The hidden costs of dietary restriction: implications for its evolutionary and mechanistic origins

Abstract

Dietary restriction (DR) consistently and universally extends health-and lifespan across taxa. Despite efforts to uncover the mechanisms underpinning DR - and ultimately translate its beneficial outcomes to humans - precise and universal mechanisms have not been identified. In biomedical science, the effects of DR are interpreted as regulating pro-longevity molecular pathways. This reasoning is guided by the conviction that DR evolved as an adaptive, pro-longevity physiological response to restricted food intake. Current evolutionary theory states that organisms should invest in their soma more heavily during periods of DR, and, when their resource availability improves, should outcompete age-matched rich-fed controls in survival and/or reproduction. Here we present a formal test of these key predictions utilising a large-scale demographic approach detailing mortality and fecundity in Drosophila melanogaster fed alternating dietary regimes (N > 66,000 flies across 11 genetic lines). Our experiments reveal surprising and substantial mortality costs when returning to a rich diet after periods of DR. These results suggest the effects of DR are not necessarily intrinsically pro-longevity and could be considered an escape from costs incurred under nutrient-rich conditions, in addition to novel, discrete costs associated with restricting dietary protein. These insights question the relevance of current evolutionary explanations of DR in interpreting the mechanistic basis of dietary restriction.