Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan

Abstract

Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from the prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which food consumption is restricted to certain hours of the day, allows the daily fasting period to last >12 hr, thus imparting pleiotropic benefits. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting-mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMDs, both basic science and translational research are warranted to develop fasting-associated interventions into feasible, effective, and inexpensive treatments with the potential to improve healthspan.

Figure 1

Conserved nutrient sensing pathways in yeast and mice.

Figure 2

The multi-systemic effects of bi-monthly FMD feeding cycles in female C57Bl6 mice. Bi-monthly cycles of a low calorie Fasting Mimicking Diet (FMD) started at 16.5 months of age caused major decreases in the size of various organs, including the liver, heart and kidneys. However, these effects of the FMD were completely reversed after 7 days of refeeding and, in the liver, were accompanied by the repopulation of newly divided (Ki67+) cells. Additionally, the FMD lowered visceral fat without affecting lean body mass, delayed and reduced cancer incidence and inflammatory diseases, rejuvenated the immune system and either delayed or partially reversed bone mineral density loss. Chronic FMD cycles also caused a major increase in embryonic–like stem/progenitor cells, induced hippocampal neurogenesis and caused improvements in a wide range of cognitive tasks. Therefore, periodic FMD started even at a relatively old age may be utilized as a regenerative approach by causing cycles of a highly coordinated process in which various cell populations undergo a rapid depletion followed by regeneration which is likely to involve stem and progenitor cells, including MSPCs. We hypothesize that these multi-systemic effects of the FMD improve health span and reduce both inflammation and cancerogenesis, which in turn may contribute to the observed healthspan extension.

Figure 3

Eating pattern and circadian clock synergistically regulate temporal expression patterns of a large number of genes. (a) Summary hepatic circadian gene expression profile of C57/B6 adult mice without or with access to food ad lib or within a defined time interval. In the absence of food, very few transcripts show oscillation, while under ad lib access to standard diet mice eat a larger portion of their daily food intake during the night and show somewhat increased number of rhythmic transcripts. Restricting food access to night time only does not reduce food intake, but increases the number of rhythmic transcripts, improves amplitude and synchronizes the phases of oscillations of rhythmic transcripts. Daytime feeding of the same diet reverses the phases of oscillation of nearly all hepatic transcripts, thus illustrating the dominant role of eating time on the peripheral circadian oscillations. The absence of a circadian clock, as in Cry1^−/−;Cry2^−/− mutant mice, disrupts eating pattern and their liver shows no significant rhythm in gene expression. Subjecting mutant mice to TRF restores oscillation of some, not all, genes that normally oscillate in the wild type mice. (b) A summary sampling of some of the pathways underlying interaction among circadian oscillator (illustrated in the top left panel and represented as a clock), nutrient sensing pathways and systemic signals that affect daily rhythms in physiology.

Figure 4

Benefits of TRF in rodents and Drosophila. TRF of 8–12 h during the night in rodents or 12 h during the day for Drosophila imparts pleiotropic benefits that involve multiple organ systems. The benefits and the direction of change imparted by TRF relative to ad lib feeding of a similar obesogenic or high sugar diet.