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Why When You Eat Might Be as Important as What You Eat

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Fasting and eating schedule
Adapted from Wilkinson MJ, Cell Metab, 2019

About 1 in 3 American adults have metabolic syndrome, a group of early warning signs for increased risk of type 2 diabetes, heart disease, and stroke. To help avoid such health problems, these folks are often advised to pay close attention to the amount and type of foods they eat. And now it seems there may be something else to watch: how food intake is spaced over a 24-hour period.

In a three-month pilot study, NIH-funded researchers found that when individuals with metabolic syndrome consumed all of their usual daily diet within 10 hours—rather than a more customary span of about 14 hours—their early warning signs improved. Not only was a longer stretch of daily fasting associated with moderate weight loss, in some cases, it was also tied to lower blood pressure, lower blood glucose levels, and other improvements in metabolic syndrome.

The study, published in Cell Metabolism, is the result of a joint effort by Satchidananda Panda, Salk Institute for Biological Sciences, La Jolla, CA, and Pam R. Taub, University of California, San Diego [1]. It was inspired by Panda’s earlier mouse studies involving an emerging dietary intervention, called time-restricted eating (TRE), which attempts to establish a consistent daily cycle of feeding and fasting to create more stable rhythms for the body’s own biological clock [2, 3].

But would observations in mice hold true for humans? To find out, Panda joined forces with Taub, a cardiologist and physician-scientist. The researchers enlisted 19 men and women with metabolic syndrome, defined as having three or more of five specific risk factors: high fasting blood glucose, high blood pressure, high triglyceride levels, low “good” cholesterol, and/or extra abdominal fat. Most participants were obese and taking at least one medication to help manage their metabolic risk factors.

In the study, participants followed one rule: eat anything that you want, just do so over a 10-hour period of your own choosing. So, for the next three months, these folks logged their eating times and tracked their sleep using a special phone app created by the research team. They also wore activity and glucose monitors.

By the pilot study’s end, participants following the 10-hour limitation had lost on average 3 percent of their weight and about 3 percent of their abdominal fat. They also lowered their cholesterol and blood pressure. Although this study did not find 10-hour TRE significantly reduced blood glucose levels in all participants, those with elevated fasting blood glucose did have improvement. In addition, participants reported other lifestyle improvements, including better sleep.

The participants generally saw their metabolic health improve without skipping meals. Most chose to delay breakfast, waiting about two hours after they got up in the morning. They also ate dinner earlier, about three hours before going to bed—and then did no late night snacking.

After the study, more than two-thirds reported that they stuck with the 10-hour eating plan at least part-time for up to a year. Some participants were able to cut back or stop taking cholesterol and/or blood-pressure-lowering medications.

Following up on the findings of this small study, Taub will launch a larger NIH-supported clinical trial involving 100 people with metabolic syndrome. Panda is now exploring in greater detail the underlying biology of the metabolic benefits observed in the mice following TRE.

For people looking to improve their metabolic health, it’s a good idea to consult with a doctor before making significant changes to one’s eating habits. But the initial data from this study indicate that, in addition to exercising and limiting portion size, it might also pay to watch the clock.

References:

[1] Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, Wang X, Fleisher JG, Panda S, Taub PR. Cell Metab. 2019 Jan 7; 31: 1-13. Epub 2019 Dec 5.

[2] Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Cell Metab. 2012 Jun 6;15(6):848-60.

[3] Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Chaix A, Zarrinpar A, Miu P, Panda S. Cell Metab. 2014 Dec 2;20(6):991-1005.

Links:

Metabolic Syndrome (National Heart, Lung, and Blood Institute/NIH)

Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Body Weight Planner (NIDDK/NIH)

Satchidananda Panda (Salk Institute for Biological Sciences, La Jolla, CA)

Taub Research Group (University of California, San Diego)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases


Anesthesia Study Yields New Insights into Neuroscience of Sleep

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Woman receiving anesthesia
Credit: iStock/herjua

General anesthesia has been around since the 1840s, when most people still traveled by horse and buggy. Yet, in this age of jet planes and electric cars, there are still many unknowns about how general anesthesia works.

The prevailing view has long been that general anesthesia exerts a sedative effect that puts us under, along with a pain-relieving effect that works by temporarily shutting down transmission of sensations from other parts of the body to the brain. Now, researchers have discovered that, at least in mice, some types of general anesthesia may actually activate a specialized area of the brain—findings that not only may provide new insights into anesthesia, but may enhance our understanding of sleep.

In a recent study in the journal Neuron, the NIH-supported lab of Fan Wang at Duke University, Durham, NC, used general anesthesia as a tool to learn more about mammalian brain activity. When they placed mice under multiple classes of general anesthesia, a cluster of neurons were activated in the brain’s hypothalamus that produce slow, oscillating waves similar to those observed in the brains of mice that were sleeping deeply. When these neurons were later artificially deactivated, the effects of general anesthesia were shortened. Experiments in sleeping mice also showed that similar deactivation disrupts natural sleep. The discovery suggests there may be a neural pathway in the mammalian brain that is shared by general anesthesia and natural sleep, perhaps opening the door to new drugs for anesthesia, pain management, and sleep disorders [1].

Specifically, Wang’s group is focused on a part of the hypothalamus called the supraoptic nucleus (SON), which consists of about 3,000 neurons. These neurons are wired into the brain’s neuroendocrine system, a vast regulatory system between brain and body. Each SON neuron has two arms: one extends to the base of the brain, where it triggers the pituitary gland to release hormones; the other directly releases peptide hormones into the general circulation.

It’s not altogether surprising that the hypothalamus would be involved regulating sleep. Previous work had indicated that another part of the hypothalamus might serve as an on-off switch between wakefulness and sleep [2]. The neurons also secrete neuropeptides, such as galanin and GABA. that inhibit areas of the brainstem involved in wakefulness.

But what most fascinated Wang is that her experiments found that SOS cells fire constantly in mice that have been kept awake past their normal bedtime, but stop firing once the animals are allowed to sleep. This prompted her team to turn its attention to the 80 percent of SON neurons that secrete the hormones dynorphin and vasopressin, which are secreted in the general circulation and send a wide range of signals to organs throughout the body.

Though mice are not humans and much more work remains to be done, Wang says her data raise the possibility that sleep, like hunger, may be regulated by a feedback loop of hormones, traveling from brain to other body parts and back. As proposed, the SON cells secrete hormones into the body during periods of wakefulness. As the level of the secreted messengers build up, the body signals to the brain that it’s tired, prompting the SOS neurons to activate a different program, sending signals that tell other parts of the brain to go to sleep.

Discovering a homeostatic sleep mechanism certainly wasn’t what surgeon William T. G. Morton had in mind when he first demonstrated the concept of general anesthesia in the 19th Century. Yet more than 175 years later, Morton’s major clinical advance is now yielding unexpected benefits for basic neuroscience research, providing yet another example of how one never knows where biomedical exploration may take us.

References:

[1] A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep. Jiang-Xie LF, Yin L, Zhao S, Prevosto V, Han BX, Dzirasa K, Wang F. Neuron. 2019 Apr 18. pii: S0896-6273(19)30296-X.

[2] Activation of ventrolateral preoptic neurons during sleep. Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Science. 1996 Jan 12;271(5246):216-219.

Links:

Anesthesia (National Institute of General Medical Sciences/NIH)

History of Anesthesia (Wood Library Museum of Anesthesiology, Schaumburg, IL)

Brain Basics: Understanding Sleep (National Institute of Neurological Disorders and Stroke/NIH)

Fan Wang (Duke University School of Medicine, Durham, NC)

NIH Support: National Institute of Mental Health


Sleep Loss Encourages Spread of Toxic Alzheimer’s Protein

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Man sleeping
Credit: iStock/bowdenimages

In addition to memory loss and confusion, many people with Alzheimer’s disease have trouble sleeping. Now an NIH-funded team of researchers has evidence that the reverse is also true: a chronic lack of sleep may worsen the disease and its associated memory loss.

The new findings center on a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease. In the healthy brain, active neurons naturally release some tau during waking hours, but it normally gets cleared away during sleep. Essentially, your brain has a system for taking the garbage out while you’re off in dreamland.

The latest findings in studies of mice and people further suggest that sleep deprivation upsets this balance, allowing more tau to be released, accumulate, and spread in toxic tangles within brain areas important for memory. While more study is needed, the findings suggest that regular and substantial sleep may play an unexpectedly important role in helping to delay or slow down Alzheimer’s disease.

It’s long been recognized that Alzheimer’s disease is associated with the gradual accumulation of beta-amyloid peptides and tau proteins, which form plaques and tangles that are considered hallmarks of the disease. It has only more recently become clear that, while beta-amyloid is an early sign of the disease, tau deposits track more closely with disease progression and a person’s cognitive decline.

Such findings have raised hopes among researchers including David Holtzman, Washington University School of Medicine, St. Louis, that tau-targeting treatments might slow this devastating disease. Though much of the hope has focused on developing the right drugs, some has also focused on sleep and its nightly ability to reset the brain’s metabolic harmony.

In the new study published in Science, Holtzman’s team set out to explore whether tau levels in the brain naturally are tied to the sleep-wake cycle [1]. Earlier studies had shown that tau is released in small amounts by active neurons. But when neurons are chronically activated, more tau gets released. So, do tau levels rise when we’re awake and fall during slumber?

The Holtzman team found that they do. The researchers measured tau levels in brain fluid collected from mice during their normal waking and sleeping hours. (Since mice are nocturnal, they sleep primarily during the day.) The researchers found that tau levels in brain fluid nearly double when the animals are awake. They also found that sleep deprivation caused tau levels in brain fluid to double yet again.

These findings were especially interesting because Holtzman’s team had already made a related finding in people. The team found that healthy adults forced to pull an all-nighter had a 30 percent increase on average in levels of unhealthy beta-amyloid in their cerebrospinal fluid (CSF).

The researchers went back and reanalyzed those same human samples for tau. Sure enough, the tau levels were elevated on average by about 50 percent.

Once tau begins to accumulate in brain tissue, the protein can spread from one brain area to the next along neural connections. So, Holtzman’s team wondered whether a lack of sleep over longer periods also might encourage tau to spread.

To find out, mice engineered to produce human tau fibrils in their brains were made to stay up longer than usual and get less quality sleep over several weeks. Those studies showed that, while less sleep didn’t change the original deposition of tau in the brain, it did lead to a significant increase in tau’s spread. Intriguingly, tau tangles in the animals appeared in the same brain areas affected in people with Alzheimer’s disease.

Another report by Holtzman’s team appearing early last month in Science Translational Medicine found yet another link between tau and poor sleep. That study showed that older people who had more tau tangles in their brains by PET scanning had less slow-wave, deep sleep [2].

Together, these new findings suggest that Alzheimer’s disease and sleep loss are even more intimately intertwined than had been realized. The findings suggest that good sleep habits and/or treatments designed to encourage plenty of high quality Zzzz’s might play an important role in slowing Alzheimer’s disease. On the other hand, poor sleep also might worsen the condition and serve as an early warning sign of Alzheimer’s.

For now, the findings come as an important reminder that all of us should do our best to get a good night’s rest on a regular basis. Sleep deprivation really isn’t a good way to deal with overly busy lives (I’m talking to myself here). It isn’t yet clear if better sleep habits will prevent or delay Alzheimer’s disease, but it surely can’t hurt.

References:

[1] The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. Science. 2019 Jan 24.

[2] Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TLS, Holtzman DM. Sci Transl Med. 2019 Jan 9;11(474).

Links:

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)

Holtzman Lab (Washington University School of Medicine, St. Louis)

NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering


Poor Sleep Habits in Adolescence Correlated with Cardiovascular Risk

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Stressed by schoolwork

Thinkstock/pixelheadphoto

Just ask any parent or teacher, most of today’s teens and pre-teens don’t seem to get enough sleep. And what sleep they do get is often poor quality—no great surprise, given that smartphones and other electronic devices are usually never far from their reach. Now, an NIH-funded team has uncovered the strongest evidence yet that this lack of quality sleep may be setting our kids up for some serious health issues later in life.

The team’s study of more than 800 adolescents, ages 11 through 13, confirmed that many are getting an insufficient amount of undisturbed, restful sleep each night. While earlier studies had found a link between sleep duration and obesity [1], the new work shows that a wide range of other cardiovascular risk factors are affected by both too little sleep and poor sleep quality [2]. When compared to well-rested kids, sleep-deprived youth were found to have higher blood pressure, bigger waistlines, and lower levels of high density lipoprotein (HDL) cholesterol, which is associated with lower risk of cardiovascular disease.


Creative Minds: Does Human Immunity Change with the Seasons?

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Micaela Martinez

Micaela Martinez

It’s an inescapable conclusion from the book of Ecclesiastes that’s become part of popular culture thanks to folk legends Pete Seeger and The Byrds: “To everything (turn, turn, turn), there is a season.” That’s certainly true of viral outbreaks, from the flu-causing influenza virus peaking each year in the winter to polio outbreaks often rising in the summer. What fascinates Micaela Martinez is, while those seasonal patterns of infection have been recognized for decades, nobody really knows why they occur.

Martinez, an infectious disease ecologist at Princeton University, Princeton, NJ, thinks colder weather conditions and the tendency for humans to stay together indoors in winter surely play a role. But she also thinks an important part of the answer might be found in a place most hadn’t thought to look: seasonal changes in the human immune system. Martinez recently received an NIH Director’s 2016 Early Independence Award to explore fluctuations in the body’s biological rhythms over the course of the year and their potential influence on our health.


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