Epigenetic clock indicates accelerated aging in glial cells of progressive multiple sclerosis patients

Background Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) characterized by irreversible disability at later progressive stages. A growing body of evidence suggests that disease progression depends on age and inflammation within the CNS. We aimed to investigate epigenetic aging in bulk brain tissue and sorted nuclei from MS patients using DNA methylation-based epigenetic clocks. Methods We applied Horvath’s multi-tissue and Shireby’s brain-specific Cortical clock on bulk brain tissue (n = 46), sorted neuronal (n = 54), and glial nuclei (n = 66) from post-mortem brain tissue of progressive MS patients and controls. Results We found a significant increase in age acceleration residuals, corresponding to 3.6 years, in glial cells of MS patients compared to controls (P = 0.0024) using the Cortical clock, which held after adjustment for covariates (Padj = 0.0263). The 4.8-year age acceleration found in MS neurons (P = 0.0054) did not withstand adjustment for covariates and no significant difference in age acceleration residuals was observed in bulk brain tissue between MS patients and controls. Conclusion While the findings warrant replication in larger cohorts, our study suggests that glial cells of progressive MS patients exhibit accelerated biological aging.

[1]  J. Kira,et al.  Serum Anti-oligodendrocyte Autoantibodies in Patients With Multiple Sclerosis Detected by a Tissue-Based Immunofluorescence Assay , 2021, Frontiers in Neurology.

[2]  U. Zettl,et al.  Systematic Review of Studies on Telomere Length in Patients with Multiple Sclerosis , 2021, Aging and disease.

[3]  M. Jagodic,et al.  DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients , 2021, medRxiv.

[4]  D. Bennett,et al.  The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes , 2021, Neurobiology of Disease.

[5]  D. Bennett,et al.  Characteristics of Epigenetic Clocks Across Blood and Brain Tissue in Older Women and Men , 2021, Frontiers in Neuroscience.

[6]  Li Li,et al.  Epigenetic age acceleration and clinical outcomes in gliomas , 2020, PloS one.

[7]  N. J. Allen,et al.  Glia: victims or villains of the aging brain? , 2020, Neurobiology of Disease.

[8]  V. Gorgoulis,et al.  Aging, Cellular Senescence, and Progressive Multiple Sclerosis , 2020, Frontiers in Cellular Neuroscience.

[9]  Alan J. Thomas,et al.  Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex , 2020, bioRxiv.

[10]  M. Jagodic,et al.  Epigenetic insights into multiple sclerosis disease progression , 2020, Journal of internal medicine.

[11]  J. Mill,et al.  Systematic underestimation of the epigenetic clock and age acceleration in older subjects , 2019, Genome Biology.

[12]  S. Horvath,et al.  DNA methylation aging clocks: challenges and recommendations , 2019, Genome Biology.

[13]  L. Alfredsson,et al.  Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis. , 2019, Epigenomics.

[14]  R. Marioni,et al.  Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing , 2019, Genome Medicine.

[15]  J. Tegnér,et al.  Neuronal methylome reveals CREB-associated neuro-axonal impairment in multiple sclerosis , 2019, Clinical Epigenetics.

[16]  Lars T. Westlye,et al.  Cross-Sectional and Longitudinal MRI Brain Scans Reveal Accelerated Brain Aging in Multiple Sclerosis , 2019, Front. Neurol..

[17]  Olga Tanaseichuk,et al.  Metascape provides a biologist-oriented resource for the analysis of systems-level datasets , 2019, Nature Communications.

[18]  P. Robson,et al.  Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis , 2019, Proceedings of the National Academy of Sciences.

[19]  N. Sousa,et al.  The Role of Astrocytic Calcium Signaling in the Aged Prefrontal Cortex , 2018, Front. Cell. Neurosci..

[20]  S. Bernard,et al.  Oligodendrocyte generation dynamics in multiple sclerosis , 2018, Nature.

[21]  H. Leonhardt,et al.  DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex , 2018, Epigenetics & Chromatin.

[22]  Alex P. Reiner,et al.  Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies , 2018, Aging.

[23]  Hannes P. Eggertsson,et al.  DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis , 2018, Nature Communications.

[24]  A. Cross,et al.  Disease-Modifying Treatment in Progressive Multiple Sclerosis , 2018, Current Treatment Options in Neurology.

[25]  M. Levine,et al.  An epigenetic biomarker of aging for lifespan and healthspan , 2018, bioRxiv.

[26]  D. Pitt,et al.  The Role of Astrocytes in Multiple Sclerosis , 2018, Front. Immunol..

[27]  Qi Huang,et al.  The role of microglia in multiple sclerosis , 2017, Neuropsychiatric disease and treatment.

[28]  A. Lo,et al.  iPS-derived neural progenitor cells from PPMS patients reveal defect in myelin injury response , 2017, Experimental Neurology.

[29]  S. Horvath,et al.  Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels , 2016, Aging.

[30]  S. Horvath,et al.  Epigenetic clock analyses of cellular senescence and ageing , 2016, Oncotarget.

[31]  Tom Michoel,et al.  Microglial brain region-dependent diversity and selective regional sensitivities to ageing , 2015, Nature Neuroscience.

[32]  M. Levine,et al.  Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning , 2015, Aging.

[33]  K. Tenbrock,et al.  Oxidative stress in multiple sclerosis: Central and peripheral mode of action , 2015, Experimental Neurology.

[34]  S. Horvath,et al.  HIV-1 Infection Accelerates Age According to the Epigenetic Clock , 2015, The Journal of infectious diseases.

[35]  Steve Horvath,et al.  Accelerated epigenetic aging in Down syndrome , 2015, Aging cell.

[36]  Steve Horvath,et al.  The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936 , 2015, International journal of epidemiology.

[37]  L. Pellerin,et al.  Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions , 2014, Glia.

[38]  J. Lechner-Scott,et al.  Risk of relapse phenotype recurrence in multiple sclerosis , 2014, Multiple sclerosis.

[39]  Jun Zhu,et al.  Epigenome-wide differences in pathology-free regions of multiple sclerosis–affected brains , 2013, Nature Neuroscience.

[40]  S. Horvath.  DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[41]  E. Koonin,et al.  Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites , 2013, Nucleic acids research.

[42]  Simon Hametner,et al.  Disease-specific molecular events in cortical multiple sclerosis lesions , 2013, Brain : a journal of neurology.

[43]  Yue Feng,et al.  Oligodendroglia and neurotrophic factors in neurodegeneration , 2013, Neuroscience Bulletin.

[44]  Martin J. Aryee,et al.  A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression , 2013, Epigenetics.

[45]  B. Weinshenker,et al.  Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis , 2013, Multiple sclerosis.

[46]  T. Ideker,et al.  Genome-wide methylation profiles reveal quantitative views of human aging rates. , 2013, Molecular cell.

[47]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[48]  Y. Ben-Shlomo,et al.  Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis , 2012, Multiple sclerosis.

[49]  H. Lassmann,et al.  Oxidative damage in multiple sclerosis lesions , 2011, Brain : a journal of neurology.

[50]  B. Pakkenberg,et al.  Neocortical glial cell numbers in human brains , 2008, Neurobiology of Aging.

[51]  C. Sanfeliu,et al.  Astrocytes aged in vitro show a decreased neuroprotective capacity , 2007, Journal of neurochemistry.

[52]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[53]  S. Vukusic,et al.  Age at disability milestones in multiple sclerosis. , 2006, Brain : a journal of neurology.

[54]  Merrill,et al.  Mechanisms of damage to myelin and oligodendrocytes and their relevance to disease , 1999, Neuropathology and applied neurobiology.