Anaerobic vs aerobic pathways of carbonyl and oxidant stress in human lens and skin during aging and in diabetes: A comparative analysis

Abstract

The effects of anaerobic (lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones (MG-H1), carboxymethyl-lysine (CML), and carboxyethyl-lysine (CEL) are several folds higher in lens than skin, and markedly increase upon incubation of lens crystallins with 5 mM ascorbic acid. Vice-versa, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones (G-H1), metal catalyzed oxidation (allysine) and H 2 O 2 dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the aging lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P<0.001) but has surprisingly little effect on the absolute level of most other advanced glycation end products (AGEs) . However, diabetes strengthens the Spearman correlation coefficients for age-related accumulation of hydrogen peroxide mediated modifications in the lens. Overall, the data suggest oxoaldehyde stress involving methylglyoxal from either glucose or ascorbate is predominant in the aging non-cataractous lens, while aging skin collagen undergoes combined attack by non-oxidative glucose mediated modifications, as well as those from metal catalyzed oxidation and H 2 O 2 . Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2011 September 1. Long lived proteins such as lens crystallins and collagen are prone to age-related accumulation of damage by glycation and oxidation which are thought to contribute to loss of protein solubility, impaired function, increased tissue stiffness and sclerosis during aging. The predilection for nucleophilic amino acids, in particular lysine and arginine residues as targets of glycation results in profound molecular changes characterized by increased anionic charge, formation of non-disulfide crossslinks [1,2], and increased binding of redox active catalytic metals [3], all of which impact both on the protein molecule itself and its interaction with ligands or cells [4,5].In the lens, crystallin modification can result in increased or decreased chaperone activity [6,7] and formation of light scattering aggregates that are observed ...

The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes

“…Similarly, there was no reduction of MG-H1 by improved glycemic control. These data, together with the recent demonstration that only three out of 23 skin collagen specimens from diabetic donors had elevated MG-H1 levels 31 suggests that tissue-bound methylglyoxal levels are sporadically elevated in diabetic humans, although serum and LDL-bound levels clearly are elevated by diabetes 37,38 . Similarly to MG-H1, CEL was not reduced by glycemic control, although it was elevated by diabetes (Fig.…”

“…While considerable work remains to be performed on the full biological effects of GSPNE, its formation in diabetes is expected to be highly deleterious because it is the single major AGE and extracellular matrix (ECM) protein crosslink discovered to date 31 . First, it is expected to dramatically decrease the turnover rate of the modified ECM and contribute to basement membrane thickening in diabetes, 32 decreasing the tissue repair rate, as observed in diabetic nephropathy 33 .…”

The LEGSKO Mouse: A Mouse Model of Age-Related Nuclear Cataract Based on Genetic Suppression of Lens Glutathione Synthesis

“…Another important function of GSH is the detoxification of the oxoaldehydes glyoxal and methylglyoxal, the latter being one of the most important sources of protein damage in aging and cataractous lenses [12], [13], [34]. For this reason we expected to find increased levels of carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL) and MG-H1 hydroimidazolone.…”

“…This is in part attributed to lowered γ-glutamyl-cysteine ligase (Gcl) activity [10] and a barrier to GSH diffusion toward the nucleus [9]. As a result ascorbic acid is increasingly oxidized throughout life leading to accelerated accumulation of crystallin-bound advanced glycation end products (AGEs) that contribute to cataractogenesis [11], [12], [13]. Concomitantly, increased protein residue oxidation is observed, as reflected by the formation of methionine sulfoxide, protein disulfides, kynurenine, and o-tyrosine from methionine, cysteine, tryptophan and phenylalanine, respectively [13], [14], [15].…”

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

“…Multiple studies have also demonstrated a decreased activity of the glyoxalase system and subsequently accumulation of MGO-derived AGEs in the ageing human lens, which can potentially contribute to the development of age-dependent cataracts [5, 56,57,[242][243][244][245]. Age-related endothelial dysfunction is ameliorated by an overexpression of the GLO1 enzyme, because it leads to the inhibition of MGO and subsequent inhibition of eNOS phosphorylation [246].…”