Proteomic Age Acceleration in Multiple Sclerosis Precedes Symptom Onset and Associates with Severity

Abstract Biological aging is accelerated in people with multiple sclerosis, but whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic (β=2.2, 95% CI 1.2–3.2, P <0.001, FDR<0.001), brain (β=1.7, 95% CI 0.6–2.7, P =0.003, FDR=0.01), muscle (β=2.5, 95% CI 1.3–3.7, P <0.001, FDR<0.001), and immune age (β=1.8, 95% CI 0.6–2.9, P =0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic (β=0.7, 95% CI 0.0–1.4, P =0.04, FDR=0.34) and brain age (3.2 years, 95% CI 2.1–4.3, P <0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset systemic: (β=1.0, 95% CI 0.4–1.7, P =0.002, FDR=0.02); brain: (β=2.4, 95% CI 1.2–3.7, P <0.001, FDR=0.002), whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score (β=0.14, 95% CI 0.05–0.24, P =0.005, FDR=0.03) and slower walking speed (β=0.02, 95% CI 0.01–0.03, P =0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score (β=0.17, 95% CI 0.10–0.24, P <0.001, FDR<0.001), poorer manual dexterity (β=0.28, 95% CI 0.04–0.52, P =0.03, FDR=0.30), slower walking speed (β=0.02, 95% CI 0.01–0.03, P =0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer (β= −0.26, 95% CI −0.41 to −0.10, P =0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses (β= −0.35; 95% CI −0.65 to −0.05; P =0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain (β= −0.002, 95% CI −0.003 to −0.001, P =0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness (β= −0.21, 95% CI −0.39 to −0.03, P =0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.