Dissecting epigenetic age acceleration in amyotrophic lateral sclerosis

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. 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 <i>C9orf72</i> expansions, we regressed the model on <i>C9orf72</i>-negative ALS patients. The predicted DunedinPACE pace of aging and telomere length additionally characterized aging dynamics. 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 <i>C9orf72</i> repeat expansion. None of the epigenetic age acceleration scores contributed to survival. Our study revealed no significant difference in the pace of biological agingbetween ALS patients and controls, except for ALS patients carrying the <i>C9orf72</i> mutation. We emphasize the importance of altered white blood cell proportions in general ALS pathophysiology as opposed to accelerated aging per se. Amyotrophic Lateral Sclerosis (ALS) is a serious disease that affects the nervous system and makes it hard for people to move. One of the main risk factors for developing ALS is getting older. Our study looked at whether people with ALS have signs of aging faster than those who don’t have the disease. To do so, we examined changes in chemical markers on DNA, called DNA methylation, that occur as people age. We studied blood samples from 5,146 ALS patients and 2,156 healthy individuals, using several tools that estimate biological age and how quickly it changes. Our results showed that differences in immune cell composition help explain why it seems like ALS patients age faster. After taking these differences into account, we found that, generally, ALS patients did not age faster than healthy controls. However, those with the <i>C9orf72</i> genetic mutation did show signs of aging more quickly. Overall, our findings suggest that changes in immune cells are very important in ALS and may be more significant than the idea of accelerated aging, except for patients with the <i>C9orf72</i> mutation.