In ALS, apparent largely disappeared after accounting for white blood cell proportions, except in C9orf72 repeat expansion carriers.
Evidence
This case-control methylome analysis compared whole-blood profiles from 5,146 ALS patients and 2,156 controls using epigenetic clocks, DunedinPACE, and telomere-length estimates.
Caveat
The findings are based on whole-blood methylation signatures and show no survival contribution from the epigenetic age acceleration scores.
Simplified
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 ofexpansions, we regressed the model on-negative ALS patients. The predicted DunedinPACE pace of aging and telomere length additionally characterized aging dynamics. C9orf72C9orf72
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 therepeat expansion. None of the scores contributed to survival. C9orf72
CONCLUSION: Our study revealed no significant difference in the pace of biological agingbetween ALS patients and controls, except for ALS patients carrying themutation. We emphasize the importance of altered white blood cell proportions in general ALS pathophysiology as opposed to accelerated aging per se. C9orf72
Key numbers
0.915
Correlation with Zhang Clock
Among 6,048 individuals with known chronological ages
5,022
Survival analysis cohort size
Subset of ALS individuals with known survival time and status
N
Patients with C9orf72 repeat expansion
Comparison of aging metrics in ALS patients
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Nicola Ticozzi received compensation for consulting services and/or speaker activities from Amylyx Pharmaceutical, Biogen, Italfarmaco, and Zambon. He received research funding from the Italian Ministry of Health, the Italian Ministry of University and Research, and AriSLA. He is associate editor of Frontiers in Aging Neuroscience and a member of the advisory board of Neurological Sciences. Jan Veldink reports having sponsored research agreements with Biogen, Eli Lilly, Trace, and AstraZeneca. Wouter van Rheenen reports having sponsored research agreements with Biogen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
