Persons with multiple sclerosis (MS) suffer neurodegeneration and functional decline despite effective management of new inflammatory lesion formation by modern treatments. We must therefore identify modifiable risk and protective factors associated with disease progression. There is high interest among people living with MS and their clinicians about the protective effects of diet, and we have linked Mediterranean diet to less cerebral atrophy and better functional outcomes, but the underlying mechanisms are unknown. This R01 will evaluate biological aging as a mediator for observed effects of diet on neurodegeneration and disease progression in MS. Our team has linked biological aging to neurodegeneration in MS, and others have linked biological aging to Mediterranean-style diets in non-MS populations, which informed our hypothesis that biological aging (BA), measured through the National Health and Nutrition Examination Survey Biological Aging Index (NHANES BAI) and leukocyte telomere length (LTL), is a mediator of observed effects of diet on neurodegeneration in MS. The study will leverage two distinct pre-existing cohorts with rich clinical and imaging data and specimen collection. The first is RADIEMS (Reserve Against Disability in Early MS), an NIH- funded longitudinal study of risk and protective factors for disability in people with early MS that enrolled 185 people with MS in 2016-2017. This cohort provides longitudinal dietary, clinical, and imaging data, and specimens. The current proposal will link into RADIEMS follow up for the next 3 years but will also be able to powerful analyses encompassing 8 years of follow up data. The second is a cross- enrolled in Project Y in 2016 at age 50. The Project Y cohort will provide additional information on an older population of individuals with MS as well as provide a data set where chronological age is constant, simplifying the biological aging analyses. The specific aims are designed to evaluate: the effect of diet on biological age in people with MS (aim 1), the impact of diet and BA on brain atrophy and the degree to which dietary relationships are mediated by BA (aim 2), the impact of diet and BA on clinical MS worsening and the degree to which dietary relationships are mediated by BA (aim 3). These will be accomplished by adding the NHANES BAI to RADIEMS (which requires participant interaction but can be done because RADIEMS is ongoing) and by adding LTL analysis to both cohorts (which can be done using banked samples). Detailed data on other health behaviors and demographics are available for both cohorts and will be considered and accounted for in all analyses. This study will contribute to a growing body of literature that will help inform a more holistic approach to MS care, which is eagerly sought by people living with MS. The results of this proposal have high potential for impact in advancing our understanding of the pathophysiology of neurodegeneration and informing recommendation...