Time-restricted eating can overcome the bad effects of faulty genes and unhealthy diet

Timing our meals can fend off diseases caused by bad genes or bad diet. Everything in our body is programmed to run on a 24-hour or circadian time table that repeats every day. Nearly a dozen different genes work together to produce this 24-hour circadian cycle. These clocks are present in all of our organs, tissues and even in every cell. These internal clocks tell us when to sleep, eat, be physically active and fight diseases. As long as this internal timing system work well and we obey them, we stay healthy.

07 sept 2018--But what happens when our clocks are broken or begin to malfunction?

Mice that lack critical clock genes are clueless about when to do their daily tasks; they eat randomly during day and night and succumb to obesity, metabolic disease, chronic inflammation and many more diseases.

Even in humans, genetic studies point to several gene mutations that compromise our circadian clocks and make us prone to an array of diseases from obesity to cancer. When these faulty clock genes are combined with an unhealthy diet, the risks and severity of these diseases skyrocket.

My lab studies how circadian clocks work and how they readjust when we fly from one time zone to another or when we switch between day and night shift. We knew that the first meal of the day synchronizes our circadian clock to our daily routine. So, we wanted to learn more about timing of meals and the implications for health.

Time-restricted eating

Eating within an eight- to 12-hour window could diminish the impact of a bad diet and a broken body clock. amornchaijj/Shutterstock.com

A few years ago we made a surprising discovery that when mice are allowed to eat within a consistent eight- to 12-hour period without reducing their daily caloric intake, they remain healthy and do not succumb to diseases even when they are fed unhealthy food rich in sugar or fat.

The benefit surpasses any modern medicine. Such an eating pattern – popularly called time restricted eating – also helps overweight and obese humans reduce body weight and lower their risk for many chronic diseases.

Decades of research had taught us what and how much we eat matters. But the new discovery about when we eat matters raised many questions.

How does simply restricting your eating times alter so many elements of personal health? The timing of eating is like an external time cue that signals the internal circadian clock to keep a balance between nourishment and repair. During the eating period, metabolism was geared toward nourishment. The gut and liver better absorbed nutrients from food, and used some for fueling the body while storing the rest.

During the fasting period, metabolism switched to rejuvenation. Unwanted chemicals were broken down, stored fat was burned and damaged cells were repaired. The next day, after the first bite, the switch flipped from rejuvenation to nourishment. This rhythm continued every day. We thought that timing of eating and fasting was giving cues to the internal clock and the clock was flipping the switch between nourishment and rejuvenation every day. However, it was not clear if a normal circadian clock was necessary to mediate the benefits of time restricted eating or whether just restricted eating times alone could flip the daily switch.

Eating late at night can disrupt circadian rhythms and raise the risk of chronic diseases including obesity. Ulza/Shutterstock.com

What if you have a broken internal clock?

In a new study, we took genetically engineered animals that lacked a functioning circadian clock either in the liver or in every cell of the body.

These mice, with faulty clocks don’t know when to eat and when to stay away from food. So, they eat randomly and develop multiple diseases. The disease severity increases if they are fed an unhealthy diet.

To test if time restricted eating works with a damaged or dysfunctional clock, we simply divided these mutant mice into two different groups – one group got to eat whenever they wanted and the other group was only given access to food during restricted times. Both groups ate the identical number of calories, but the restricted eaters finished their daily ration within nine to 10 hours.

We thought that even though these mice had restricted eating times, having the bad clock gene would doom them to obesity and many metabolic diseases. But to our utter surprise the restricted eating times trumped the bad effects of faulty clock genes. The mice without a functioning clock that were destined to be morbidly sick, were as healthy as normal mice when they consumed food during a certain period.

The results have many implications for human health.

The good news

First of all, it raises a big question: What is the connection between our genetically encoded circadian clock timing system and external time of eating? Do these two different timing systems work together like co-pilots in a plane, so that even if one is incapacitated, the other one can still fly the plane?

As we age, our body clocks become less accurate, and we become more prone to chronic diseases. Keeping regular, restricted eating times can keep us healthy longer. LightField Studios/Shutterstock.com

Deep analyses of mice in our experiment revealed that time restricted eating triggers many internal programs that improve our body’s resilience – enabling us to fight off any unhealthy consequences of bad nutrition or any other stress. This boost in internal resilience may be the key to these surprising health benefits.

For human health the message is simple, as I say in my new book “The Circadian Code.” Even if we have faulty circadian genes as in many congenital diseases, such as Prader-Willi syndrome or Smith-Magenis syndrome, or carry a malfunctioning copy of nearly a dozen different clock genes, as long as we have some discipline and restrict eating times, we can still fend off the bad effects of bad genes.

Similarly, other researchers have shown as we get older our circadian clock system weakens. The genes don’t function correctly so our sleep-wake cycles are disrupted – just as if we had a faulty clock. So, lifestyle becomes more important for older people who are at higher risk for many chronic diseases such as diabetes, heart disease, high cholesterol, fatty liver disease and cancer.

As a potential translation to human health, we have created a website where anyone from anywhere in the world can sign up for an academic study and download a free app called MyCircadianClock and start self-monitoring the timing of eating and sleeping.

Research has shown that our daily eating, sleeping and activity patterns can affect health and determine our long-term risk for various diseases. This app is part of a research project that uses smartphones to advance research into biological rhythms in the real world, while also helping you understand your body’s rhythms. http://mycircadianclock.org/#about-study, CC BY-SA

The app provides tips and guidance on how to adopt a time restricted eating lifestyle to improve health and prevent or manage chronic diseases. By collecting data from people with varying risk for disease, we can explore how eating times can help to increase our healthy lifespan.

We understand everyone’s lifestyle around home, work and other responsibilities is unique and one size may not fit all. So, we hope people can use the app and some tips to build their personalized circadian routine. By selecting their own time window of eight to 12 hours for eating that best fits their lifestyle, they may reap many health benefits.

Food for thought -- regulating energy supply to the brain during fasting

LA JOLLA, CA, 06 oct 2008—If the current financial climate has taught us anything, it's that a system where over-borrowing goes unchecked eventually ends in disaster. It turns out this rule applies as much to our bodies as it does to economics. Instead of cash, our body deals in energy borrowed from muscle and given to the brain.
Unlike freewheeling financial markets, the lending process in the body is under strict regulation to ensure that more isn't lent than can be afforded. New research by scientists at the Salk Institute for Biological Studies reveals just how this process is implemented.
"We have all seen the sub-prime mortgage crisis," says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study. "If you take out a loan, sooner or later you've got to pay your debt, and the same is true in fasting metabolism."
The Salk researchers' findings, which are published ahead of print in the Oct. 5 edition of the journal Nature, may pave the way for novel therapies for sufferers of metabolic diseases in whom such regulation can spiral out of control.
Most tissues in our bodies respond to fasting by switching from their usual high-octane energy source—glucose—to burning a low-octane, cheaper alternative-fat. For our brains, however, only the high-performance fuel will do. If no food-derived glucose is available, the body must manufacture its own supply to maintain the brain in the manner to which it is accustomed. It does so by taking energy from muscle in the form of protein and converting it to glucose in the liver, a process known as gluconeogenesis. The sugar is then shipped via the bloodstream to the brain to keep it running smoothly.
Gluconeogenesis needs to be turned on rapidly in response to fasting, but shutting it off again is just as crucial. "You don't want gluconeogenesis to be prolonged," says postdoctoral researcher and co-first author Yi Liu, Ph.D. "Because it uses muscle as a protein source, it will eventually lead to muscle wastage." Adds Montminy, "The question has always been how is the production of glucose turned on, and how is shut off again?"
Previous work by the Montminy lab and others has shown that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting. CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating. FOXO1, on the other hand, is activated when levels of the food-stimulated hormone insulin drop below a certain threshold. CRTC2's and FOXO1's activity needs to be tightly regulated, since producing too much glucose would result in over-borrowing of energy from muscle tissue.
To uncover the mechanism that ensures that this doesn't happen, the Salk researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies, engineered in such a way that it was only turned on when CRTC2 was active. Using imaging equipment, they could then detect CRTC2 activity in the livers of live mice simply by measuring how much they glowed.
When the mice were fasted, CRTC2 was rapidly activated, and the livers lit up, but to the scientists' surprise, after six hours the light went out. Experimentally decreasing the levels of CRTC2 or FOXO1 confirmed there was a two-stage fasting-response. Lowering CRTC2 reduced gluconeogenesis only early on, while less FOXO1 only affected late glucose production. As in a relay race, during fasting the baton for glucose production appeared to be passed from CRTC2 in stage one to FOXO1 in stage two.
The crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage. Yi discovered that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter, and thus the baton is safely transferred from CRTC2 to the FOXO1.
Why does the body want to change between these two regulators of glucose production? Again, it comes down to body economics. CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagon. Switching to FOXO1 later on slows down this production to more sustainable levels, while at the same time helping to produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle. "It is just like paying your loan back," says Montminy. "Later on you produce blood sugar at a different rate than you did at the beginning."
Knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients. In, particular, chemical activators of the SIRT1 switch may be key. "This way we could provide control for patients with insulin resistance," says Montminy, "as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active." Perhaps, then, a pharmacological rescue package for patients whose lending systems have been left unregulated may be on the horizon.