Longevity

Study Shows Time-Restricted Feeding Enhances Longevity Benefits of Caloric Restriction in Mice

While caloric restriction alone increases lifespan by 10%, caloric restriction within a 2-hour feeding window at night increases the lifespan of mice by 35%.

Nicoleta Ionescu
By Daniel R. Miranda, Ph.D.

Key Points: 

  • Circadian alignment — aligning feeding time with circadian rhythms — combined with caloric restriction prolongs lifespan further than caloric restriction alone. 
  • Twelve hours (vs. twenty-two hours) of circadian-aligned fasting is sufficient to extend lifespan. 
  • Circadian alignment and caloric restriction restore more age-related gene changes than caloric restriction alone.

Caloric restriction — reducing food intake without malnourishment or starvation — may be the ultimate life-extending medicine. Many health-enthusiasts achieve caloric restriction through time-restricted feeding — eating within a specific time window. A new study reveals that when it comes to prolonging lifespan and preventing age-related diseases, this may be the way to go. 

As reported in Science, Acosta-Rodriguez and colleagues from the University of Texas show that a 30% caloric deficit extends the lifespan of mice by 10%. However, if the feeding window aligns with circadian rhythms (wake/sleep), lifespan is extended by 35%. The enhanced benefits of circadian alignment include improvements in hormone levels, such as insulin and leptin, and protection against age-related gene changes, including inflammatory genes. These findings demonstrate that circadian alignment enhances the benefits of caloric restriction.

Circadian Alignment Increases Lifespan 

Acosta-Rodriguez and colleagues found that if calorically restricted (30% caloric deficit) mice are fed at night, they live longer than if fed in the day. Since mice are nocturnal, they are awake at night and sleep during the day. Thus, the mice fed at night were in circadian alignment. Furthermore, when comparing a nighttime 2-hour feeding window to a 12-hour window, lifespan was prolonged further. However, this increase was not statistically significant, suggesting that a 12-hour circadian-aligned feeding window is sufficient for the enhanced benefits of CR.

(Acosta-Rodriguez et al., 2022 | Science) Nighttime Caloric Restriction Increases Lifespan Further than Daytime Caloric Restriction. Compared to mice fed an unrestricted diet (AL – ad libitum), calorically restricted (CR) mice with no feeding window/fasting (CR-spread) lived 10.5% longer, mice fed within a daytime 12-hour feeding window (CR-day-12h) lived 18.9% longer, mice fed within a daytime 2-hour window (CR-day-2h) lived 21.1% longer, mice fed within a nighttime 12-hour window (CR-night-12h) lived 33.6% longer, and mice fed within a nighttime 2-hour window lived 34.8% longer.

Mice with unrestricted feeding (AL) gradually increased in body weight until 20 months of age, after which they showed an age-related decline in weight. In contrast, all the CR mice maintained a lower body weight throughout their lifespan, indicating that circadian alignment does not increase the reduction in body weight caused by CR. Daily locomotor activity was associated with a longer lifespan but was considered a marker of healthspan because a previous study showed that locomotor activity does not affect mouse lifespan. Therefore, it seems that increased activity does not account for the enhanced benefits of circadian alignment with CR.

All the mice died of similar diseases, mainly consisting of different types of cancers, the highest incidence being in the liver. Compared to AL mice, CR mice died of these diseases later in life. When looking at hormone levels, CR mice had improvements in insulin sensitivity, suggesting protection against diabetes. Leptin — the hormone that inhibits hunger — showed an age-related increase in AL mice that did not occur in CR, which could be indicative of leptin resistance, which is associated with obesity. This data is in line with previous studies, suggesting that CR can slow down or prevent age-related disease.

Age-Related Gene Changes Protected by Caloric Restriction  

The changes in gene activation that occur with aging often underlie the cellular dysfunction that leads to age-related diseases. To examine age-related changes in gene activation, Acosta-Rodriguez and colleagues analyzed genes from the liver, which was the most affected by aging. CR mice with a 2-hour feeding window at night had the smallest percentage of gene changes, having the most protection against age-related gene changes. 

Among the genes protected by CR, in general, were those linked to Alzheimer’s disease. Genes specifically protected in the CR-night group were linked to reduced inflammation and oxidative stress, both hallmarks of aging. While CR, in general, is known to reduce inflammation and oxidative stress, circadian aligned CR seems to add another level of protection against these detriments. Overall, these results suggest that a lower percentage of age-related gene changes is associated with a longer lifespan.

(Acosta-Rodriguez et al., 2022 | Science) Caloric Restriction Protects Against Age-Related Gene Changes. Aging leads to an overactivation (up) of some genes and underactivation (down) of other genes, leading to age-related disease. Compared to all other groups, CR mice fed within a 2-hour window at night (CR.night.2h) were protected against the most gene changes, with only 2% overactivated and 2% underactivated.

When Should You Eat?

Acosta-Rodriguez and colleagues’ study largely agrees with other mouse studies, pointing to CR as a mediator of extended lifespan via reduced inflammation and oxidative stress associated with improved hormone levels. CR has also been shown to decrease inflammation in humans. Circadian alignment combined with CR seems to increase these benefits. Other studies have shown that circadian alignment increases the lifespan of flies and promotes health in humans. Since many human CR studies are already circadian aligned (participants eat in the daytime), it may be no surprise that CR during the active daytime hours is healthier than eating at night.

This study supports what many health-enthusiasts have already been doing — consuming a calorically restricted diet within a given feeding window during the daytime. But how long should that feeding window be during the day? When it comes to lifespan extension, the results from this study show that a 2-hour window is not significantly better than a 12-hour window, so it would seem that any 12-hour window during waking hours could be beneficial. Indeed, a recent exploratory study of 20 to 40 year old overweight and obese adults showed that while caloric restriction leads to reduced body weight and improved glucose levels, the feeding window does not make a difference. The feeding windows compared in this study were all in the daytime (8:00 am to 4:00 pm, 12:00 pm to 8:00 pm, and 8:00 am to 8:00 pm), so eating a calorically restricted diet any time during the day could improve metabolic health parameters, possibly leading to increased lifespan.

Source

Acosta-Rodríguez V, Rijo-Ferreira F, Izumo M, Xu P, Wight-Carter M, Green CB, Takahashi JS. Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice. Science. 2022 May 5:e. doi: 10.1126/science.abk0297. Epub ahead of print. PMID: 35511946.

 

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