Abstract
Background: There is strong evidence that epigenetic age acceleration is associated with increased risk of later-life diseases and all-cause mortality. However, there is currently limited evidence that suggests accelerated epigenetic age is associated with dementia risk.
Objective: This study aims to clarify whether epigenetic biomarkers of accelerated aging can predict dementia risk, which is an important consideration as aging is the greatest risk factor for the disease.
Methods: DNA methylation was measured in peripheral blood samples provided by 160 participants from the ASPirin in Reducing Events in the Elderly study, including 73 pre-symptomatic dementia cases and 87 controls matched for age, sex, and smoking and education status. Epigenetic age was calculated using Horvath, Hannum, GrimAge and PhenoAge DNA methylation clocks, and age acceleration (the disparity between chronological age and epigenetic age) was determined.
Results: There was no difference in age acceleration between dementia cases and controls. In males, only Hannum’s intrinsic epigenetic age acceleration was increased in pre-symptomatic dementia cases compared to controls (Δ +1.8 years, p = 0.03).
Conclusion: These findings provide no strong evidence that accelerated epigenetic aging measured in peripheral blood can predict dementia risk.
Keywords: Accelerated Aging, dementia, DNA methylation, epigenetic clock, grimAge, hannum, horvath, phenoAge.
[1]
Hickman RA, Faustin A, Wisniewski T. Alzheimer disease and its growing epidemic: Risk factors, biomarkers, and the urgent need for therapeutics. Neurol Clin 2016; 34(4): 941-53.[http://dx.doi.org/10.1016/j.ncl.2016.06.009] [PMID: 27720002]
[2]
Booth LN, Brunet A. The aging epigenome. Mol Cell 2016; 62(5): 728-44.[http://dx.doi.org/10.1016/j.molcel.2016.05.013] [PMID: 27259204]
[3]
Zhang W, Qu J, Liu G-H, Belmonte JCI. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol 2020; 21(3): 137-50.[http://dx.doi.org/10.1038/s41580-019-0204-5] [PMID: 32020082]
[4]
Campbell RR, Wood MA. How the epigenome integrates information and reshapes the synapse. Nat Rev Neurosci 2019; 20(3): 133-47.[http://dx.doi.org/10.1038/s41583-019-0121-9] [PMID: 30696992]
[5]
Lyko F. The DNA methyltransferase family: A versatile toolkit for epigenetic regulation. Nat Rev Genet 2018; 19(2): 81-92.[http://dx.doi.org/10.1038/nrg.2017.80] [PMID: 29033456]
[6]
Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacol 2013; 38(1): 23-38.[http://dx.doi.org/10.1038/npp.2012.112]
[7]
Jin Z, Liu Y. DNA methylation in human diseases. Genes Dis 2018; 5(1): 1-8.[http://dx.doi.org/10.1016/j.gendis.2018.01.002] [PMID: 30258928]
[8]
Nebbioso A, Tambaro FP, Dell’Aversana C, Altucci L. Cancer epigenetics: Moving forward. PLoS Genet 2018; 14(6): e1007362.[http://dx.doi.org/10.1371/journal.pgen.1007362] [PMID: 29879107]
[9]
Soler-Botija C, Gálvez-Montón C, Bayés-Genís A. Epigenetic biomarkers in cardiovascular diseases. Front Genet 2019; 10(950): 950.[http://dx.doi.org/10.3389/fgene.2019.00950] [PMID: 31649728]
[10]
Fransquet PD, Ryan J. The current status of blood epigenetic biomarkers for dementia. Crit Rev Clin Lab Sci 2019; 56(7): 435-57.[http://dx.doi.org/10.1080/10408363.2019.1639129] [PMID: 31328605]
[11]
Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018; 19(6): 371-84.[http://dx.doi.org/10.1038/s41576-018-0004-3] [PMID: 29643443]
[12]
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013; 14(10): R115.[http://dx.doi.org/10.1186/gb-2013-14-10-r115] [PMID: 24138928]
[13]
Hannum G, Guinney J, Zhao L, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 2013; 49(2): 359-67.[http://dx.doi.org/10.1016/j.molcel.2012.10.016] [PMID: 23177740]
[14]
Fransquet PD, Wrigglesworth J, Woods RL, Ernst ME, Ryan J. The epigenetic clock as a predictor of disease and mortality risk: A systematic review and meta-analysis. Clin Epigenetics 2019; 11(1): 62.[http://dx.doi.org/10.1186/s13148-019-0656-7] [PMID: 30975202]
[15]
Ryan J, Wrigglesworth J, Loong J, Fransquet PD, Woods RL. A systematic review and meta-analysis of environmental, lifestyle, and health factors associated with DNA methylation age. J Gerontol A Biol Sci Med Sci 2020; 75(3): 481-94.[http://dx.doi.org/10.1093/gerona/glz099] [PMID: 31001624]
[16]
Levine ME. Modeling the rate of senescence: Can estimated biological age predict mortality more accurately than chronological age? J Gerontol A Biol Sci Med Sci 2013; 68(6): 667-74.[http://dx.doi.org/10.1093/gerona/gls233] [PMID: 23213031]
[17]
Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 2018; 10(4): 573-91.[http://dx.doi.org/10.18632/aging.101414] [PMID: 29676998]
[18]
Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY) 2019; 11(2): 303-27.[http://dx.doi.org/10.18632/aging.101684] [PMID: 30669119]
[19]
Degerman S, Josefsson M, Nordin Adolfsson A, et al. Maintained memory in aging is associated with young epigenetic age. Neurobiol Aging 2017; 55: 167-71.[http://dx.doi.org/10.1016/j.neurobiolaging.2017.02.009] [PMID: 28292535]
[20]
Horvath S, Ritz BR. Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging (Albany NY) 2015; 7(12): 1130-42.[http://dx.doi.org/10.18632/aging.100859] [PMID: 26655927]
[21]
Beam CR, Kaneshiro C, Jang JY, Reynolds CA, Pedersen NL, Gatz M. Differences between women and men in incidence rates of dementia and Alzheimer’s disease. J Alzheimers Dis 2018; 64(4): 1077-83.[http://dx.doi.org/10.3233/JAD-180141] [PMID: 30010124]
[22]
Miller IN, Cronin-Golomb A. Gender differences in Parkinson’s disease: Clinical characteristics and cognition. Mov Disord 2010; 25(16): 2695-703.[http://dx.doi.org/10.1002/mds.23388] [PMID: 20925068]
[23]
Horvath S, Gurven M, Levine ME, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol 2016; 17(1): 171-93.[http://dx.doi.org/10.1186/s13059-016-1030-0] [PMID: 27511193]
[24]
Hillary RF, Stevenson AJ, Cox SR, et al. An epigenetic predictor of death captures multi-modal measures of brain health. Mol Psychiatry 2019.[http://dx.doi.org/10.1038/s41380-019-0616-9] [PMID: 31796892]
[25]
McNeil JJ, Woods RL, Nelson MR, et al. Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci 2017; 72(11): 1586-93.[http://dx.doi.org/10.1093/gerona/glw342] [PMID: 28329340]
[26]
Ryan J, Woods RL, Britt C, et al. Normative performance of healthy older individuals on the Modified Mini-Mental State (3MS) examination according to ethno-racial group, gender, age, and education level. Clin Neuropsychol 2019; 33(4): 779-97.[http://dx.doi.org/10.1080/13854046.2018.1488996] [PMID: 29976121]
[27]
Jones TG, Schinka JA, Vanderploeg RD, Small BJ, Graves AB, Mortimer JA. 3MS normative data for the elderly. Arch Clin Neuropsychol 2002; 17(2): 171-7.[http://dx.doi.org/10.1093/arclin/17.2.171] [PMID: 14589746]
[28]
Smith A. Symbol digit modalities test : Manual Los Angeles Western Psychological Services 1982.
[29]
Ruff RM, Light RH, Parker SB, Levin HS. Benton controlled oral word association test: Reliability and updated norms. Arch Clin Neuropsychol 1996; 11(4): 329-38.[http://dx.doi.org/10.1093/arclin/11.4.329] [PMID: 14588937]
[30]
Ryan J, Woods RL, Murray AM, et al. Normative performance of older individuals on the Hopkins Verbal Learning Test-Revised (HVLT-R) according to ethno-racial group, gender, age and education level. Clin Neuropsychol 2020; 1-17.[http://dx.doi.org/10.1080/13854046.2020.1730444] [PMID: 32100619]
[31]
Benedict RHB, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test – Revised: Normative data and analysis of inter- form and test-retest reliability. Clin Neuropsychol 1998; 12(1): 43-55.[http://dx.doi.org/10.1076/clin.12.1.43.1726]
[32]
First MB, Frances A, Pincus HA. DSM-IV-TR handbook of differential diagnosis. Arlington, VA, US American Psychiatric Publishing, Inc 2002.[http://dx.doi.org/10.1176/appi.books.9781585622658]
[33]
Triche TJ Jr, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD. Low-level processing of Illumina Infinium DNA Methylation BeadArrays. Nucleic Acids Res 2013; 41(7): e90-0.[http://dx.doi.org/10.1093/nar/gkt090] [PMID: 23476028]
[34]
Ryan J, Storey E, Murray AM, et al. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology 2020; 95(3): e320-31.[http://dx.doi.org/10.1212/WNL.0000000000009277] [PMID: 32213642]
[35]
Sibbett RA, Altschul DM, Marioni RE, Deary IJ, Starr JM, Russ TC. DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: A study of the Lothian Birth Cohort 1921. BMC Psychiatry 2020; 20(1): 91.[http://dx.doi.org/10.1186/s12888-020-2469-9] [PMID: 32111184]
[36]
El Khoury LY, Gorrie-Stone T, Smart M, et al. Systematic underestimation of the epigenetic clock and age acceleration in older subjects. Genome Biol 2019; 20(1): 283.[http://dx.doi.org/10.1186/s13059-019-1810-4] [PMID: 31847916]
[37]
Bell CG, Lowe R, Adams PD, et al. DNA methylation aging clocks: Challenges and recommendations. Genome Biol 2019; 20(1): 249.[http://dx.doi.org/10.1186/s13059-019-1824-y] [PMID: 31767039]
[38]
Palma-Gudiel H, Eixarch E, Crispi F, Morán S, Zannas AS, Fañanás L. Prenatal adverse environment is associated with epigenetic age deceleration at birth and hypomethylation at the hypoxia-responsive EP300 gene. Clin Epigenetics 2019; 11(1): 73.[http://dx.doi.org/10.1186/s13148-019-0674-5] [PMID: 31072398]
[39]
Salas LA, Koestler DC, Butler RA, et al. An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray. Genome Biol 2018; 19(1): 64.[http://dx.doi.org/10.1186/s13059-018-1448-7] [PMID: 29843789]
[41]
Pidsley R, Zotenko E, Peters TJ, et al. Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol 2016; 17(1): 208-08.[http://dx.doi.org/10.1186/s13059-016-1066-1] [PMID: 27717381]
[42]
McEwen LM, Jones MJ, Lin DTS, et al. Systematic evaluation of DNA methylation age estimation with common preprocessing methods and the Infinium MethylationEPIC BeadChip array. Clin Epigenetics 2018; 10(1): 123.[http://dx.doi.org/10.1186/s13148-018-0556-2] [PMID: 30326963]
[43]
Zhang Q, Vallerga CL, Walker RM, et al. Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing. Genome Med 2019; 11(1): 54.[http://dx.doi.org/10.1186/s13073-019-0667-1] [PMID: 31443728]
[44]
Braun PR, Han S, Hing B, et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl Psychiatry 2019; 9(1): 47.[http://dx.doi.org/10.1038/s41398-019-0376-y] [PMID: 30705257]
[45]
Shireby GL, Davies JP, Francis PT, et al. Recalibrating the epigenetic clock: Implications for assessing biological age in the human cortex. Brain 2020; 143(12): 3763-75.[http://dx.doi.org/10.1093/brain/awaa334] [PMID: 33300551]
[46]
Grodstein F, Lemos B, Yu L, Iatrou A, De Jager PL, Bennett DA. Characteristics of epigenetic clocks across blood and brain tissue in older women and men. Front Neurosci 2021; 14: 555307-07.[http://dx.doi.org/10.3389/fnins.2020.555307] [PMID: 33488342]
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