When we eat does matter. The researcher who discovered the first biological clock gene in mammals relates biorhythms to longevity

• Joseph Takahashi visited CNIO as a guest speaker. He has shown that one method that prolongs life in model animals is more effective if it takes into account biological rhythms.
   
• Takahashi believes “that the biological clock is the basis of all mechanisms related to longevity,” he said.
   
• Genes give instructions for the functioning of the body. We now know that each of those instructions is read by cells at a certain time of day, to adapt to the Earth’s light/dark cycle.

The human biological clock is controlled by a dozen genes. Together they form an important molecular mechanism for evolution, something that we know because very diverse beings –flies, worms and even fungi– all have a very similar one. Neurobiologist Joseph Takahashi has spent decades deciphering how the biological clock works and its role in our behaviour, after discovering the first gene related to it in mammals.

Takahashi’s research shows that the biological clock influences numerous bodily functions more than we previously thought, particularly metabolism. At a conference he gave at the National Cancer Research Centre (CNIO), he stated that there is a direct relationship between biological clock and health, and understanding it at a molecular level will open up new avenues against cancer and other diseases.

Takahashi was presented by CNIO researcher María Casanova, who is working to improve cancer therapies by adjusting the time of administration to biorhythms, and also studying how the immune system reacts according to the time of day.

Biological rhythms and longevity

Proof of the importance of our biological clock is its relationship with longevity. In a recent article in Science, Takahashi demonstrates that an experimental method used to prolong life in animal models, which involves restricting calories (ingesting fewer calories in a controlled manner), is more effective when biological rhythms are taken into account.

In the research, several groups of mice ate 30% less than usual throughout their life, but some did so with time restrictions. Those who could eat at any time of day lived 10% longer; those who only ate during daytime lived 20% longer; and those who only ate at night, when mice are more active, lived 35% longer.

“This surprised the whole longevity community a great deal, because it shows that when you eat is perhaps the most important factor,” Takahashi says. “The power of this experiment is that animals eat exactly the same thing every day, the only difference is the time pattern they follow when doing so. We are very excited about this finding.”

“Our hypothesis is that the biological clock is the basis of all the bodily mechanisms that we know are related to longevity,” Takahashi said at CNIO.

An energy cycle turned into a cycle of genetic instructions

That biological rhythms are important makes sense, given the environmental changes brought by the light/dark cycle: “It’s actually an energy cycle. Not only plants, which get energy from the sun, but all living systems have developed clocks to anticipate and take advantage of the energy cycle on Earth,” Takahashi explained.

He and others have shown in recent decades that, on a molecular scale, adaptation to this energy cycle implies that there is also a cycle in the ‘reading’ (or ‘transcription’) of our genes. Genes give instructions for the daily functioning of the body, and we now know that each of those orders comes into play at a certain time of day. As Takahashi says, “There is a gene transcription cycle that takes 24 hours to complete.”

The ‘CLOCK’ gene

The first gene related to circadian rhythms was identified in the fruit fly — Drosophila melanogaster— in the 1970s. Over the next few years, there was a race to find more genetic bases of circadian clocks. Takahashi found the CLOCK gene in 1997, and shortly after BMAL1. These are genes that activate the reading of others involved in circadian rhythms, of which a dozen are already known.

These genes interact forming a system that synchronises with the environment, and their action influences thousands of other genes. Takahashi has found that about 10% of the genes expressed in any tissue are under circadian control. Many genes are involved in metabolic and cell cycle pathways.

In his calorie-restricted research, he observed that in the liver, the reading (transcription) patterns of about 2,500 genes varied depending on whether the animals ate during the day or at night. The group in which this reading of genetic instructions deviated less than usual was that of the longest-lived mice – those who ate only at night, coinciding with their natural period of activity. The researchers also reported greater weight loss in this group.

Takahashi’s group now wants to investigate whether altering the CLOCK gene has effects on longevity, and they are also looking to modulate the activity of this gene using a drug.

A clock in each cell

Before zooming in on the molecular scale, the researchers addressed the physiology of the biological clock. Today we know that biorhythms are also maintained in the absence of external signals, such as light – which is only one of the signals that can influence the circadian rhythm. These signals, however, are important for resetting and synchronising our clock.

It has also been important to discover that there is no single clock in the brain, as was previously thought: “Mammalian circadian clock research has long focused on the suprachiasmatic nucleus of the hypothalamus, but we now know that each cell has its own clock, and the central nervous system, the brain, synchronises them,” Takahashi said.