Flies, Clocks, and the Nobel Prize

By Steven N. Austad, PhD - Scientific Director, American Federation for Aging Research (AFAR); Distinguished Professor and  Chair, Department of Biology, and Director of the Nathan Shock Center of Excellence in the Basic Biology of Aging, University of Alabama at Birmingham.

Recently, the 2017 Nobel Prize in Physiology or Medicine was awarded to three scientists who spent their careers discovering why flies sleep best during the night.

That may sound silly, but it isn’t. The Prize was awarded for figuring out how biological clocks work. Flies have those clocks and so do you. What is a biological clock and why should you--and why did the Nobel Prize award committee--care?

Biological clocks keep flies, frogs, fish, and people on an approximately 24-hour schedule without requiring any outside information, such as whether it is day or night. Flies or mice kept in a constantly dark incubator, or people living in lightless caves for months on end, still sleep, wake, and eat on an approximately 24 hour cycle.

The Nobel Prize was awarded for figuring out how such clocks work--what genes made them tick, so to speak. Biologists know that the basic processes of life operate similarly in most species and, as it is much easier to discover what genes do in flies compared to people, why not use flies? A simplified version of their discovery is that clock genes when turned on produce a protein that turns the same genes off once enough of the protein accumulates. However, the protein is gradually degraded over time and when enough of it has disappeared, the clock genes turn back on again. This cycle of on-off gene activity occurs over approximately 24 hours in virtually everything, even plants and single-cell animals. Moreover, those cycles affect nearly every aspect of their – and your -- body.

Once these genes were discovered in fly brains, it became easy to look at other species such as ourselves to see if we had similar genes and if those genes behaved similarly. Yes, we do and yes, they do.

Now came some surprises. Clocks were found in many parts of the fly, not just the brain. And this is true in people too. Your main clock is located deep in your brain, but like flies you have local clocks almost everywhere. For instance, your liver, lungs, heart, and even your immune system, all have their own clocks. Even individual cells operate on clock time. The cells of your body are most likely to repair themselves at certain hours and are most likely to divide at certain other times.

The medical implications of having all these clocks are profound. They imply, for instance, that there may be certain times of day (or night) at which medications will be most (or least) effective: that is, when you get your flu shot or your cancer chemotherapy, could make a difference. Evidence is also accumulating that for maintaining your health, the timing of when you eat may be as important as what you eat. Short-term fasts, studied by American Federation for Aging Research (AFAR) grantees Valter Longo, PhD and Luigi Fontana, MD, PhD, are looking better and better for your health, for instance.

It is the job of your brain’s main clock to coordinate the setting of all the body’s other clocks. Its own time is set by exposure to light. For 99.9% of human history, our master clock was set by the daily appearance of light at dawn and its gradual disappearance at dusk. However, in modern times we have found creative ways to disrupt our clocks. We fly across multiple time zones, experiencing day and night at unexpected times. We work under bright lights and stare at bright television or computer screens long after the sun has gone down. We even send people into earth orbit where they experience day/night cycles every 90 minutes; in 1998 the late Senator—and AFAR honorary board member--John Glenn returned to space to study sleep disturbance on older bodies.

Good clocks appear to help us live longer. In a recent study, it was found that mice with the best clocks--those that kept closest to exactly 24 hour days even in complete darkness--lived longer than mice with less reliable clocks.

So it should not be surprising to learn that clock disruption has health consequences. Nighttime shift workers are well known to be at higher risk than the rest of us for insomnia obesity, diabetes, heart disease, ulcers, and some types of cancer as well as depression and dementia. For example, David Holtzman, MD, has studied how sleep – that is, clock -- disturbances, instead of being symptoms of neurological diseases as previously though, may actually help cause such diseases.

Kristine Yaffe, MD, has also investigated how disruption of normal activity rhythms can increase the risk of dementia and mild cognitive impairment in older women.

However because we increasingly understand how our biological clocks work, medical practices will likely soon begin making use of these biological rhythms. Researchers are also working on clock-regulating medications to protect us against the dangers of clock disruption.

All this, because a few scientists noticed that flies like people sleep best at night and wondered why.

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