Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension.

Calorie restriction (CR) can prolong human lifespan, but enforcing long-term CR is difficult. Thus, a drug that reproduces the effects of CR without CR is required. More than 10 drugs have been listed as CR mimetics (CRM), and some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, whereas the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Intriguingly, recent reports have revealed the beneficial effects of CRMs on the body such as improving the host body condition via intestinal bacteria and their metabolites. This beneficial effect of gut microbiota may lead to lifespan extension. Thus, CRMs may have a dual effect on longevity. However, no reports have collectively discussed them as CRMs; hence, our knowledge about CRM and its physiological effects on the host remains fragmentary. This study is the first to present and collectively discuss the accumulative evidence of CRMs improving the gut environments for healthy lifespan extension, after enumerating the latest scientific findings related to the gut microbiome and CR. The conclusion drawn from this discussion is that CRM may partially extend the lifespan through its effect on the gut microbiota. CRMs increase beneficial bacteria abundance by decreasing harmful bacteria rather than increasing the diversity of the microbiome. Thus, the effect of CRMs on the gut could be different from that of conventional prebiotics and seemed similar to that of next-generation prebiotics.