Project 2 Biological Age in Myasthenia Gravis: Impact on Stratification and Treatment Response

PROJECT 2 ABSTRACT Traditional approaches have predominantly used chronological age for disease stratification and treatment planning. However, emerging evidence suggests that biological age—an integrative measure incorporating genetic, environmental, and lifestyle factors—may offer a more accurate assessment of overall health and treatment response. We hypothesize that patients with myasthenia gravis (MG) may have a biological age that exceeds their chronological age and that effective treatment could lead to a reduction in biological age. Specific Aim 1 will characterize biological age using proteomic, transcriptomic, and methylation profiles from specimens obtained at the time of enrollment in the MGTX clinical trial of thymectomy (NCT00294658), which includes patients aged 18 to 65 years. We hypothesize that MG patients will exhibit a biological age greater than their chronological age. Specific Aim 2 will investigate the primary drivers of autoreactivity by assessing the relationship between immunological aging—measured by mitochondrial activity and DNA methylation in T lymphocytes—and the chronological onset of myasthenia gravis. We utilize the EXPLORE-MG biobank developed by the MGNet in its initial funding period. Specific Aim 3 will evaluate whether MG treatment is associated with a reduction in biological age and if a higher biological age predicts treatment resistance using MGTX trial specimens. This study is pioneering in its application of biological age metrics in MG, moving beyond chronological age to provide a more nuanced understanding of disease mechanisms and treatment response. By establishing biological age as a biomarker in MG, this study aims to enhance subject stratification for clinical trials, identify biological age as a treatment-responsive biomarker, and contribute to the broader field of personalized medicine. The findings could pave the way for biological age to become a standard outcome measure in future clinical trials of myasthenia gravis.