For many decades the theory and practice of cross‐linking (bonding that ties two or more large molecules together side to side) have been developed in industry, but only since the 1940's has the theory been considered in the field of medicine as a primary reaction underlying age‐dependent changes.
Crosslinking is damaging to the tissues and involves loss of elasticity, reduced swelling capacity, increased resistance to hydrolases and probably enzymes generally, and thus an increase in molecular weight and a tendency toward embrittlement. There is a growing amount of direct evidence and much indirect evidence for postulating the relationship between crosslinking and aging.
Crosslinking agents present in the living organism include aldehydes, lipid oxidation products, sulfur, alkylating agents, quinones, free radicals induced by ionizing radiation, antibodies, polybasic acids, polyhalo derivatives and polyvalent metals. The latter four types of compound are slow‐acting but can also accumulate in the body to form a frozen metabolic pool. Sufficient amounts of all these potential crosslinking materials are present in the body to make the changes of aging unavoidable.
Evidence is presented which indicates that an interaction occurs between proteins and an autoxidizing unsaturated lipid. Using a model system approach, it has been established that two purified proteins (gelatin and insulin) are chemically modified in the presence of an autoxidizing lipid, methyl linoleate.
The insulin‐methyl linoleate interaction has been studied chromatographically after acid and alkaline hydrolysis, and also by using the Sanger end group analysis method. The data indicate that lipid intermediates react with theॉ‐amino group of lysine, and also with phenylalanine and glycine, the N‐terminal amino groups of insulin.
Hydrogen fluoride solubility and enzyme hydrolysis determinations indicate that the autoxidation products of methyl linoleate interact with protein to produce new chemical entities through cross‐linking.
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