• Draghici C, Wang T, Spiegel DA. Concise total synthesis of glucosepane. Science 2015;350(6258):294-298. doi:10.1126/science.aac9655. PubMed: 26472902. Categories: GlycoSENS

    Concise total synthesis of glucosepane.

    Science 2015;350(6258):294-298. doi:10.1126/science.aac9655.

    Concise total synthesis of glucosepane.

    Draghici C, Wang T, Spiegel DA.

    Abstract

    Abstract:

    Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.

  • Bains, W. More than genes and cells: drug discovery in the ECM. Drug Discovery World. 2013/14 Winter:65-70. Read on external site. Categories: GlycoSENS

    More than genes and cells: drug discovery in the ECM.

    Drug Discovery World. 2013/14 Winter:65-70.

    More than genes and cells: drug discovery in the ECM.

    Bains, W.

    Abstract

    Abstract:

    Drug discovery in the last few decades has focused on the cellular and genetic mechanisms of disease. This has been very successful in cancer, which is a disease of somatic genetics, and moderately successful elsewhere. But the declining productivity of pharmaceutical and biotechnology investment in drug discovery and development suggests that we should be alert to other approaches. One is to look outside the cell, at the extracellular superstructure of the body. Once viewed as an inert structure that is just the biological equivalent of a petri dish, the extracellular milieu is now being seen as a therapeutic target, especially for diseases of old age. Importantly, targeting the scaffold of the body might be a much faster route to treatment for some conditions than attempting to find, and fix, underlying cellular or genetic aetiology of disease.

  • Wang T, Douglass EF Jr, Fitzgerald KJ, Spiegel DA. A "turn-on" fluorescent sensor for methylglyoxal. J Am Chem Soc. 2013 Aug 21;135(33):12429-33. doi: 10.1021/ja406077j. Epub 2013 Aug 9. PubMed: 23931147. Categories: GlycoSENS

    A "turn-on" fluorescent sensor for methylglyoxal.

    J Am Chem Soc. 2013 Aug 21;135(33):12429-33. doi: 10.1021/ja406077j. Epub 2013 Aug 9.

    A "turn-on" fluorescent sensor for methylglyoxal.

    Wang T, Douglass EF Jr, Fitzgerald KJ, Spiegel DA.

    Abstract

    Abstract:

    Methylglyoxal (MGO), a dicarbonyl metabolite produced by all living cells, has been associated with a number of human diseases. However, studies of the role(s) MGO plays biologically have been handicapped by a lack of direct methods for its monitoring and detection. To address this limitation, we have developed a fluorescent sensor (methyl diaminobenzene-BODIPY, or "MBo") that can detect MGO under physiological conditions. We show that MBo is selective for MGO over other biologically relevant dicarbonyls and is suitable for detecting MGO in complex environments, including that of living cells. In addition, we demonstrate MBo's utility in estimating plasma concentrations of MGO. The results reported herein have the potential to advance both clinical and basic science research and practice.

  • Kim T, Spiegel DA. The unique reactivity of N-phenacyl-derived thiazolium salts toward alpha-dicarbonyl compounds. Rejuvenation Res. 2013 Feb;16(1):43-50. doi: 10.1089/rej.2012.1370. PubMed: 23186164. Categories: GlycoSENS

    The unique reactivity of N-phenacyl-derived thiazolium salts toward alpha-dicarbonyl compounds.

    Rejuvenation Res. 2013 Feb;16(1):43-50. doi: 10.1089/rej.2012.1370.

    The unique reactivity of N-phenacyl-derived thiazolium salts toward alpha-dicarbonyl compounds.

    Kim T, Spiegel DA.

    Abstract

    Abstract:

    Advanced glycation end-products (AGEs), a heterogenous mixture of compounds formed by non-enzymatic chemical reactions between sugars and the nucleophilic residues of proteins, have been implicated in the pathogenesis of a number of diseases. ALT-711 is an N-phenacyl-derived thiazolium carbene developed as a therapeutic agent for cardiovascular diseases that is proposed to function through cleaving pre-formed AGE-protein crosslinks. However, despite promising results in animal models and clinical trials, its mechanism of action still remains controversial. Herein, we report the first systematic investigations into dicarbonyl cleavage by ALT-711. We demonstrate that it is capable of cleaving α-diketones more efficiently and likely via a distinct mechanism compared with other N-heterocyclic carbene precursors. We also show that ALT-711 reacts rapidly with α-keto aldehydes to form cyclic diol products, and can efficiently scavenge methylglyoxal under physiological conditions to protect E. coli from lethal concentrations of this reactive α-keto aldehyde. This work suggests ALT-711 may be especially suited for α-dicarbonyl clearance in vivo, and supports a mode of action similar to that originally proposed. To this end, our findings may provide insights into the development of next-generation crosslink breakers.

  • Wang T, Kartika R, Spiegel DA. Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones. J Am Chem Soc. 2012 May 30;134(21):8958-67. PubMed: 22591136. Categories: GlycoSENS

    Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones.

    J Am Chem Soc. 2012 May 30;134(21):8958-67.

    Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones.

    Wang T, Kartika R, Spiegel DA.

    Abstract

    Abstract:

    The methylglyoxal-derived hydroimidazolones (MG-Hs) comprise the most prevalent class of non-enzymatic, post-translational modifications of protein arginine residues found in nature. These adducts form spontaneously in the human body, and are also present at high levels in the human diet. Despite numerous lines of evidence suggesting that MG-H-arginine adducts play critical roles in both healthy and disease physiology in humans, detailed studies of these molecules have been hindered by a lack of general synthetic strategies for their preparation in chemically homogeneous form, and on scales sufficient to enable detailed biochemical and cellular investigations. To address this limitation, we have developed efficient, multigram-scale syntheses of all MG-H-amino acid building blocks, suitably protected for solid-phase peptide synthesis, in 2-3 steps starting from inexpensive, readily available starting materials. Thus, MG-H derivatives were readily incorporated into oligopeptides site-specifically using standard solid-phase peptide synthesis. Access to synthetic MG-H-peptide adducts has enabled detailed investigations, which have revealed a series of novel and unexpected findings. First, one of the three MG-H isomers, MG-H3, was found to possess potent, pH-dependent antioxidant properties in biochemical and cellular assays intended to replicate redox processes that occur in vivo. Computational and mechanistic studies suggest that MG-H3-containing constructs are capable of participating in mechanistically distinct H-atom-transfer and single-electron-transfer oxidation processes. Notably, the product of MG-H3 oxidation was unexpectedly observed to disassemble into the fully unmodified arginine residue and pyruvate in aqueous solution. We believe these observations provide insight into the role(s) of MG-H-protein adducts in human physiology, and expect the synthetic reagents reported herein to enable investigations into non-enzymatic protein regulation at an unprecedented level of detail.

  • Sjöberg JS, Bulterijs S. Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link. Rejuvenation Res 2009;12(2):137-48. PubMed: 19415980. Categories: GlycoSENS

    Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link.

    Rejuvenation Res 2009;12(2):137-48.

    Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link.

    Sjöberg JS, Bulterijs S.

    Abstract

    Abstract:

    Advanced glycation end products are the results of a series of chemical reactions collectively known as the Maillard reaction, or nonenzymatic glycation, and sometimes cross-link proteins, thereby impairing their normal function. Glucosepane is the most abundant protein cross-link found in vivo so far and mainly has been shown to accumulate in the extracellular matrix, where it cross-links collagen. Levels of glucosepane increase with aging. By increasing collagen stiffness, glucosepane cross-links may have significant implications in several age-related diseases, such as cardiovascular disease, diabetes, and osteoporosis. Although the formation pathways for glucosepane are relatively well researched, much is still unknown about the accumulation and pathophysiology of glucosepane.

  • O'Rourke MF. Arterial aging: pathophysiological principles Vasc Med. 2007 Nov;12(4):329-41 PubMed: 18048471. Categories: GlycoSENS, RepleniSENS

    Arterial aging: pathophysiological principles

    Vasc Med. 2007 Nov;12(4):329-41

    Arterial aging: pathophysiological principles

    O'Rourke MF.

    Abstract

    Abstract:

    In the nineteenth century, prior to the introduction of the cuff sphygmomanometer, arteriosclerosis (stiffening of arteries) was recognized by clinicians and by life insurance companies as an indicator of vascular aging and cardiovascular risk, even in asymptomatic individuals. Through the twentieth century, views on aging came to focus on values of systolic and diastolic pressure and on obstructive atherosclerotic disease. Such focus deflected attention from the primary aging change which occurs in all societies, and is represented by stiffening and dilation of the proximal aorta. This review emphasizes the cushioning function of elastic arteries - principally the aorta - and how in youth this results in optimal interaction with the heart, and optimal steady flow through peripheral resistance vessels. Aortic stiffening with age is principally due to fatigue and fracture of elastin lamellae, with transfer of stress to stiffer collagenous components. Stiffening increases left ventricular load and myocardial blood requirement, but limits the capacity for blood supply during diastole. Consequences are cardiac failure and predisposition to ischaemia. The second, under-appreciated effect of aortic stiffening is transmission of flow pulsations downstream into vasodilated organs, principally brain and kidney, where pulsatile energy is dissipated and fragile microvessels are damaged. This accounts for micro infarcts and microhaemorrhages, with specialized cell damage, cognitive decline and renal failure. The aging process can be best monitored by change in the arterial pressure wave rather than by reliance on the cuff sphygmomanometer. This reintroduces the approaches by clinicians and life insurance examiners of the nineteenth century, endorses modern treatments for established disease, and holds the promise of detecting premature arterial degeneration, and better applying lifestyle measures and vasoactive medications to modify the aging process.

  • de Grey ADNJ. Foreseeable pharmaceutical repair of age-related extracellular damage. Curr Drug Targets. 2006 Nov;7(11):1469-77. PubMed: 17100587. Categories: ApoptoSENS, GlycoSENS

    Foreseeable pharmaceutical repair of age-related extracellular damage.

    Curr Drug Targets. 2006 Nov;7(11):1469-77.

    Foreseeable pharmaceutical repair of age-related extracellular damage.

    de Grey ADNJ.

    Abstract

    Abstract:

    Various molecular and cellular alterations to our tissues accumulate throughout life as intrinsic side-effects of metabolism. These alterations are initially harmless, but some, which we may term "damage", are pathogenic when sufficiently abundant. The slowness of their accumulation explains why decline of tissue and organismal function generally does not appear until the age of 40 or older. Aging is thus best viewed as a two-part process in which metabolism causes accumulating damage and sufficiently abundant damage causes pathology. Hence, a promising approach to avoiding age-related pathology is periodically to repair the various types of damage and so maintain them at a sub-pathogenic level. Some examples of such types of damage are intracellular and others extracellular. Several types of intracellular damage are highly challenging--sophisticated cellular and genetic therapies will be needed to combat them, which are surely at least 20 years away and maybe much more. Extracellular damage, by contrast, generally appears more amenable to pharmaceutical repair which may be feasible in a shorter timeframe. In this article, the major types of age-related extracellular damage and promising avenues for their repair are reviewed.

  • Port SC, Goodarzi MO, Boyle NG, Jennrich RI. Blood glucose: a strong risk factor for mortality in nondiabetic patients with cardiovascular disease. Am Heart J 2005;150(2):209-214. PubMed: 16086919. Categories: GlycoSENS

    Blood glucose: a strong risk factor for mortality in nondiabetic patients with cardiovascular disease.

    Am Heart J 2005;150(2):209-214.

    Blood glucose: a strong risk factor for mortality in nondiabetic patients with cardiovascular disease.

    Port SC, Goodarzi MO, Boyle NG, Jennrich RI.

    Abstract

    Abstract:

    BACKGROUND: The prognostic significance of blood glucose (BG) for nondiabetic patients in a stable chronic phase of cardiovascular disease (CVD) has been sparsely investigated, especially for glucose within the normal range. In particular, it is unknown if for these patients there is a graded relation of mortality to glucose or if there is a lower threshold. METHODS: We used the Framingham Heart Study 30-year data to determine 2-year all-cause, cardiovascular mortality (CVM), and non-CVM risk adjusted for age, sex, and typical cardiovascular risk factors (systolic blood pressure, total cholesterol, body mass index, cigarette smoking, and use of antihypertensive drugs) by levels of random whole BG for non-glucose-intolerant subjects (glucose intolerance includes diabetes mellitus) with existing CVD. RESULTS: There were steep graded relations of 2-year all-cause, CVM, and non-CVM to BG throughout the normal and subdiabetic range with no evidence of a lower threshold. Two-year mortality continuously increased from 2.99% at the bottom of the normal range (BG = 60 [plasma equivalent = 67] mg/dL) to 7.23% at the top of the normal range (89 [plasma equivalent = 100] mg/dL) (a 2.42-fold increase) and then continued to further continuously increase, reaching 11.38% at 119 [plasma equivalent = 133] mg/dL, the top of the glucose range considered (P for trend < .0001). There were analogous steep increases for CVM and non-CVM. CONCLUSIONS: Blood glucose, even within the normal range, is a strong independent predictor of 2-year all-cause, CVM, and non-CVM in nondiabetic subjects with CVD and therefore of prognostic significance for these high-risk patients.

  • Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ. Ketosis leads to increased methylglyoxal production on the Atkins diet. Ann N Y Acad Sci 2005;1043:201-210. PubMed: 16037240. Categories: GlycoSENS

    Ketosis leads to increased methylglyoxal production on the Atkins diet.

    Ann N Y Acad Sci 2005;1043:201-210.

    Ketosis leads to increased methylglyoxal production on the Atkins diet.

    Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ.

    Abstract

    Abstract:

    In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of beta-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recognized as a significant cause of blood vessel and tissue damage, we measured methylglyoxal, acetone, and acetol in subjects on the Atkins diet. We found that by 14-28 days, methylghyoxal levels rose 1.67-fold (P = 0.039) and acetol and acetone levels increased 2.7- and 6.12-fold, respectively (P = 0.012 and 0.028). Samples from subjects with ketosis showed even greater increases in methylglyoxal (2.12-fold), as well as acetol and acetone, which increased 4.19- and 7.9-fold, respectively; while no changes were seen in samples from noncompliant, nonketotic subjects. The increase in methylglyoxal implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program.

  • Mustata GT, Rosca M, Biemel KM, Reihl O, Smith MA, Viswanathan A, Strauch C, Du Y, Tang J, Kern TS, Lederer MO, Brownlee M, Weiss MF, Monnier VM. Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking. Diabetes 2005;54(2):517-526. PubMed: 15677510. Categories: GlycoSENS

    Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking.

    Diabetes 2005;54(2):517-526.

    Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking.

    Mustata GT, Rosca M, Biemel KM, Reihl O, Smith MA, Viswanathan A, Strauch C, Du Y, Tang J, Kern TS, Lederer MO, Brownlee M, Weiss MF, Monnier VM.

    Abstract

    Abstract:

    We tested the hypothesis that green tea prevents diabetes-related tissue dysfunctions attributable to oxidation. Diabetic rats were treated daily with tap water, vitamins C and E, or fresh Japanese green tea extract. After 12 months, body weights were decreased, whereas glycated lysine in aorta, tendon, and plasma were increased by diabetes (P < 0.001) but unaffected by treatment. Erythrocyte glutathione and plasma hydroperoxides were improved by the vitamins (P < 0.05) and green tea (P < 0.001). Retinal superoxide production, acellular capillaries, and pericyte ghosts were increased by diabetes (P < 0.001) and improved by green tea and the vitamins (P variable). Lens crystallin fluorescence at 370/440 nm was ameliorated by green tea (P < 0.05) but not the vitamins. Marginal effects on nephropathy parameters were noted. However, suppressed renal mitochondrial NADH-linked ADP-dependent and dinitrophenol-dependent respiration and complex III activity were improved by green tea (P variable). Green tea also suppressed the methylglyoxal hydroimidazolone immunostaining of a 28-kDa mitochondrial protein. Surprising, glycoxidation in tendon, aorta, and plasma was either worsened or not significantly improved by the vitamins and green tea. Glucosepane cross-links were increased by diabetes (P < 0.001), and green tea worsened total cross-linking. In conclusion, green tea and antioxidant vitamins improved several diabetes-related cellular dysfunctions but worsened matrix glycoxidation in selected tissues, suggesting that antioxidant treatment tilts the balance from oxidative to carbonyl stress in the extracellular compartment.

  • Little WC, Zile MR, Kitzman DW, Hundley WG, O'Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11(3):191-195. PubMed: 15812746. Categories: GlycoSENS

    The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure.

    J Card Fail 2005;11(3):191-195.

    The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure.

    Little WC, Zile MR, Kitzman DW, Hundley WG, O'Brien TX, Degroof RC.

    Abstract

    Abstract:

    BACKGROUND: Despite its high prevalence, optimal therapy for diastolic heart failure (DHF) has not been determined. Alagebrium chloride (ALT-711) is a novel compound that breaks glucose crosslinks and may improve ventricular and arterial compliance. METHODS AND RESULTS: A total of 23 patients, mean age 71 years, with stable DHF, ejection fraction (EF) >50%, were enrolled in a 16-week, open-label trial of alagebrium 420 mg per day. Assessments included: peak exercise oxygen consumption, aortic distensibility, and left ventricular EF and mass by magnetic resonance imaging, Doppler diastolic filling, and quality of life by the Minnesota Living with Heart Failure questionnaire. One patient discontinued treatment because of a myocardial infarction after 12 days of treatment, and a second died suddenly after 10 weeks of treatment. Thus 21 patients completed the study. Left ventricular mass was 124 +/- 35 g at baseline and decreased to 119 +/- 34 g at follow up ( P = .036). This was accompanied by a decrease in the ratio of Doppler early diastolic flow velocity to Doppler early diastolic mitral annulus velocity (E') from 10.6 +/- 2.7 to 9.4 +/- 1.9 ( P = .076) and an increase in E' from 7.3 +/- 1.2 to 8.4 +/- 1.7 cm/s ( P = .045). The Minnesota Living with Heart Failure total score improved from 41 +/- 21 to 32 +/- 21 ( P = .01). There were no changes in EF (64 +/- 4% at baseline), blood pressure, peak exercise oxygen consumption, and aortic distensibility. CONCLUSION: Sixteen weeks of treatment with the glucose crosslink breaker, alagebrium, resulted in a decrease in left ventricular mass and improvements in left ventricular diastolic filling and quality of life in patient with DHF.

  • Cheng R, Feng Q, Argirov OK, Ortwerth BJ. Structure elucidation of a novel yellow chromophore from human lens protein. J Biol Chem 2004;279(44):45441-45449. PubMed: 15316021. Categories: GlycoSENS

    Structure elucidation of a novel yellow chromophore from human lens protein.

    J Biol Chem 2004;279(44):45441-45449.

    Structure elucidation of a novel yellow chromophore from human lens protein.

    Cheng R, Feng Q, Argirov OK, Ortwerth BJ.

    Abstract

    Abstract:

    We report here the isolation of a novel acid-labile yellow chromophore from the enzymatic digest of human lens proteins and the identification of its chemical structure by liquid chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, and (1)H, (13)C, and two-dimensional NMR. This new chromophore exhibited a UV absorbance maximum at 343 nm and fluorescence at 410 nm when excited at 343 nm. Analysis of the purified compound by reversed-phase HPLC with in-line electrospray ionization mass spectrometry revealed a molecular mass of 370 Da. One- and two-dimensional NMR analyses elucidated the structure to be 1-(5-amino-5-carboxypentyl)-4-(5-amino-5-carboxypentylamino)-3-hydroxy-2,3-dihydropyridinium, a cross-link between the epsilon-amino groups of two lysine residues, and a five-carbon ring. Because this cross-link contains two lysine residues and a dihydropyridinium ring, we assigned it the trivial name of K2P. Quantitative determinations of K2P in individual normal human lens or cataract lens water-soluble and water-insoluble protein digests were made using a high-performance liquid chromatograph equipped with a diode array detector. These measurements revealed a significant enhancement of K2P in cataract lens proteins (613 +/- 362 pmol/mg of water-insoluble sonicate supernatant (WISS) protein or 85 +/- 51 pmol/mg of WS protein) when compared with aged normal human lens proteins (261 +/- 93 pmol/mg of WISS protein or 23 +/- 15 pmol/mg of water-soluble (WS) protein). These data provide chemical evidence for increased protein cross-linking during aging and cataract development in vivo. This new cross-link may serve as a quantitatively more significant biomarker for assessing the role of lens protein modifications during aging and in the pathogenesis of cataract.

  • Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE, Spinowitz BS, Whittier FC, Wuerth JP; ACTION I Investigator Group. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004;24(1):32-40. PubMed: 14685005. Categories: GlycoSENS

    Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy.

    Am J Nephrol 2004;24(1):32-40.

    Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy.

    Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE, Spinowitz BS, Whittier FC, Wuerth JP; ACTION I Investigator Group.

    Abstract

    Abstract:

    BACKGROUND/AIMS: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. METHODS: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2-4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. RESULTS: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m(2) as compared with 9.80 ml/min/1.73 m(2) in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p

  • Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 2004;17(12 Pt 2):23S-30S. PubMed: 15607432. Categories: GlycoSENS

    Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process.

    Am J Hypertens 2004;17(12 Pt 2):23S-30S.

    Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process.

    Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S.

    Abstract

    Abstract:

    Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.

  • de Grey ADNJ. Challenging but essential targets for genuine anti-ageing drugs. Expert Opin Ther Targets. 2003 Feb;7(1):1-5. PubMed: 12556198. Categories: ApoptoSENS, GlycoSENS, SENS Overviews

    Challenging but essential targets for genuine anti-ageing drugs.

    Expert Opin Ther Targets. 2003 Feb;7(1):1-5.

    Challenging but essential targets for genuine anti-ageing drugs.

    de Grey ADNJ.

    Abstract

    Abstract:

    Contrary to what one might conclude from the popular press, anti-ageing drugs do not yet exist, in the sense in which the term 'drug' is normally used. Since a drug is assumed to be effective against its target human pathology and since the vast majority of deaths in the developed world are from ageing-related causes, it is inappropriate to describe something as an anti-ageing drug unless one has good reason to believe that it will appreciably extend the life expectancy of those in the developed world who receive it. A drug that rejuvenates aspects of the aged body but does not increase life expectancy is an antifrailty drug, not an anti-ageing one. This distinction is critical for decision makers in the drug discovery sphere because, while the market for antifrailty drugs (even unproven ones) is large, that for genuine anti-ageing drugs - which, as the author explains, are now foreseeable - will certainly be far larger. In this article, the author surveys the main aspects of age-related degeneration that are believed to be essential targets for genuine anti-ageing drugs - that is, without whose amelioration human life expectancy probably cannot be greatly increased - and some promising strategies for the design of such drugs.

  • Biemel KM, Friedl DA, Lederer MO. Identification and quantification of major maillard cross-links in human serum albumin and lens protein. Evidence for glucosepane as the dominant compound. J Biol Chem 2002;277(28):24907-24915. PubMed: 11978796. Categories: GlycoSENS

    Identification and quantification of major maillard cross-links in human serum albumin and lens protein. Evidence for glucosepane as the dominant compound.

    J Biol Chem 2002;277(28):24907-24915.

    Identification and quantification of major maillard cross-links in human serum albumin and lens protein. Evidence for glucosepane as the dominant compound.

    Biemel KM, Friedl DA, Lederer MO.

    Abstract

    Abstract:

    Glycation reactions leading to protein modifications (advanced glycation end products) contribute to various pathologies associated with the general aging process and long term complications of diabetes. However, only few relevant compounds have so far been detected in vivo. We now report on the first unequivocal identification of the lysine-arginine cross-links glucosepane 5, DOGDIC 6, MODIC 7, and GODIC 8 in human material. For their accurate quantification by coupled liquid chromatography-electrospray ionization mass spectrometry, (13)C-labeled reference compounds were synthesized independently. Compounds 5-8 are formed via the alpha-dicarbonyl compounds N(6)-(2,3-dihydroxy-5,6-dioxohexyl)-l-lysinate (1a,b), 3-deoxyglucosone (), methylglyoxal (), and glyoxal (), respectively. The protein-bound dideoxyosone 1a,b seems to be of prime significance for cross-linking because it presumably is not detoxified by mammalian enzymes as readily as 2-4. Hence, the follow-up product glucosepane 5 was found to be the dominant compound. Up to 42.3 pmol of 5/mg of protein was identified in human serum albumin of diabetics; the level of 5 correlates markedly with the glycated hemoglobin HbA(1c). In the water-insoluble fraction of lens proteins from normoglycemics, concentration of 5 ranges between 132.3 and 241.7 pmol/mg. The advanced glycoxidation end product GODIC 8 is elevated significantly in brunescent lenses, indicating enhanced oxidative stress in this material. Compounds 5-8 thus appear predestined as markers for pathophysiological processes.

  • Sell DR, Nelson JF, Monnier VM. Effect of chronic aminoguanidine treatment on age-related glycation, glycoxidation, and collagen cross-linking in the Fischer 344 rat. J Gerontol A Biol Sci Med Sci 2001;56(9):B405-B411. PubMed: 11524442. Categories: GlycoSENS

    Effect of chronic aminoguanidine treatment on age-related glycation, glycoxidation, and collagen cross-linking in the Fischer 344 rat.

    J Gerontol A Biol Sci Med Sci 2001;56(9):B405-B411.

    Effect of chronic aminoguanidine treatment on age-related glycation, glycoxidation, and collagen cross-linking in the Fischer 344 rat.

    Sell DR, Nelson JF, Monnier VM.

    Abstract

    Abstract:

    Aminoguanidine (AG) is an inhibitor of protein modification by the advanced Maillard reaction. We evaluated its effects in preventing age-related collagen cross-linking, glycation, and glycoxidation in Fischer 344 rats by administering the drug in their drinking water at 1 g/l from the time they were 6 months until they were 24 months of age. Body weight and food and water consumption were consistently recorded throughout the study. Plasma glucose was measured by the glucose oxidase method, and collagen cross-linking was assessed by tail tendon break time (TBT) in urea. Glycation (furosine) and glycoxidation (pentosidine and carboxymethyllysine) were assessed by high-performance liquid chromatography in acid hydrolysates of skin and tendon collagen. Water consumption dramatically increased (p <.0001) after 20 months of age and was accelerated in the control versus AG-treated rats (p <.0001). Plasma glucose increased approximately 20% at age 19 months in both groups (p <.0001). TBT, glycation, and glycoxidation all increased significantly (p <.0001) with age. However, except for a modest decrease of TBT at all ages that approached significance (p =.077), AG had no effect on collagen glycation or glycoxidation. These results are important because they suggest that alpha,beta-dicarbonyl compounds that can be trapped by aminoguanidine do not play a major role in collagen aging in the rat. Instead, post-Amadori pathways involving oxidative or nonoxidative fragmentation of the Amadori product emerge as the more likely mechanism of collagen cross-linking in aging.

  • Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, Vasan S, Wagle DR, Ulrich P, Brines M, Wuerth JP, Cerami A, Lakatta EG. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci USA 2001;98(3):1171-1175. PubMed: 11158613. Categories: GlycoSENS

    A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys.

    Proc Natl Acad Sci USA 2001;98(3):1171-1175.

    A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys.

    Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, Vasan S, Wagle DR, Ulrich P, Brines M, Wuerth JP, Cerami A, Lakatta EG.

    Abstract

    Abstract:

    Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after 11 intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 +/- 4.4% of baseline (B), P = 0.007; AGI to 41 +/- 7.3% of B, P = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke volume index (SV(index)) to 173.1 +/- 40.1% of B, P = 0.01; and systolic fractional shortening to 180 +/- 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SV(index), an estimate of total LV vascular load, decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/SV(index), an estimate of arterio-ventricular coupling, was improved (decreased to 54.3 +/- 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased.

  • Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 2001;104(13):1464-1470. PubMed: 11571237. Categories: GlycoSENS

    Improved arterial compliance by a novel advanced glycation end-product crosslink breaker.

    Circulation 2001;104(13):1464-1470.

    Improved arterial compliance by a novel advanced glycation end-product crosslink breaker.

    Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG.

    Abstract

    Abstract:

    BACKGROUND: Arterial stiffening with increased pulse pressure is a leading risk factor for cardiovascular disease in the elderly. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening. METHODS AND RESULTS: Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures >60 mm Hg and systolic pressures >140 mm Hg to once-daily ALT-711 (210 mg; n=62) or placebo (n=31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. Morning upright blood pressure, stroke volume, cardiac output, systemic vascular resistance, total arterial compliance, carotid-femoral pulse wave velocity, and drug tolerability were assessed. ALT-711 netted a greater decline in pulse pressures than placebo (-5.3 versus -0.6 mm Hg at day 56; P=0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 (P=0.056). Mean pressure declined similarly in both groups (-4 mm Hg; P<0.01 for each group, P=0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711-treated subjects versus no change with placebo (P=0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 (P<0.05 at day 56, P=0.08 for treatment effect). Systemic arterial resistance, cardiac output, and heart rate did not significantly change in either group. CONCLUSIONS: ALT-711 improves total arterial compliance in aged humans with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension.

  • Sell DR, Kleinman NR, Monnier VM. Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice. FASEB J 2000;14(1):145-156. PubMed: 10627289. Categories: GlycoSENS

    Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice.

    FASEB J 2000;14(1):145-156.

    Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice.

    Sell DR, Kleinman NR, Monnier VM.

    Abstract

    Abstract:

    In 1988, the National Institute on Aging launched a 10-year program aimed at identification of biomarkers of aging. Previous results from our laboratory showed that pentosidine, an advanced glycation product, formed in skin collagen at a rate inversely related to maximum life span across several mammalian species. As part of the Biomarkers Program, we investigated the hypothesis that longitudinal determination of glycation and glycoxidation rates in skin collagen could predict longevities in ad libitum-fed (AL) and caloric restricted (CR) mice. C57BL/6NNia male mice were biopsied at age 20 months and at natural death. Glycation (furosine method) was assessed by gas chromatography/mass spectrometry (GC/MS) and the glycoxidation products carboxymethyllysine (CML) and pentosidine were determined by GC/MS and HPLC, respectively. CR vs. AL significantly (P<0.0001) increased both mean (34 vs. 27 months) and maximum (47 vs. 31 months) life spans. Skin collagen levels of furosine (pmol/micromol lysine) were approximately 2.5-fold greater than CML levels and 100-fold greater than pentosidine. Individual accumulation rates modeled as linear equations were significantly (P<0.001) inhibited by CR vs. AL for all parameters and in all cases varied inversely with longevity (P<0.1 to <0.0001). The incidence of three tissue pathologies (lymphoma, dermatitis, and seminal vesiculitis) was found to be attenuated by CR and the latter pathology correlated significantly with longevities (r=0.54, P=0. 002). The finding that markers of skin collagen glycation and glycoxidation rates can predict early deaths in AL and CR C57BL/6NNia mice strongly suggests that an age-related deterioration in glucose tolerance is a life span-determining process.

  • Asif M, Egan J, Vasan S, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 2000;97(6):2809-2813. PubMed: 10706607. Categories: GlycoSENS

    An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness.

    Proc Natl Acad Sci USA 2000;97(6):2809-2813.

    An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness.

    Asif M, Egan J, Vasan S, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ.

    Abstract

    Abstract:

    Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals. A potential explanation for this decreased elasticity is that glucose can react nonenzymatically with long-lived proteins, such as collagen and lens crystallin, and link them together, producing advanced glycation endproducts (AGEs). Previous studies have shown that aminoguanidine, an AGE inhibitor, can prevent glucose cross-linking of proteins and the loss of elasticity associated with aging and diabetes. Recently, an AGE cross-link breaker (ALT-711) has been described, which we have evaluated in aged dogs. After 1 month of administration of ALT-711, a significant reduction ( approximately 40%) in age-related left ventricular stiffness was observed [(57.1 +/- 6.8 mmHg x m(2)/ml pretreatment and 33.1 +/- 4.6 mmHg x m(2)/ml posttreatment (1 mmHg = 133 Pa)]. This decrease was accompanied by improvement in cardiac function.

  • Manuel y Keenoy B, Vertommen J, De Leeuw I. The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients. Diabetes Nutr Metab 1999;12(4):256-263. PubMed: 10782751. Categories: GlycoSENS

    The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients.

    Diabetes Nutr Metab 1999;12(4):256-263.

    The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients.

    Manuel y Keenoy B, Vertommen J, De Leeuw I.

    Abstract

    Abstract:

    Amongst the numerous co-adjuvant therapies which could influence the incidence and progression of diabetic complications, antioxidants and flavonoids are currently being tested in several clinical trials. In this study we investigated the effects of Daflon 500, which is made up of the flavonoids diosmin (90%) and hesperidin (10%), in a group of 28 Type 1 diabetic patients in a double blind placebo-controlled study. Parameters of glycation and oxidative stress were measured before and after the intervention. Treatment with this flavonoid had no side effects and was followed by a decrease in HbA1c, from 8.85+/-1.57 to 8.47+/-1.40% (p=0.017). This decrease was more pronounced in the patients with higher initial HbA1c but was unrelated to glycaemic control as monitored by the mean and fluctuations of daily glycaemia. Decrease in HbA1c was accompanied by an increase in glutathione peroxidase activity, from 119+/-68 to 145+/-42 U/l haemolysate (p=0.015), a tendency for increase in plasma protein thiols and an increase in the lag time of the copper-induced in vitro oxidability of non-HDL lipoproteins, from 96+/-24 to 111+/-28 min (p=0.005). These parameters did not change significantly after receiving placebo. Other parameters of antioxidant capacity such as blood GSH, catalase and superoxide dismutase activities, as well as in vitro formation of thiobarbituric acid reactive substances (TBARS), were unaffected by either flavonoid or placebo. Our results suggest that the flavonoid-induced decrease in glycation is associated with an increase in the antioxidant component dependent on the levels and activities of thiol-containing proteins such as glutathione peroxidase. One mechanism which could explain these effects is the protection of vitamin C and E from consumption by oxidative processes.

  • Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW. The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest 1999;104(1):103-113. PubMed: 10393704. Categories: GlycoSENS

    The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation.

    J Clin Invest 1999;104(1):103-113.

    The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation.

    Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW.

    Abstract

    Abstract:

    Reactive aldehydes derived from reducing sugars and peroxidation of lipids covalently modify proteins and may contribute to oxidative tissue damage. We recently described another mechanism for generating reactive aldehydes from free alpha-amino acids. The pathway begins with myeloperoxidase, a heme enzyme secreted by activated neutrophils. Conversion of alpha-amino acids to aldehydes requires hypochlorous acid (HOCl), formed from H2O2 and chloride by myeloperoxidase. When L-serine is the substrate, HOCl generates high yields of glycolaldehyde. We now demonstrate that a model protein, ribonuclease A (RNase A), exposed to free L-serine and HOCl exhibits the biochemical hallmarks of advanced glycation end (AGE) products -- browning, increased fluorescence, and cross-linking. Furthermore, Nepsilon-(carboxymethyl)lysine (CML), a chemically well-characterized AGE product, was generated on RNase A when it was exposed to reagent HOCl-serine, the myeloperoxidase-H2O2-chloride system plus L-serine, or activated human neutrophils plus L-serine. CML production by neutrophils was inhibited by the H2O2 scavenger catalase and the heme poison azide, implicating myeloperoxidase in the cell-mediated reaction. CML was also generated on RNase A by a myeloperoxidase-dependent pathway when neutrophils were activated in a mixture of amino acids. Under these conditions, we observed both L-serine-dependent and L-serine-independent pathways of CML formation. The in vivo production of glycolaldehyde and other reactive aldehydes by myeloperoxidase may thus play an important pathogenic role by generating AGE products and damaging tissues at sites of inflammation.

  • Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, Vanpatten S, Lee A, Al-Abed Y, Vlassara H, Bucala R, Cerami A. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci USA 1997;94(25):13915-13920. PubMed: 9391127. Categories: GlycoSENS

    Tobacco smoke is a source of toxic reactive glycation products.

    Proc Natl Acad Sci USA 1997;94(25):13915-13920.

    Tobacco smoke is a source of toxic reactive glycation products.

    Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, Vanpatten S, Lee A, Al-Abed Y, Vlassara H, Bucala R, Cerami A.

    Abstract

    Abstract:

    Smokers have a significantly higher risk for developing coronary and cerebrovascular disease than nonsmokers. Advanced glycation end products (AGEs) are reactive, cross-linking moieties that form from the reaction of reducing sugars and the amino groups of proteins, lipids, and nucleic acids. AGEs circulate in high concentrations in the plasma of patients with diabetes or renal insufficiency and have been linked to the accelerated vasculopathy seen in patients with these diseases. Because the curing of tobacco takes place under conditions that could lead to the formation of glycation products, we examined whether tobacco and tobacco smoke could generate these reactive species that would increase AGE formation in vivo. Our findings show that reactive glycation products are present in aqueous extracts of tobacco and in tobacco smoke in a form that can rapidly react with proteins to form AGEs. This reaction can be inhibited by aminoguanidine, a known inhibitor of AGE formation. We have named these glycation products "glycotoxins." Like other known reducing sugars and reactive glycation products, glycotoxins form smoke, react with protein, exhibit a specific fluorescence when cross-linked to proteins, and are mutagenic. Glycotoxins are transferred to the serum proteins of human smokers. AGE-apolipoprotein B and serum AGE levels in cigarette smokers were significantly higher than those in nonsmokers. These results suggest that increased glycotoxin exposure may contribute to the increased incidence of atherosclerosis and high prevalence of cancer in smokers.

  • Sell DR, Lane MA, Johnson WA, Masoro EJ, Mock OB, Reiser KM, Fogarty JF, Cutler RG, Ingram DK, Roth GS, Monnier VM. Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc Natl Acad Sci USA 1996;93(1):485-490. PubMed: 8552666. Categories: GlycoSENS

    Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence.

    Proc Natl Acad Sci USA 1996;93(1):485-490.

    Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence.

    Sell DR, Lane MA, Johnson WA, Masoro EJ, Mock OB, Reiser KM, Fogarty JF, Cutler RG, Ingram DK, Roth GS, Monnier VM.

    Abstract

    Abstract:

    A fundamental question in the basic biology of aging is whether there is a universal aging process. If indeed such a process exists, one would expect that it develops at a higher rate in short- versus long-lived species. We have quantitated pentosidine, a marker of glycoxidative stress in skin collagen from eight mammalian species as a function of age. A curvilinear increase was modeled for all species, and the rate of increase correlated inversely with maximum life-span. Dietary restriction, a potent intervention associated with increased life-span, markedly inhibited glycoxidation rate in the rodent. On the assumption that collagen turnover rate is primarily influenced by the crosslinking due to glycoxidation, these results suggest that there is a progressive age-related deterioration of the process that controls the collagen glycoxidation rate. Thus, the ability to withstand damage due to glycoxidation and the Maillard reaction may be under genetic control.