Published online before print April 19, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061281

Accepted for publication February 20, 2007.

Article

Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet. Association with Increased AGER1 Expression

Weijing Cai^*, John Cijiang He, Li Zhu^*, Xue Chen^*, Sylvan Wallenstein, Gary E. Striker, and Helen Vlassara^*@

From the Department of Geriatrics,* Division of Experimental Diabetes and Aging, the BioMath Department, and the Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, New York, New York

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

	Abstract

Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg_AGE) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low_AGE), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low_AGE diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66^shc levels compared with mice pair-fed the regular (Reg_AGE) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low_AGE mice, compared with Reg_AGE mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.

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