Transglutaminse 2 and EGGL, the Protein Cross-Link Formed by Transglutaminse 2, As Therapeutic Targets for Disabilities of Old Age

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.

Role of Magnesium Deficiency in Promoting Atherosclerosis, Endothelial Dysfunction, and Arterial Stiffening as Risk Factors for Hypertension

“…TG2 activity is associated with arterial stiffening in humans and rats. TG2 forms glutamine-lysine cross-links between variety of extracellular proteins, including collagen and elastin [ 62 ]. TG2 is secreted through a Golgi-independent mechanism to the ECM, where it can be activated to a Ca 2+ -bound open conformation to catalyze the formation of isopeptide bonds [ 61 ].…”

“…TG2 is secreted through a Golgi-independent mechanism to the ECM, where it can be activated to a Ca 2+ -bound open conformation to catalyze the formation of isopeptide bonds [ 61 ]. Thus, Ca 2+ may be limiting TG2 activity in the ECM [ 62 ]. TG2 is activated by Ca 2+ , and inhibited by Mg 2+ [ 63 ].…”

Commentary on Some Recent Theses Relevant to Combating Aging: February 2015

“…Although accelerated in diabetes, this process occurs throughout the life span in all human tissues, and a method for breaking existing cross-links is expected to be an essential component of a comprehensive rejuvenation program. 24 (The solutions evolved by hyper-thermophilic microbes to repair early stages in the glycation process before long-lived cross-links form at all 25 might also be employed prophylactically to reduce the rate of accumulation.) The identification in this study of a number of pathological phenomena that correlate specifically with stiffness, particularly increased angiogenic branching and impaired barrier function, will lend further support to the still-neglected strategy of cross-link removal by emphasizing its relevance to the headline diseases of cancer and atherosclerosis.…”

Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency

“…The consequences of TG2 deficiency in humans are unknown. However, it has been suggested that TG2-mediated cross-linking occurs predominantly in damaged or ageing human tissues [11]. Amongst affected tissues, TG2 is strongly expressed in human atherosclerotic plaques, where it may contribute to plaque stability.…”