PURPOSE OF REVIEW: The focus of this review is on current research involving long-term calorie restriction and the resulting changes observed in possible biomarkers of aging. Special emphasis will be given to the basic and clinical science studies which are currently investigating the effects of controlled, high-quality energy-restricted diets on both biomarkers of longevity and on the development of chronic diseases related to age and obesity in humans. RECENT FINDINGS: Prolonged calorie restriction has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats, and mice. Mechanisms of this lifespan extension via calorie restriction are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity, and functional changes in both the neuroendocrine and sympathetic nervous systems. Ongoing studies of prolonged energy restriction in humans are now making it possible to analyze changes in these aging biomarkers to unravel some of the mechanisms of its antiaging phenomenon. SUMMARY: With the incremental expansion of research endeavors in the area of energy or calorie restriction, data on the effects of calorie restriction in animal models and humans are becoming more accessible. Detailed analyses from controlled human trials involving long-term calorie restriction will allow investigators to link observed alterations in body composition down to changes in molecular pathways and gene expression, with their possible effects on the biomarkers of aging.