Skip to main content Accessibility help
Hostname: page-component-cd4964975-96cn4 Total loading time: 0 Render date: 2023-03-31T23:35:00.625Z Has data issue: true Feature Flags: { "useRatesEcommerce": false } hasContentIssue true

Chapter 3 - Cellular and Molecular Mechanisms for Age-Related Cognitive Decline

Published online by Cambridge University Press:  30 November 2019

Kenneth M. Heilman
University of Florida
Stephen E. Nadeau
University of Florida
Get access


Aging is often associated with a progressive decline of cognitive functions, due in part to the susceptibility of specific brain regions to stressors of aging. However, chronological age is a poor predictor of cognition. Cognitive decline is variable in terms of onset and progression, suggesting that biological age, due to differences in biological mechanisms that regulate vulnerability, is a better predictor of cognitive decline. As with humans, animal models exhibit variability in age-related cognitive decline, and this variability has been employed to determine biomarkers and mechanisms of cognitive impairment. Based on these animal models, theories of age-related cognitive decline have evolved. Recent work has focused on senescent physiology, rather than cell death associated with neurodegenerative disease. The results suggest that age-related alterations in redox stress modify Ca2+ regulation to alter learning and memory mechanisms, as well as signaling cascades from the synapse to the nucleus. Furthermore, the stressors of aging, senescent physiology, and environmental factors interact with epigenetic mechanisms contributing variability in gene transcription, resulting in variability in resiliency, onset, and the progression of the aging phenotype.

Publisher: Cambridge University Press
Print publication year: 2019

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.)


de Flores, R, La Joie, R, Chetelat, G. Structural imaging of hippocampal subfields in healthy aging and Alzheimer’s disease. Neuroscience. 2015;309:2950.CrossRefGoogle ScholarPubMed
Kerchner, GA, Bernstein, JD, Fenesy, MC, Deutsch, GK, Saranathan, M, Zeineh, MM, et al. Shared vulnerability of two synaptically-connected medial temporal lobe areas to age and cognitive decline: a seven tesla magnetic resonance imaging study. J Neurosci. 2013;33(42):16666–72.CrossRefGoogle ScholarPubMed
Kirchhoff, BA, Gordon, BA, Head, D. Prefrontal gray matter volume mediates age effects on memory strategies. Neuroimage. 2014;90:326–34.CrossRefGoogle ScholarPubMed
Raz, N, Gunning, FM, Head, D, Dupuis, JH, McQuain, J, Briggs, SD, et al. Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex. 1997;7(3):268–82.CrossRefGoogle ScholarPubMed
Salat, DH, Buckner, RL, Snyder, AZ, Greve, DN, Desikan, RS, Busa, E, et al. Thinning of the cerebral cortex in aging. Cereb Cortex. 2004;14(7):721–30.CrossRefGoogle Scholar
Wolf, D, Fischer, FU, de Flores, R, Chetelat, G, Fellgiebel, A. Differential associations of age with volume and microstructure of hippocampal subfields in healthy older adults. Hum Brain Mapp. 2015;36(10):3819–31.CrossRefGoogle ScholarPubMed
Raz, N, Ghisletta, P, Rodrigue, KM, Kennedy, KM, Lindenberger, U. Trajectories of brain aging in middle-aged and older adults: regional and individual differences. Neuroimage. 2010;51(2):501–11.CrossRefGoogle ScholarPubMed
Jackson, TC, Rani, A, Kumar, A, Foster, TC. Regional hippocampal differences in AKT survival signaling across the lifespan: implications for CA1 vulnerability with aging. Cell Death Differ. 2009;16(3):439–48.CrossRefGoogle ScholarPubMed
McEwen, BS, Morrison, JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79(1):1629.CrossRefGoogle ScholarPubMed
Wang, X, Michaelis, EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci. 2010;2:12.Google Scholar
Abd El Mohsen, MM, Iravani, MM, Spencer, JP, Rose, S, Fahim, AT, Motawi, TM, et al. Age-associated changes in protein oxidation and proteasome activities in rat brain: modulation by antioxidants. Biochem Biophys Res Commun. 2005;336(2):386–91.CrossRefGoogle ScholarPubMed
Dominguez, M, de Oliveira, E, Odena, MA, Portero, M, Pamplona, R, Ferrer, I. Redox proteomic profiling of neuroketal-adducted proteins in human brain: regional vulnerability at middle age increases in the elderly. Free Radic Biol Med. 2016;95:115.CrossRefGoogle ScholarPubMed
Horvath, S, Mah, V, Lu, AT, Woo, JS, Choi, OW, Jasinska, AJ, et al. The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY). 2015;7(5):294306.CrossRefGoogle ScholarPubMed
Kumar, A, Gibbs, JR, Beilina, A, Dillman, A, Kumaran, R, Trabzuni, D, et al. Age-associated changes in gene expression in human brain and isolated neurons. Neurobiol Aging. 2013;34(4):1199–209.CrossRefGoogle ScholarPubMed
Ianov, L, De Both, M, Chawla, MK, Rani, A, Kennedy, AJ, Piras, I, et al. Hippocampal transcriptomic profiles: subfield vulnerability to age and cognitive impairment. Front Aging Neurosci. 2017;9:383.CrossRefGoogle ScholarPubMed
Foster, TC. Biological markers of age-related memory deficits: treatment of senescent physiology. CNS Drugs. 2006;20(2):153–66.CrossRefGoogle ScholarPubMed
Febo, M, Foster, TC. Preclinical magnetic resonance imaging and spectroscopy studies of memory, aging, and cognitive decline. Front Aging Neurosci. 2016;8:158.CrossRefGoogle ScholarPubMed
Goh, JO, An, Y, Resnick, SM. Differential trajectories of age-related changes in components of executive and memory processes. Psychol Aging. 2012;27(3):707–19.CrossRefGoogle ScholarPubMed
McAvinue, LP, Habekost, T, Johnson, KA, Kyllingsbaek, S, Vangkilde, S, Bundesen, C, et al. Sustained attention, attentional selectivity, and attentional capacity across the lifespan. Atten Percept Psychophys. 2012;74(8):1570–82.CrossRefGoogle ScholarPubMed
Guidi, M, Kumar, A, Foster, TC. Impaired attention and synaptic senescence of the prefrontal cortex involves redox regulation of NMDA receptors. J Neurosci. 2015;35(9):3966–77.CrossRefGoogle ScholarPubMed
Jones, DN, Barnes, JC, Kirkby, DL, Higgins, GA. Age-associated impairments in a test of attention: evidence for involvement of cholinergic systems. J Neurosci. 1995;15(11):7282–92.CrossRefGoogle Scholar
Fortenbaugh, FC, DeGutis, J, Germine, L, Wilmer, JB, Grosso, M, Russo, K, et al. Sustained attention across the life span in a sample of 10,000: dissociating ability and strategy. Psychol Sci. 2015;26(9):1497–510.CrossRefGoogle Scholar
Bimonte, HA, Nelson, ME, Granholm, AC. Age-related deficits as working memory load increases: relationships with growth factors. Neurobiol Aging. 2003;24(1):3748.CrossRefGoogle ScholarPubMed
Bopp, KL, Verhaeghen, P. Aging and verbal memory span: a meta-analysis. J Gerontol B Psychol Sci Soc Sci. 2005;60(5):P223–33.CrossRefGoogle ScholarPubMed
Brockmole, JR, Logie, RH. Age-related change in visual working memory: a study of 55,753 participants aged 8–75. Front Psychol. 2013;4:12.CrossRefGoogle ScholarPubMed
Dellu-Hagedorn, F, Trunet, S, Simon, H. Impulsivity in youth predicts early age-related cognitive deficits in rats. Neurobiol Aging. 2004;25(4):525–37.CrossRefGoogle ScholarPubMed
Moss, MB, Killiany, RJ, Lai, ZC, Rosene, DL, Herndon, JG. Recognition memory span in rhesus monkeys of advanced age. Neurobiol Aging. 1997;18(1):1319.CrossRefGoogle ScholarPubMed
Tapp, PD, Siwak, CT, Estrada, J, Holowachuk, D, Milgram, NW. Effects of age on measures of complex working memory span in the beagle dog (Canis familiaris) using two versions of a spatial list learning paradigm. Learn Mem. 2003;10(2):148–60.CrossRefGoogle ScholarPubMed
Robbins, TW, James, M, Owen, AM, Sahakian, BJ, Lawrence, AD, McInnes, L, et al. A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge Neuropsychological Test Automated Battery. J Int Neuropsychol Soc. 1998;4(5):474–90.CrossRefGoogle Scholar
Rhodes, MG. Age-related differences in performance on the Wisconsin card sorting test: a meta-analytic review. Psychology Aging. 2004;19(3):482–94.CrossRefGoogle ScholarPubMed
Fisk, JE, Sharp, CA. Age-related impairment in executive functioning: updating, inhibition, shifting, and access. J Clin Exp Neuropsychol. 2004;26(7):874–90.CrossRefGoogle Scholar
Ianov, L, Rani, A, Beas, BS, Kumar, A, Foster, TC. Transcription profile of aging and cognition-related genes in the medial prefrontal cortex. Front Aging Neurosci. 2016;8:113.CrossRefGoogle ScholarPubMed
Small, GW. What we need to know about age related memory loss. BMJ. 2002;324(7352):1502–5.CrossRefGoogle ScholarPubMed
Cansino, S. Episodic memory decay along the adult lifespan: a review of behavioral and neurophysiological evidence. Int J Psychophysiol. 2009;71(1):64–9.CrossRefGoogle ScholarPubMed
Uttl, B, Graf, P. Episodic spatial memory in adulthood. Psychol Aging. 1993;8(2):257–73.CrossRefGoogle ScholarPubMed
Nyberg, L, Lovden, M, Riklund, K, Lindenberger, U, Backman, L. Memory aging and brain maintenance. Trends Cogn Sci. 2012;16(5):292305.CrossRefGoogle ScholarPubMed
Foster, TC. Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity. Prog Neurobiol. 2012;96(3):283303.CrossRefGoogle ScholarPubMed
Khachaturian, ZS. Hypothesis on the regulation of cytosol calcium concentration and the aging brain. Neurobiol Aging. 1987;8(4):345–6.CrossRefGoogle ScholarPubMed
Michaelis, ML, Johe, K, Kitos, TE. Age-dependent alterations in synaptic membrane systems for Ca2+ regulation. Mech Ageing Dev. 1984;25(1–2):215–25.CrossRefGoogle ScholarPubMed
Landfield, PW, Pitler, TA. Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science. 1984;226(4678):1089–92.CrossRefGoogle ScholarPubMed
Rapp, PR, Gallagher, M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA. 1996;93(18):9926–30.CrossRefGoogle ScholarPubMed
West, MJ, Coleman, PD, Flood, DG, Troncoso, JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet. 1994;344(8925):769–72.CrossRefGoogle ScholarPubMed
Barnes, CA, McNaughton, BL. An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behav Neurosci. 1985;99(6):1040–8.CrossRefGoogle ScholarPubMed
Foster, TC, Kumar, A. Susceptibility to induction of long-term depression is associated with impaired memory in aged Fischer 344 rats. Neurobiol Learn Mem. 2007;87(4):522–35.CrossRefGoogle ScholarPubMed
Norris, CM, Korol, DL, Foster, TC. Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J Neurosci. 1996;16(17):5382–92.CrossRefGoogle ScholarPubMed
Kumar, A, Foster, TC. Linking redox regulation of NMDAR synaptic function to cognitive decline during aging. J Neurosci. 2013;33(40):15710–15.CrossRefGoogle ScholarPubMed
Elman, JA, Oh, H, Madison, CM, Baker, SL, Vogel, JW, Marks, SM, et al. Neural compensation in older people with brain amyloid-beta deposition. Nat Neurosci. 2014;17(10):1316–18.CrossRefGoogle ScholarPubMed
O’Brien, JL, O’Keefe, KM, LaViolette, PS, DeLuca, AN, Blacker, D, Dickerson, BC, et al. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology. 2010;74(24):1969–76.Google ScholarPubMed
Foster, TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell. 2007;6(3):319–25.CrossRefGoogle ScholarPubMed
Bodhinathan, K, Kumar, A, Foster, TC. Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II. J Neurosci. 2010;30(5):1914–24.CrossRefGoogle ScholarPubMed
Foster, TC, Norris, CM. Age-associated changes in Ca(2+)-dependent processes: relation to hippocampal synaptic plasticity. Hippocampus. 1997;7(6):602–12.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Kumar, A, Foster, TC. Enhanced long-term potentiation during aging is masked by processes involving intracellular calcium stores. J Neurophysiol. 2004;91(6):2437–44.CrossRefGoogle ScholarPubMed
Bodhinathan, K, Kumar, A, Foster, TC. Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: role for ryanodine receptor mediated calcium signaling. J Neurophysiol. 2010;104(5):2586–93.CrossRefGoogle ScholarPubMed
Kumar, A, Foster, TC. Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging. Brain Res. 2005;1031(1):125–8.CrossRefGoogle ScholarPubMed
Homayoun, H, Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27(43):11496–500.CrossRefGoogle ScholarPubMed
Porges, EC, Woods, AJ, Edden, RA, Puts, NA, Harris, AD, Chen, H, et al. Frontal gamma-aminobutyric acid concentrations are associated with cognitive performance in older adults. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2(1):3844.CrossRefGoogle ScholarPubMed
Morgan, CJ, Curran, HV. Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology (Berl). 2006;188(4):408–24.CrossRefGoogle ScholarPubMed
Forette, F, Seux, ML, Staessen, JA, Thijs, L, Babarskiene, MR, Babeanu, S, et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002;162(18):2046–52.CrossRefGoogle ScholarPubMed
Lovell, MA, Abner, E, Kryscio, R, Xu, L, Fister, SX, Lynn, BC. Calcium channel blockers, progression to dementia, and effects on amyloid beta peptide production. Oxid Med Cell Longev. 2015;2015:787805.CrossRefGoogle ScholarPubMed
Trompet, S, Westendorp, RG, Kamper, AM, de Craen, AJ. Use of calcium antagonists and cognitive decline in old age. The Leiden 85-plus study. Neurobiol Aging. 2008;29(2):306–8.CrossRefGoogle ScholarPubMed
Barnes, CA. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol. 1979;93(1):74104.CrossRefGoogle ScholarPubMed
Daselaar, SM, Iyengar, V, Davis, SW, Eklund, K, Hayes, SM, Cabeza, RE. Less wiring, more firing: low-performing older adults compensate for impaired white matter with greater neural activity. Cereb Cortex. 2015;25(4):983–90.CrossRefGoogle ScholarPubMed
Kumar, A, Foster, TC. Neurophysiology of old neurons and synapses. In: Riddle, DR, editor. Brain Aging: Models, Methods, and Mechanisms. Frontiers in Neuroscience. Boca Raton, FL, 2007.Google ScholarPubMed
Neuman, KM, Molina-Campos, E, Musial, TF, Price, AL, Oh, KJ, Wolke, ML, et al. Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. Brain Struct Funct. 2015;220(6):3143–65.CrossRefGoogle ScholarPubMed
Mormino, EC, Brandel, MG, Madison, CM, Marks, S, Baker, SL, Jagust, WJ. Aβ deposition in aging is associated with increases in brain activation during successful memory encoding. Cereb Cortex. 2012;22(8):1813–23.CrossRefGoogle ScholarPubMed
Kennedy, KM, Rodrigue, KM, Bischof, GN, Hebrank, AC, Reuter-Lorenz, PA, Park, DC. Age trajectories of functional activation under conditions of low and high processing demands: an adult lifespan fMRI study of the aging brain. Neuroimage. 2015;104:2134.CrossRefGoogle ScholarPubMed
Reuter-Lorenz, PA, Park, DC. Human neuroscience and the aging mind: a new look at old problems. J Gerontol B Psychol Sci Soc Sci. 2010;65(4):405–15.Google Scholar
Davis, SW, Dennis, NA, Daselaar, SM, Fleck, MS, Cabeza, R. Que PASA? The posterior-anterior shift in aging. Cereb Cortex. 2008;18(5):1201–9.CrossRefGoogle Scholar
Oberman, L, Pascual-Leone, A. Changes in plasticity across the lifespan: cause of disease and target for intervention. Prog Brain Res. 2013;207:91120.CrossRefGoogle ScholarPubMed
Kumar, A, Yegla, B, Foster, TC. Redox signaling in neurotransmission and cognition during aging. Antioxid Redox Signal. 2018;28:17241745.CrossRefGoogle ScholarPubMed
Harman, D. Aging and oxidative stress. J Int Fed Clin Chem. 1998;10(1):24–7.Google ScholarPubMed
Lee, WH, Kumar, A, Rani, A, Foster, TC. Role of antioxidant enzymes in redox regulation of N-methyl-D-aspartate receptor function and memory in middle-aged rats. Neurobiol Aging. 2014;35(6):1459–68.CrossRefGoogle ScholarPubMed
Lee, WH, Kumar, A, Rani, A, Herrera, J, Xu, J, Someya, S, et al. Influence of viral vector-mediated delivery of superoxide dismutase and catalase to the hippocampus on spatial learning and memory during aging. Antioxid Redox Signal. 2012;16(4):339–50.CrossRefGoogle ScholarPubMed
Streit, WJ, Xue, QS, Tischer, J, Bechmann, I. Microglial pathology. Acta Neuropathol Commun. 2014;2:142.CrossRefGoogle Scholar
Rafnsson, SB, Deary, IJ, Smith, FB, Whiteman, MC, Rumley, A, Lowe, GD, et al. Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc. 2007;55(5):700–7.CrossRefGoogle ScholarPubMed
Scheinert, RB, Asokan, A, Rani, A, Kumar, A, Foster, TC, Ormerod, BK. Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats. Brain Behav Immun. 2015;49:216–32.CrossRefGoogle ScholarPubMed
Bean, LA, Ianov, L, Foster, TC. Estrogen receptors, the hippocampus, and memory. Neuroscientist. 2014;20(5):534–45.CrossRefGoogle ScholarPubMed
Foster, TC. Interaction of rapid signal transduction cascades and gene expression in mediating estrogen effects on memory over the life span. Front Neuroendocrinol. 2005;26(2):5164.CrossRefGoogle ScholarPubMed
Bean, LA, Kumar, A, Rani, A, Guidi, M, Rosario, AM, Cruz, PE, et al. Re-opening the critical window for estrogen therapy. J Neurosci. 2015;35(49):16077–93.CrossRefGoogle ScholarPubMed
Kumar, A, Foster, TC. 17beta-estradiol benzoate decreases the AHP amplitude in CA1 pyramidal neurons. J Neurophysiol. 2002;88(2):621–6.CrossRefGoogle ScholarPubMed
Foster, TC, Sharrow, KM, Kumar, A, Masse, J. Interaction of age and chronic estradiol replacement on memory and markers of brain aging. Neurobiol Aging. 2003;24(6):839–52.CrossRefGoogle ScholarPubMed
Vedder, LC, Bredemann, TM, McMahon, LL. Estradiol replacement extends the window of opportunity for hippocampal function. Neurobiol Aging. 2014;35(10):2183–92.CrossRefGoogle ScholarPubMed
Lopez-Grueso, R, Gambini, J, Abdelaziz, KM, Monleon, D, Diaz, A, El Alami, M, et al. Early, but not late onset estrogen replacement therapy prevents oxidative stress and metabolic alterations caused by ovariectomy. Antioxid Redox Signal. 2014;20(2):236–46.CrossRefGoogle Scholar
Moorthy, K, Sharma, D, Basir, SF, Baquer, NZ. Administration of estradiol and progesterone modulate the activities of antioxidant enzyme and aminotransferases in naturally menopausal rats. Exp Gerontol. 2005;40(4):295302.CrossRefGoogle ScholarPubMed
McCarrey, AC, Resnick, SM. Postmenopausal hormone therapy and cognition. Horm Behav. 2015;74:167–72.CrossRefGoogle ScholarPubMed
Aenlle, KK, Foster, TC. Aging alters the expression of genes for neuroprotection and synaptic function following acute estradiol treatment. Hippocampus. 2010;20(9):1047–60.CrossRefGoogle ScholarPubMed
Blalock, EM, Chen, KC, Sharrow, K, Herman, JP, Porter, NM, Foster, TC, et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci. 2003;23(9):3807–19.CrossRefGoogle ScholarPubMed
Prolla, TA. DNA microarray analysis of the aging brain. Chem Senses. 2002;27(3):299306.CrossRefGoogle ScholarPubMed
VanGuilder, HD, Bixler, GV, Brucklacher, RM, Farley, JA, Yan, H, Warrington, JP, et al. Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation. 2011;8:138.CrossRefGoogle Scholar
Fraga, MF, Ballestar, E, Paz, MF, Ropero, S, Setien, F, Ballestar, ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102(30):10604–9.CrossRefGoogle ScholarPubMed
Starnawska, A, Tan, Q, McGue, M, Mors, O, Borglum, AD, Christensen, K, et al. Epigenome-wide association study of cognitive functioning in middle-aged monozygotic twins. Front Aging Neurosci. 2017;9:413.CrossRefGoogle ScholarPubMed
Leu, YW, Yan, PS, Fan, M, Jin, VX, Liu, JC, Curran, EM, et al. Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res. 2004;64(22):8184–92.CrossRefGoogle ScholarPubMed
Moreno-Piovano, GS, Varayoud, J, Luque, EH, Ramos, JG. Long-term ovariectomy increases BDNF gene methylation status in mouse hippocampus. J Steroid Biochem Mol Biol. 2014;144 Pt B:243–52.CrossRefGoogle ScholarPubMed
Carter, SD, Mifsud, KR, Reul, JM. Distinct epigenetic and gene expression changes in rat hippocampal neurons after Morris water maze training. Front Behav Neurosci. 2015;9:156.CrossRefGoogle ScholarPubMed
Han, Y, Han, D, Yan, Z, Boyd-Kirkup, JD, Green, CD, Khaitovich, P, et al. Stress-associated H3K4 methylation accumulates during postnatal development and aging of rhesus macaque brain. Aging Cell. 2012;11(6):1055–64.CrossRefGoogle ScholarPubMed
Kenworthy, CA, Sengupta, A, Luz, SM, Ver Hoeve, ES, Meda, K, Bhatnagar, S, et al. Social defeat induces changes in histone acetylation and expression of histone modifying enzymes in the ventral hippocampus, prefrontal cortex, and dorsal raphe nucleus. Neuroscience. 2014;264:8898.CrossRefGoogle ScholarPubMed
Oh, JE, Chambwe, N, Klein, S, Gal, J, Andrews, S, Gleason, G, et al. Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment. Transl Psychiatry. 2013;3:e218.CrossRefGoogle ScholarPubMed
Ianov, L, Riva, A, Kumar, A, Foster, TC. DNA methylation of synaptic genes in the prefrontal cortex is associated with aging and age-related cognitive impairment. Front Aging Neurosci. 2017;9:249.CrossRefGoogle ScholarPubMed
Foster, TC, Sharrow, KM, Masse, JR, Norris, CM, Kumar, A. Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci. 2001;21(11):4066–73.CrossRefGoogle ScholarPubMed
Penner, MR, Parrish, RR, Hoang, LT, Roth, TL, Lubin, FD, Barnes, CA. Age-related changes in Egr1 transcription and DNA methylation within the hippocampus. Hippocampus. 2016;26(8):1008–20.CrossRefGoogle ScholarPubMed
Penner, MR, Roth, TL, Chawla, MK, Hoang, LT, Roth, ED, Lubin, FD, et al. Age-related changes in Arc transcription and DNA methylation within the hippocampus. Neurobiol Aging. 2011;32(12):2198–210.CrossRefGoogle ScholarPubMed
Grinan-Ferre, C, Puigoriol-Illamola, D, Palomera-Avalos, V, Perez-Caceres, D, Companys-Alemany, J, Camins, A, et al. Environmental enrichment modified epigenetic mechanisms in SAMP8 mouse hippocampus by reducing oxidative stress and inflammaging and achieving neuroprotection. Front Aging Neurosci. 2016;8:241.CrossRefGoogle ScholarPubMed
Weaver, IC, Champagne, FA, Brown, SE, Dymov, S, Sharma, S, Meaney, MJ, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25(47):11045–54.CrossRefGoogle ScholarPubMed
Zhang, TY, Keown, CL, Wen, X, Li, J, Vousden, DA, Anacker, C, et al. Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus. Nat Commun. 2018;9(1):298.CrossRefGoogle ScholarPubMed
Cechinel, LR, Basso, CG, Bertoldi, K, Schallenberger, B, de Meireles, LC, Siqueira, IR. Treadmill exercise induces age and protocol-dependent epigenetic changes in prefrontal cortex of Wistar rats. Behav Brain Res. 2016;313:82–7.CrossRefGoogle ScholarPubMed
Cosin-Tomas, M, Alvarez-Lopez, MJ, Sanchez-Roige, S, Lalanza, JF, Bayod, S, Sanfeliu, C, et al. Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise. Front Aging Neurosci. 2014;6:51.Google ScholarPubMed
Feil, R. Environmental and nutritional effects on the epigenetic regulation of genes. Mutat Res. 2006;600(1–2):4657.CrossRefGoogle ScholarPubMed
Rani, A, O’Shea, A, Ianov, L, Cohen, RA, Woods, AJ, Foster, TC. miRNA in circulating microvesicles as biomarkers for age-related cognitive decline. Front Aging Neurosci. 2017;9:323.CrossRefGoogle ScholarPubMed
Freedman, JE, Gerstein, M, Mick, E, Rozowsky, J, Levy, D, Kitchen, R, et al. Diverse human extracellular RNAs are widely detected in human plasma. Nat Commun. 2016;7:11106.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the or variations. ‘’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats