The reduction in dietary intake leads to changes in metabolism and gene expression that increase lifespan, reduce the incidence of heart disease, kidney disease, Alzheimer’s disease, type-2 diabetes and cancer. While all the molecular pathways which result in extended lifespan as a result of calorie restriction are not fully understood, some of these pathways that have resulted in lifespan expansion have been identified. Three molecular pathways activated by calorie restriction are also shown to be activated by supplementing the diet with the metabolite oxaloacetic acid. Animal studies supplementing oxaloacetic acid show an increase in lifespan and other substantial health benefits including mitochondrial DNA protection, and protection of retinal, neural and pancreatic tissues. Human studies indicate a substantial reduction in fasting glucose levels and improvement in insulin resistance. Supplementation with oxaloacetic acid may be a safer method to mimic calorie restriction than the use of traditional diabetes drugs.