|Abstract:||Osteoarthritis (OA) is among the top 10 diseases limiting human healthspan, and no disease modifying therapies currently exist. OA is a degenerative disease of the whole joint, characterized by articular cartilage loss, subchondral bone sclerosis, meniscal calcification, synovitis, and skeletal muscle dysfunction. Inhibiting the mechanistic target of rapamycin (mTOR) and stimulating AMP-activated protein kinase (AMPK) has extended lifespan and protected against post-traumatic (secondary) OA in mice. However, it remains unknown if manipulation of these pathways can protect against naturally occurring, age-related (primary) OA, the form most commonly observed in humans. The outbred Dunkin-Hartley (DH) guinea pig develops primary OA beginning at 5 months of age and displays high histological similarity to human OA. Therefore, at 5 months we sacrificed a group of DH guinea pigs to serve as young control and the remaining animals were randomized to receive a standard diet (age-matched controls) or diets enriched with rapamycin (Rap; 14ppm), metformin (Met; 1000ppm), or a combination of rapamycin plus metformin (Rap+Met) for 3 months. Hind limbs were collected for histopathological and radiographic evaluation of the knee joint. Histological OA scores in DH guinea pigs receiving Rap and Rap+Met were significantly lower than their age-matched controls. Rap treatment also reduced subchondral cortical bone thickness in the medial and lateral tibia, while Rap+Met reduced cortical thickness only in the lateral tibia. Both OA scores and cortical thickness were highly correlated with bodyweight, suggesting reduced joint loading could be contributing to the protective effects of Rap and Rap+Met. The minimal effect of Met may be attributed to low dose and indicates that Rap likely drove the protective effects of Rap+Met. Together, these data are the first to suggest that mTOR inhibition delays the onset of primary, age- related OA in the DH guinea pig.