1932

Abstract

The past two decades have seen remarkable progress in our understanding of the multifactorial drivers of hippocampal aging and cognitive decline. Recent findings have also raised the possibility of functional rejuvenation in the aged hippocampus. In this review, we aim to synthesize the mechanisms that drive hippocampal aging and evaluate critically the potential for rejuvenation. We discuss the functional changes in synaptic plasticity and regenerative potential of the aged hippocampus, followed by mechanisms of microglia aging, and assess the cross talk between these proaging processes. We then examine proyouth interventions that demonstrate significant promise in reversing age-related impairments in the hippocampus and, finally, attempt to look ahead toward novel therapeutics for brain aging.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-neuro-072116-031357
2017-07-25
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/neuro/40/1/annurev-neuro-072116-031357.html?itemId=/content/journals/10.1146/annurev-neuro-072116-031357&mimeType=html&fmt=ahah

Literature Cited

  1. Aimone JB, Deng W, Gage FH. 2011. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70:4589–96 [Google Scholar]
  2. Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A. et al. 2014. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 344:6184598–602 [Google Scholar]
  3. Bach ME, Barad M, Son H, Zhuo M, Lu YF. et al. 1999. 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. PNAS 96:95280–85 [Google Scholar]
  4. Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH. et al. 2011. Fractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol. Aging 32:112030–44 [Google Scholar]
  5. Bannerman DM, Rawlins JNP, McHugh SB, Deacon RMJ, Yee BK. et al. 2004. Regional dissociations within the hippocampus—memory and anxiety. Neurosci. Biobehav. Rev. 28:3273–83 [Google Scholar]
  6. Barrientos RM, Kitt MM, Watkins LR, Maier SF. 2015. Neuroinflammation in the normal aging hippocampus. Neuroscience 309:84–99 [Google Scholar]
  7. Baruch K, Deczkowska A, David E, Castellano JM, Miller O. et al. 2014. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346:620589–93 [Google Scholar]
  8. Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E. et al. 2013. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. PNAS 110:62264–69 [Google Scholar]
  9. Ben Abdallah NMB, Slomianka L, Vyssotski AL, Lipp HP. 2010. Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol. Aging 31:1151–61 [Google Scholar]
  10. Bouchard J, Villeda SA. 2014. Aging and brain rejuvenation as systemic events. J. Neurochem. 132:15–19 [Google Scholar]
  11. Burdette JH, Laurienti PJ, Espeland MA, Morgan A, Telesford Q. et al. 2010. Using network science to evaluate exercise-associated brain changes in older adults. Front. Aging Neurosci. 2:23 [Google Scholar]
  12. Cameron HA, McKay RD. 1999. Restoring production of hippocampal neurons in old age. Nat. Neurosci. 2:10894–97 [Google Scholar]
  13. Castellano JF, Fletcher BR, Kelley-Bell B, Kim DH, Gallagher M, Rapp PR. 2012. Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus. PLOS ONE 7:3e33249 [Google Scholar]
  14. Chen H, Dzitoyeva S, Manev H. 2012. Effect of aging on 5-hydroxymethylcytosine in the mouse hippocampus. Restor. Neurol. Neurosci. 30:3237–45 [Google Scholar]
  15. Cho S-H, Chen JA, Sayed F, Ward ME, Gao F. et al. 2015. SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. . J. Neurosci. 35:2807–18 [Google Scholar]
  16. Chouliaras L, van den Hove DLA, Kenis G, Draanen MV, Hof PR. et al. 2013. Histone deacetylase 2 in the mouse hippocampus: attenuation of age-related increase by caloric restriction. Curr. Alzheimer Res. 10:8868–76 [Google Scholar]
  17. Christian KM, Song H, Ming G-L. 2014. Functions and dysfunctions of adult hippocampal neurogenesis. Annu. Rev. Neurosci. 37:1243–62 [Google Scholar]
  18. Conboy IM, Conboy MJ, Rebo J. 2015. Systemic problems: a perspective on stem cell aging and rejuvenation. Aging 7:10754–65 [Google Scholar]
  19. Costello DA, Lyons A, Denieffe S, Browne TC, Cox FF, Lynch MA. 2011. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: a role for Toll-like receptor activation. J. Biol. Chem. 286:4034722–32 [Google Scholar]
  20. Cox FF, Carney D, Miller A-M, Lynch MA. 2012. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav. Immun. 26:5789–96 [Google Scholar]
  21. Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ. 2010. Running enhances spatial pattern separation in mice. PNAS 107:52367–72 [Google Scholar]
  22. Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J. et al. 2012. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J. Neuroinflamm. 9:1179 [Google Scholar]
  23. Datwani A, McConnell MJ, Kanold PO, Micheva KD, Busse B. et al. 2009. Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron 64:4463–70 [Google Scholar]
  24. de Fiebre NC, Sumien N, Forster MJ, de Fiebre CM. 2006. Spatial learning and psychomotor performance of C57BL/6 mice: age sensitivity and reliability of individual differences. Age 28:3235–53 [Google Scholar]
  25. Deupree DL, Bradley J, Turner DA. 1993. Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol. Aging 14:3249–58 [Google Scholar]
  26. Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. 2013. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PLOS ONE 8:11e79977 [Google Scholar]
  27. Dong W, Wang R, Ma L-N, Xu B-L, Zhang J-S. et al. 2015. Autophagy involving age-related cognitive behavior and hippocampus injury is modulated by different caloric intake in mice. Int. J. Clin. Exp. Med. 8:711843–53 [Google Scholar]
  28. Dos Santos Sant' Anna G, Rostirola Elsner V, Moysés F, Reck Cechinel L, Agustini Lovatel G, Rodrigues Siqueira I. 2013. Histone deacetylase activity is altered in brain areas from aged rats. Neurosci. Lett. 556:152–54 [Google Scholar]
  29. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza P-V, Abrous DN. 2003. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. PNAS 100:2414385–90 [Google Scholar]
  30. Driscoll I, Hamilton DA, Petropoulos H, Yeo RA, Brooks WM. et al. 2003. The aging hippocampus: cognitive, biochemical and structural findings. Cereb. Cortex 13:121344–51 [Google Scholar]
  31. Duzel E, van Praag H, Sendtner M. 2016. Can physical exercise in old age improve memory and hippocampal function. ? Brain 139:Pt. 3662–73 [Google Scholar]
  32. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN. et al. 2015. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 22:1164–74 [Google Scholar]
  33. Eichenbaum H. 2004. Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44:1109–20 [Google Scholar]
  34. Ekdahl CT, Claasen J-H, Bonde S, Kokaia Z, Lindvall O. 2003. Inflammation is detrimental for neurogenesis in adult brain. PNAS 100:2313632–37 [Google Scholar]
  35. Encinas JM, Michurina TV, Peunova N, Park J-H, Tordo J. et al. 2011. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8:5566–79 [Google Scholar]
  36. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A. et al. 2011. Exercise training increases size of hippocampus and improves memory. PNAS 108:73017–22 [Google Scholar]
  37. Filomeni G, De Zio D, Cecconi F. 2015. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ 22:3377–88 [Google Scholar]
  38. Flood DG, Coleman PD. 1990. Hippocampal plasticity in normal aging and decreased plasticity in Alzheimer's disease. Prog. Brain Res. 83:435–43 [Google Scholar]
  39. Freeman WM, VanGuilder HD, Bennett C, Sonntag WE. 2009. Cognitive performance and age-related changes in the hippocampal proteome. Neuroscience 159:1183–95 [Google Scholar]
  40. Fuentealba LC, Obernier K, Alvarez-Buylla A. 2012. Adult neural stem cells bridge their niche. Stem Cell 10:6698–708 [Google Scholar]
  41. Gebara E, Sultan S, Kocher-Braissant J, Toni N. 2013. Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging. Front. Neurosci. 7:145 [Google Scholar]
  42. Geinisman Y, de Toledo-Morrell L, Morrell F. 1986. Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. PNAS 83:93027–31 [Google Scholar]
  43. Gemma C, Bachstetter AD, Bickford PC. 2010. Neuron-microglia dialogue and hippocampal neurogenesis in the aged brain. Aging Dis 1:3232–44 [Google Scholar]
  44. Gibbons TE, Pence BD, Petr G, Ossyra JM, Mach HC. et al. 2014. Voluntary wheel running, but not a diet containing (−)-epigallocatechin-3-gallate and β-alanine, improves learning, memory and hippocampal neurogenesis in aged mice. Behav. Brain Res. 272:131–40 [Google Scholar]
  45. Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK. et al. 2016. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19:3504–16 [Google Scholar]
  46. Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA. 2006. The age-related attenuation in long-term potentiation is associated with microglial activation. J. Neurochem. 99:41263–72 [Google Scholar]
  47. Guan J-S, Haggarty SJ, Giacometti E, Dannenberg J-H, Joseph N. et al. 2009. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:724355–60 [Google Scholar]
  48. Guerrieri D, van Praag H. 2015. Exercise-mimetic AICAR transiently benefits brain function. Oncotarget 6:2118293–313 [Google Scholar]
  49. Hedden T, Gabrieli JDE. 2004. Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5:287–96 [Google Scholar]
  50. Heine VM, Maslam S, Joëls M, Lucassen PJ. 2004. Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation. Neurobiol. Aging 25:3361–75 [Google Scholar]
  51. Hertzog C, Dixon RA, Hultsch DF, MacDonald SWS. 2003. Latent change models of adult cognition: Are changes in processing speed and working memory associated with changes in episodic memory. ? Psychol. Aging 18:4755–69 [Google Scholar]
  52. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S. et al. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:6286712–16 [Google Scholar]
  53. Hu D, Serrano F, Oury TD, Klann E. 2006. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J. Neurosci. 26:153933–41 [Google Scholar]
  54. Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM. et al. 2000. Functional requirement for class I MHC in CNS development and plasticity. Science 290:54992155–59 [Google Scholar]
  55. Jang S, Dilger RN, Johnson RW. 2010. Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J. Nutr. 140:101892–98 [Google Scholar]
  56. Jaskelioff M, Muller FL, Paik J-H, Thomas E, Jiang S. et al. 2011. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469:7328102–6 [Google Scholar]
  57. Kaiser J. 2014. “Rejuvenation factor” in blood turns back the clock in old mice. Science 344:6184570–71 [Google Scholar]
  58. Kang W, Hebert JM. 2015. FGF signaling is necessary for neurogenesis in young mice and sufficient to reverse its decline in old mice. J. Neurosci. 35:2810217–23 [Google Scholar]
  59. Kantarci K, Senjem ML, Lowe VJ, Wiste HJ, Weigand SD. et al. 2010. Effects of age on the glucose metabolic changes in mild cognitive impairment. AJNR Am. J. Neuroradiol. 31:71247–53 [Google Scholar]
  60. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS. et al. 2014. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:6184630–34 [Google Scholar]
  61. Kempermann G. 2015. Activity dependency and aging in the regulation of adult neurogenesis. Cold Spring Harb. Perspect. Biol. 7:11a018929 [Google Scholar]
  62. Kempermann G, Gast D, Gage FH. 2002. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52:2135–43 [Google Scholar]
  63. Khacho M, Clark A, Svoboda DS, Azzi J, MacLaurin JG. et al. 2016. Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell 19:2232–47 [Google Scholar]
  64. Kodali M, Megahed T, Mishra V, Shuai B, Hattiangady B, Shetty AK. 2016. Voluntary running exercise-mediated enhanced neurogenesis does not obliterate retrograde spatial memory. J. Neurosci. 36:318112–22 [Google Scholar]
  65. Kohman RA, Rodriguez-Zas SL, Southey BR, Kelley KW, Dantzer R, Rhodes JS. 2011. Voluntary wheel running reverses age-induced changes in hippocampal gene expression. PLOS ONE 6:8e22654 [Google Scholar]
  66. Kuipers SD, Schroeder JE, Trentani A. 2015. Changes in hippocampal neurogenesis throughout early development. Neurobiol. Aging 36:1365–79 [Google Scholar]
  67. Kumar A, Rani A, Tchigranova O, Lee W-H, Foster TC. 2012. Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology. Neurobiol. Aging 33:4828.e1–e17 [Google Scholar]
  68. Lazarczyk MJ, Kemmler JE, Eyford BA, Short JA, Varghese M. et al. 2016. Major histocompatibility complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain. Sci. Rep. 6:26199 [Google Scholar]
  69. Lee H, Brott BK, Kirkby LA, Adelson JD, Cheng S. et al. 2014. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509:7499195–200 [Google Scholar]
  70. Lee H-K, Takamiya K, Han J-S, Man H, Kim C-H. et al. 2003. Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:5631–43 [Google Scholar]
  71. Lee J, Giordano S, Zhang J. 2012. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J. 441:2523–40 [Google Scholar]
  72. Levenson JM, Roth TL, Lubin FD, Miller CA, Huang I-C. et al. 2006. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J. Biol. Chem. 281:2315763–73 [Google Scholar]
  73. Levy AD, Omar MH, Koleske AJ. 2014. Extracellular matrix control of dendritic spine and synapse structure and plasticity in adulthood. Front. Neuroanat. 8:116 [Google Scholar]
  74. Lezi E, Burns JM, Swerdlow RH. 2014. Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation. Neurobiol. Aging 35:112574–83 [Google Scholar]
  75. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR. 2001. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107:4603–13 [Google Scholar]
  76. Ling D, Salvaterra PM. 2011. Brain aging and Aβ1–42 neurotoxicity converge via deterioration in autophagy-lysosomal system: a conditional Drosophila model linking Alzheimer's neurodegeneration with aging. Acta Neuropathol 121:2183–91 [Google Scholar]
  77. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF. et al. 2010. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. PNAS 107:3214164–69 [Google Scholar]
  78. Liu P, Smith PF, Darlington CL. 2008. Glutamate receptor subunits expression in memory-associated brain structures: regional variations and effects of aging. Synapse 62:11834–41 [Google Scholar]
  79. Long JM, Kalehua AN, Muth NJ, Calhoun ME, Jucker M. et al. 1998. Stereological analysis of astrocyte and microglia in aging mouse hippocampus. Neurobiol. Aging 19:5497–503 [Google Scholar]
  80. Lopes KO, Sparks DL, Streit WJ. 2008. Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 56:101048–60 [Google Scholar]
  81. Lu CB, Vreugdenhil M, Toescu EC. 2012. The effect of aging-associated impaired mitochondrial status on kainate-evoked hippocampal gamma oscillations. Neurobiol. Aging 33:112692–703 [Google Scholar]
  82. Lukiw WJ. 2004. Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum of stress-related signaling. Neurochem. Res. 29:61287–97 [Google Scholar]
  83. Maass A, Düzel S, Goerke M, Becke A, Sobieray U. et al. 2015. Vascular hippocampal plasticity after aerobic exercise in older adults. Mol. Psychiatry 20:5585–93 [Google Scholar]
  84. Markham JA, McKian KP, Stroup TS, Juraska JM. 2005. Sexually dimorphic aging of dendritic morphology in CA1 of hippocampus. Hippocampus 15:197–103 [Google Scholar]
  85. Marschallinger J, Schäffner I, Klein B, Gelfert R, Rivera FJ. et al. 2015. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat. Commun. 6:8466 [Google Scholar]
  86. Mayer JL, Klumpers L, Maslam S, de Kloet ER, Joels M, Lucassen PJ. 2006. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosterone-induced reduction of adult hippocampal neurogenesis. J. Neuroendocrinol. 18:8629–31 [Google Scholar]
  87. Merrill DA, Karim R, Darraq M, Chiba AA, Tuszynski MH. 2003. Hippocampal cell genesis does not correlate with spatial learning ability in aged rats. J. Comp. Neurol. 459:2201–7 [Google Scholar]
  88. McConnell MJ, Huang YH, Datwani A, Shatz CJ. 2009. H2-Kb and H2-Db regulate cerebellar long-term depression and limit motor learning. PNAS 106:166784–89 [Google Scholar]
  89. Miller CA, Sweatt JD. 2007. Covalent modification of DNA regulates memory formation. Neuron 53:6857–69 [Google Scholar]
  90. Miranda CJ, Braun L, Jiang Y, Hester ME, Zhang L. et al. 2012. Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell 11:3542–52 [Google Scholar]
  91. Monje ML, Toda H, Palmer TD. 2003. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:56511760–65 [Google Scholar]
  92. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP. et al. 2015. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85:2296–302 [Google Scholar]
  93. Moon HY, Becke A, Berron D, Becker B, Sah N. et al. 2016. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24:2332–40 [Google Scholar]
  94. Morgenstern NA, Lombardi G, Schinder AF. 2008. Newborn granule cells in the ageing dentate gyrus. J. Physiol. 586:163751–57 [Google Scholar]
  95. Mostany R, Anstey JE, Crump KL, Maco B, Knott G, Portera-Cailliau C. 2013. Altered synaptic dynamics during normal brain aging. J. Neurosci. 33:94094–104 [Google Scholar]
  96. Mouton PR, Long JM, Lei D-L, Howard V, Jucker M. et al. 2002. Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res 956:130–35 [Google Scholar]
  97. Moyer JR, Brown TH. 2006. Impaired trace and contextual fear conditioning in aged rats. Behav. Neurosci. 120:3612–24 [Google Scholar]
  98. Navarro A, López-Cepero JM, Bández MJ, Sánchez-Pino M-J, Gómez C. et al. 2008. Hippocampal mitochondrial dysfunction in rat aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294:2R501–9 [Google Scholar]
  99. Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y. 2004. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J. Neurosci. 24:357648–53 [Google Scholar]
  100. Niewoehner B, Single FN, Hvalby O, Jensen V, Meyer zum Alten Borgloh S. et al. 2007. Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus. Eur. J. Neurosci. 25:3837–46 [Google Scholar]
  101. Niibori Y, Yu T-S, Epp JR, Akers KG, Josselyn SA, Frankland PW. 2012. Suppression of adult neurogenesis impairs population coding of similar contexts in hippocampal CA3 region. Nat. Commun. 3:1253 [Google Scholar]
  102. Norris CM, Korol DL, Foster TC. 1996. Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J. Neurosci. 16:175382–92 [Google Scholar]
  103. Oberauer K, Wendland M, Kliegl R. 2003. Age differences in working memory—the roles of storage and selective access. Mem. Cogn. 31:4563–69 [Google Scholar]
  104. O'Callaghan RM, Griffin EW, Kelly AM. 2009. Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampus. Hippocampus 19:101019–29 [Google Scholar]
  105. Okamoto M, Inoue K, Iwamura H, Terashima K, Soya H. et al. 2011. Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J 25:103570–82 [Google Scholar]
  106. Oliveira AMM, Hemstedt TJ, Bading H. 2012. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nat. Neurosci. 15:81111–13 [Google Scholar]
  107. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR. et al. 2013. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:71596–609 [Google Scholar]
  108. Pavlopoulos E, Jones S, Kosmidis S, Close M, Kim C. et al. 2013. Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci. Transl. Med. 5:200200ra115 [Google Scholar]
  109. Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S. et al. 2010. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:5979753–56 [Google Scholar]
  110. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R. et al. 2007. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. PNAS 104:135638–43 [Google Scholar]
  111. Rao MS, Hattiangady B, Shetty AK. 2006. The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 5:6545–58 [Google Scholar]
  112. Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD. et al. 2004. Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 25:3311–14 [Google Scholar]
  113. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM. et al. 2011. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31:4516241–50 [Google Scholar]
  114. Rosenzweig ES, Rao G, McNaughton BL, Barnes CA. 1997. Role of temporal summation in age-related long-term potentiation-induction deficits. Hippocampus 7:5549–58 [Google Scholar]
  115. Sahay A, Scobie KN, Hill AS, O'Carroll CM, Kheirbek MA. et al. 2011. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:7344466–70 [Google Scholar]
  116. Sanchis-Gomar F, Alis R, Lippi G. 2015. Circulating irisin detection: Does it really work?. Trends Endocrinol. Metab. 26:7335–36 [Google Scholar]
  117. Sato Y, Yamanaka H, Toda T, Shinohara Y, Endo T. 2005. Comparison of hippocampal synaptosome proteins in young-adult and aged rats. Neurosci. Lett. 382:1–222–26 [Google Scholar]
  118. Seib DRM, Corsini NS, Ellwanger K, Plaas C, Mateos A. et al. 2013. Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Stem Cell 12:2204–14 [Google Scholar]
  119. Seki T, Arai Y. 1995. Age-related production of new granule cells in the adult dentate gyrus. NeuroReport 6:182479–82 [Google Scholar]
  120. Shatz C. 2009. MHC class I: an unexpected role in neuronal plasticity. Neuron 64:140–45 [Google Scholar]
  121. Shehata M, Matsumura H, Okubo-Suzuki R, Ohkawa N, Inokuchi K. 2012. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci. 32:3010413–22 [Google Scholar]
  122. Shetty AK, Hattiangady B, Shetty GA. 2005. Stem/progenitor cell proliferation factors FGF-2, IGF-1, and VEGF exhibit early decline during the course of aging in the hippocampus: role of astrocytes. Glia 51:3173–86 [Google Scholar]
  123. Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S. et al. 2015. Complement C3-deficient mice fail to display age-related hippocampal decline. J. Neurosci. 35:3813029–42 [Google Scholar]
  124. Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G. et al. 2010. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:4483–95 [Google Scholar]
  125. Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K. 2007. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55:4412–24 [Google Scholar]
  126. Sinha M, Jang YC, Oh J, Khong D, Wu EY. et al. 2014. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:6184649–52 [Google Scholar]
  127. Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E. et al. 2016. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife 5:e15092 [Google Scholar]
  128. Smith LK, He Y, Park J-S, Bieri G, Snethlage CE. et al. 2015. β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat. Med. 21:8932–37 [Google Scholar]
  129. Soto I, Graham LC, Richter HJ, Simeone SN, Radell JE. et al. 2015. APOE stabilization by exercise prevents aging neurovascular dysfunction and complement induction. PLOS Biol 13:10e1002279 [Google Scholar]
  130. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M. et al. 2013. Dynamics of hippocampal neurogenesis in adult humans. Cell 153:61219–27 [Google Scholar]
  131. Speisman RB, Kumar A, Rani A, Foster TC, Ormerod BK. 2013. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav. Immun. 28:25–43 [Google Scholar]
  132. Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA. et al. 2013. A dramatic increase of C1q protein in the CNS during normal aging. J. Neurosci. 33:3313460–74 [Google Scholar]
  133. Stilling RM, Fischer A. 2011. The role of histone acetylation in age-associated memory impairment and Alzheimer's disease. Neurobiol. Learn. Mem. 96:119–26 [Google Scholar]
  134. Streit WJ. 2006. Microglial senescence: Does the brain's immune system have an expiration date?. Trends Neurosci 29:9506–10 [Google Scholar]
  135. Szulwach KE, Li X, Li Y, Song C-X, Wu H. et al. 2011. 5-Hmc–mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat. Neurosci. 14:121607–16 [Google Scholar]
  136. Tack W, Wree A, Schleicher A. 1989. Local cerebral glucose utilization in the hippocampus of old rats. Histochemistry 92:5413–19 [Google Scholar]
  137. Udeochu JC, Shea JM, Villeda SA. 2016. Microglia communication: parallels between aging and Alzheimer's disease. Clin. Exp. Neuroimmunol. 7:2114–25 [Google Scholar]
  138. van Praag H. 2005. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25:388680–85 [Google Scholar]
  139. VanGuilder HD, Yan H, Farley JA, Sonntag WE, Freeman WM. 2010. Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome. J. Neurochem. 113:61577–88 [Google Scholar]
  140. Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B. et al. 2016. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534:7608538–43 [Google Scholar]
  141. Végh MJ, Rausell A, Loos M, Heldring CM, Jurkowski W. et al. 2014. Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline. Mol. Cell Proteom. 13:112975–85 [Google Scholar]
  142. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M. et al. 2011. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:736290–94 [Google Scholar]
  143. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI. et al. 2014. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20:6659–63 [Google Scholar]
  144. Volianskis A, France G, Jensen MS, Bortolotto ZA, Jane DE, Collingridge GL. 2015. Long-term potentiation and the role of N-methyl-d-aspartate receptors. Brain Res 1621:5–16 [Google Scholar]
  145. Voss MW, Prakash RS, Erickson KI, Basak C, Chaddock L. et al. 2010. Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front. Aging Neurosci. 2:32 [Google Scholar]
  146. Vukovic J, Colditz MJ, Blackmore DG, Ruitenberg MJ, Bartlett PF. 2012. Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J. Neurosci. 32:196435–43 [Google Scholar]
  147. Weinreb O, Drigues N, Sagi Y, Reznick AZ, Amit T, Youdim MBH. 2007. The application of proteomics and genomics to the study of age-related neurodegeneration and neuroprotection. Antioxid. Redox Signal. 9:2169–79 [Google Scholar]
  148. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J. et al. 2013. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 18:5649–59 [Google Scholar]
  149. Wu MV, Luna VM, Hen R. 2015. Running rescues a fear-based contextual discrimination deficit in aged mice. Front. Syst. Neurosci. 9:114 [Google Scholar]
  150. Yanai S, Endo S. 2016. Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8). Behav. Brain Res. 308:187–95 [Google Scholar]
  151. Yang Y-J, Chen H-B, Wei B, Wang W, Zhou P-L. et al. 2015. Cognitive decline is associated with reduced surface GluR1 expression in the hippocampus of aged rats. Neurosci. Lett. 591:176–81 [Google Scholar]
  152. Yao B, Christian KM, He C, Jin P, Ming G-L, Song H. 2016. Epigenetic mechanisms in neurogenesis. Nat. Rev. Neuro 17:9537–49 [Google Scholar]
  153. Yousef H, Conboy MJ, Morgenthaler A, Schlesinger C, Bugaj L. et al. 2015. Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget 6:1411959–78 [Google Scholar]
  154. Zhang R-R, Cui Q-Y, Murai K, Lim YC, Smith ZD. et al. 2013. Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell 13:2237–45 [Google Scholar]
  155. Ziv Y, Ron N, Butovsky O, Landa G, Sudai E. et al. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9:2268–75 [Google Scholar]
/content/journals/10.1146/annurev-neuro-072116-031357
Loading
/content/journals/10.1146/annurev-neuro-072116-031357
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error