Circadian clocks, metabolism and longevity



After a long and stimulating Day 1 of SfN, I fought against my circadian clock’s natural urge to sleep in and made it to the Convention Center early to catch Dr. Joseph Takahashi’s Special Lecture, titled “Molecular Architecture of the Circadian Clock in Mammals”.

In mammals, daily rhythms of physiology and behavior are synchronized to the 24 hour light-dark (LD) cycle by the suprachiasmatic nucleus (SCN), the master circadian clock located in the hypothalamus. When people think of circadian rhythms, they typically think of sleep, and how the circadian system transmits timing information to other regions of the brain that induce rest or arousal.

However, virtually every cell in the body contains its own autonomous circadian clock, the core of which is a transcriptional/translational feedback loop controlled by specific gene products. These single-cell oscillators interact to generate tissue-wide rhythms in organs from the lungs to the liver. While long-held wisdom says that the SCN is in charge of synchronizing these so-called “peripheral” clocks, we are now learning that they can be entrained by non-light cues independently of the SCN. In his lecture, Dr. Takahashi gave an overview of decades of pioneering work uncovering the molecular basis of the circadian clock, and offered new insights from his lab into how the circadian clock in the liver drives metabolism and affects the lifespan of mice.

Doing my best this morning to spite my late chronotype during Dr. Takahashi’s talk.

Dr. Takahashi’s claim to fame came in 1997, when his lab undertook a massive forward genetic screen in mice, chemically inducing mutations at random and screening individuals for abnormal circadian behavior. Their efforts paid off when they identified and cloned the first circadian rhythm gene in mammals, known as Clock. This opened the door for the discovery of other important clock genes including BMAL1 and Period, and provided circadian biologists and behavioral neuroscientists with an extremely powerful framework to explore how genes drive behavior.

A simplified schematic of the core mammalian circadian clockwork.

In his current work, Dr. Takahashi continues to use innovative genetic approaches to characterize the circadian system. Dr. Takahashi described recent experiments using ChIP-sequencing technology to identify the binding sites of the core circadian transcription factor BMAL1 in the liver. Amazingly, his team found that BMAL1 has over 3,000 target genes in the mouse liver alone, allowing it to regulate virtually every basic metabolic pathway in a circadian fashion. Other work demonstrated that mice with brain-specific knockouts of BMAL1 were behaviorally arrhythmic. In these mice, the rhythms of the SCN and peripheral oscillators such as the liver were out of phase with each other under constant darkness conditions. However, time-restricting the availability of food in these mice re-synchronized circadian clocks in the liver and kidney. These studies provided important evidence that peripheral oscillators like the liver can be differentially affected by non-light cues, which can have important consequences for metabolism.

Next, Dr. Takahashi described work by his collaborator Dr. Satchidananda Panda at the Salk Institute exploring how time-restricting feeding without restricting caloric intake affects metabolism in mice. In this set of experiments, mice were given a high-fat diet and given ad libitum access to food, or had their food access restricted to either day or night. Incredibly, mice that had their food restricted to the nighttime (when they are normally active) did not gain weight and were protected against metabolic diseases, unlike their counterparts with ad libitum or daytime-restricted food access. These results aligned nicely with classic work described by Richard Weindruch, which demonstrated that restricting caloric intake increased the lifespan of mice. Inspired, Dr. Takahashi reviewed this literature and realized that the feeding protocol described in these studies resulted in several potentially confounding effects such as mice being fed when they would normally be sleeping, and inadvertently being forced to fast for days at a time. This led him to ask the question - Is time restriction or caloric restriction the critical factor for increasing lifespan?

To begin to answer this question, Dr. Takahashi’s team built an automatic feeding system that gave them full control of the timing, amount and duration of food availability. Using this system, the researchers used a combination of time (TR) and caloric (CR) food-restriction protocols in different groups of mice. While both day and night TR mice, as well as CR mice with day or night time restrictions ate less food than their counterparts with ad libitum food access, only the CR mice with nighttime food-restriction lost weight. Unexpectedly, these mice also self-imposed a 2-hour time restriction of food intake at the end of their active phase, which resulted in a brief increase in activity during their normal rest phase. These results suggested the relationship between feeding behavior and metabolism are more complicated than previously thought.

Dr. Takahashi’s team is now embarking on a new study they hope will allow them to further separate the effects of time and caloric food restriction on metabolism and longevity, which they predict will take 4 years to complete. For now, it’s hard to say definitively whether time restriction, caloric intake, or some combination of both is most important for increasing lifespan - only time will tell.

For more on sleep and circadian rhythms, be sure to head down to the posters today between 1 and 5, check out the Sleep: Key Advances Nanosymposium from 1-3, and keep an eye out for my write ups on these events later on!