The human body contains many long-lived proteins (LLPs) [1]. With age, these LLPs deteriorate,with consequences both for aging and disease [2]. LLPs undergo a range of modifications with some, such as glycationand oxidation, being the result of external reactive molecules. The majority of modifications appear to be spontaneous, and occur due to the structures of amino acid side chains and their local environment e.g. unstructured regions permit more allowable conformations and larger degrees of modification. Certain amino acids, in particular Asn, Asp, Gln, Cys, Thr and Ser, are especially susceptible to deterioration and their spontaneous modifications result in racemization, deamidation and protein cleavage [2]. Another common modification associated with aged LLPs is non-disulphide covalent crosslinking. This has been observed in a number of aged proteins however, the mechanisms underpinning the formation of such non-disulphide crosslinks have, until very recently, been poorly understood. Some examples where the mechanism underlying such covalent crosslink formation has been elucidated, will be outlined.
Three human age-related diseases; cataract, multiple sclerosis and Alzheimer’s disease will be used to illustrate the spectrum of spontaneous protein modifications and how these could play a role in the onset of the conditions. The fact that a number of separate events typically occur along the backbone sequence of any individual aged LLP, makes modelling these processes extremely difficult, and thus ascribing disease causation to such modifications is not straightforward. In such cases correlation may have to suffice. Despite this limitation, it will nevertheless be important for a thorough understanding of many human age-related diseases to recognise the role played by degraded old proteins.