Published online before print April 19, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2007.061281v1 170/6/1893    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cai, W. Articles by Vlassara, H. Search for Related Content PubMed Articles by Cai, W. Articles by Vlassara, H.

(American Journal of Pathology. 2007;170:1893-1902.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061281

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

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.