How much of the improvement in health and extension of life span produced by calorie restriction in mouse studies is due to lowered calorie intake versus length of time spent fasting between meals? In most past studies, calorie restricted mice were fed once a day, resulting in long periods of fasting and hunger-induced metabolic changes between meals. It may be that this timing is important, and of late researchers have started to run studies intended to assess this question.
Data obtained to date strongly suggests that, yes, time of fasting does matter and does contribute to health and longevity benefits in mice independently of reduced calorie intake. Today's research materials further support that conclusion. The authors report on a study in which calorie restricted mice are fed at different intervals. Allowing these mice to eat throughout the day reduces the gain in life span usually observed in calorie restriction studies.
Timing feedings to match the active period of the circadian cycle extended the life span of lab mice more than three times as much as caloric restriction alone. Mice that ate as much and whenever they wanted lived nearly 800 days median life span - an average period for their species. Restricting calories but making food available around the clock extended their lives only 10% to 875 days despite restricting calories by 30-40%. Restricting this reduced-calorie diet to the inactive period of the circadian cycle boosted lifespan by nearly 20% to an average of 959 days. Offering the low-calorie diet only during the active period of the cycle extended their median life span to about 1,068 days, an increase of almost 35% over the unrestricted eaters.
Further investigation showed that the mice that lived the longest had significantly better metabolic health, with higher insulin sensitivity and blood sugar stability. They tended to get diseases that killed the younger mice, such as various forms of cancer, at far more advanced ages. Gene expression experiments showed fewer changes in the activity of genes associated with inflammation, metabolism and aging in the long-lived animals compared to the shorter-lived ones.
Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.