Long-lived proteins are found at several sites in the body and they undergo numerous changes as a result of prolonged exposure to physiological conditions. Truncation is a common modification and many cleavages appear to be non-enzymatic, however little is known about the processes involved. In this study we demonstrate, using synthetic peptides that incorporate the sequence of a protein that is known to cleave in older lenses, that truncation on the N-terminal side of serine residues can occur at neutral pH. A mechanism that incorporates an N,O-acyl shift, which is analogous to intein cleavage, is proposed. Such cleavages may explain the origin of abundant peptides derived from crystallins in aged human lenses.