Increased oxidative stress (OS) underlies many chronic diseases prevalent in aging. Data in humans confirm the hypothesis that advanced glycation end products (AGEs) and other oxidants derived from the diet may be major contributors to increased OS in normal adults as well as those with diabetes mellitus or kidney failure. Mice fed a diet with a lowered (approximately 50%) content of AGEs or a typical calorie-restricted (CR) diet, accumulated a smaller amount of AGEs, maintained normal levels of AGE receptor-1 (AGER1), and did not have increased oxidant stress or cardiac or kidney fibrosis with aging. However, the findings in mice fed a CR diet with an increased content of AGEs resembled those in mice fed a nonrestricted diet that had the usual higher content of AGEs. Thus, there was an inverse correlation between the dietary AGE content, the AGER1 to receptor for AGE (RAGE) ratio, OS, organ damage, and life span. In both humans and mice, there was an inverse correlation between the AGER1 to RAGE ratio and the levels of OS.