Metabolic syndrome threatens health gains made during the past century. Physiological processes degraded by this syndrome are often oppositely affected by calorie restriction, which extends lifespan and prevents disease in rodents. Recent research in the field of ageing has begun to identify important mediators of calorie restriction, offering the hope of new drugs to improve healthspan. Moreover, if metabolic syndrome and calorie restriction are opposite extremes of the same metabolic spectrum, calorie restriction mimetics might provide another therapeutic approach to metabolic syndrome. Sirtuins and other important metabolic pathways that affect calorie restriction may serve as entry points for drugs to treat metabolic syndrome.