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.