Epigenetic Age Acceleration Shows Association With Secondary Progressive Multiple Sclerosis


New findings from a study presented at the 2024 ACTRIMS Forum revealed an increase in epigenetic age acceleration among a subgroup of patients with multiple sclerosis.

Yinan Zhang, MD, assistant professor of neurology at The Ohio State University Wexner Medical Center

Yinan Zhang, MD,

Credit: The Ohio State University Wexner Medical Center

New interim findings from an ongoing study presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, in West Palm Beach, Florida, showed an increase of epigenetic age acceleration (EAA) in a subset of patients with secondary progressive multiple sclerosis (MS). These data, compared with other MS subgroups, suggest a potential association between accelerated aging and patients with secondary progressive MS.1

In this study, investigators obtained data from 95 participants (relapsing remitting MS, n = 30; secondary progressive MS, n = 29; primary progressive MS, n = 10; controls, n = 27). Among these groups, EAA was highest in patients with secondary progressive MS using the Horvath (mean = 6.1 [SD, 8.8]), Hannum (mean = 8.3[SD, 10.8]), GrimAge (mean = 2.3[SD, 4.9]), and PhenoAge (mean = 8.9 [SD, 12.9]) clocks. Notably, authors observed no expressive differences in EAA for patients with MS who were treated with anti-CD20 therapy compared with other disease-modifying therapies or no treatment.

Top Clinical Takeaways

  • The study highlights an association between accelerated aging, as indicated by increased EAA, and patients with secondary progressive multiple sclerosis.
  • Despite a positive correlation between p16INK4a and chronological age in the control group, this correlation was not observed in patients with multiple sclerosis.
  • Anti-CD20 therapy did not show expressive differences in EAA compared to other disease-modifying therapies or no treatment.

Presented by lead author Yinan Zhang, MD, assistant professor of neurology at The Ohio State University Wexner Medical Center, multiple epigenetic clock-based predictors and p16INK4a expression were measured in patients with MS and age- and sex-matched controls without MS. Authors also investigated the effects of anti-CD20 therapy on EAA and p16INK4a, a tumor suppressor, as well as assessed the correlations between p16INK4a with chronological age and EAA. Using multiple epigenetic clock algorithms, researchers measured EAA to assess methylation patterns in peripheral blood T lymphocyte (PBTL) DNA. Additionally, authors noted that EAA was the fitting residual between clock-based prediction and regression on chronological age and technical variables for the controls, and as prediction residuals for patients with MS. The p16INK4a expression was measured in PBTL, and researchers analyzed extracted RNA samples using a custom Nanostring CodeSet.

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All told, p16INK4a expression demonstrated moderate positive correlation with chronological age among the control group (r = 0.44) but not in the groups of patients with MS (r = 0.05). Similarly, investigators observed positive correlations between p16INK4a and different epigenetic clock measurements of EAA in controls compared in MS. Thus, authors noted that because of the lack of anticipated association between p16INK4a and chronological age in MS, more research is needed to determine the correlations between aging biomarkers and MS disease outcomes.1

In a prior study using DNA methylation-based epigenetic clocks published in Frontiers in Aging Neuroscience, findings showed glial cells of patients with MS had an increased epigenetic age acceleration compared with non-neurological controls, suggesting glial cells of progressive MS exhibit accelerated biological aging.2 Additionally, investigators observed significant sex-specific differences in age acceleration residuals only in neurons using Horvath’s clock. Authors noted that future approaches, such as epigenetic-based therapies, might assist with slowing down or halting age acceleration of the brain of patients with MS because epigenetic changes are reversible by nature.

Conducted by lead author Lara Kular, PhD, assistant professor of clinical neuroscience at Karolinska Institutet, and colleagues, additional findings from that study showed a significant increase in age acceleration residuals, corresponding to 3.6 years, among the glial cells of patients with MS in comparison with the controls (P = .0024) using the Cortical clock, which held following the adjustment for covariates (Padj = 0.0263). Notably, the 4.8-year age acceleration authors observed in MS neurons (P = 0.0054) did not withstand adjustment for covariates and displayed no significant difference in age acceleration residuals in bulk brain tissue between patients with MS and controls.

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1. Zhang Y, Tunyi J, Bhagwat A, et al. Assessment of Biological Aging in People With Multiple Sclerosis Using Epigenetic Clocks and p16INK4a. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. CE1.4.
2. Kular L, Klose D, Urdánoz-Casado A, et al. Epigenetic clock indicates accelerated aging in glial cells of progressive multiple sclerosis patients. Front Aging Neurosci. 2022;14:926468. Published 2022 Aug 24. doi:10.3389/fnagi.2022.926468
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