Bonding between glucose molecules and proteins leads to the buildup of glucose molecules on protein surfaces. Dubbed Advanced Glycosylation Endproducts (AGEs), these glucose-protein complexes are also thought to lead to the formation of protein crosslinks as multiple proteins become associated with the AGE complex. These crosslinks are thought to be a major marker and possible impetus in aging in general, an often cited example of crosslinking being the wrinkling of the skin. Recently the role of these AGEs and crosslink complexes have gained attention within the context of diabetes and also with the development of a number or novel drugs.
Diabetes is a disease wherein the pancreas is incapable of secreting enough insulin to metabolize the glucose from our food, resulting in high blood sugar levels. Over time high blood sugar levels lead to increased AGE formation, and subsequently the crosslinking of proteins. Ramipril is a drug used to lower the blood pressure of diabetic patients and it has stopped the buildup of AGEs in diabetic rats. It belongs to a class of drugs called ACE inhibitors, for their ability to block the action of "angiotensin converting enzyme." The specific mechanism of these drugs efficacies in glucose regulation isn't completely clear, but it is interesting to think of the role similar drugs might play in the future with non-diabetic patients. Might the blocking of AGE buildup be accomplished by similar drugs in patients without diabetes? Side effects of ACE inhibitors might not grant them such a role, but they're not the only drugs on the market for combating AGEs and crosslinks.
Alteon, in Ramsey New Jersey, has developed drugs that inhibit the formation of crosslinks, as well as break them. They've completed Phase II/III trials with Pimagedine, an agent that inhibits the formation of AGEs. ALT-711 has reached Phase II trials as a crosslink-breaking agent. Hopefully, as more experiments pan out, the resulting data will be as good as the preliminary results seem. Such drugs could have far reaching implications for the attentuation of aging. Crosslinking seems to be a major component of aging, and thus as agents for treating pathologies like diabetes become more refined, the developement of agents that slow glycosylation or resolve AGE-related diseases in non-diabetics holds more potential for increasing longevity.
Recent Related References:
- Effects of advanced glycosylation endproducts on perlecan core protein of glomerular epithelium. Ha TS, Song CJ, Lee JH. Pediatr Nephrol. 2004 Nov. PMID: 15449170
- A receptor for advanced glycosylation endproducts (AGEs) is colocalized with neurofilament-bound AGEs and SOD1 in motoneurons of ALS: immunohistochemical study. Chou SM, Han CY, Wang HS et al. J Neurol Sci. 1999 Oct 31. PMID: 10540014
- Receptors for advanced glycosylation endproducts in human brain: role in brain homeostasis. Li JJ, Dickson D, Hof PR et al. Mol Med. 1998 Jan. PMID: 9513189
- Advanced glycosylation endproducts in diabetic renal disease: clinical measurement, pathophysiological significance, and prospects for pharmacological inhibition. Bucala R, Vlassara H. Blood Purif. 1995. PMID: 7619388
- Transposition of an Alu-containing element induced by DNA-advanced glycosylation endproducts. Bucala R, Lee AT, Rourke L et al. Proc Natl Acad Sci U S A. 1993 Apr 1. PMID: 8385341
- Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. Hogan M, Cerami A, Bucala R. J Clin Invest. 1992 Sep. PMID: 1522220
- Two novel rat liver membrane proteins that bind advanced glycosylation endproducts: relationship to macrophage receptor for glucose-modified proteins. Yang Z, Makita Z, Horii Y et al. J Exp Med. 1991 Sep 1. PMID: 1651976
- Advanced glycosylation endproducts on erythrocyte cell surface induce receptor-mediated phagocytosis by macrophages. A model for turnover of aging cells. Vlassara H, Valinsky J, Brownlee M et al. J Exp Med. 1987 Aug 1. PMID: 3598465
- Leishmania promastigotes are recognized by the macrophage receptor for advanced glycosylation endproducts. Mosser DM, Vlassara H, Edelson PJ et al. J Exp Med. 1987 Jan 1. PMID: 3025330
- Accumulation of advanced glycosylation endproducts on proteins and nucleic acids: role in ageing. Cerami A. Prog Clin Biol Res. 1985. PMID: 4059281
