Conformational drift of long-lived proteins in the human eye: Insights into post-translational modifications and...

Long-lived proteins provide a uniquely informative substrate for studying the molecular chemistry of human ageing, and the eye offers one of the most accessible and spatially resolved systems for examining this process. The lens remains the principal model: its central crystallins are synthesized during embryonic and early postnatal life and are retained throughout the lifespan, thereby preserving a cumulative record of irreversible chemical damage. We then extend this framework to other ocular compartments that contain long-lived or slowly turned-over proteins, including Bruch's membrane, the lens capsule and membrane proteome, the trabecular meshwork, and the corneal stroma, where cumulative chemical damage to structural proteins and extracellular matrices may likewise shape tissue ageing and disease susceptibility. With age, these proteins acquire extensive post-translational modifications, including deamidation, isoaspartate formation, racemization, truncation, oxidation, disulfide rearrangement, glycation, carbamylation, and photochemical adducts, which progressively reshape their conformational landscape. This review, we propose that the progressive, cumulative effect of these modifications constitutes a process defined as conformational drift: a chemically encoded displacement of protein ensembles away from their native conformational states toward heterogeneous, destabilized, poorly soluble, and aggregation-prone forms. For instance, in the lens, this process disrupts crystallin packing, depletes the chaperone reserve of α-crystallin, promotes phase separation and light scattering, and contributes to age-related stiffening of the lens nucleus. Finally, we critically evaluate current analytical strategies for mapping these molecular events and argue that the human eye offers an underused model for mechanistic geroscience beyond ophthalmology.