Associations of biological aging with outcomes and immune dysregulation 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 afflicting around one million people in the United States. The disease often presents with a relapsing-remitting phase followed by gradual conversion to secondary progressive MS (SPMS) characterized by irreversible accrual of disability and unresponsiveness to current disease-modifying therapies for MS. Age carries the highest risk for developing SPMS, yet the underlying cellular, molecular, and genetic processes contributing to biological aging are understudied in MS. Recent progress in aging research have led to the emergence of geroscience as an interdisciplinary approach that seeks to reduce the incidence and severity of chronic age- related diseases by understanding aging physiology and developing clinical interventions targeting aging mechanisms. However, no studies to date have investigated the role of biological aging in MS using established markers of cellular senescence (p16INK4a) and epigenetic aging (age-associated DNA methylation patterns, or epigenetic clocks). The Trans-NIH Geroscience Interest Group recently emphasized a need to engage researchers and clinicians across multidisciplinary specialties to translate geroscience discoveries into effective clinical practices. Through the completion of this career development award, Dr. Zhang will become one of few clinician scientists in the country whose research combines principles of geroscience with neurology. This proposed study will investigate the associations of biological aging with clinical outcomes (aim 1), neuroimaging findings (aim 2), and immune dysregulation (aim 3) in people with MS. The study will consist of a cross-sectional analysis of baseline associations of biological aging with MS outcomes and a 2-year longitudinal analysis of the rate of biological aging with changes in MS outcomes. Dr. Zhang has assembled a multidisciplinary mentorship team to achieve his career development goals of establishing a geroscience framework to study MS by integrating clinical, neuroimaging, and molecular mechanistic studies. The successful completion of this project will enable future studies to 1) use biological aging as a prognostic biomarker in MS to employ early aggressive treatment in individuals with accelerated biological aging and 2) conduct trials of anti-aging therapies in combination with MS disease-modifying therapies to mitigate or even prevent MS progression.
