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Neurodegeneration During Aging: The Role of Oxidative Stress Through Epigenetic Modifications

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Models, Molecules and Mechanisms in Biogerontology

Abstract

With global rise in elderly population, there is an increase in the incidence of age-related neurological problems. Hence, achieving healthy aging is a great challenge for scientists, medical practitioners, and social workers. Aging is characterized by enormous remarkable changes in the brain at morphological, cellular, biochemical, and physiological levels leading to cognitive impairment. A key player in this process is reactive oxygen species (ROS) which causes intracellular damage leading to progressive loss of control over biological homeostasis, oxidative stress, and thereby degeneration of different neurons in the brain. Such neurodegeneration is a crucial feature of aging as well as age-related neurological disorders. Therefore, understanding the processes leading to aging and associated neurological problems will help to develop the new therapeutic avenues. The cognitive processes during aging and age-associated neurological disorders are regulated by epigenetic modifications of chromatin. The expression of chromatin-modifying enzymes in turn is regulated by various factors including oxidative stress. As antioxidants prevent oxidative stress, this article reviews the role of ROS in accumulation of intracellular damage along with epigenetic modifications during aging and age-associated neurological disorders and suggests that antioxidants may prove beneficial therapies for these pathologies.

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References

  1. Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–1224

    Article  CAS  Google Scholar 

  2. Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581

    Article  CAS  Google Scholar 

  3. Lee CK, Klopp RG, Weindruch R, Prolla TA (1999) Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390–1393

    Article  CAS  Google Scholar 

  4. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction and aging. Science 273:59–63

    Article  CAS  Google Scholar 

  5. Jagust W (2013) Vulnerable neural systems and the borderland of brain aging and neurodegeneration. Neuron Rev 77:219–234

    Article  CAS  Google Scholar 

  6. Cortés-Mendoza J, León-Guerrero SD, Pedraza-Alva G, Pérez-Martínez L (2013) Shaping synaptic plasticity: the role of activity-mediated epigenetic regulation on gene transcription. Int J Dev Neurosci 31:359–369

    Article  Google Scholar 

  7. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One 6:e27265. https://doi.org/10.1371/journal.pone.0027265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gautam A, Wadhwa R, Thakur MK (2013) Involvement of hippocampal Arc in amnesia and its recovery by alcoholic extract of Ashwagandha leaves. Neurobiol Learn Mem 106:177–184

    Article  Google Scholar 

  9. Singh P, Thakur MK (2014) Reduced recognition memory is correlated with decrease in DNA methyltransferase1 and increase in histone deacetylase2 protein expression in old male mice. Biogerontology 15:339–346

    Article  CAS  Google Scholar 

  10. Kumar D, Thakur MK (2014) Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice. AGE 37:17

    Article  Google Scholar 

  11. Konar A, Singh P, Thakur MK (2015) Age-associated cognitive decline: insights into molecular switches and recovery avenues. Aging Dis. https://doi.org/10.14336/AD.2015.1004

    Article  Google Scholar 

  12. Singh P, Konar A, Kumar A, Srivas S, Thakur MK (2015) Hippocampal chromatin modifying enzymes are pivotal for scopolamine-induced synaptic plasticity gene expression changes and memory impairment. J Neurochem 134:642–651

    Article  CAS  Google Scholar 

  13. Kumari A, Singh P, Baghel MS, Thakur MK (2016) Social isolation mediated anxiety like behavior is associated with enhanced expression and regulation of BDNF in the female mouse brain. Physiol Behav 158:34–42

    Article  CAS  Google Scholar 

  14. Thakur MK, Konar A, Kumar D, Baghel MS, Singh P (2016) Recovery of age-related memory loss: hopes and challenges. Topics in Biomedical Gerontology Publisher: Springer, Singapore, pp 267–278

    Google Scholar 

  15. Srivas S, Thakur MK (2016) Epigenetic regulation of neuronal immediate early genes is associated with decline in their expression and memory consolidation in scopolamine-induced amnesic mice. Mol Neurobiol. https://doi.org/10.1007/s12035-016-0047-4

    Article  Google Scholar 

  16. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74

    Article  CAS  Google Scholar 

  17. Mora F, Segovia G, del Arco A (2007) Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev 55:78–88

    Article  CAS  Google Scholar 

  18. Foster TC (2007) Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell 6:319–325

    Article  CAS  Google Scholar 

  19. Foster TC (1999) Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res Brain Res Rev 30:236–249

    Article  CAS  Google Scholar 

  20. Gordeeva AV, Zvyagilskaya RA, Labas YA (2003) Cross-talk between reactive oxygen species and calcium in living cells. Biochemistry (Mosc) 68:1077–1080

    Article  CAS  Google Scholar 

  21. Yan Y, Wei CL, Zhang WR, Cheng HP, Liu J (2006) Cross-talk between calcium and reactive oxygen species signaling. Acta Pharmacol Sin 27:821–826

    Article  CAS  Google Scholar 

  22. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344

    Article  CAS  Google Scholar 

  23. Adam-Vizi V, Chinopoulos C (2006) Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645

    Article  CAS  Google Scholar 

  24. Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB (2007) Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation. Aging Dis 2:242–256

    Google Scholar 

  25. Kasai H (1997) Analysis of a form of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 387:147–163

    Article  CAS  Google Scholar 

  26. Chen JH, Hales CN, Ozanne SE (2007) DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 35:7417–7428

    Article  CAS  Google Scholar 

  27. Barzilai A, Biton S, Shiloh Y (2008) The role of the DNA damage response in neuronal development, organization and maintenance. DNA Repair (Amst) 7:1010–1027

    Article  CAS  Google Scholar 

  28. Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA (2015) DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb Perspect Med 5:a025130

    Article  Google Scholar 

  29. Borgesius NZ, de Waard MC, van der Pluijm I, Omrani A, Zondag GC, van der Horst GT, Melton DW, Hoeijmakers JH, Jaarsma D, Elgersma Y (2011) Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair. J Neurosci 31:12543–12553

    Article  CAS  Google Scholar 

  30. Radaka Z, Martona O, Nagya E, Koltaia E, Goto S (2013) The complex role of physical exercise and reactive oxygen species on brain. J Sport Health Sci 2:87–93

    Article  Google Scholar 

  31. Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147

    Article  CAS  Google Scholar 

  32. Richter C (1992) Reactive oxygen and DNA damage in mitochondria. Mutat Res 275:49–55

    Google Scholar 

  33. Capel F, Rimbert V, Lioger D, Diot A, Rousset P, Mirand PP, Boirie Y, Morio B, Mosoni L (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateral is muscle although oxidative capacity is preserved. Mech Ageing Dev 126:505–511

    Article  CAS  Google Scholar 

  34. Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1366:211–223

    Article  CAS  Google Scholar 

  35. Chinnery PF, Samuels DC, Elson J, Turnbull DM (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360:1323–1325

    Article  CAS  Google Scholar 

  36. Singh KK (2004) Mitochondrial dysfunction is a common phenotype in aging and cancer. Ann N Y Acad Sci 1019:260–264

    Article  CAS  Google Scholar 

  37. Trifunovic A (2006) Mitochondrial DNA and ageing. Biochim Biophys Acta Bioenerg 1757:611–617

    Article  CAS  Google Scholar 

  38. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  CAS  Google Scholar 

  39. Schapira AH (2008) Mitochondrial dysfunction in neurodegenerative diseases. Neurochem Res 33:2502–2509

    Article  CAS  Google Scholar 

  40. Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV (2014) Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 2014:238463

    PubMed  PubMed Central  Google Scholar 

  41. Snigdha S, Smith ED, Prieto GA, Cotman CW (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 28:14–24

    Article  CAS  Google Scholar 

  42. Ball MJ (1977) Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol 37:111–118

    Article  CAS  Google Scholar 

  43. Brizzee KR (1987) Neurons numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol Aging 8:579–580

    Article  CAS  Google Scholar 

  44. Morterá P, Herculano-Houzel S (2012) Age-related neuronal loss in the rat brain starts at the end of adolescence. Front Neuroanat 6:45

    Article  Google Scholar 

  45. Zhao Z, Fan L, Frick KM (2010) Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation. Proc Natl Acad Sci U S A 107:5605–5610

    Article  CAS  Google Scholar 

  46. Wong CC, Mill J, Fernandes C (2011) Drugs and addiction: an introduction to epigenetics. Addiction 106:480–489

    Article  Google Scholar 

  47. Fragou D, Fragou A, Kouidou S, Njau S, Kovatsi L (2011) Epigenetic mechanisms in metal toxicity. Toxicol Mech Methods 21:343–352

    Article  CAS  Google Scholar 

  48. Menke A, Klengel T, Binder EB (2012) Epigenetics, depression and antidepressant treatment. Curr Pharm Des 18:5879–5889

    Article  CAS  Google Scholar 

  49. Cencioni C, Spallotta F, Martelli F, Valente S, Mai A, Zeiher AM, Gaetano C (2013) Oxidative stress and epigenetic regulation in ageing and age-related diseases. Int J Mol Sci 14:17643–17663

    Article  Google Scholar 

  50. Shao C, Li Q, Chen S, Zhang P, Lian J, Hu Q, Sun B, Jin L, Liu S, Wang Z, Zhao H, Jin Z, Liang Z, Li Y, Zheng Q, Zhang Y, Wang J, Zhang G (2014) Epigenetic modification and inheritance in sexual reversal of fish. Genome Res 24:604–615

    Article  CAS  Google Scholar 

  51. Li Y, Mukherjee I, Thum KE, Tanurdzic M, Katari MS, Obertello M, Edwards MB, McCombie WR, Martienssen RA, Coruzzi GM (2015) The histone methyltransferase SDG8 mediates the epigenetic modification of light and carbon responsive genes in plants. Genome Biol 19:16–79

    Google Scholar 

  52. Murphy TM, O’Donovan A, Mullins N, O’Farrelly C, McCann A, Malone K (2015) Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes. Psychiatr Genet 25:71–78

    Article  CAS  Google Scholar 

  53. Gu X, Sun J, Li S, Wu X, Li L (2013) Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Ab production. Neurobiol Aging 34:1069–1079

    Article  CAS  Google Scholar 

  54. Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J (2011) Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging 32:1161–1180

    Article  CAS  Google Scholar 

  55. Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, Steinbusch HW, Coleman PD, Rutten BP, van den Hove DL (2013) Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging 34:2091–2099

    Article  CAS  Google Scholar 

  56. Oliveira AMM, Hemstedt TJ, Bading H (2012) Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nat Neurosci 15:1111–1113

    Article  CAS  Google Scholar 

  57. Morrison LD, Smith DD, Kish SJ (1996) Brain S adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 67:1328–1331

    Article  CAS  Google Scholar 

  58. Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G (2004) Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med 42:1032–1035

    CAS  PubMed  Google Scholar 

  59. Coppedè F (2010) One-carbon metabolism and Alzheimer’s disease: focus on epigenetics. Curr Genomics 11:246–260

    Article  Google Scholar 

  60. Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH (2012) An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–226

    Article  Google Scholar 

  61. Zhao H, Han Z, Ji X, Luo Y (2016) Epigenetic regulation of oxidative stress in ischemic stroke. Aging Dis 7:295–306

    Article  Google Scholar 

  62. Afanas’ev I (2014) Mechanism of superoxide signaling in epigenetic processes: relation to aging and cancer. Age Dis 6:216–227

    Article  Google Scholar 

  63. Fischer LR, Glass JD (2010) Oxidative stress induced by loss of Cu, Zn-superoxide dismutase (SOD1) or superoxide-generating herbicides causes axonal degeneration in mouse DRG cultures. Acta Neuropathol 119:249–259

    Article  CAS  Google Scholar 

  64. Chouliaras L, van den Hove DLA, Kenis G, Keitel S, Hof PR, Os JV, Steinbusch HWM, Schmitz C, Rutten BPF (2012) Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction. Neurobiol Aging 33:1672–1681

    Article  CAS  Google Scholar 

  65. Chouliaras L, van den Hove DLA, Kenis G, Keitel S, Hof PR, Os JV, Steinbusch HWM, Schmitz C, Rutten BPF (2012) Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction. Curr Alzheimer Res 9:536–544

    Article  CAS  Google Scholar 

  66. Anderson OS, Sant KE, Dolinoy DC (2012) Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem 23:853–859

    Article  CAS  Google Scholar 

  67. Dauncey MJ (2014) Nutrition, the brain and cognitive decline: insights from epigenetics. Eur J Clin Nutr 68:1179–1185

    Article  CAS  Google Scholar 

  68. Pogribny IP, Karpf AR, James SR, Melnyk S, Han T, Tryndyak VP (2008) Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet. Brain Res 1237:25–34

    Article  CAS  Google Scholar 

  69. Kim KC, Friso S, Choi SW (2009) DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging. J Nutr Biochem 20:917–926

    Article  CAS  Google Scholar 

  70. Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D’Anselmi F, Coluccia P, Calamandrei G, Scarpa S (2007) B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice. Mol Cell Neurosci 37:731–746

    Article  Google Scholar 

  71. Fuso A, Nicolia V, Ricceri L, Cavallaro RA, Isopi E, Mangia F et al (2012) S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice. Neurobiol Aging 33:1482

    Article  Google Scholar 

  72. Kalani A, Kamat PK, Givvimani S, Brown K, Metreveli N, Tyagi SC, Tyagi N (2014) Nutri-epigenetics ameliorates blood–brain barrier damage and neurodegeneration in hyperhomocysteinemia: role of folic acid. J Mol Neurosci 52:202–215

    Article  CAS  Google Scholar 

  73. Sánchez-Hernándeza D, Poona AN, Kubanta R, Kima H, Huota PSP, Choa CE, Panniaa E, Reza-Lópeza SA, Pausovaa Z, Bazineta RP, Andersona GH (2016) High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring. J Nutr Biochem 27:104–111

    Article  Google Scholar 

  74. He XB, Kim M, Kim SY, Yi SH, Rhee YH, Kim T, Lee EH, Park CH, Dixit S, Harrison FE, Lee SH (2015) Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner. Stem Cells 33:1320–1332

    Article  CAS  Google Scholar 

  75. Chiu S, Woodbury-Farina MA, Shad MU, Husni M, Copen J, Bureau Y, Cernovsky Z, Hou JJ, Rahen H, Terpstra K, Sanchez V, Hategan A, Kaushal M, Campbell R (2014) The role of nutrient-based epigenetic changes in buffering against stress, aging, and Alzheimer’s disease. Psychiatr Clin N Am 37:591–623

    Article  Google Scholar 

  76. Ayissi VBO, Ebrahimi A, Schluesenner H (2014) Epigenetic effects of natural polyphenols: a focus on SIRT1-mediated mechanisms. Mol Nutr Food Res 58:22–32

    Article  CAS  Google Scholar 

  77. Wong YT, Gruber J, Jenner MJ, Ng MPE, Ruan R, Tay FEH (2009) Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: protection by chronic oral intake of resveratrol. Free Radic Biol Med 46:799–809

    Article  CAS  Google Scholar 

  78. Zhu HR, Wang ZY, Zhu XL, Wu XX, Li EG, Xu Y (2010) Icariin protects against brain injury by enhancing SIRT1-dependent PGC-1α expression in experimental stroke. Neuropharmacology 59:70–76

    Article  CAS  Google Scholar 

  79. Longpré F, Garneau P, Christen Y, Ramassamy C (2006) Protection by EGb 761 against beta-amyloid-induced neurotoxicity: involvement of NF-kappaB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation. Free Radic Biol Med 41:1781–1794

    Article  Google Scholar 

  80. Brondino N, Re S, Boldrini A, Cuccomarino A, Lanati N, Barale F, Politi P (2014) Curcumin as a therapeutic agent in dementia: a mini systematic review of human studies. Sci World J. https://doi.org/10.1155/2014/174282

    Article  Google Scholar 

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Acknowledgments

SS and PS are recipients of Senior Research Fellowship from the University Grants Commissions and the Council of Scientific and Industrial Research, India. MSB is a recipient of Junior Research Fellowship from the Department of Biotechnology, India. This work was supported by grants from the Department of Science and Technology, India (DST-P-07-447); Council of Scientific and Industrial Research, India (CSIR-P-25/312); UGC-UPE Focus Area II; UGC-CAS Phase V; and Department of Zoology to MKT.

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  1. Authors Sweta Srivas, Meghraj Singh Baghel and Padmanabh Singh have equally contributed to this chapter.

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  1. Biochemistry and Molecular Biology Laboratory, Centre for Advanced Studies, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India

    Sweta Srivas, Meghraj Singh Baghel, Padmanabh Singh & Mahendra K. Thakur

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  1. Sweta Srivas
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  2. Meghraj Singh Baghel
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  1. School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

    Pramod C. Rath

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Srivas, S., Baghel, M.S., Singh, P., Thakur, M.K. (2019). Neurodegeneration During Aging: The Role of Oxidative Stress Through Epigenetic Modifications. In: Rath, P. (eds) Models, Molecules and Mechanisms in Biogerontology. Springer, Singapore. https://doi.org/10.1007/978-981-13-3585-3_3

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