To address the need for early knee osteoarthritis (OA) markers by testing if longitudinal cartilage thickness changes are associated with specific biomechanical and biological measures acquired at a baseline test in asymptomatic aging subjects. Thirty-eight asymptomatic subjects over age 45 years were studied at baseline and at an average of 7-9 year follow-up. Gait mechanics and knee MRI were measured at baseline and MRI was obtained at follow-up to assess cartilage thickness changes. A subset of the subjects (n=12) also had serum cartilage oligomeric matrix protein measured at baseline in response to a mechanical stimulus (30-minwalk) (mCOMP). Baseline measures, including the knee extension (KEM), flexion (KFM), adduction (KAM) moments and mCOMP, were tested for associations with cartilage thickness changes in specific regions of the knee. Cartilage change in the full medial femoral condyle (p=0.005) and external medial femoral region (p=0.041) was negatively associated with larger early stance peak KEM. Similarly, cartilage change in the full medial femoral region (p=0.009) and medial femoral external region (p=0.043) was negatively associated with larger first peak KAM, while cartilage change in the anterior medial tibia was positively associated with larger first peak KAM (p=0.003). Cartilage change in the anterior medial tibia was also significantly associated (p=0.011) with mCOMP levels 5.5-hpost-activity (percentage of pre-activity levels). Interactions found between gait, mechanically-stimulated serum biomarkers, and cartilage thickness in an at-risk aging asymptomatic population suggest the opportunity for early detection of OA with new approaches that bridge across disciplines and scales.