Time-restricted feeding (TRF) is a dietary intervention in which daily feeding patterns align with behavioral patterns, synchronizing feeding times with periods of higher activity, e.g. humans eating only during the day or rodents (nocturnal animals) at night. TRF has been shown to improve cardiac health in Drosophila melanogaster, reduce metabolic markers in rodent models, and reduce glycemic indices in prediabetic men. However, the mechanism and long-term effects of this intervention remain elusive. To understand the effect of TRF on longevity we used the fruit fly Drosophila melanogaster, which is a useful model for longevity, sleep and circadian studies because of its wellestablished sleep behavior, tractable genetics, and short lifespan. We found that TRF extends longevity of fruit flies only in mated females, while showing no effect on mated males or virgin females. We measured the amount of food consumed by flies on TRF and confirmed that TRF does not act through caloric restriction, which has been previously shown to extend longevity. Remarkably, animals undergoing TRF eat more, yet have lower body weight in comparison to animals on constant food. TRF-mediated lifespan extension is dependent on the molecular clock, as arrhythmic clock mutants fail to respond to TRF under light-dark conditions, suggesting that TRF may act as a zeitgeber to improve the animals' health by coordinating activity patterns with food availability. In addition to its effect on wild-type animals, TRF also improves longevity in animals with reduced lifespan, such as sleep mutants. Further studies show that TRF changes the sleep architecture of wild-type females by increasing the amount of day sleep, while also promoting integrity of the blood-brain barrier. TRF life-extension effects show that this dietary intervention has potential to reveal a deeper understanding of the biology of ageing and how it interacts with feeding and circadian rhythms, placing a larger emphasis on time of intake rather than calories.

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy