al.  The p66shc adaptor protein controls oxidative stress response and life span in mammals , 1999, Nature.

[124]  L A Beckett,et al.  Age-specific incidence of Alzheimer's disease in a community population. , 1995, JAMA.

[125]  J. Rommens,et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene , 1995, Nature.

[126]  L. Mucke,et al.  Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model , 2007, Science.

[127]  Y. Jan,et al.  Genome-wide study of aging and oxidative stress response in Drosophila melanogaster. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[128]  S. Chandra,et al.  A second cytotoxic proteolytic peptide derived from amyloid β-protein precursor , 2000, Nature Medicine.

[129]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[130]  L. Carstensen,et al.  Socioemotional Selectivity Theory and the Regulation of Emotion in the Second Half of Life , 2003 .

[131]  V. Bohr,et al.  Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner , 2006, Neurobiology of Aging.

[132]  J. Logan,et al.  Under-Recruitment and Nonselective Recruitment Dissociable Neural Mechanisms Associated with Aging , 2002, Neuron.

[133]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[134]  P. Mecocci,et al.  Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain , 1993, Annals of neurology.

[135]  D. Wallace.  A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[136]  Patrick L. McGeer,et al.  Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease , 1996, Neurology.

[137]  P. Puigserver,et al.  Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α , 2006, Cell.

[138]  Kyle Duke,et al.  Transcriptional Profile of Aging in C. elegans , 2002, Current Biology.

[139]  Takashi Morihara,et al.  Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model , 2004, Neuron.

[140]  J. Hoeijmakers,et al.  A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis , 2006, Nature.

[141]  D. Borchelt,et al.  Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins , 1997, Neuron.

[142]  B. Ames,et al.  Normal oxidative damage to mitochondrial and nuclear DNA is extensive. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[143]  J. Connor,et al.  Iron, brain ageing and neurodegenerative disorders , 2004, Nature Reviews Neuroscience.

[144]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[145]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[146]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[147]  Fred H. Gage,et al.  Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice , 2005, The Journal of Neuroscience.

[148]  Phuong Chung,et al.  Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan , 2003, Nature.

[149]  Min Xu,et al.  Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 , 2000, Nature.

[150]  Fred H. Gage,et al.  An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus , 2007, Proceedings of the National Academy of Sciences.

[151]  M. C. Newman,et al.  Early detection of probable idiopathic Parkinson's disease: I. development of a diagnostic test battery , 2000, Movement disorders : official journal of the Movement Disorder Society.

[152]  Patrizia Mecocci,et al.  Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease , 1994, Annals of neurology.

[153]  R. de Cabo,et al.  Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging , 2006, Proceedings of the National Academy of Sciences.

[154]  Philip W. Landfield,et al.  Increase in Single L-Type Calcium Channels in Hippocampal Neurons During Aging , 1996, Science.

[155]  R. Malinow,et al.  AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss , 2006, Neuron.

[156]  M. Roth,et al.  Correlation between Scores for Dementia and Counts of ‘Senile Plaques’ in Cerebral Grey Matter of Elderly Subjects , 1966, Nature.

[157]  M. Ohno,et al.  A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. , 2006, Genome research.

[158]  J. Manson,et al.  Physical activity, including walking, and cognitive function in older women. , 2004, JAMA.

[159]  M. Morris.  Docosahexaenoic acid and Alzheimer disease. , 2006, Archives of neurology.

[160]  Zhongmao Guo,et al.  Does oxidative damage to DNA increase with age? , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[161]  Ilana S. Hairston,et al.  Environmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice , 2005, Cell.

[162]  A. Elia,et al.  Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons , 1998, Nature Genetics.

[163]  T. Foster,et al.  Increased Susceptibility to Induction of Long-Term Depression and Long-Term Potentiation Reversal during Aging , 1996, The Journal of Neuroscience.