Abstract
BACKGROUND AND OBJECTIVES: Older chronological age is associated with decreased multiple sclerosis (MS) relapse rates and increased risk of progressive disease. Measurement of biological age may be more precise than birthdate in understanding these aging effects. In addition to normal aging, MS-related accelerated aging may contribute. Measurement of biological age in adults may be confounded by the effects of natural aging and age-related comorbidities. Examining age extremes can be informative, and demonstrating accelerated biological aging in children would support a hypothesis of MS driving premature aging. We sought to compare epigenetic age in participants with pediatric-onset MS (POMS) and age-similar controls. METHODS: We performed a multicenter case-control analysis of epigenetic age in a prospectively collected set of whole blood DNA samples and clinical data. Quantitative methylation scores were derived for approximately 850,000 cytosine-phosphate-guanine (CpG) sites. Epigenetic age was calculated based on 4 established epigenetic clock algorithms. Epigenetic age and age acceleration residual (AAR) were compared between participants with POMS and age-similar controls using multivariate regression analysis, adjusted for demographic variables. RESULTS: Epigenetic age and AAR were greater in cases (n = 125, mean age 15.7 years [SD = 2.6], 63.2% female) compared with controls (n = 145, mean age 15.3 years [SD = 3.4], 63.5% female) after adjusting for age, sex, body mass index, tobacco exposure, and socioeconomic status. This difference was statistically significant for 2 of the 4 epigenetic clocks used (Horvath β = 0.31 years [CI = -0.32-0.94], p = 0.33; Hannum β = 1.50 years [CI = 0.58-2.42], p = 0.002; GrimAge β = 0.33 years [CI = -0.30-0.96], p = 0.29; PhenoAge β = 1.72 years [CI = 0.09-3.35], p = 0.004). DISCUSSION: We observed greater point estimates of epigenetic age in participants with POMS compared with healthy controls in all epigenetic clocks tested. This difference was statistically significant for the Hannum and PhenoAge clocks after multivariable modeling. These results are consistent with those of studies in adult MS and suggest that accelerated aging may be present even in the youngest people living with MS.