Fruit fly study reveals the "hidden costs" of intermittent fasting

Jumping on and off the diet wagon may seem like a tempting way to lose weight or improve long-term health. But a new study suggests swinging between periods of dietary restriction and eating rich foods may have “hidden costs” for reproductive health and perhaps even lifespan.

In the study, which was conducted in fruit flies, researchers find that switching back to a plentiful diet after cutting consumption causes flies to lay fewer eggs and die prematurely as compared to flies that lived on a rich diet consistently.

Of course, “fruit flies aren’t humans,” study co-author Mirre Simons tells Inverse. More research is needed to see how diet switching plays out in the human body. But if future studies confirm the findings, it could be bad news for the thousands of people who diet on-and-off, or incorporate intermittent fasting in their routines.

“Intermittent fasting could have negative health consequences under certain dietary or temporal regimes,” Simons, a researcher at the University of Sheffield, says.

Switching from restriction to re-feeding, or resuming normal eating, may have negative health consequences that may occur within a short timeline, the results suggest.

“A level of caution is therefore warranted when rapidly changing diet, especially at least that is what our work suggests, increasing intake after a period of restriction," he says.

The findings were published Friday in the journal Science Advances.

Bug models

Typically, when fruit flies' diets are restricted, their risk of death drops significantly within 24 hours, Simons says. But rebounding after dietary restriction by eating a rich diet appears to cause an “overshoot effect" in the flies, resulting in "substantial" and "unexpected" mortality costs.

To test how sudden diet shifts affect fruit flies, a model often used in biology as a “stand-in” for humans, Simons' team cycled a large group of mostly female flies through periods of eating very little and periods of eating four times as much food.

The researchers tracked how many bugs lived or died throughout the study, and how many eggs the flies laid. After switching from four-day dietary restriction to a rich-food diet, flies’ risk of death went up and their fertility went down.

The effect of diet switching remained significant after controlling for different confounders, including the flies’ microbiomes, water consumption, social dynamics, and gender.

The experiment was repeated in over 66,000 flies across 11 genetic lines. As a group, the short-term diet switches have “surprising” effects on flies’ health, the researchers say.

Mortality risk during intermittent 4-day periods of dietary restriction was 1.6 times higher than in flies kept on a restricted diet without breaks. During the 4-day timelines, the flies’ risk of death appears to peak 48 hours after each diet switch.

During shorter, 2-day time periods, the team did not see significant effects on the flies’ risk of death. This finding suggests timing matters, and negative effects pop up after a certain number of days after a diet switch.

Survival mode

This study pushes against the popular theory that dietary restriction triggers a “survival strategy” in humans and animals.

The theory goes that humans and animals invest in maintaining and repairing the body in times of low food availability, to await times when food availability increases again. This ability to thrive under a constrained energy budget seems to benefit their long-term survival. Indeed, dietary restriction — not starvation or nutrient deprivation — has been shown to extend animal lifespans in multiple studies.

A huge number of species — from yeast to rhesus monkeys — show similar responses to dietary restriction, suggesting dietary restriction is an “evolutionary conserved response,” Simons says.

“The explanation why this response is so universally found in the animal kingdom is that organisms go into a survival mode during times of scarcity, invest in maintaining themselves, therefore age less fast, to await times when food availability increases again,” he says.

The theory is “attractive and intuitive,” but it has not been subject to rigorous testing, Simons says.

In this study, the researchers test the theory's assumption that cutting food intake prepares animals for periods of food abundance.

But the results indicate flies are “ill-prepared” for rich-food conditions after experiencing dietary restriction. Rather than waiting for food availability to increase in the future, the flies instead appear to be essentially waiting to die on a restricted diet, the researchers say.

The team conducted several follow-up experiments to make sure this effect was "real," interesting biology, Simons says. However, the work does still need to be validated in a separate sample.

Instead of dietary restriction triggering a survival mechanism, the researchers offer an alternate theory: Perhaps, dietary restriction is an escape from the damaging costs of a rich diet, which are currently unknown, they say.

What that "escape" means and if it translates to real-life health outcomes isn't clear at this stage.

"Our work is a considerable step forward in the fundamental understanding of dietary restriction — one of the best known and studied ways to make animals, and most likely also our own species, live longer and healthier," Simons says.

Ultimately, the study suggests limiting food intake may affect longevity, and in some cases, hamper reproductive abilities and heighten the risk of death. Diet changes should be taken with care, the researchers caution.

Abstract: Dietary restriction (DR) extends life span across taxa. Despite considerable research, precise and universal mechanisms of DR have not been identified, limiting its translational potential. In biomedical science, DR is interpreted as stimulating pro-longevity molecular pathways. This rationale is guided by the conviction that DR evolved as an adaptive, pro-longevity physiological response to food scarcity. Current evolutionary theory states that organisms invest in their soma during DR, and thus when resource availability improves, should outcompete rich-fed controls in survival and/or reproduction. Here, we test this prediction using large populations of Drosophila melanogaster (N > 66,000 across 11 genetic lines). Our experiments reveal substantial, unexpected mortality costs when flies return 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.