Calorie restriction mimetics: Can you have your cake and eat it, too?

Strong consensus exists regarding the most robust environmental intervention for attenuating aging processes and increasing healthspan and lifespan: calorie restriction (CR). Over several decades, this paradigm has been replicated in numerous nonhuman models, and has been expanded over the last decade to formal, controlled human studies of CR. Given that long-term CR can create heavy challenges to compliance in human diets, the concept of a calorie restriction mimetic (CRM) has emerged as an active research area within gerontology. In past presentations on this subject, we have proposed that a CRM is a compound that mimics metabolic, hormonal, and physiological effects of CR, activates stress response pathways observed in CR and enhances stress protection, produces CR-like effects on longevity, reduces age-related disease, and maintains more youthful function, all without significantly reducing food intake, at least initially. Over 16 years ago, we proposed that glycolytic inhibition could be an effective strategy for developing CRM. The main argument here is that inhibiting energy utilization as far upstream as possible provides the highest chance of generating a broad spectrum of CR-like effects when compared to targeting a singular molecular target downstream. As an initial candidate CRM, 2-deoxyglucose, a known anti-glycolytic, was shown to produce a remarkable phenotype of CR, but further investigation found that this compound produced cardiotoxicity in rats at the doses we had been using. There remains interest in 2DG as a CRM but at lower doses. Beyond the proposal of 2DG as a candidate CRM, the field has grown steadily with many investigators proposing other strategies, including novel anti-glycolytics. Within the realm of upstream targeting at the level of the digestive system, research has included bariatric surgery, inhibitors of fat digestion/absorption, and inhibitors of carbohydrate digestion. Research focused on downstream sites has included insulin receptors, IGF-1 receptors, sirtuin activators, inhibitors of mTOR, and polyamines. In the current review we discuss progress made involving these various strategies and comment on the status and future for each within this exciting research field.