Markers of Biological Aging in Multiple Sclerosis
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PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the central nervous system affecting nearly one million people in the United States. Age is the predominant driver of disease progression in MS, and older individuals with MS are at higher risk of conversion to secondary-progressive MS (SPMS), which is a disease phenotype marked by progressive worsening of neurological function over time and resistance to MS disease-modifying therapies. The onset of SPMS can be delayed or prevented through early aggressive treatment of MS; nevertheless, this strategy involves using higher risk therapies, so it is important to identify those who will derive the most benefit from this treatment strategy. Current understanding of aging in MS is mostly limited to epidemiological studies of chronological age in patients with MS. Increasing evidence on the biological mechanisms of aging shows variations among individuals that are often inaccurately reflected by their chronological age. These mechanisms involve genetic pathways and biochemical processes that regulate the accumulation of damage over time, which eventually overwhelm compensatory repair mechanisms and lead to age-related decline. Measuring biological age in MS would uncover mechanisms by which age affects disease course and identify patients at risk of conversion to SPMS. Nevertheless, differences in biological age among people with MS have not been adequately characterized, and the effects of biological aging on disease course remain unknown. This proposed study will be the first to measure multiple distinct hallmarks of biological aging using established aging biomarkers including leukocyte telomere length reflecting telomere attrition, p16INK4a as a marker of cellular senescence, and the epigenetic clock as a measure of age-associated DNA methylation patterns. For aim 1, we will measure the aforementioned serum aging biomarkers in patients with MS and age- and sex-matched healthy controls. For aim 2, we will determine associations between biomarkers of aging and their associations with MS disease characteristics in a cross- sectional study and with exploratory longitudinal observations for one year. This research will determine the differential contributions of various aging mechanism to MS disease outcomes and represents a critical step to identifying patients at risk of worse disease outcomes who may benefit from early high-intensity therapies to prevent or delay the onset of SPMS. This award will support the applicant’s development as a clinician scientist by integrating principles of geroscience with neurology. The successful completion of the aims will lay the foundation for a future career development award application and lead to opportunities for incorporating measurements of biological aging to identify individuals with RRMS at higher risk for conversion to SPMS who may benefit from early aggressive treatment.
