Unlike many trendy diets, intermittent fasting appears to deliver real benefits—provided dieters can stick to the schedule, which usually restricts eating to an eight-hour window each day. Dieters, however, may be able to pad their eating schedules while trimming their waistlines—and extending their healthspans—if the results of a new study can be exploited pharmacologically.
This study, from researchers based at Columbia University, demonstrated that in fruit flies, the benefits of intermittent fasting are attributable to circadian autophagy. The researchers suggest that circadian-regulated autophagy could be stimulated not just by intermittent fasting, but by pharmaceutical interventions.
Details of the study (“Circadian autophagy drives iTRF-mediated longevity”) appeared September 29 in the journal Nature. According to the study, the Columbia researchers used a convenient model, the fruit fly Drosophila melanogaster, to develop an intermittent time-restricted feeding (iTRF) dietary regimen that robustly extended fly lifespan and delayed the onset of aging markers in the muscles and gut.
“We found that iTRF enhanced circadian-regulated transcription and that iTRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway,” the article’s authors reported. “Night-specific induction of autophagy was both necessary and sufficient to extend lifespan on an ad libitum diet and also prevented further iTRF-mediated lifespan extension.”
The study’s senior author, Mimi Shirasu-Hiza, PhD, associate professor of genetics and development at Columbia University Vagelos College of Physicians and Surgeons, noted that fruit flies have similar biological clocks to humans, staying active during daylight and sleeping at night, while also sharing roughly 70% of human disease-related genes. She added that fruit flies are an excellent model for aging because fruit flies and humans age in similar ways. Fruit flies live only two months, so aging experiments are more technically feasible in fruit flies than in humans.
“Because intermittent fasting restricts the timing of eating, it’s been hypothesized that natural biological clocks play a role,” Shirasu-Hiza pointed out. To explore this possibility, Shirasu-Hiza and colleagues put their flies on one of four different schedules: 24-hour unrestricted access to food; 12-hour daytime access to food; 24-hour fasting following by 24-hour unrestricted feeding; or iTRF (20 hours of fasting followed by a recovery day of unlimited feeding).
Among the four eating schedules, only iTRF significantly extended the lifespan—18% for females and 13% for males.
And the timing of the 20-hour fast was critical: Lifespan increased only for flies that fasted at night and broke their fast around lunchtime. The lifespans of flies that instead fasted all day, eating only at night, did not change.
For the researchers, the role of time was a big clue to how fasting is linked to longevity. They found that autophagy, a cell-cleaning process, kicks in after fasting, but only when fasting occurs during the night. Autophagy (Greek for self-eating) is known to slow aging by cleaning up and recycling damaged components of the cell.
“We found that the life-extending benefits of iTRF require a functional circadian rhythm and autophagy components,” Shirasu-Hiza declared. “When either of those processes were disrupted, the diet had no effect on the animals’ longevity.”
Besides increasing the flies’ lifespan, iTRF improved the flies’ “healthspan,” increasing muscle and neuron function, reducing age-related protein aggregation, and delaying the onset of aging markers in muscles and intestinal tissues.
Human cells use the same cell-cleaning processes, so the findings raise the possibility that behavioral changes or drugs that stimulate the cleaning process could provide people with similar health benefits, delaying age-related diseases and extending the lifespan.
Unlike dietary restriction, which reduces caloric intake, intermittent fasting does not. It merely limits feeding to specific hours of the day. Nonetheless, intermittent fasting is far from effortless.
“Any type of restricted eating is difficult,” said Matt Ulgherait, PhD, an associate research scientist in Shirasu-Hiza’s laboratory and the study’s first author. “It requires a lot of discipline, and most studies of time-restricted fasting in humans have built in a cheat day to make it more tolerable. It would be much easier to get the same health benefits if we could enhance autophagy pharmacologically, specifically at night.”
The potential for pharmacological applications may be realized if researchers continue to study how circadian regulation and autophagy control aging and lifespan. In the current study, the researchers identified circadian clock components (Tim, Per, Cyc, and Clk) and essential autophagy components Atg1 and Atg8a as both necessary and sufficient for the anti-aging, lifespan-extending benefits of iTRF. “With a diversity of cellular autophagy targets (proteins, lipids, nucleotides, and organelles),” the researchers noted, “identifying the major tissues and specific targets involved in iTRF-mediated, autophagy-associated health benefits are challenges for future work.”
