Proposing the Cross-Link EGGL as a Target in Aging Tissue
Between our cells is the complex support structure of the extracellular matrix. It becomes extensively damaged in aging by the formation of cross-linked proteins, stuck together by sugars and other metabolic byproducts that the body fails to clear. This causes loss of elasticity in tissues like skin and blood vessels, as well as numerous other forms of harm. Glucosepane is by far the most important of these cross-linking compounds, but there is comparatively little work being done on ways to break down glucosepane, and thus reverse its effects on tissues, and remove this contribution to degenerative aging.
Here one of the researchers involved in present work on clearing glucosepane advances another target cross-link compound that might also be addressed:
Ageing 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. In this paper I review the role of EGGL, a cross-link formed by transglutaminase enzymes, and particularly the widely expressed isozyme 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 outwith 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. I review blockade of TG and active removal of EGGL as therapeutic strategies, and conclude 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.