Ageing and Brain Health (McMurran Group)

Multiple Sclerosis is most commonly diagnosed in young adults, but it is a chronic condition 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.

Dr Chris McMurran and Dr Jonathon Holland were awarded the 2024 Vera Down grant to support research into ageing and brain repair in MS. In the video below, they discuss the research that this funding will support.

Age and remyelination

Damage to the myelin sheaths around nerve fibres can be repaired in a regenerative process called remyelination. However, much like wound healing in the skin, this repair process becomes less effective as people get older. In the CCMR One trial, we showed that the response to the remyelinating drug bexarotene was strongest in patients under the age of 42 (McMurran… Cunniffe, 2022, Ann Clin Transl Neurol.).

This result aligns with laboratory studies that have demonstrated problems in the oligodendrocyte progenitor cells, the immune response and the efficiency of remyelination in older animals.

Our systematic review of ageing and remyelination, led by Dr Trisha Mukherjee, was recently published in the journal Brain.

Age-related decline in remyelination is thought to be an important driver for secondary neuronal loss and increasing disability as people with MS get older. We are investigating this hypothesis in the ARMOUR-One study. In this observational cohort study, people with MS across the lifespan from childhood to old age have their myelin dynamics and axonal health mapped over time using visual assessments, MRI, clinical scores and blood biomarkers.

The treatment effect of bexarotene on VEP latency improvement (a biomarker for remyelination) reduces with increasing chronological age. From McMurran et al., 2022.

Biological ageing

Ageing is more than the simple passage of time. It is mediated by biological processes that vary between individuals due to genetic and environmental influences. The idea that people can age at different rates is a concept known as biological ageing. For example, two people aged 40 may show biological profiles more typical of age 20 and 60 respectively, reflecting differences in their physiology and disease risk.

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).

Our research aims to understand the relationship between remyelination, neuronal loss and biological ageing in people with MS. We do this by generating different measures of biological age in our clinical cohorts and linking these to remyelination 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

Our recently completed CCMR Two trial showed that the combination of metformin and clemastine can promote remyelination in people with relapsing remitting MS. The study tested a novel concept: whether an intervention that targets the underlying mechanisms of ageing can boost remyelination and neuronal protection in humans.

Metformin is an oral diabetes medication 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.

Pilot Healthy Brain Ageing Clinic

Outside of a research context, many opportunities already exist to improve brain health by targeting biological ageing. These include boosting physical activity, supporting other healthy behaviours and optimising the management of any co-existing medical conditions.

With involvement from patient and public contributors (including our Public Collaborators Ageing in MS focus group) we are launching a pilot Healthy Brain Ageing Clinic, funded by the NIHR Cambridge Biomedical Research Centre.

Participants will have a comprehensive review of their health and lifestyle, learn about their biological age, and work with a multi-disciplinary professional team to develop personalised strategies to improve long-term brain health.