Dissecting epigenetic age acceleration in amyotrophic lateral sclerosis

Aim: We compared signatures of epigenetic aging in amyotrophic lateral sclerosis (ALS) patients and healthy controls to investigate the role of potential confounders and genetic subgroups. Methods: We used whole-blood methylome profiles for 5,146 ALS patients and 2,156 controls available for Project MinE. We predicted biological age with three generations of epigenetic clocks and estimated age acceleration by regressing our model on control individuals to evaluate case/control differences. To investigate the contribution of C9orf72 expansions, we regressed the model on C9orf72-negative ALS patients. The predicted DunedinPACE pace of aging and telomere length additionally characterized aging dynamics. Results: We found that white blood cell type proportions confound the previously observed increase in the pace of biological aging in ALS. When correcting for cell counts, there is no evidence for accelerated epigenetic aging compared to controls, except for ALS patients with the C9orf72 repeat expansion. None of the epigenetic age acceleration scores contributed to survival. Conclusion: Our study revealed no significant difference in the pace of biological agingbetween ALS patients and controls, except for ALS patients carrying the C9orf72 mutation. We emphasize the importance of altered white blood cell proportions in general ALS pathophysiology as opposed to accelerated aging per se.