Dietary restriction and the pursuit of effective mimetics

Dietary restriction (DR) has been shown to extend both median and maximum lifespan in a range of animals, although recent findings suggest that these effects are not universally enjoyed across all animals. In particular, the lifespan effect following DR in mice is highly strain-specific and there is little current evidence that DR induces a positive effect on all-cause mortality in non-human primates. However, the positive effects of DR on health appear to be highly conserved across the vast majority of species, including human subjects. Despite these effects on health, it is highly unlikely that DR will become a realistic or popular life choice for most human subjects given the level of restraint required. Consequently significant research is focusing on identifying compounds that will bestow the benefits of DR without the obligation to adhere to stringent reductions in daily food intake. Several such compounds, including rapamycin, metformin and resveratrol, have been identified as potential DR mimetics. Although these compounds show significant promise, there is a need to properly understand the mechanisms through which these drugs act. This review will discuss the importance in understanding the role that genetic background and heterogeneity play in mediating the lifespan and healthspan effects of DR. It will also provide an overview of the most promising current DR mimetics and their effects on healthy lifespan