Effect of MDL-800 induced SIRT6 activation on gene expression of primary human chondrocytes

SIRT6, a nuclear deacetylase that regulates multiple aging-related pathways, is an attractive target for age-associated OA, yet its specific role in this context remains poorly defined. Here, we show that weekly administration of the small-molecule SIRT6 activator, MDL-800, to mice from 18 to 24 months of age significantly attenuates OA pathology.

RNA sequencing demonstrates that MDL-800 suppresses pathways linked to angiogenesis and bone formation while enhancing epigenetic regulation, telomere maintenance, and mitochondrial function in older chondrocytes. In vitro, SIRT6 activation by MDL-800 reduces oxidative stress–induced p38 MAP kinase signaling in aged human chondrocytes and enhances DNA repair in OA human and aged murine synovial fibroblasts. These findings support SIRT6 activation as a promising therapeutic approach to target multiple hallmarks of aging and slow age-associated OA progression.