Shorter Eating Window, Longer Life? New Study Finds Intermittent and Time-Restricted Fasting Boosts Longevity in Fruit Flies

Intermittent fasting has been touted in recent years as a dietary regimen with a myriad of health benefits. Although the exact eating style can vary, intermittent fasting typically involves forgoing food and caloric beverages for 14 to 16 hours per day, limiting the eating window to 8 to 10 hours. Despite its benefits, this restrictive diet can be challenging for many to stick with long term, leading researchers to search for ways to bottle up the benefits of fasting into an easier-to-swallow pill.

Now, a study out of Columbia University finds that shortening that eating window and fasting for 20 hours every other day — a feat that not many people could comfortably manage — extends lifespan and improves age-related markers of physical decline in fruit flies. Published in the journal Nature, Ulgherait and colleagues ​find the optimal intermittent fasting strategy to increase lifespan in flies, and with it, identify future targets for pharmaceutical intervention that could potentially delay aging and expand lifespan in people.

The Multiple Facets of Fasting

As opposed to caloric restriction, which typically reduces daily calories by 20-40%, intermittent fasting targets the timing of eating instead of the amount of food. Although long-term caloric restriction has been linked more often to increased lifespan in animal studies, this style of eating may cause people to become underweight or develop disordered eating patterns. For this reason — and the fact that cutting calories by almost half can be difficult to do — researchers are looking to intermittent fasting or time-restricted eating to see if the same longevity benefits apply. 

In this study, Ulgerhait and colleagues split fruit flies into four groups: a control group that ate whenever they wanted (“ad libitum”), a second group that fasted for a full 24 hours followed by 24 hours of unrestricted feeding, a third that fasted for 12 hours of each day, and the fourth, which fasted for 20 hours per day followed by a recovery day of ad libitum feeding (“iTRF,” or intermittent time-restricted fasting). 

Tick, Tock, Longevity and Circadian Clocks

A somewhat surprising finding was that only one form of intermittent fasting significantly extended lifespan — the iTRF group. In fact, the group that fasted for 24 hours even had a decrease in average lifespan, showing that there can be too much of a good thing. Fasting for 20 hours, with a full 24 hours of recovery between each fasting day, was the only method that promoted longevity, with an 18% and 13% increase in average lifespan in the female and male fruit flies, respectively. 

However, switching to this eating style as the flies reached ‘elderly’ status (days 40-50 in their typically 50-days-long life) did not provide the same lifespan-extending effects. This indicates that starting intermittent fasting in early-to-mid life may be needed to see the longevity benefits.  Plus, ​​the timing of breaking the 20-hour fast was important, as lifespan was increased only for the flies that fasted at night and started eating again in the late morning or early afternoon. 

Conversely, the flies who fasted all day and ate during the night did not see any change. Ulgherait and colleagues chalk this up to the circadian rhythm — the internal biological clock that runs on a 24-hour cycle. As the senior author, Mimi Shirasu-Hiza, Ph.D., associate professor of genetics and development at Columbia University, states, “Because intermittent fasting restricts the timing of eating, it’s been hypothesized that natural biological clocks play a role.” 

There are two crucial proteins, aptly named Clock and Cycle, that activate and regulate circadian-related genes. In this study, the fruit flies on the iTRF diet had enhanced circadian gene activity, especially during the fasting nighttime periods. On the other hand, flies with dysfunctional versions of the Clock or Cycle proteins did not experience the same lifespan extension while on the iTRF diet. These results suggest that having a functional circadian clock is necessary for the longevity-related benefits of fasting to occur. 

Bottling Up the Benefits of Autophagy

The intermittent time-restricted fasting flies also experienced some benefits related to healthspan — how long we live without developing age-related bodily decline. The iTRF flies showed significantly improved muscle and brain cell function compared to the ad libitum flies, as measured by a climbing ability test. The iTRF group also exhibited fewer markers of protein clumping in the muscles and reduced signs of poor intestinal function, both of which are markers of aging.

Lastly, Ulgherait and colleagues looked at how iTRF affected autophagy — the body’s way of clearing out dysfunctional or damaged cells, cell parts, and proteins. A reduction in autophagic ability goes hand in hand with aging and its associated conditions, while boosting autophagy is often linked to longer health- and lifespans. 

Flies on the iTRF diet showed elevated activity of two vital proteins that mediate autophagy, especially during the nighttime fasting period. Plus, flies without the circadian clock proteins did not have increased autophagy during fasting, indicating that a properly working circadian rhythm is necessary for fasting-mediated autophagy to take place. As Shirasu-Hiza states, “We found that the life-extending benefits of iTRF require a functional circadian rhythm and autophagy components. When either of those processes were disrupted, the diet had no effect on the animals’ longevity.”   

Remarkably, the researchers were also able to pharmacologically enhance the nighttime activity of one of the autophagy-regulating proteins in flies on the ad libitum diet. These flies, who did not fast but had boosted circadian-related autophagic activity, experienced lifespan extension similar to the iTRF group. 

As Ulgherait reflects on how this discovery could benefit humans, ​​“Any type of restricted eating is difficult. 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.” 

Fasting Your Way to Old Age

Although we’ve known many of the weight- and metabolism-related benefits of intermittent fasting for some time, it’s been relatively unclear how time-restricted eating affects lifespan. Now, this study provides evidence that two components are necessary for intermittent fasting to promote longevity: healthy circadian rhythms and autophagic abilities — in fruit flies, at least.  

The authors conclude in their paper, “As a simple dietary intervention strategy, iTRF appears to be both efficient and pleiotropic [producing more than one effect], with health benefits for multiple tissues, and offers a potential method of choice to combat aging.” However, eating in a 4-hour window is likely not an attractive or feasible option for many. Thus, the researchers are hopeful that a novel pharmacological therapy to promote increased autophagy at night could benefit those of us unwilling to part with our three square meals per day. 

References:

Ulgherait, M., Midoun, A.M., Park, S.J. et al. Circadian autophagy drives iTRF-mediated longevity. Nature (2021). https://doi.org/10.1038/s41586-021-03934-0