The role of AGEs in aging: causation or correlation

doi:10.1016/S0531-5565(01)00138-3

Experimental Gerontology

Volume 36, Issue 9, September 2001, Pages 1527-1537

https://doi.org/10.1016/S0531-5565(01)00138-3 Get rights and content

Abstract

Over a dozen advanced glycation end-products (AGEs) have been identified in tissue proteins by chemical or immunological methods. Of these, about half are known to accumulate with age in collagen at a rate that correlates with the half-life of the collagen. AGEs may be formed by oxidative and non-oxidative reactions and are in some cases identical to advanced lipoxidation end-products (ALEs) formed in protein during lipid peroxidation reactions. AGEs affect the biochemical and physical properties of proteins and the extracellular matrix (ECM), including the charge, hydrophobicity, turnover and elasticity of collagen, and the cell adhesion, permeability and pro-inflammatory properties of the ECM. A number of scavenger and AGE-specific receptors have been identified that may mediate the turnover of AGE-proteins, catalyze the local production of reactive oxygen species and attract and activate tissue macrophages. Although AGEs in proteins are probably correlative, rather than causative, with respect to aging, they accumulate to high levels in tissues in age-related chronic diseases, such as atherosclerosis, diabetes, arthritis and neurodegenerative disease. Inhibition of AGE formation in these diseases may limit oxidative and inflammatory damage in tissues, retarding the progression of pathophysiology and improve the quality of life during aging.

Introduction

Life is sustained by biochemical processes that harness the energy of chemical reactions for useful work. According to chemical theories of aging, the rate of unintended side-reactions during metabolism is the critical factor eroding the performance of biological systems and determining their rates of aging and death. Our cellular and extracellular fluids are complex mixtures, fertile ground for inorganic and organic chemistry. Despite sophisticated genetic and enzymatic regulation of metabolism, spontaneous, uncatalyzed chemical reactions undoubtedly occur with high frequency in this milieu. From one perspective, the human body might be viewed as an extraordinarily complex mixture of chemicals reacting in a low temperature (37°C) oven with a 76-year cooking cycle. Under these conditions, non-enzymatic reactions between carbohydrates and proteins, known collectively as Maillard or browning reactions, produce a wide range of age-related chemical modifications and crosslinks in tissue proteins (Table 1). The same Maillard reaction products that accumulate in long-lived tissue proteins with age are also formed in the crust of bread and pretzels during baking. In foods, these products retard the digestion and reduce the nutritional value of the protein. In the body, they alter the structure and compromise the function of proteins.

Maillard reaction products are only a part of the spectrum of chemical modifications that are detectable in aging proteins. Others, addressed elsewhere in this volume, include racemization, deamidation and oxidation of amino acids, formation of adducts involving reactive nitrogen and chlorine species, and chemical modification of proteins by products of lipid peroxidation reactions (lipoxidation). The question that I wish to address in this article is whether the accumulation of Maillard reaction products and, by inference, other chemical modifications of proteins are causative or correlative with respect to aging. This is an important question. If causative, then inhibition of Maillard reactions may be a reasonable approach for extension of maximum lifespan. Even if only correlative, inhibition of Maillard reactions may retard the decline in physiological function in chronic, age-related degenerative diseases, leading to both an increase in mean lifespan and better health during old age.

Section snippets

Origin of AGEs (Baynes and Thorpe, 1999a)

The end-stage products of Maillard reactions in biological systems are known as AGEs (Baynes and Thorpe, 1999a). The first relatively stable product of glycation of protein is an Amadori rearrangement product known as fructoselysine. Glycation is a reversible reaction and the Amadori compound is not an age-dependent chemical modification of protein. The steady-state level of fructoselysine in a protein is determined by the ambient glucose concentration and the half-life or lifespan of the

Advanced lipoxidation end-products

Fig. 1 illustrates that some compounds that are commonly described as AGEs may not, in fact, be AGEs (Baynes and Thorpe, 2000). Thus, CML and CEL may be formed from glyoxal and methylglyoxal, generated during peroxidation of polyunsaturated fatty acids in triglycerides and phospholipids. Protein crosslinks such as GOLD and MOLD (Table 1) are also likely to be derived, in part, from lipids. When derived from lipids, these compounds are properly termed ALEs. When their origin is uncertain, they

The role of oxidation (Baynes and Thorpe, 1999b)

The interplay between glycative and oxidative modification of proteins during aging is complex. Oxidative stress may be involved in AGE formation, and AGEs may induce oxidative stress. Most, but not all AGEs that accumulate in proteins with age are, in fact, glycoxidation products — their formation from glucose or ascorbate requires oxidation chemistry. However, crosslines can be formed from glucose without oxidation, so that not all age-dependent carbohydrate modifications of proteins require

AGE receptors and the biological fate of AGEs

AGE receptors have been identified in macrophages, endothelial cells and several other cell types in the body, and are implicated in protein turnover, tissue remodeling and inflammation (Thornalley, 1998, Schmidt et al., 2000). The multiplicity of AGE receptors parallels the multiplicity of scavenger receptors for oxidized lipoproteins. Because of the structural identity between some AGEs and ALEs, such as CML and CEL, scavenger receptors, originally identified as receptors for modified

AGEs and aging

Although AGE/ALEs increase in tissue proteins with age, inter-species comparisons of tissue AGE concentrations vs. age argue strongly against a role for AGE/ALEs as a fundamental cause of aging. AGEs accumulate at a more rapid rate in tissues in short-lived mammals, such as mice and rats compared to humans (Sell et al., 1996), and their rate of accumulation correlates inversely with lifespan in rodents (Sell et al., 2000). However, the cumulative damage at old age is decreased because of both

The merits of age-inhibition in gerontology

Maillard reactions, in the widest sense of the term, include both carbohydrate- and lipid-dependent modifications of proteins. The resultant AGE/ALEs may affect altered gene expression, apoptosis and necrosis, both directly (Munch et al., 1998) and via oxidative stress induced by interactions with AGE receptors (Mohamed et al., 1999, Wautier et al., 2001). Because the formation of both AGEs and ALEs involves generation of reactive carbonyl intermediates, AGE inhibitors, such as AG (Miyata et

Conclusion

AGEs are only one of many types of chemical modifications that accumulate in long-lived proteins with age. AGEs may contribute to the decline in tissue and organ function with age, especially in age-related chronic disease, but the rate of their accumulation in proteins is unlikely to be a primary determinant of the maximum lifespan or rate of aging of species. Cumulative damage to the genome as a result of Maillard and other non-enzymatic reactions is likely to be the primary determinant of

Acknowledgements

This research was supported by Research Grant DK-19971 from the National Institute of Diabetes, Digestive and Kidney Disease.

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The role of AGEs in aging: causation or correlation

Abstract

Introduction

Section snippets

Origin of AGEs (Baynes and Thorpe, 1999a)

Advanced lipoxidation end-products

The role of oxidation (Baynes and Thorpe, 1999b)

AGE receptors and the biological fate of AGEs

AGEs and aging

The merits of age-inhibition in gerontology

Conclusion

Acknowledgements

Free Radical Biol. Med.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Arch. Biochem. Biophys.

J. Biol. Chem.

Metabolism

Mech. Ageing Dev.

Biochem. Biophys. Res. Commun.

Am. J. Hypertens

Mech. Ageing Dev.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochem. Biophys. Res. Commun.