Aspirin ameliorates lens biomechanics by improving protein solubility and chaperone activity of αB-crystallin

Lens is an avascular tissue with no protein turnover. As a result, post-translational modifications (PTMs) on lens protein continue to accumulate with age and are implicated in presbyopia and cataract formation. Delaying or treating cataracts or presbyopia remains challenging. Previously, we demonstrated that lysine acetylation is an important post-translational modification of lens proteins, which can reduce lens stiffness. However, the successful delivery of acetyl donors into the lens of non-human primates and the study of its efficacy in reducing lens stiffness remains unexplored. In this study, we investigated the effect of aspirin on lens protein solubility and stiffness. Treatment with aspirin increased the solubility of water-insoluble lens proteins. Aspirin treatment which increased endogenous acetyllysine levels, concurrently enhanced the stability of bovine lens proteins and chaperone activity of human αB-crystallin proteins. Aspirin-mediated acetylation dissociated the oligomeric assembly and increased the surface hydrophobicity of αB-crystallin. Aspirin treatment significantly reduced the stiffness of ex-vivo cultured mouse lenses and in-vivo mouse eyes when applied topically, while also increasing endogenous acetylation levels in lens proteins. Altogether, our experimental findings support the development of aspirin and its derivatives as potential therapeutic agents to treat presbyopia.