The focus here is on research involving long-term calorie restriction (CR) to prevent or delay the incidence of the metabolic syndrome with age. The current societal environment is marked by overabundant accessibility of food coupled with a strong trend to reduced physical activity, both leading to the development of a constellation of disorders including central obesity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome). Prolonged CR has been shown to extend median and maximal lifespan in a variety of lower species (yeast, worms, fish, rats, and mice). Mechanisms of this lifespan extension by CR are not fully elucidated, but possibly involve alterations in energy metabolism, oxidative damage, insulin sensitivity, and functional changes in neuroendocrine systems. Ongoing studies of CR in humans now makes it possible to identify changes in 'biomarkers of aging' to unravel some of the mechanisms of its anti-aging phenomenon. Analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition down to changes in molecular pathways and gene expression, with their possible effects on the metabolic syndrome and aging.