Calorie restriction (CR) has a variety of effects on extending lifespan and delaying the onset of age-related diseases, and it is accepted as the only established experimental antiaging intervention. Several pharmacological agents that can replicate the beneficial effects of CR, called calorie restriction mimetics (CRMs), have been identified. The nutrient-sensing pathways including those involving sirtuins (especially SIRT1) and mammalian target of rapamycin (mTOR) may regulate the physiology of CR, and candidate CRMs that modulate these specific pathways have been identified and investigated using animal models. In this chapter, we focus on candidate CRMs including sirtuin-activating compounds (STACs) and mTOR inhibitors, their slowing of aging, and methods for evaluation of lifespan and metabolic disorders.