Calorie restriction, eating up to 40% fewer calories while maintaining optimal micronutrient intake, near universally improves health and extends life across species assessed to date. Flies are a noteworthy exception to the reliability of this effect; the evidence is decidedly mixed for intermittent fasting and calorie restriction to work in flies in the same way that it does in nematodes, mice, and other laboratory species. Where it does work, it might not be working for the same reasons as it does in other species. The results here are somewhat characteristic of examinations of dietary restriction in flies, finding another way in which their response differs from that of, say, mice.
Dietary restriction (DR) extends health and life span across taxa, from baker's yeast to mice, with very few exceptions. The reduction in total calories - or restriction of macronutrients, such as protein - extends life span reliably. Although the precise universal mechanisms that connect DR to ageing remain elusive, translation of DR's health benefits to human medicine is deemed possible. The widespread assumption of DR's translational potential originates from the notion that DR's beneficial effects are facilitated by shared evolutionary conserved mechanisms, as beneficial effects of DR are observed across taxa. Experiments on our close evolutionary relatives, rhesus monkeys (Macaca mulatta), have demonstrated that DR could be translational. Still, the mechanisms by which these benefits are accrued physiologically may differ between species, as no single genetic or pharmaceutical manipulation mimicking the benefits of DR across model organisms exists.
Shared universal mechanisms can only be inferred from the ubiquity of the DR longevity response in the animal kingdom, when the selection pressures responsible for such evolutionary conservation are understood. The DR response itself may have evolved once, and mechanisms might be conserved. Alternatively, DR could have undergone convergent evolution, either using similar mechanisms - or by adopting alternative ones. Only if the DR response is rooted in ancient physiology (i.e., evolved once or through convergent evolution) can possible translation of mechanistic research on model organisms be confidently inferred.
Guided by the conviction that DR evolved as an adaptive, pro-longevity physiological response to food scarcity, biomedical science has interpreted DR as an activator of pro-longevity molecular pathways. Current evolutionary theory predicts that organisms invest in their somatic tissues during DR, and thus, when resource availability improves, should outcompete rich-fed controls in survival and/or reproduction. Testing this prediction in Drosophila melanogaster (more than 66,000 individuals across 11 genotypes), our experiments revealed substantial, unexpected mortality costs when flies returned to a rich diet following DR. The physiological effects of DR should therefore not be interpreted as intrinsically pro-longevity, acting via somatic maintenance. We suggest DR could alternatively be considered an escape from costs incurred under nutrient-rich conditions, in addition to costs associated with DR.