The Maillard or non-enzymatic glycosylation reaction is the reaction which occurs between reducing sugars and proteins. It leads to the formation of protein adducts and crosslinks thought to be responsible for age- and diabetes-related stiffening of collagen-rich tissues. With previous funding from the National Institute on Aging, our laboratory has contributed toward establishing the structure of the first fluorescent cross- link of the Maillard reaction in vivo, the role of pyrroles in protein aging by glucose, the biological significance of glycoxidation in aging and age- related diseases, especially diabetes and end stage renal disease, and the relationship between glycation, glycoxidation and longevity. Finally, our laboratory has discovered, characterized and cloned deglycating enzymes (Amadoriases) from soil organisms. These data, together with those from other laboratories, now implicate a strong link between the formation of advanced of advanced Maillard products (AGEs), metabolic pathways along the glucose axis, and age- related crosslinking of collagen. However, whereas a general picture is now emerging, it is unclear why, e.g., dog collagen is becoming crosslinked at much higher rate than human collagen, and which crosslinks are important in dictating the physical-chemical properties of the aging extracellular matrix.
In Specific Aim 1 (part 1), we hypothesize that non-UV active and/or labile crosslinks must be forming during the advanced Maillard reaction which comprise besides lys-lys, also lys-arg and arg-arg crosslinks. Some of these may involve amide and amidine bonds whereby dicarbonyl compounds are expected to play major roles in their formation. In part 2 of Specific Aim 1 we will initiate research into the role of the non- oxidative pathway, so called 2,3-enolization pathway of the Maillard reaction in crosslink formation and develop specific probe for its occurrence in vivo.
In Specific Aim 2, we will collaborate with Dr. Julie Kornfield's group at Caltech and attempt to identify the crosslinks that are most determinant in dictating the physical-chemical properties of collagen in the reaction initiated by glyceraldehyde.
In Specific Aim 3, we will identify the nature and sites of crosslinks that are responsible for the accelerated crosslinking in the glyceraldehyde (Specific Aim 2) and the dog model of accelerated aging. We will also investigate the potential role of ornithine as a novel crosslinking amino acid in aging human collagen. Our approach, we expect, will result in the first comprehensive, hierarchical map of collagen crosslinks that for, during aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Special Emphasis Panel (ZRG1-PBC (03))
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Finkelstein, David B
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Case Western Reserve University
Schools of Medicine
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Dammann, Philip; Sell, David R; Begall, Sabine et al. (2012) Advanced glycation end-products as markers of aging and longevity in the long-lived Ansell's mole-rat (Fukomys anselli). J Gerontol A Biol Sci Med Sci 67:573-83
Sell, David R; Strauch, Christopher M; Shen, Wei et al. (2008) Aging, diabetes, and renal failure catalyze the oxidation of lysyl residues to 2-aminoadipic acid in human skin collagen: evidence for metal-catalyzed oxidation mediated by alpha-dicarbonyls. Ann N Y Acad Sci 1126:205-9
Dai, Zhenyu; Wang, Benlian; Sun, Gang et al. (2008) Identification of glucose-derived cross-linking sites in ribonuclease A. J Proteome Res 7:2756-68
Sell, David R; Strauch, Christopher M; Shen, Wei et al. (2007) 2-aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin: effects of diabetes, renal failure and sepsis. Biochem J 404:269-77
Fan, Xingjun; Reneker, Lixing W; Obrenovich, Mark E et al. (2006) Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model. Proc Natl Acad Sci U S A 103:16912-7
Genuth, Saul; Sun, Wanjie; Cleary, Patricia et al. (2005) Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications p Diabetes 54:3103-11
Sell, David R; Biemel, Klaus M; Reihl, Oliver et al. (2005) Glucosepane is a major protein cross-link of the senescent human extracellular matrix. Relationship with diabetes. J Biol Chem 280:12310-5
Sell, David R; Monnier, Vincent M (2005) Ornithine is a novel amino acid and a marker of arginine damage by oxoaldehydes in senescent proteins. Ann N Y Acad Sci 1043:118-28
Sell, David R; Monnier, Vincent M (2004) Conversion of arginine into ornithine by advanced glycation in senescent human collagen and lens crystallins. J Biol Chem 279:54173-84
Rutter, Kathryn; Sell, David R; Fraser, Nalani et al. (2003) Green tea extract suppresses the age-related increase in collagen crosslinking and fluorescent products in C57BL/6 mice. Int J Vitam Nutr Res 73:453-60

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