Dissecting epigenetic age acceleration in amyotrophic lateral sclerosis

Area of Science:

• Epigenetics
• Neurodegenerative Diseases
• Aging Research

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
• Epigenetic aging, or the biological age measured by DNA methylation, has been explored as a potential factor in ALS.
• Previous studies suggested accelerated epigenetic aging in ALS patients.

Purpose of the Study:

• To investigate epigenetic aging signatures in amyotrophic lateral sclerosis (ALS) patients compared to healthy controls.
• To identify the role of potential confounders, such as white blood cell proportions, in epigenetic aging estimates.
• To examine differences in epigenetic aging between ALS patients with and without C9orf72 expansions.

Main Methods:

• Utilized whole-blood methylome profiles from 5,146 ALS patients and 2,156 controls from Project MinE.
• Predicted biological age using three generations of epigenetic clocks.
• Estimated age acceleration by regressing models on control individuals and specifically analyzing C9orf72-negative ALS patients.

Main Results:

• White blood cell type proportions were identified as a significant confounder for previously observed accelerated biological aging in ALS.
• After correcting for cell counts, no significant difference in epigenetic aging pace was found between ALS patients and controls, except for those with C9orf72 repeat expansions.
• Epigenetic age acceleration scores did not correlate with patient survival.

Conclusions:

• There is no significant difference in the pace of biological aging between ALS patients and controls, with the exception of ALS patients carrying the C9orf72 mutation.
• Altered white blood cell proportions play a crucial role in general ALS pathophysiology, rather than accelerated aging itself.
• The findings underscore the need to account for cellular composition when assessing epigenetic aging in disease studies.