Healthy aging is a shared goal of most humans, but the body has a nasty habit of breaking down over time. Tantalizing research suggests it is possible to develop nutrition and lifestyle interventions that can delay aging and extend healthspan. In model organisms, including rodents and nonhuman primates, caloric restriction (CR) has proven to be an effective method for mitigating aging-related deterioration of biological functions and for extending healthspan and life-span. But more than 80 years since its discovery, the underlying mechanisms by which caloric restriction extends either are still largely undefined.
Researchers have linked a number of biochemical pathways to longevity, including those involved with nutrient signaling, metabolism, growth, genome stability, and oxidative stress. Translating this knowledge, derived mostly from mouse studies, to humans is an additional barrier that must be overcome. For example, it is almost impossible for the majority of people to maintain severe dietary restriction over their lifetime. Thus, more viable solutions for promoting health- and lifespan in humans must be found.
We have been studying the behavioral effects of CR in mice and have found that it leads to dramatic changes in feeding behavior. In contrast to mice given continual access to unlimited food, which spread their daily food consumption over the course of the day and night, mice on caloric restriction adopt a stark feeding and fasting pattern in which they consume all of the food provided within a few hours each day. Thus, under CR, mice not only consume fewer calories, they voluntarily adopt a time-restricted feeding pattern with a long fasting interval. All these factors have been shown to have numerous health benefits, again primarily in animal models.
More than 80 years since its discovery, the underlying mechanisms by which caloric restriction extends lifespan are still largely undefined.
To disentangle the contributions to longevity of calorie restriction, periods of fasting, and alignment of eating with an animal’s circadian “clock,” we recently completed a comprehensive study that contrasts these three factors (Science, doi:10.1126/science. abk0297). We found that CR is sufficient to extend lifespan but that the pattern and circadian alignment of eating act synergistically to extend life-span further. While CR alone increases lifespan by approximately 10 percent, eating that CR diet only at night, when mice are normally awake, extends life-span by more than 35 percent compared to mice eating regular diets. We also found that circadian alignment of feeding enhances CR-mediated benefits for survival independently of fasting duration (2 vs. 22 hours) and body weight. Aging promotes increases in inflammation and decreases in metabolism in the livers of mice with constant access to food, whereas a CR diet fed at night ameliorates most of these aging-related changes. Thus, eating only at certain times of day appears to promote longevity in animals and could provide a new mechanism for the treatment and management of aging in humans.
A significant aspect of our study was that there were no significant effects of the pattern or time of eating on body weight in mice. In addition, body weight was not associated with lifespan. This finding is consistent with a recent report in the New England Journal of Medicine(NEJM) comparing weight loss in two groups of human subjects that were assigned to CR alone or CR with an 8-hour time-restricted eating window (386:1495–504, 2022). The authors of this paper report no differences between these groups and conclude that there was no benefit of time-restricted eating for body weight. As we showed in our study, however, body weight does not serve as a good biomarker for longevity under CR conditions. So it would have been more useful in the NEJM study to have measured other endpoints besides body weight, such as inflammatory biomarkers associated with aging. In addition, previous studies that demonstrated health benefits of time-restricted eating were performed under conditions of overeating, not CR. Obviously, CR and overeating engage fundamentally different metabolic processes, and thus time-restricted eating of a CR diet should not be expected to yield the same results as time-restricted eating of a calorie-rich diet.
Our discovery that CR functions in concert with time-restricted eating and circadian alignment to optimally extend healthspan and lifespan is potentially transformative because it may yield a novel method for promoting healthy aging and lifespan increases in humans. Because lifespan in humans is primarily determined by lifestyle (less than 25 percent is genetically determined), these findings may be translated in future work to humans and are amenable to widespread adoption because they can be achieved by behavioral intervention: a CR diet eaten at the correct circadian time of day—i.e., when one is normally awake. This might involve, for example, a 12-hour eating window that begins at breakfast time.
A significant aspect of our study was that there were no significant effects of the pattern or time of eating on body weight in mice.
In addition, ongoing research in our labs seeks to test whether enhancing circadian clock function by behavioral (lifestyle), genetic, or pharmacological means can delay the aging process. Pharmaceutical agents we’re identifying in our labs that enhance circadian clock function may one day be used in humans as comprehensive therapies for aging. For now, we’re planning experiments for testing their anti-aging and pro-longevity effects in mice. Our lab and others have already provided evidence that the circadian clock system is an upstream regulator of all of the known anti-aging and pro-longevity pathways. So enhancing circadian clock function may rescue multiple aging pathways at the same time. We are testing this hypothesis by boosting Clock gene expression in genetically engineered mice. These animal studies can then lay the groundwork for the isolation of small molecules that target the Clock protein and the development of drugs that might safely modulate clock function and enhance health and longevity in people.
Joseph S. Takahashi is an investigator in the Howard Hughes Medical Institute and professor and chair of the Department of Neuroscience at the University of Texas Southwestern Medical Center’s Peter O’ Donnell Jr. Brain Institute. He is also a member of The Scientist Editorial Advisory Board. Carla B. Green is a professor and Distinguished Scholar in the Department of Neuroscience at the same institution.