Existing Theory Explaining the Effects of Restricted Diet on Lifespan Challenged

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Drosophila melanogaster cages containing adult flies for monitoring ageing and deaths of flies. Attached are vials of media to feed the adult flies. [Gracie Adams]

A University of Sheffield-led team of scientists has reported on studies in fruit flies that suggest switching to a rich diet after eating a restricted diet can decrease life expectancy and have negative effects on health. Research in many species has shown that restricting food intake—which is known as caloric, or dietary restriction (DR)—can extend lifespan, but the new findings challenge the existing evolutionary theory of why DR increases longevity. The results also provide new insight into why, as well as how diets could benefit humans in terms of slowing aging and the onset of age-related disease, and indicate that changing diet repeatedly or abruptly could be harmful to health in certain situations.

“The effects of diet on health are huge, but we understand little of the exact mechanisms, said Mirre Simons, PhD, from the University of Sheffield’s department of animal and plant sciences. “Our work has now uncovered a surprising property of dietary restriction, in that it makes flies ill-prepared for rich diets. This was contrary to our expectations and contrary to current evolutionary theory. In the biology of aging, field evolutionary biology has been highly influential in guiding the interpretation of more mechanistic research. Our work thereby contributes to the broader understanding of dietary restriction and the efforts to translate its benefits to humans.”

Simons and colleagues reported their findings in Science Advances, in a paper titled, “The hidden costs of dietary restrictions: Implications for its evolutionary and mechanistic origins.”

Studies have shown that DR extends health and lifespan across different taxa, from yeast to mice, and with very few exceptions, the authors noted. “The reduction in total calories—or restriction of macronutrients, such as protein—extends life span reliably,” they wrote. “Although the precise universal mechanisms that connect DR to aging remain elusive, translation of DR’s health benefits to human medicine is deemed possible.”

The common evolutionary theory of why this phenomenon exists is based on the premise that dietary restriction—a reduction of particular or total nutrient intake without causing malnutrition—triggers a survival strategy in humans and animals. The theory suggests that this is because humans and animals invest in maintaining and repairing the body in times of low food availability, to wait for times when food availability increases. “DR presents an enigma,” the team noted. “Why do organisms live longer on a constrained energy budget? The currently accepted evolutionary model for DR uses a life-history perspective on aging to explain this enigma. The model proposes that below a certain resource threshold, organisms will reallocate energy almost exclusively toward somatic maintenance… ” and this would allow them to survive periods of famine. “The optimal, fitness-maximizing strategy under these harsh conditions would be to terminate investment into reproduction and use this energy to gain fitness when conditions improve.”

In fact, there are few alternatives to this somatic maintenance response model that can explain the evolutionary biology of DR, the scientists continued. “This attractive evolutionary rationale has given credibility to the assumption that physiological changes in the DR animal are inherently pro-longevity, since it implies DR increases investment into somatic maintenance.” The model supports a key prediction, that with organisms increasing investment in somatic maintenance during periods of DR, when the availability of resources improves, these individuals should “outcompete age-matched rich-fed controls in survival and/or reproduction … Resources allocated to somatic maintenance should result in higher fitness,” the team pointed out.

Working with scientists at Brown University, the University of Sheffield’s Healthy Lifespan Institute scientists tested the current evolutionary theory and the resulting prediction, using the fruit fly (Drosophilia melanogaster) as an experimental model. Their findings, surprisingly now challenge the theory, and demonstrated that fruit flies fed a restricted diet and then returned to a rich diet were more likely to die, and laid less eggs, compared with flies that spent their whole lives on a rich diet. The results showed that, rather than waiting for food availability to increase in the future, the flies were essentially waiting to die on a restricted diet. “ … we find that periods of DR did not result in a superior soma and instead resulted in large increases in mortality and reductions in fecundity, when nutrient availability returned to plentiful,” the authors wrote. “Our results question the current explanation of DR’s evolutionary origins and, thereby, its relevance in interpreting DR’s mechanistic origins.”

The researchers suggested that instead of dietary restriction increasing repair and maintenance mechanisms, it could actually be an escape from the damaging effects of a rich diet. This new interpretation could help scientists understand why and how diet can have such profound effects on health. Study lead Andrew McCracken, a PhD student at the University of Sheffield’s department of animal and plant sciences, commented, “Dietary restriction is an unusual paradox which has attracted a great deal of interest within the field of aging. Our results have now pointed us towards a more refined explanation of why it occurs, and have the potential to wholly shift the focus of future research. Our most surprising finding was that under certain circumstances, restricted diets can also be the origin of particular types of damage to the individual. This enhanced understanding of the penalties and benefits of certain types of diets, will expedite the quest to identify pharmaceutical interventions which mimic dietary restriction.”

Bottles of Drosophila melanogaster larvae and pupae. Bottles contain a medium to feed the developing larvae and adult flies. [Gracie Adams]
The researchers acknowledged that the mechanisms underpinning the increased mortality observed when the flies returned to a rich diet after a period of DR aren’t understood. “We have excluded water balance, social effects, the microbiome, and sex-specific effects as being wholly responsible for our observations,” they stated. “We, therefore, conclude that in conjunction with physiological costs associated with a rich diet, there are hidden costs associated with DR. These costs appear only when a rich diet is resumed after DR.”

They point out that all current evidence to date suggests that uptake of the macronutrient protein is responsible for the effects of diet on longevity, and with that in mind, they continued, “We suggest that DR’s effect on longevity is not via increased investment in somatic maintenance, but the result from a forced escape from the intrinsically harmful effects of dietary protein … We suggest that the quest to identify the mechanisms of DR will be aided by acceptance that somatic maintenance is not necessarily responsible for the life extension seen under DR.”

The authors also pointed out that their results could have implications for continuing research on the potential benefits of intermittent fasting on health. Previous studies in mice have suggested that intermittent fasting can extend lifespan in a similar manner to caloric restriction. “Human data on intermittent fasting are promising and have potential application in specific diseases,” the scientists continued, although conclusive evidence from clinical trials is lacking, they noted. “Our work now suggests that intermittent DR, dependent on its duration, can have negative consequences.” The observations from their reported studies also fit with refeeding syndrome—a clinical condition that occurs at refeeding after a period of starvation. “It remains to be determined which duration of starvation or DR would instigate such harmful physiological effects upon refeeding to the extent that it offsets its physiological benefits in humans,” they noted.

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