In a new study published in Science, researchers show that calorie restriction and time-restricted feeding have an additive effect on life expectancy in mice [1].
A known intervention
Calorie restriction is considered the first intervention that conclusively shows that aging is a malleable phenomenon. The first trials were done on rats in the 1930s and showed that drastic caloric restriction of 20% to 30% significantly increased life expectancy compared to a freely fed (ad libitum) control group. [2].
As promising as these early results were, the reality is more complicated. First, lab animals tend to overeat when food is plentiful, so calorie restriction might bring calorie counts down to normal levels, so it might not work as well in people who already count their calories; There have been virtually no human trials of drastic caloric restriction, because it is difficult to maintain.
Second, in most of the rodent experiments, the animals were fed once a day. They frantically consumed their limited amount of food in about two hours and then involuntarily fasted for 22 hours straight. Today, this would be called intermittent fasting, another intervention gaining popularity for its purported health-promoting qualities. [3]. There are several intermittent fasting regimens, including “day after day,” but some of the most popular involve eating only for a period of 2 to 12 hours.
Therefore, it is difficult to determine whether it is fewer calories or fewer hours of feeding that makes calorie restriction work so well in mice and rats. This new study attempts to provide an answer using something that scientists in the 1930s didn’t have: automatic feeders.
If you are a mouse, eat at night.
The researchers divided the male mice into six groups. The control group was fed ad libitum, with readily available food during the night and day. All other groups were calorie restricted, receiving 30% fewer calories than the AL mice consumed. The first calorie-restricted group received food throughout the day, and an automatic feeder dispensed a pellet of food every 160 minutes, eliminating the influence of intermittent fasting. The second calorie-restricted group was fed only for 2 hours during the day, the third for 12 hours during the day, the fourth for 2 hours at night, and the fifth for 12 hours at night.
In the free-feeding group, the median lifespan was 792 days, which is quite normal for this particular very popular strain (Black 6). This is important, because in some studies, the controls are of short duration, which can cast doubt on the results.
All calorie restriction groups demonstrated significant gains in life expectancy compared to controls, but there were important differences. The first group, the mice that were being fed throughout the day, lived only 10% longer than the controls. The two groups that were fed during the day moved closer to each other: the second group lived 21% longer and the third group lived 19% longer on average than the controls. The final two groups were clear winners, with a 35% increase in median lifespan for the fourth group and 33.4% for the fifth group.
Obviously, the mice that were fed at intervals during the day had their sleep disrupted, which could have slowed the gains in life expectancy. The researchers admit that this requires further investigation. Mice are nocturnal animals, so if they are forced to eat during the day, this is not natural for them and could explain the difference between the diurnal and nocturnal groups.
There are two important takeaways from the data: calorie restriction and intermittent fasting have an additive effect, and reducing the eating window to 2 hours appears to add little value compared to a 12-hour window.
Additional benefits
The researchers confirmed that caloric restriction confers clear metabolic benefits. While insulin levels increased with age in the control group, this increase was attenuated in all restricted groups. Although the insulin levels of the young calorie-restricted mice were comparable to those of the young mice in the control group, the former had lower blood glucose levels, indicating better insulin sensitivity.
The researchers also looked at gene expression in the liver. The transcriptomes of young and old mice in the control group were pooled separately due to obvious age-related changes. Transcriptomes from young mice in the calorie restriction group were pooled separately, signifying that calorie restriction affects gene expression in young mice.
Finally, all calorie-restricted old mice also clustered in their transcriptomes, between old mice in the control group and young calorie-restricted mice, demonstrating that the intervention attenuates age-related transcriptomic changes. About 50% of the age-related changes in gene expression were reversed with all calorie restriction regimens.
The researchers found 159 genes that responded specifically to intermittent fasting rather than calorie restriction, confirming that its effects are at least somewhat additive. 69 genes were specifically protected against age-related changes in expression in groups that were restricted to low-calorie evening meals.
conclusion
This study attempts to disentangle the effects of calorie restriction and intermittent fasting and give us a better understanding of how those two interventions work. Since humans can hardly achieve drastic calorie reduction in real life, the suggestion that time-based eating might be partly responsible for the life-prolonging effect of calorie restriction is encouraging. The lack of gender diversity is a serious limitation as many life-prolonging interventions appear to work differently in men and women. Hopefully this will be addressed in future research.
Literature
[1] Acosta-Rodriguez, V., Rijo-Ferreira, F., Izumo, M., Xu, P., Wight-Carter, M., Green, CB, & Takahashi, JS (2022). Circadian alignment of early-onset caloric restriction promotes longevity in male C57BL/6J mice. Scienceand.
[2] McCay, C.M., Crowell, M.F., and Maynard, L.A. (1935). The effect of stunting on lifespan and final body size: one number. The Nutrition Journal, 10(1), 63-79.
[3] de Cabo, R. and Mattson, MP (2019). Effects of intermittent fasting on health, aging and disease. New England Journal of Medicine, 381(26), 2541-2551.
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