J.D. Furber

Extracellular aging -- accumulating molecular damage by glycation, oxidation, and crosslinking of long-lived extracellular proteins, mainly collagen and elastin -- is a major cause of several important human aging pathologies. Crosslinking increases mechanical stiffness of blood vessels and urinary bladder. Crosslinking impairs functioning of kidney, heart, retina, and other tissues and organs. Glycation adducts trigger inflammatory signaling, provoking tissue damage and cancers. Crosslinking tightens up the extracellular matrix (ECM), hardening it against natural turnover processes. Known crosslink breakers (eg. alagebrium, of the thiazolium halide family) are only partly effective because they break only a subset of AGE crosslink structures (sugar-derived alpha-diketone bridges). So far, no agent has been found which breaks the more prevalent glucosepane crosslink structures. Enzymes which are able to recognize and disassemble glycation products are too big to migrate into the ECM and repair collagen or elastin in vivo. Two approaches to therapy development are presented: ECM Turnover Stimulation would activate or enhance natural processes to digest old ECM and replace it with new. It will be important to tune the collagen degradation to a rate slow enough to prevent dire side effects, such as hemorrhage from leaky blood vessels as collagen molecules are removed and replaced. Glucosepane Breaker Discovery would use rational drug design and high-throughput screening to find small molecules which are able to break glucosepane crosslinks of extracellular proteins. Candidates would be further screened for selectivity in order to ensure that only glucosepane gets broken.

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