Clinical MS Research Group
Ageing in Multiple Sclerosis (McMurran Group)
Multiple Sclerosis is most commonly diagnosed in young adults, but it is a chronic disease that people live with as they get older. Increasing age is associated with worse recovery after relapses, reduced benefit from disease-modifying therapies and a higher chance of progressive disease. Older patients are also more likely to have other medical conditions and medications, both of which can interact with their MS.
Recently, Dr Chris McMurran and Dr Jonathon Holland were awarded the 2024 Vera Down grant. In the video below, they discuss the research that this funding will support.
The treatment effect of bexarotene on VEP latency improvement (a biomarker for remyelination) reduces with increasing chronological age. From McMurran et al., 2022.
Age and remyelination
Damaged myelin sheaths can regenerate in a process called remyelination. Just like healing of a skin wound, this repair process becomes less effective as people get older. We have shown that the response to the remyelinating drug bexarotene in the CCMR One trial was best in patients under the age of 42 (McMurran… Cunniffe, 2022, Ann Clin Transl Neurol.).
This result is consistent with laboratory studies that have demonstrated problems in the oligodendrocyte progenitor cells, the immune response and the efficiency of remyelination in older animals.
It is thought that the age-related decline in remyelination is an important driver for secondary neuronal loss and increasing disability as people with MS get older. We are testing this hypothesis in the ARMOUR-One study. In this observational cohort study, people with MS from childhood to old age have their myelin dynamics and axonal health mapped over time using visual assessments, MRI, clinical scores and blood biomarkers.
Biological age
Ageing is more than the simple passage of time, but is instead mediated by biological processes. These processes can vary with genetic and environmental factors, such that different people can age at different rates – a concept known as biological age. For example, two people aged 40 might have biological ages of 20 and 60, representing different degrees of age-related changes in their physiology.
Many different approaches exist to measure biological age, including the use of clinical blood test results, DNA methylation patterns or volumetric brain MRI data. We have shown that for two healthy people with the same chronological age, an older blood- or methylation-based biological increases the risk of developing various neurological conditions in the future (McMurran et al., 2023, Brain; Mak & McMurran et al., 2023, JNNP).
We seek to understand the relationship between remyelination, neuronal loss and biological age in people with MS. We do this by generating different measures of biological age in our clinical cohorts and linking these to remyelination outcomes. We also use big data approaches to measure biological age in large international MS cohorts and explore how this relates to clinical outcomes.
Understanding the interaction between biological age and MS could lead to more accurate prognostic information for people with MS. Additionally, a growing class geroprotective drugs aims to target the biological mechanisms that drive ageing. These interventions hold promise as a means to delay or prevent problems that people with MS face as they get older.
Geroprotective drugs in MS
The CCMR Two trial tests the combination of metformin and clemastine to promote remyelination in participants with relapsing remitting MS. Metformin is an oral diabetes drug that has an evidence base as a geroprotective drug: it can slow or postpone multiple age-related pathologies in laboratory models, as well as in people. Giving metformin to aged mice or rats rejuvenates their oligodendrocyte progenitor cells so that they respond better to remyelinating drugs like clemastine.
This exciting clinical trial tests whether an intervention that targets the underlying mechanisms of ageing can boost remyelination and neuronal protection in humans.