Abstract
Aging of the extracellular matrix (ECM), the protein matrix that surrounds and penetrates the tissues and binds the body together, contributes significantly to functional aging of tissues. ECM proteins become increasingly cross-linked with age, and this cross-linking is probably important in the decline of the ECM's function. This article reviews the role of ε-(γ-glutamyl)-lysine (EGGL), a cross-link formed by transglutaminase enzymes, and particularly the widely expressed isozyme transglutaminase 2 (TG2), in the aging ECM. There is little direct data on EGGL accumulation with age, and no direct evidence of a role of EGGL in the aging of the ECM with pathology. However, several lines of circumstantial evidence suggest that EGGL accumulates with age, and its association with pathology suggests that this might reflect degradation of ECM function. TG activity increases with age in many circumstances. ECM protein turnover is such that some EGGL made by TG is likely to remain in place for years, if not decades, in healthy tissue, and both EGGL and TG levels are enhanced by age-related diseases. If further research shows EGGL does accumulate with age, removing it could be of therapeutic benefit. Also reviewed is the blockade of TG and active removal of EGGL as therapeutic strategies, with the conclusion that both have promise. EGGL removal may have benefit for acute fibrotic diseases, such as tendinopathy, and for treating generalized decline in ECM function with old age. Extracellular TG2 and EGGL are therefore therapeutic targets both for specific and more generalized diseases of aging.