The open access paper noted here is an example of present day intermittent fasting research, in flies in this case, in which researchers attempt to obtain a better understanding of how this dietary adjustment influences the pace of aging. The paper caught my eye for the examination of intestinal function. If you have been following the field in recent years, you may recall that the research community believes that intestinal function is central to the aging of flies, probably much more so than is the case in mammals. We can say that flies die from intestinal dysfunction in the same way we can say that humans die of cancer and heart disease - it is the dominant feature of decline and mortality in that species.
Intermittent fasting has been shown in a variety of species to have a broadly similarly effect to the more usual form of calorie restriction approaches, at least when the overall intake of calories is still restricted in comparison to a normal diet. However, it also extends life to some degree even when overall intake of calories is not restricted. Rodents on diets that have the same caloric intake but a different scheduling of that intake exhibit differences in the pace of aging. Time spent hungry appears important, in terms of triggering the nutrient-related stress responses that keep cells healthier and less damaged. This isn't to say that the processes under the hood are identical: researchers have found considerable differences in gene expression between calorie restriction and intermittent fasting.
The time spent hungry hypothesis falters somewhat in the evidence from this study, not least because the background of historical evidence for intermittent fasting in flies is mixed. The evidence noted below suggests that intermittent fasting in flies, provided it is carried out in early life only, slows aging to benefit life span for reasons that are not the same as the usual nutrient-sensing mechanisms associated with calorie restriction. That is an interesting discovery. It may well be peculiar to flies due to the role of intestinal function in aging in those species, but I think that in general we should expect the effects of caloric intake to be more complex than simply a reflection of total calories over a period of time. That is probably true for any species.
Intermittent fasting (IF), an umbrella term for diets that cycle between a period of fasting and non-fasting, has become increasingly popular as a weight loss regime (e.g., "every-other-day fasting" and the "5:2" diet). Advocates of IF argue that it shows many of the benefits seen with traditional daily energy restriction diets but with a simplified nutritional regime and increased compliance. Recent pilots and clinical trials used a fasting mimicking diet (FMD) (consisting of monthly cycles of a 5-day fast during which daily food intake was reduced to ∼50% normal caloric intake), which reduced multiple health risk factors during the post-fast recovery period, including lowered blood pressure, and reduced blood glucose and insulin-like growth factor-1 (IGF-1) levels. IF can extend lifespan in a variety of organisms, including bacteria, yeast, nematode worms, and mice. In animal models, IF has been shown to reduce the risk of developing a variety of age-related pathologies. IF is effective in preventing neurodegeneration in rodents and can attenuate cancer and cardiometabolic diseases, such as type II diabetes.
Reduced activity of nutrient-sensing pathways, with corresponding decrease in global protein translation, is implicated as an important mechanism underlying the pro-longevity effects of dietary interventions, such as dietary restriction (DR). Reduced TOR signaling is a hallmark of pro-longevity interventions, including DR, and treatment with the TOR inhibitor rapamycin extends healthy lifespan in a range of organisms. Although DR may exert some of its pro-longevity effects through reduced fecundity, DR can still extend lifespan in sterile Drosophila, implying that fecundity and lifespan can be uncoupled and that other mechanisms are also important.
Previous studies examining potential pro-longevity effects of IF in flies have produced mainly negative results. The first studies, almost 90 years ago, found that 6 hr of starvation in every 24 hr was beneficial and could extend lifespan. However, the effects of this IF regime may be strain or food medium specific, because a similar, more rigorous experiment ∼80 years later found that daily bouts of either 3 hr or 6 hr starvation throughout the adult life of the fly had neither a positive nor a negative effect on lifespan.
Here, we investigated a variety of IF regimes in flies and their effects on a range of health outcomes, including feeding behavior, gut and metabolic health, survival after stress, and lifespan. Importantly, short-term IF (the "2:5" diet) confined to early life robustly increased subsequent lifespan, particularly in females, independent of TOR signaling. Short-term IF also led to long-lasting health improvements, including increased stress resistance and a lower incidence of gut pathology that was associated with reduced bacterial abundance. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health.