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Epigenetics of Brain Aging: Lessons from Chemo Brain and Tumor Brain

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Biomarkers of Human Aging

Part of the book series: Healthy Ageing and Longevity ((HAL,volume 10))

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Abstract

The world’s population is rapidly aging. Aging is a complex and multifaceted process of the loss of viability and increase in vulnerability that affects the entire organism, and encompasses a progressive decline on various levels—molecular, cellular, tissue, and organismal. Indeed, both internal and various external environmental factors—such as life style, diet, exercise, smoking, alcohol consumption, as well as exposures to physical, chemical factors, drugs, toxins, and pathogens can contribute to aging processes in the brain as a part of integrated genome and epigenome response orchestrated via altered expression of genes and pathways. It is also apparent that various environmental exposures which affect the brain may influence pathological processes implicated in aging. Moreover, various co-morbidities can impact the brain—such as age-related cardiovascular and other diseases, and cancer. Of the latter, cancer is of particular interest. Here, we discuss the effects of non-CNS tumor growth and chemotherapy on the brain and the effects of these phenomena on brain aging. We introduce the epigenetic theory of chemo and tumor brain, and the role of epigenetic mechanisms in tumor brain, chemo brain, neurodegeneration and aging.

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Abbreviations

4-HNE:

4-hydroxynonenal

5hmC:

5-hydroxymethylcytosine

5mC:

5-methyl-cytosine

BDNF:

Brain-derived neurotrophic factor

CA:

Cornu Ammonis

CNS:

Central nervous system

CPP:

Cyclophosphomide

DG:

Dentate gyrus

DNMT:

DNA methyltransferase

MBD:

Methyl-binding domain

miRNA/miR:

MicroRNA

MMC:

Mitomycin C

NPAS4:

Neuronal PAS domain protein 4

PDX:

Patient derived xenograft

piRNA:

Piwi-interacting RNA

PFC:

Prefrontal cortex

PR + BC:

Progesterone receptor positive breast cancer

siRNA:

Small interfering RNA

TNBC:

Triple negative breast cancer

References

  • Ahles TA (2012) Brain vulnerability to chemotherapy toxicities. Psychooncology 21:1141–1148

    Article  Google Scholar 

  • Ahles TA, Saykin AJ (2002) Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer 3(Suppl 3):S84–S90

    Article  CAS  Google Scholar 

  • Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7:192–201

    Article  CAS  Google Scholar 

  • Ahles TA, Saykin AJ, McDonald BC, Furstenberg CT, Cole BF, Hanscom BS, Mulrooney TJ, Schwartz GN, Kaufman PA (2008) Cognitive function in breast cancer patients prior to adjuvant treatment. Breast Cancer Res Treat 110:143–152

    Article  CAS  Google Scholar 

  • Andres AL, Gong X, Di KJ, Bota DA (2014) Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’ brain? Exp Neurol 255:137–144

    Article  CAS  Google Scholar 

  • Apple AC, Ryals AJ, Alpert KI, Wagner LI, Shih PA, Dokucu M, Cella D, Penedo FJ, Voss JL, Wang L (2017) Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns. Neuroimage Clin 14:685–691

    Article  Google Scholar 

  • Barbato C, Ruberti F, Cogoni C (2009) Searching for MIND: microRNAs in neurodegenerative diseases. J Biomed Biotechnol 2009:871313

    Google Scholar 

  • Briones TL, Woods J (2014) Dysregulation in myelination mediated by persistent neuroinflammation: possible mechanisms in chemotherapy-related cognitive impairment. Brain Behav Immun 35:23–32

    Article  CAS  Google Scholar 

  • Chen Y, Damayanti NP, Irudayaraj J, Dunn K, Zhou FC (2014) Diversity of two forms of DNA methylation in the brain. Front Genet 5:46

    PubMed  PubMed Central  Google Scholar 

  • Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL (2012) Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 18:1954–1965

    Article  CAS  Google Scholar 

  • Dalley RNL, Guillozet-Bongaarts A (2008) Dentate gyrus. Nat Preced

    Google Scholar 

  • Dao T, Cheng RY, Revelo MP, Mitzner W, Tang W (2014) Hydroxymethylation as a novel environmental biosensor. Curr Environ Health Rep 1:1–10

    Article  CAS  Google Scholar 

  • Delgado-Morales R, Agis-Balboa RC, Esteller M, Berdasco M (2017) Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clin Epigenetics 9:67

    Article  Google Scholar 

  • Dietrich J, Prust M, Kaiser J (2015) Chemotherapy, cognitive impairment and hippocampal toxicity. Neuroscience 309:224–232

    Article  CAS  Google Scholar 

  • Downie FP, Mar Fan HG, Houede-Tchen N, Yi Q, Tannock IF (2006) Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patient interview after formal assessment. Psychooncology 15:921–930

    Article  Google Scholar 

  • Esteller M, Herman JG (2002) Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol 196:1–7

    Article  CAS  Google Scholar 

  • Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13:423–430

    Article  CAS  Google Scholar 

  • Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  CAS  Google Scholar 

  • Follin C, Erfurth EM, Johansson A, Latt J, Sundgren PC, Osterberg K, Spulber G, Mannfolk P, Bjorkman-Burtscher IM (2016) Impaired brain metabolism and neurocognitive function in childhood leukemia survivors despite complete hormone supplementation in adulthood. Psychoneuroendocrinology 73:157–165

    Article  CAS  Google Scholar 

  • Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108

    Article  CAS  Google Scholar 

  • Globisch D, Munzel M, Muller M, Michalakis S, Wagner M, Koch S, Bruckl T, Biel M, Carell T (2010) Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS ONE 5:e15367

    Article  CAS  Google Scholar 

  • Group TG (2002) Chemotherapy. In: Gale encyclopedia of cancer

    Google Scholar 

  • Guo JU, Su Y, Zhong C, Ming GL, Song H (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423–434

    Article  CAS  Google Scholar 

  • Hassan MS, Ansari J, Spooner D, Hussain SA (2010) Chemotherapy for breast cancer (review). Oncol Rep 24:1121–1131

    Article  CAS  Google Scholar 

  • Hearps S, Seal M, Anderson V, Mccarthy M, Connellan M, Downie P, De Luca C (2016) The relationship between cognitive and neuroimaging outcomes in children treated for acute lymphoblastic leukemia with chemotherapy only: a systematic review. Pediatr Blood Cancer

    Google Scholar 

  • Hurria A, Somlo G, Ahles T (2007) Renaming “chemobrain”. Cancer Invest 25:373–377

    Article  Google Scholar 

  • Isaev NK, Genrikhs EE, Oborina MV, Stelmashook EV (2018) Accelerated aging and aging process in the brain. Rev Neurosci 29:233–240

    Article  Google Scholar 

  • Isaev NK, Stelmashook EV, Genrikhs EE (2019) Neurogenesis and brain aging. Rev Neurosci

    Google Scholar 

  • Iskandar BJ, Rizk E, Meier B, Hariharan N, Bottiglieri T, Finnell RH, Jarrard DF, Banerjee RV, Skene JH, Nelson A, Patel N, Gherasim C, Simon K, Cook TD, Hogan KJ (2010) Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest 120:1603–1616

    Article  CAS  Google Scholar 

  • Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254

    Article  CAS  Google Scholar 

  • Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080

    Article  CAS  Google Scholar 

  • Kaiser J, Bledowski C, Dietrich J (2014) Neural correlates of chemotherapy-related cognitive impairment. Cortex 54:33–50

    Article  Google Scholar 

  • Kayl AE, Meyers CA (2006) Side-effects of chemotherapy and quality of life in ovarian and breast cancer patients. Curr Opin Obstet Gynecol 18:24–28

    Article  Google Scholar 

  • Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97

    Article  CAS  Google Scholar 

  • Kolb B, Whishaw IQ (2014) An introduction to brain and behavior. Worth Publishers, New York, NY

    Google Scholar 

  • Kolb B, Whishaw IQ (2015) Fundamentals of human neuropsychology. Worth Publishers, a Macmillan Education Imprint, New York

    Google Scholar 

  • Kolb B, Mychasiuk R, Muhammad A, Li Y, Frost DO, Gibb R (2012) Experience and the developing prefrontal cortex. Proc Natl Acad Sci U S A 109(Suppl 2):17186–17193

    Article  CAS  Google Scholar 

  • Kosik KS (2006) The neuronal microRNA system. Nat Rev Neurosci 7:911–920

    Article  CAS  Google Scholar 

  • Koturbash I, Zemp F, Kolb B, Kovalchuk O (2011) Sex-specific radiation-induced microRNAome responses in the hippocampus, cerebellum and frontal cortex in a mouse model. Mutat Res 722:114–118

    Article  CAS  Google Scholar 

  • Koturbash I, Jadavji NM, Kutanzi K, Rodriguez-Juarez R, Kogosov D, Metz GAS, Kovalchuk O (2016) Fractionated low-dose exposure to ionizing radiation leads to DNA damage, epigenetic dysregulation, and behavioral impairment. Environ Epigenet 2:dvw025

    Google Scholar 

  • Kovalchuk A, Kolb B (2017) Chemo brain: from discerning mechanisms to lifting the brain fog—an aging connection. Cell Cycle 16:1345–1349

    Article  CAS  Google Scholar 

  • Kovalchuk I, Kovalchuk O (2012) Epigenetics in health and disease. FT Press, Upper Saddle River, NJ

    Google Scholar 

  • Kovalchuk A, Mychasiuk R, Muhammad A, Hossain S, Ilnytskyy S, Ghose A, Kirkby C, Ghasroddashti E, Kovalchuk O, Kolb B (2016a) Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour. Oncotarget 7:4385–4398

    Article  Google Scholar 

  • Kovalchuk A, Mychasiuk R, Muhammad A, Hossain S, Ilnytskyy Y, Ghose A, Kirkby C, Ghasroddashti E, Kolb B, Kovalchuk O (2016b) Profound and sexually dimorphic effects of clinically-relevant low dose scatter irradiation on the brain and behavior. Front Behav Neurosci 10:84

    Article  Google Scholar 

  • Kovalchuk A, Rodriguez-Juarez R, Ilnytskyy Y, Byeon B, Shpyleva S, Melnyk S, Pogribny I, Kolb B, Kovalchuk O (2016c) Sex-specific effects of cytotoxic chemotherapy agents cyclophosphamide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus—an aging connection. Aging (Albany NY) 8:697–711

    Article  CAS  Google Scholar 

  • Kovalchuk A, Ilnytskyy Y, Rodriguez-Juarez R, Katz A, Sidransky D, Kolb B, Kovalchuk O (2017a) Growth of malignant extracranial tumors alters microRNAome in the prefrontal cortex of TumorGraft mice. Oncotarget 8:88276–88293

    Article  Google Scholar 

  • Kovalchuk A, Ilnytskyy Y, Rodriguez-Juarez R, Shpyleva S, Melnyk S, Pogribny I, Katz A, Sidransky D, Kovalchuk O, Kolb B (2017b) Chemo brain or tumor brain—that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice. Aging (Albany NY) 9:1660–1676

    Article  CAS  Google Scholar 

  • Kovalchuk A, Ilnytskyy Y, Rodriguez-Juarez R, Katz A, Sidransky D, Kolb B, Kovalchuk O (2018a) Growth of triple negative and progesterone positive breast cancer causes oxidative stress and down-regulates neuroprotective transcription factor NPAS4 and NPAS4-regulated genes in hippocampal tissues of TumorGraft mice—an aging connection. Front Genet 9:58

    Article  Google Scholar 

  • Kovalchuk A, Nersisyan L, Mandal R, Wishart D, Mancini M, Sidransky D, Kolb B, Kovalchuk O (2018b) Growth of malignant non-CNS tumors alters brain metabolome. Front Genet 9:41

    Article  Google Scholar 

  • Kunin-Batson A, Kadan-Lottick N, Neglia JP (2014) The contribution of neurocognitive functioning to quality of life after childhood acute lymphoblastic leukemia. Psychooncology 23:692–699

    Article  Google Scholar 

  • Mandelblatt JS, Jacobsen PB, Ahles T (2014) Cognitive effects of cancer systemic therapy: implications for the care of older patients and survivors. J Clin Oncol 32:2617–2626

    Article  Google Scholar 

  • McGowan PO, Meaney MJ, Szyf M (2008) Diet and the epigenetic (re)programming of phenotypic differences in behavior. Brain Res 1237:12–24

    Article  CAS  Google Scholar 

  • Mehler MF (2008) Epigenetics and the nervous system. Ann Neurol 64:602–617

    Article  CAS  Google Scholar 

  • Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202

    Article  CAS  Google Scholar 

  • Nelson PT, Wang WX, Rajeev BW (2008) MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 18:130–138

    Article  CAS  Google Scholar 

  • Nugent BM, McCarthy MM (2015) Epigenetic influences on the developing brain: effects of hormones and nutrition. Adv Genom Genet 5:215–225

    Google Scholar 

  • Olson K, Hewit J, Slater LG, Chambers T, Hicks D, Farmer A, Grattan K, Steggles S, Kolb B (2016) Assessing cognitive function in adults during or following chemotherapy: a scoping review. Support Care Cancer 24:3223–3234

    PubMed  Google Scholar 

  • Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717

    Article  CAS  Google Scholar 

  • Pogribny IP, Beland FA (2012) DNA methylome alterations in chemical carcinogenesis. Cancer Lett

    Google Scholar 

  • Raji MA (2005) Management of chemotherapy-induced side-effects. Lancet Oncol 6:357

    Article  Google Scholar 

  • Renthal W, Nestler EJ (2008) Epigenetic mechanisms in drug addiction. Trends Mol Med 14:341–350

    Article  CAS  Google Scholar 

  • Saito Y, Jones PA (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222

    Article  CAS  Google Scholar 

  • Sandoval J, Esteller M (2012) Cancer epigenomics: beyond genomics. Curr Opin Genet Dev 22:50–55

    Article  CAS  Google Scholar 

  • Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35:729–741

    Article  Google Scholar 

  • Seigers R, Schagen SB, Beerling W, Boogerd W, van Tellingen O, van Dam FS, Koolhaas JM, Buwalda B (2008) Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res 186:168–175

    Article  CAS  Google Scholar 

  • Seigers R, Pourtau L, Schagen SB, van Dam FS, Koolhaas JM, Konsman JP, Buwalda B (2010a) Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor. Brain Res Bull 81:472–476

    Article  CAS  Google Scholar 

  • Seigers R, Timmermans J, van der Horn HJ, de Vries EF, Dierckx RA, Visser L, Schagen SB, van Dam FS, Koolhaas JM, Buwalda B (2010b) Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav Brain Res 207:265–272

    Article  CAS  Google Scholar 

  • Seigers R, Schagen SB, van Tellingen O, Dietrich J (2013) Chemotherapy-related cognitive dysfunction: current animal studies and future directions. Brain Imaging Behav 7:453–459

    Article  CAS  Google Scholar 

  • Seigers R, Loos M, van Tellingen O, Boogerd W, Smit AB, Schagen SB (2015) Cognitive impact of cytotoxic agents in mice. Psychopharmacology 232:17–37

    Article  CAS  Google Scholar 

  • Seigers R, Loos M, van Tellingen O, Boogerd W, Smit AB, Schagen SB (2016) Neurobiological changes by cytotoxic agents in mice. Behav Brain Res 299:19–26

    Article  CAS  Google Scholar 

  • Sherwani SI, Khan HA (2015) Role of 5-hydroxymethylcytosine in neurodegeneration. Gene

    Google Scholar 

  • Silberfarb PM (1983) Chemotherapy and cognitive defects in cancer patients. Annu Rev Med 34:35–46

    Article  CAS  Google Scholar 

  • Silberfarb PM, Maurer LH, Crouthamel CS (1980a) Psychosocial aspects of neoplastic disease: I. Functional status of breast cancer patients during different treatment regimens. Am J Psychiatry 137:450–455

    Article  CAS  Google Scholar 

  • Silberfarb PM, Philibert D, Levine PM (1980b) Psychosocial aspects of neoplastic disease: II. Affective and cognitive effects of chemotherapy in cancer patients. Am J Psychiatry 137:597–601

    Article  CAS  Google Scholar 

  • Szulwach KE, Li X, Li Y, Song CX, Wu H, Dai Q, Irier H, Upadhyay AK, Gearing M, Levey AI, Vasanthakumar A, Godley LA, Chang Q, Cheng X, He C, Jin P (2011) 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 14:1607–1616

    Article  CAS  Google Scholar 

  • Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367

    Article  CAS  Google Scholar 

  • Vardy J, Tannock I (2007) Cognitive function after chemotherapy in adults with solid tumours. Crit Rev Oncol Hematol 63:183–202

    Article  Google Scholar 

  • Wang XM, Walitt B, Saligan L, Tiwari AFY, Cheung CW, Zhang ZJ (2015) Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine 72:86–96

    Article  CAS  Google Scholar 

  • Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA (2004) ‘Chemobrain’ in breast carcinoma?: a prologue. Cancer 101:466–475

    Article  Google Scholar 

  • Weiss HD, Walker MD, Wiernik PH (1974a) Neurotoxicity of commonly used antineoplastic agents (first of two parts). N Engl J Med 291:75–81

    Article  CAS  Google Scholar 

  • Weiss HD, Walker MD, Wiernik PH (1974b) Neurotoxicity of commonly used antineoplastic agents (second of two parts). N Engl J Med 291:127–133

    Article  CAS  Google Scholar 

  • Wen L, Tang F (2014) Genomic distribution and possible functions of DNA hydroxymethylation in the brain. Genomics 104:341–346

    Article  CAS  Google Scholar 

  • Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25:2436–2452

    Article  CAS  Google Scholar 

  • Yu Z (2008) Non-coding RNAs in gene regulation. In: TOST J (ed) Epigenetics. Caister Academic Press, Norfolk, UK

    Google Scholar 

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Authors and Affiliations

  1. University of Lethbridge, Lethbridge, AB, Canada

    Anna Kovalchuk, Bryan Kolb & Olga Kovalchuk

  2. University of Calgary, Calgary, AB, Canada

    Anna Kovalchuk

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  1. Anna Kovalchuk
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  2. Bryan Kolb
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  3. Olga Kovalchuk
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Correspondence to Olga Kovalchuk .

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  1. Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Center of RAS, Syktyvkar, Komi Republic, Russia

    Alexey Moskalev

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Kovalchuk, A., Kolb, B., Kovalchuk, O. (2019). Epigenetics of Brain Aging: Lessons from Chemo Brain and Tumor Brain. In: Moskalev, A. (eds) Biomarkers of Human Aging. Healthy Ageing and Longevity, vol 10. Springer, Cham. https://doi.org/10.1007/978-3-030-24970-0_13

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