Published online before print July 3, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080152

Accepted for publication April 24, 2008.

Article

Oral Glycotoxins Determine the Effects of Calorie Restriction on Oxidant Stress, Age-Related Diseases, and Lifespan

Weijing Cai^*, John C. He, Li Zhu^*, Xue Chen^*, Feng Zheng^*, Gary E. Striker, and Helen Vlassara^*@

From the Department of Geriatrics,* Division of Experimental Diabetes and Aging, and the Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, New York, New York; and the Departments of Medicine and Surgery, Miller School of Medicine, University of Miami, Miami, Florida

^@ To whom correspondence should be addressed. E-mail: helen.vlassara{at}mssm.edu.

	Abstract

We previously showed that the content of advanced glycation end products (AGEs) in the diet correlates with serum AGE levels, oxidant stress (OS), organ dysfunction, and lifespan. We now show that the addition of a chemically defined AGE (methyl-glyoxal-BSA) to low-AGE mouse chow increased serum levels of AGEs and OS, demonstrating that dietary AGEs are oxidants that can induce systemic OS. OS predisposes to the development of cardiovascular and chronic kidney diseases; calorie restriction (CR) is the most studied means to decrease OS, increase longevity, and reduce OS-related organ damage in mammals. Because reduction of food intake also decreases oxidant AGE s intake, we asked whether the beneficial effects of CR in mammals are related to the restriction of oxidants or energy. Pair-fed mice were provided either a CR diet or a high-AGE CR diet in which AGEs were elevated by brief heat treatment (CR-high). Old CR-high mice developed high levels of 8-isoprostanes, AGEs, RAGE, and p66^shc, coupled with low AGER1 and GSH/GSSG levels, insulin resistance, marked myocardial and renal fibrosis, and shortened lifespan. In contrast, old CR mice had low OS, p66^shc, RAGE, and AGE levels, but high AGER1 levels, coupled with longer lifespan. Therefore, the beneficial effects of a CR diet may be partly related to reduced oxidant intake, a principal determinant of oxidant status in aging mice, rather than decreased energy intake.