New research says circadian rhythm of genes in brain changes with aging

Researchers at the University of Pittsburgh School of Medicine discovered that a 24-hour circadian rhythm controls almost all brain and body processes, such as the sleep/wake cycle, metabolism, alertness and cognition.

According to Wikipedia, Circadian Rhythm is any biological process that displays an endogenous, entrainable oscillation of about 24 hours. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi, and cyanobacteria.

The first-of-its-kind study, published in the journal Proceedings of the National Academy of Sciences, also suggest that a novel biological clock begins ticking only in the older brain.

"Studies have reported that older adults tend to perform complex cognitive tasks better in the morning and get worse through the day,"

"We know also that the circadian rhythm changes with aging, leading to awakening earlier in the morning, fewer hours of sleep and less robust body temperature rhythms.” said Colleen McClung, Ph.D., associate professor of psychiatry, Pitt School of Medicine.

Etienne Sibille, PhD, senior co-investigator and Campbell Family Chair in Clinical Neuroscience at the Centre for Addiction and Mental Health at the University of Toronto - had also previously shown that gene changes or "molecular aging" occurs in the brain.

Both teams set out to investigate the effects of normal aging on molecular rhythms in the human prefrontal cortex – part of the brain responsible for learning, memory and other aspects of cognitive performance. [ওজন কমাতে প্রতিদিন আপনার কতটুকু কার্বোহাইড্রেট খাওয়া উচিৎ?]

The researchers analyzed thousands of genes from brain samples of 146 people with no history of mental health or neurological problems whose families had donated their remains for medical research and for whom the time of death was known.

The brains were categorized depending on whether they had come from a person younger than 40 or older than 60. Next, they analyzed two tissue samples from the prefrontal cortex for rhythmic activity, or expression, of thousands of genes by using a newly developed statistical technique.

They used information about the time of death and identified 235 core genes that make up the molecular clock in this part of the brain.

The team discovered that the daily rhythm in all the classic “clock” genes were present in younger people. Older people however, seemed to have lost rhythm in many of these genes.

"As we expected, younger people had that daily rhythm in all the classic 'clock' genes," said Dr. McClung.

"But there was a loss of rhythm in many of these genes in older people, which might explain some of the alterations that occur in sleep, cognition and mood in later life."

The team was surprised to find a set of genes that gained rhythmicity in older individuals.

The findings could be helpful in developing treatments for cognitive impairment and sleep problems that may occur with aging, as well as a possible treatment for "sundowning," a condition which makes older people with dementia become agitated and confused in the evening.

Dr. Sibille explained the usefulness of the findings, saying:
"Since depression is associated with accelerated molecular aging, and with disruptions in daily routines, these results also may shed light on molecular changes occurring in adults with depression."

For further studies, the team is planning to explore the function of the brain's circadian-rhythm genes in lab and animal models. They also find out whether these circadian-rhythm genes altered in people with psychiatric or neurological illnesses,

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Drug slows Alzheimer’s by boosting brain’s ‘garbage disposal’ system

A drug that increases activity in the brain’s "garbage disposal" system has been shown to reduce levels of toxic proteins associated with Alzheimer's disease and other neurodegenerative disorders and improve cognitive functions in mice.

The first of its kind research was conductedby neuroscientists at Columbia University Medical Center (CUMC) and published in the journal Nature Medicine.

Karen E.Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer'sDisease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute explained the findings:

"We have shown for the first time that it's possible to use a drug to activate this disposal system in neurons and effectively slow down disease.”

"This has the potential to open up new avenues of treatment for Alzheimer's and many other neurodegenerative diseases."

The drug used is known as rolipram. The drug is not considered safe to use in humans because it incurs side effect of nausea. However, other similar drugs do not cause nausea and could be used in clinical trials soon. [Read more Scientistsreport significant breakthrough in anti-aging]

Brain cells need to continuously clear out old, worn, or damaged proteins in order to stay healthy. A small molecular cylinder called proteasome does the clearing out job. It acts as a garbage disposal and grinds up the old proteins so they can be recycled into new ones.

In the brains of patients with neurodegenerative diseases, the proteasomes become damaged and they cannot do their job of clearing up. As a result, worn out proteins accumulate in the brain’s neurons. [ওজন কমাতে প্রতিদিন আপনার কতটুকু কার্বোহাইড্রেট খাওয়া উচিৎ?]

In Alzheimer’s disease, destruction and death of nerve cells causes the memory failure, personality changes and problems in carrying out daily activities.

The brains of people with AD have an abundance of two abnormal structures: 1) Amyloid plaques – consisting largely insoluble deposits of an apparently toxic protein peptide, or fragment, called beta-amyloid, and 2) Neurofibrillary tangles – abnormal collections of twisted protein threads whose main component is a protein called tau.

Scientists used a mousemodel of neurodegeneration and found that tau protein sticks to the proteasome and slows down the process of protein disposal.

When rolipram was administered in mice, it activated the proteasome and restored protein disposal to normal levels. The drug also improved the memory of diseased mice to levels seen in healthy mice. [Read more Bloodtest for Alzheimer’s? New antibody test could accurately detect Alzheimer’sbefore symptoms appear]

Past studies have shown rolipram’s effectiveness in improving memory in mice, but the mechanism wasn’t clear to scientists.

The new research pinpointed the mechanism, which showed that rolipram inhibits PDE-4 enzyme, thereby produces a a physical change in the proteasome that increases its activity.

The study’s first author, Natura Myeku, PhD, an associate research scientist in pathology and cell biology at CUMC tried to shed light on the mechanism:

"We still don't know exactly where the activation is happening, but what's new is that we can modify the proteasome to increase its activity. There could be many other ways to do this."

Researchers believe, drugs that work by targeting proteasomes should work for any disease caused by the accumulation of abnormal proteins, including Alzheimer's, Huntington's, Parkinson's and frontotemperoraldementia.

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