A gene linked to job-related exhaustion in shift workers increases the risk of Alzheimer's

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Greyhound
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A gene linked to job-related exhaustion in shift workers increases the risk of Alzheimer's

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A few items on research related to melatonin will posted.

"Peer-Reviewed Publication

University of Helsinki

A Finnish study published in the respected SLEEP journal shows that a variation in the melatonin receptor 1A (MTNR1A) gene is linked to the risk of Alzheimer's disease in the elderly. The same research team has previously demonstrated that the same genetic variation reduces tolerance to shift work among the working age population.

Alzheimer's disease is a memory disorder that causes the brain to deteriorate. One of its risk factors is disruption of sleep and the circadian rhythm. Lack of sleep and disruption of the circadian rhythm are common among shift workers. Tolerance to the negative effects of shift work varies between individuals and is partially linked to intrinsic genetic factors.

The study lead by Professor Tiina Paunio, University of Helsinki and National Institute for Health and Welfare (THL), Finland, showed that in addition to Alzheimer's diagnosis, the MTNR1A gene variation is linked to brain lesions visible in post-mortem brain tissues. In addition, when the expression of the MTNR1A gene was reduced in the cell culture, beta-amyloid protein characteristic of Alzheimer's disease started to accumulate.

The previous study observed that the same gene variation that predisposes to shift work fatigue is associated with lower levels of the MTNR1A gene expression in the brain. This means that the previous findings are compatible with the new findings made in the epidemiological cohorts and cell cultures.

A genetic predisposition combined with a lifestyle that disrupts the circadian rhythm can increase the risk of Alzheimer's disease

The circadian rhythm regulates the release of melatonin, which in turn supports the circadian rhythm through its receptors. The link between a weaker signalling of endogenous melatonin and Alzheimer's disease supports the view that regulation of the circadian rhythm plays a role in the development of Alzheimer's disease.

"The finding of a common risk gene for both job-related exhaustion in shift workers and Alzheimer's disease doesn't directly mean that shift work would predispose to Alzheimer's disease. However, the combination of genetic predisposition and a lifestyle that disrupts the circadian rhythm can increase the risk of Alzheimer's disease," says Lic. Med Sonja Sulkava from the National Institute for Health and Welfare (THL). "Another possible interpretation is that the brain dysfunctions related to Alzheimer's disease impair the tolerance to shift work decades before the onset of the clinical disease."

"Even though our results demonstrate a new molecule-level connection between the tolerance to shift work and incipient Alzheimer's disease, the now discovered genetic variation has a minimal effect on the individual level and it can't be used to risk assessment or prediction," reminds professor Paunio.

The research cohorts consisted of over 85-year-olds living in Vantaa and over 75-year-olds living in Kuopio and of Alzheimer patients and healthy controls living in Eastern Finland. The link could be seen in elderly cohorts but not in the younger patient and control cohorts.
https://www.eurekalert.org/news-releases/811894
Greyhound
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Re: A gene linked to job-related exhaustion in shift workers increases the risk of Alzheimer's

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Higher dose of melatonin improved sleep in older adults

In a small study of healthy adults aged 55 and older, 5 mg of melatonin increased total sleep time compared to placebo
Peer-Reviewed Publication

Brigham and Women's Hospital

Melatonin is one of the most used supplements in the United States. Among older adults, its use has tripled in the last two decades. But there is no consensus on the right dosage of melatonin, and studies of its effects on sleep quality in older adults have had mixed results. Researchers from Brigham and Women’s Hospital conducted a study in 24 healthy, older adults to evaluate whether a high-dose or a low-dose melatonin supplement could improve sleep. The team found that the higher dose had a significant impact, increasing total sleep time compared to placebo by more than 15 minutes for nighttime sleep and by half an hour for daytime sleep. Results are published in The Journal of Pineal Research.

“Sleep deficiency becomes more common as people age, and, given the drawbacks to many prescription sleep aids, many older adults report taking melatonin,” said senior author Charles Czeisler, PhD, MD, chief of the Brigham’s Division of Sleep and Circadian Disorders. “But we’ve had little evidence on the effects of melatonin on the sleep health of older adults. Our study provides new evidence and insight, and points to the importance of considering dosage and timing when it comes to the effects of supplements like melatonin, especially in older people.”

The body naturally produces the hormone melatonin, which helps regulate a person’s sleep-wake cycle with night and day. Melatonin levels peak at night. But among older people, levels of the hormone are often lower. Exogenous melatonin is sold over the counter and can be taken before bedtime as a dietary supplement, usually in the form of a pill or capsule.

To rigorously evaluate the effects of melatonin supplements, the study’s authors focused on healthy, older adults with no history of major sleep complaints. All potential participants were screened for sleep disorders. The study included 24 participants (13 women, 11 men) between the ages of 55 and 78.

During the month-long study period, participants lived in individual study rooms with no windows, clocks, or other indications of time of day. Participants followed a forced desynchrony protocol — instead of experiencing 24-hour cycles of days and nights, they were on schedules of 20-hour cycles to disentangle the effects of rest-activity from the circadian clock. This allowed the sleep to be scheduled both at night and during the day, but with a similar duration of waking before each sleep. Participants were randomly assigned to receive two weeks of a placebo pill and two weeks of either a low (0.3 mg) or high (5 mg) dose of melatonin 30 minutes before bedtime. Researchers used polysomnography to record brain waves, eye movement, muscle tone, and other key sleep metrics.

The team found that the low dose of melatonin did not lead to a statistically significant change in overall sleep time and that the changes that were seen were when sleep was scheduled during the biological day. Participants taking the 5 mg dose had a significant increase in total sleep time and sleep efficiency regardless of whether sleep was scheduled during the day or night.

The authors note that their study will need to be replicated in larger trials and with other doses of melatonin to determine whether a dose between 0.3 and 5mg may work as well. The study did not include participants who had a significant sleep disorder and the study’s findings may not be applicable to people who do.

“It’s exciting to see evidence that melatonin may have an impact on sleep at night for older adults because we know that so many older people have trouble sleeping,” said lead author Jeanne Duffy, MBA, PhD, of the Division of Sleep and Circadian Disorders. “But before taking a dietary supplement, it’s important for people to talk to their primary care physician and get a referral to a sleep specialist to rule out an undiagnosed sleep disorder.”
https://www.eurekalert.org/news-releases/953021

Melatonin exacerbates asthma discovers research group
Patients with asthma often experience a worsening of asthmatic symptoms at night in so-called "nocturnal asthma." According to reports, more than 50% of asthma deaths occur at night, exposing a link between nocturnal asthma symptoms and asthma deaths. Although some have proposed several triggers that explain the pathogenesis of nocturnal asthma, the precise mechanisms regulating this asthma phenotype remain obscure.

Now, a research group led by Kentaro Mizuta from Tohoku University Graduate School of Dentistry has discovered that melatonin, a sleep hormone, worsens asthma.

Asthma patients suffer from bronchoconstriction, where the smooth muscles of the bronchus - the pathway that moves air to and from your lungs - contract. To ease this, many take a bronchodilator, a medicine which widens the bronchus.

However, melatonin, which is often prescribed for insomnia, favors a state of bronchoconstriction and weakens the relaxing effect of a bronchodilator through the activation of the melatonin MT2 receptor.

To elucidate this, the research group identified the expression of the melatonin MT2 receptor in human airway smooth muscle. They observed that the activation of the melatonin MT2 receptor with higher doses of melatonin or melatonin receptor agonist ramelteon greatly potentiated the bronchoconstriction. Furthermore, melatonin attenuated the relaxing effects of the widely used bronchodilator β-adrenoceptor agonist.

"Although serum concentration of melatonin did not significantly induce the airway constriction, greater doses of melatonin, which is clinically used to treat insomnia, jet lag, or cancer, worsened asthma symptoms and impaired the therapeutic effect of bronchodilators," said Mizuta.

First author of the paper Haruka Sasaki adds, "The pharmacological therapy that blocks the melatonin MT2 receptor could inhibit the detrimental effects of melatonin on airways."

The research paper was published in the American Journal of Physiology Lung Cellular and Molecular Physiology on November 16, 2021.
https://www.eurekalert.org/news-releases/937537

A good night's sleep may be in sight

Researchers plan to develop new sleep disorder treatments based on new 3D models of two melatonin cell receptors created by an international team; the studies were published in Nature this week
Peer-Reviewed Publication

University of Southern California

A third of all Americans have difficulty with sleeping, and many of them turn to melatonin supplements to catch some Zs. However, scientists don't fully understand melatonin's role in the biological clock, which has made it difficult to develop drugs for sleep disorders without several side effects.

Now, an international team of scientists has shed much-needed light on melatonin's effects, opening the door to the development of new drugs for sleep disorders -- and other health issues affected by melatonin. They developed 3D models of the tiny antennae -- called receptors -- on the surface of cells that synchronize the body's internal clock with the day and night cycle.

"Our goal is to provide the structural information to other researchers who can use it for designing new drug compounds or to study mutations of these receptors in patients," said corresponding author Vadim Cherezov, a scientist at the Bridge Institute at USC Michelson Center for Convergent Bioscience.

Creating the 3D maps of the two melatonin receptors, MT1 and MT2, is critical for understanding how the biological clock works. The scientists can use this information to design drug molecules that bind to the melatonin receptors and monitor the potential effects. The benefits could go beyond improving sleep.

"This data will help us design drugs that interact only with these receptors, with the hope we can treat a variety of conditions including diabetes, cancers, and sleep disorders, in a more targeted way," said Dr. Bryan L. Roth, pharmacology professor at the UNC School of Medicine.

The findings on the melatonin receptors were published in two letters on Wednesday, April 24, in the journal Nature.

Melatonin comes from the 'soul'

Melatonin is generated in the center of the brain by the pineal gland, once described by the philosopher Descartes as the "soul" of the brain and body.

Humans respond naturally to daylight changes through the pineal gland, near the hypothalamus. As night falls, the gland produces more melatonin, which then binds to the MT1 and MT2 receptors of the cells. Before dawn, the gland decreases melatonin levels, signaling that it's time to wake.

Two of hundreds

MT1 and MT2 are among an estimated 800 receptors in the human body. These receptors, known as "G protein-coupled receptors," (GPCRs) appear on the surface of a cell. The receptors act as a sort of email inbox, relaying information into the cell to set off a cascade of activity.

About a third of all drugs on the market are designed to bind with GPCRs. Each receptor has a different role in regulating functions in the body, many of which are critical for basic survival, such as hunger and reproductivity. The bulk of these receptors also have some role in the human olfactory system -- taste and smell.

Scientists around the world have obtained structures of less than one-tenth of these receptors so far. MT1 and MT2 are among the latest. The MT1 and MT2 receptors are important for multiple processes, including reproduction and even some cancers.

"By comparing the 3D structures of the MT1 and MT2 receptors, we can better discern the unique, structural differences that distinguish the two receptors from each other -- and their roles in the biological clock," said Wei Liu of Arizona State University's Biodesign Institute. "Armed with this knowledge, it becomes easier to design drug-like molecules that will bind to only one receptor or the other, but not both. This selective binding is important as it will minimize unwanted side-effects."

The structures of both receptors were obtained using a laser, called the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory, which uses X-rays to take stop-action pictures of the receptor atoms and molecules in motion.

"Due to the tiny size of the crystals, it wouldn't have been possible to make these measurements anywhere other than LCLS," says co-author Alex Batyuk, a scientist at SLAC National Accelerator Laboratory. "Because of the extreme brightness and short pulse duration of LCLS, we were able to collect hundreds of thousands of images of the crystals to figure out the three-dimensional structure of these receptors."
https://www.eurekalert.org/news-releases/470374

I hope this helps someone understand where we are
Highly Recommend reading Why we Sleep by Mathew Walker PhD
his work is described in the book,

more below
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412427/
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