Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue

Megha Murthy; Gemma Shireby; Yasuo Miki; Emmanuelle Viré; Tammaryn Lashley; Thomas T Warner; Jonathan Mill; Conceição Bettencourt

doi:10.1111/nan.12872

Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue

Neuropathol Appl Neurobiol. 2023 Feb;49(1):e12872. doi: 10.1111/nan.12872.

Authors

Megha Murthy^{1

2}, Gemma Shireby³, Yasuo Miki^{1

4}, Emmanuelle Viré⁵, Tammaryn Lashley^{1

6}, Thomas T Warner^{1

2

7}, Jonathan Mill³, Conceição Bettencourt^{1

6}

Affiliations

¹ Queen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London, London, UK.
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
³ University of Exeter Medical School, University of Exeter, Exeter, UK.
⁴ Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
⁵ UCL Institute of Prion Diseases, MRC Prion Unit at UCL, University College London, London, UK.
⁶ Department of Neurodegenerative Disease, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
⁷ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.

Abstract

Aims: Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter.

Methods: We analysed the performances of two DNA methylation-based clocks, DNAmClock_Multi and DNAmClock_Cortical , in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes.

Results: Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClock_Cortical , r = [0.80-0.97], p < 0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClock_Multi significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClock_Cortical tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p = 6.1 × 10^-5 ) suggested that this cell type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClock_Cortical (r > 0.31, p < 0.05), and similar trends were obtained with DNAmClock_Multi . Although increased age acceleration was observed in MSA compared with controls, no significant differences were detected upon adjustment for possible confounders (e.g., cell-type proportions).

Conclusions: Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.

Keywords: DNA methylation ageing; epigenetic clock; multiple system atrophy; oligodendrocytes; post-mortem brain tissue; white matter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / metabolism
DNA Methylation
Epigenesis, Genetic
Gray Matter / metabolism
Humans
Multiple System Atrophy* / metabolism
Oligodendroglia / metabolism

Abstract

Publication types

MeSH terms

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