Does accumulation of advanced glycation end products contribute to the aging phenotype?

Abstract

Background: Aging is a complex multifactorial process characterized by accumulation of deleterious changes in cells and tissues, progressive deterioration of structural integrity and physiological function across multiple organ systems, and increased risk of death.

Methods: We conducted a review of the scientific literature on the relationship of advanced glycation end products (AGEs) with aging. AGEs are a heterogeneous group of bioactive molecules that are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids.

Results: Humans are exposed to AGEs produced in the body, especially in individuals with abnormal glucose metabolism, and AGEs ingested in foods. AGEs cause widespread damage to tissues through upregulation of inflammation and cross-linking of collagen and other proteins. AGEs have been shown to adversely affect virtually all cells, tissues, and organ systems. Recent epidemiological studies demonstrate that elevated circulating AGEs are associated with increased risk of developing many chronic diseases that disproportionally affect older individuals.

Conclusions: Based on these data, we propose that accumulation of AGEs accelerate the multisystem functional decline that occurs with aging, and therefore contribute to the aging phenotype. Exposure to AGEs can be reduced by restriction of dietary intake of AGEs and drug treatment with AGE inhibitors and AGE breakers. Modification of intake and circulating levels of AGEs may be a possible strategy to promote health in old age, especially because most Western foods are processed at high temperature and are rich in AGEs.

Figure 1.

Formation of advanced glycation end products. Nonenzymatic reactions of the carbonyl groups of reducing sugars with primary amino groups of proteins produce corresponding Schiff bases, which undergo Amadori rearrangement to give ketoamines. Further glycoxidations and auto-oxidations yield highly reactive carbonyl compounds, which react with protein amino groups forming a variety of AGEs such as carboxymethyl-lysine and hydroimidazolone.

Figure 2.

Model for advanced glycation end products–receptors of receptor for advanced glycation end products (RAGE) interactions. Activated RAGE upregulates inflammatory cytokines, adhesion molecules, and its own receptors via NF-κB.

Figure 3.

Carboxymethyl-lysine content of selected dairy products, bread, and meat using liquid chromatography–mass spectrometry. Adapted from Assar and colleagues (29).

Figure 4.

Conceptual model of the effects of AGEs in multiple organ systems during aging.

Figure 5.

Survival curves for all-cause mortality of adults, aged 65 years and older, in the InCHIANTI Study, by plasma carboxymethyl-lysine levels in the highest versus lower two tertiles (p < .001 by log-rank test). Reproduced with permission of the Journal of the American Geriatric Society.