Glycation, ageing and carnosine: Are carnivorous diets beneficial?

doi:10.1016/j.mad.2005.05.002

Mechanisms of Ageing and Development

Volume 126, Issue 10, October 2005, Pages 1034-1039

https://doi.org/10.1016/j.mad.2005.05.002 Get rights and content

Abstract

Non-enzymic protein glycosylation (glycation) plays important roles in ageing and in diabetes and its secondary complications. Dietary constituents may play important roles in accelerating or suppressing glycation. It is suggested that carnivorous diets contain a potential anti-glycating agent, carnosine (β-alanyl-histidine), whilst vegetarians may lack intake of the dipeptide. The possible beneficial effects of carnosine and related structures on protein carbonyl stress, AGE formation, secondary diabetic complications and age-related neuropathology are discussed.

Introduction

A number of recent papers (Ahmed, 2005, Suji and Sivakami, 2004, Chen et al., 2004, Davydov et al., 2004, Kikuchi et al., 2003, Miller et al., 2003) have (i) discussed the importance of non-enzymic protein glycosylation or glycation mediated by glucose (and more reactive aldehydes) in ageing, neurodegeneration, diabetes and its related complications and (ii) outlined possible mechanisms of intervention, pharmacological and dietary. In their review Davydov et al. (2004) emphasize the role of aldehydes as sources of protein modification and the importance of the ameliorating effects of aldehyde-scavenging enzymes generally, and Chen et al. (2004) highlight specifically the action of glyoxalase-1 against the deleterious effects of the highly reactive aldehyde methylglyoxal in Alzheimer's disease. Ahmed (2005) suggests the properties which putative, non-enzymic, anti-glycating agents should possess to help suppress aldehyde-mediated protein modification and consequential secondary diabetic complications. Suji and Sivakami (2004) discuss how diet might influence glycation and cite the observations of Krajcovicova-Kudlackova et al. (2002) who found that levels of advanced glycosylation end products (AGEs) in the plasma of vegetarians were higher than those detected in omnivours. As an explanation Krajcovicova-Kudlackova et al. (2002) suggested that the higher intake of fructose by the vegetarians induces the raised AGE plasma levels. There is, however, an additional or alternative explanation that should be considered.

Section snippets

Carnosine and aldehydes

The dipeptide carnosine (β-alanyl-l-histidine), discovered more than a century ago (Gulewitsch and Amiradzibi, 1900), is found exclusively in animal tissue, especially muscle (Maynard et al., 2001) and brain (de Marchis et al., 2000) sometimes in millimolar concentrations (see also Quinn et al., 1992 and Bonfanti et al., 1999 for reviews). There is an increasing body of evidence that shows that carnosine may be an effective anti-glycating agent, at least in model systems (Hipkiss et al., 1995,

Diabetes, carnosine and glycation

Many of the secondary complications of diabetes result from protein glycation and oxidation (glycoxidation) (see Brownlee, 2001 and Ahmed, 2005 and Refs. therein) mediated by agents and processes against which carnosine may, theoretically, protect (Hipkiss, 1998); some preliminary supportive evidence from animal studies has been obtained (Hipkiss et al., 2001). Additionally there are a number of observations which suggest an inverse relationship between diabetes and carnosine: the concentration

Protective roles of carnosine

Carnosine has some ameliorative effects on ageing at cellular and whole animal levels. Carnosine suppresses senescence in cultured human fibroblasts and even rejuvenates senescent cells (McFarland and Holliday, 1994, McFarland and Holliday, 1999). More recently, carnosine was shown to protect telomeres of cultured cells against oxidative damage (Shao et al., 2004). Beneficial effects of carnosine on the survival of senescence-accelerated mice (Yuneva et al., 1999, Boldyrev et al., 2004),

Could carnosine suppress carbonyl stress-induced pathology?

Carnosine's pluripotency may provide protective function, at a variety of levels, against the development of pathologies where glycoxidative events and the generation of protein carbonyls might be causative (see Levine, 2002, Dalle-Donne et al., 2003 for reviews). For example cataractogenesis is often a diabetes-related. Carnosine's potential here has been most clearly demonstrated by Barbizhayev and et al. who have repeatedly shown that carnosine and its acetylated pro-drug acetyl-carnosine

Carnosine's effects on humans

There is some evidence that suggests beneficial effects of the dipeptide in humans, despite the presence of serum and cellular carnosinases, enzymes which hydrolyse the dipeptide to histidine and β-alanine. Antonini et al. (2002) showed that both meat and carnosine-supplemented diets increased total anti-oxidant activity in human sera. Chez et al. (2002) found that dietary carnosine-supplementation improved behaviour of autistic children. The mechanisms involved are totally unknown but

Diets and carnosine

It is suggested that macromolecular glycation and associated pathologies induced by sugars, deleterious aldehydes and ketones, (Brownlee, 2001) and glycotoxins produced during cooking (Koschinsky et al., 1997), might be ameliorated by carnivorous diets containing carnosine and possibly the related peptides, acetyl-carnosine, homocarnosine and anserine. In contrast any diet which is exclusively vegetarian would lack carnosine, a likely anti-glycating agent; therefore the observations of

The carnosinase paradox

Clearly serum and tissue carnosinases could present major obstacles towards any ameliorative actions of carnosine in vivo. However hydrolysis of the dipeptide into β-alanine and histidine would immediately double the molarity of available amino groups for aldehyde-scavenging etc. Consequently carnosinase activity need not be regarded as counterproductive with respect to carnosine's anti-glycating and aldehyde/carbonyl scavenging actions.

Other putative anti-glycating agents

It should be pointed out that a number of other naturally occurring putative anti-glycating agents have been proposed, these include polyamines (Gugliucci and Menini, 2003), pyridoxamine (Baynes, 2002, Amarnath et al., 2004), thiamine (Hammes et al., 2003) and various Chinese herb extracts (Yokozawa and Nakagawa, 2004, Tang et al., 2004: Kim et al., 2004); other possible carbonyl scavengers include aminoguanidine (Thornalley, 2003) and d-penicillamine (see Wondrak et al., 2002, Rahbar and

Conclusions

It is clear that much research is required to determine whether carnivorous diets or carnosine-supplementation do in fact suppress protein glycation and the secondary complications of diabetes. Similarly it is unknown whether carnosine and related dipeptides (e.g. homocarnosine) exerts any protection action with respect to Alzheimer's disease or other neurodegenerative conditions where glycoxidative events are involved. The present discussion has outlined a case for more research in this area,

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ReviewGlycation, ageing and carnosine: Are carnivorous diets beneficial?

Abstract

Introduction

Section snippets

Carnosine and aldehydes

Diabetes, carnosine and glycation

Protective roles of carnosine

Could carnosine suppress carbonyl stress-induced pathology?

Carnosine's effects on humans

Diets and carnosine

The carnosinase paradox

Other putative anti-glycating agents

Conclusions

Diab. Res. Clin. Pract.

Biochem. Biophys. Res. Commun.

Arch. Gerontol. Geriatr. Suppl.

Int. Congr. Ser.

Int. Congr. Ser.

Neuroscience

Prog. Neurobiol.

Free Rad. Biol. Med.

Toxicology

Trends Mol. Med.

Exp. Gerontol.

Clin. Biochem.

Neurobiol. Aging

Int. J. Biochem. Cell Biol.

Mech. Ageing Dev.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Neurosci. Lett.

Biochim. Biophys. Acta

Life Sci.

Brain Res.

Comp. Biochem. Physiol. Part B Biochem. Mol. Biol.

Biochem. Biophys. Res. Commun.

Brain Res. Rev.

J. Ethnopharmacol.

Biochimie

Eur. J. Pharmacol.

Free Rad. Biol. Med.

J. Nutr.

Med. Hypotheses

Exp. Cell Res.

Exp. Gerontol.

Bioorg. Med. Chem.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Biochim. Biophys. Acta

Toxicol. Appl. Pharmacol.

Neurosci. Lett.

Mol. Aspects Med.

Arch. Biochem. Biophys.

J. Mag. Reson.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Neurobiol. Aging

Arch. Gerontol. Geriat.

Free Rad. Biol. Med.

Arch. Biochem. Biophys.

Nutrit. Biochem.

Review
Glycation, ageing and carnosine: Are carnivorous diets beneficial?