Development of Calorie Restriction Mimetics as Therapeutics for Obesity, Diabetes, Inflammatory and Neurodegenerative Diseases

Takuya      Chiba; Tomoshi      Tsuchiya; Toshimitsu      Komatsu; Ryoichi      Mori; Hiroko      Hayashi; Isao      Shimokawa

Abstract

Calorie restriction (CR) is the most robust intervention that decreases morbidity and mortality, and thereby increases the lifespan of many organisms. Although the signaling pathways involved in the beneficial effects of CR are not yet fully understood. Several candidate pathways and key molecules have been identified. The effects of CR are highly conserved from lower organisms such as yeast to higher mammals such as rodents and monkeys. Recent studies have also demonstrated beneficial effects of CR in humans, although we need much longer studies to evaluate whether CR also increases the lifespan of humans. In reality, it is difficult for us to conduct CR interventions in humans because the subjects must be kept in a state of hunger and the duration of this state needed to achieve a clinically meaningful effect is still unknown. Thus, research in this field is focusing on the development of molecules that mimic the beneficial effects of CR without reducing food intake. Some of these candidate molecules include plant-derived functional chemicals (phytochemicals), synthetic small molecules, and endocrine molecules such as adipokines. Several studies have already shown that this research field may yield novel drugs for the treatment of age-related diseases such as diabetes. In this article, we describe the target pathways, candidate molecules, and strategies to develop CR mimetics.

Keywords: Biosensing, calorie restriction, cancer, drug discovery, metabolism, neurodegeneration, leptin, –, neuropeptide, hydroepiandrosterone sulfate, CALERIE, Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy, Metformin, liver kinase B1, adenosine monophosphate, Adipokines, NPY, rapamycin, TOR, Resveratrol, SIRT1, Sir2, CRISP, CR-Imitating agent Screening Platform