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Signalling pathway in brain helps prevent cognitive deficit

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A new study led by University of Cincinnati researchers sheds new light on the role of a signalling pathway in the brain to maintain health and prevent inflammation and cognitive deficits.

UC’s Agnes (Yu) Luo, PhD, is corresponding author on the research, published June 21 in the journal Nature Communications, and focused on a signalling pathway called TGF-β that plays a number of roles depending on where it is located in the body.

Luo explained that signalling pathways in the body control different cell functions and require two components: a type of molecule called a ligand and a receptor that the ligand binds to and activates to start the signalling.

Prior to this study, it was known that the TGF-β signalling pathway was important in brain immune cells called microglia in maintaining their balance, but its role in maintaining cognitive function was largely unknown. Additionally, the precise source of the TGF-β ligand in the brain was also unknown.

Luo said the researchers used state-of-the-art tools and found for the first time that microglia make the TGF-β ligand in the brain to prevent neuroinflammation.

“Microglia cells are the innate immune cells of the brain, and what surprised us most is that they each make their own TGF-β ligand,” said Luo, professor and vice chair in the Department of Molecular and Cellular Biosciences in UC’s College of Medicine. “This TGF-β ligand binds to the receptor on the microglia cell itself, and they use this signalling to stay in homeostasis. This self-produced ligand binds to receptors on the cell’s surface to keep each cell in a constantly balanced, and not in an inflamed, state.”

While it was previously known that TGF-β signalling helps keep microglia in balance, Luo said it was not known that microglia make the ligands themselves in a “spatially and precisely controlled” manner carried out by each individual cell, a mechanism called autocrine signalling.

“You can think of these microglia cells as being, in a way, ‘selfish,’ as they only make the ligand to keep themselves in balance and not inflamed,” said graduate student and study co-author Elliot Wegman. “This, thereby, provides a very precise mechanism to regulate local states of inflammation in the microenvironment of the brain.”

Using animal models, the team additionally found that when the TGF-β ligand is genetically deleted from microglia, it leads to global neuroinflammation in the brain.

“This suggests that the neuroinflammation in microglia is sufficient by itself without other causes to drive cognitive deficit,” Luo said. “We show the direct cause and link between these events.”

Moving forward, the team will investigate whether cognitive deficit can be slowed, stopped or potentially reversed by boosting the TGF-β ligand and signalling pathway in the brain under conditions where TGF-β signalling becomes compromised.

“We’re investigating whether restoring the TGF-β signalling pathway and revitalizing its signalling can then ameliorate disease-related or age-associated cognitive deficits,” she said. “The long-term goal of our research is to modify the brain environment to better support the survival of the neurons or promote repair of the brain after injury or damage.”

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Quit Googling to stave off dementia onset, expert urges

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Resisting the temptation to search the web for information that could otherwise be recalled be exercising your brain could help to reduce the risk of dementia.

That is according to Canadian academic Professor Mohamed I. Elmasry who believes simple daily habits such as afternoon naps, memory ‘workouts’ and not reaching for a smartphone can increase the odds of healthy aging.

His new book, iMind: Artificial and Real Intelligence, says the focus has shifted too far away from RI (natural, or real) intelligence in favour of AI (machine, or artificial) intelligence. Elmasry instead calls us to nurture our human mind which, like smartphones, has ‘hardware’, ‘software’ and ‘apps’ but is many times more powerful – and will last much longer with the right care.

Professor Elmasry, an internationally recognised expert in microchip design and AI, was inspired to write the book after the death of his brother-in-law from Alzheimer’s and others very close to him, including his mother, from other forms of dementia.

Although he says that smart devices are ‘getting smarter all the time’, he argues in iMind that none comes close to ‘duplicating the capacity, storage, longevity, energy efficiency, or self-healing capabilities of the original human brain-mind’.

He writes that: “The useful life expectancy for current smartphones is around 10 years, while a healthy brain-mind inside a healthy human body can live for 100 years or longer.

“Your brain-mind is the highest-value asset you have, or will ever have. Increase its potential and longevity by caring for it early in life, keeping it and your body healthy so it can continue to develop.

“Humans can intentionally develop and test their memories by playing ‘brain games,’ or performing daily brain exercises. You can’t exercise your smartphone’s memory to make it last longer or encourage it to perform at a higher level.”

In iMind: Artificial and Real Intelligence Professor Elmasry shares an anecdote about his grandchildren having to use the search engine on their smartphones to name Cuba’s capital—they had just spent a week in the country with their parents.

The story illustrates how young people have come to rely on AI smartphone apps instead of using their real intelligence (RI), he says, adding: “A healthy memory goes hand-in-hand with real intelligence. Our memory simply can’t reach its full potential without RI.”

Published by Routledge, iMind: Artificial and Real Intelligence includes extensive background on the history of microchip design, machine learning and AI and their role in smartphones and other technology.

The book also explains how both AI and human intelligence really work, and how brain function links the mind and memory. It compares the human mind and brain function with that of smartphones, ChatGPT and other AI-based systems.

Drawing on comprehensive existing research, iMind aims to narrow the knowledge gap between real and artificial intelligence, to address the current controversy around AI, and to inspire researchers to find new treatments for Alzheimer’s, other neurodegenerative conditions and cancer.

It argues that current or even planned AI cannot match the capabilities of the human brain-mind for speed, accuracy, storage capacity and other functions. Healthy aging, Professor Elmasry notes, is as important as climate change but doesn’t attract a fraction of the publicity.

He calls for policymakers to adopt a series of key reforms to promote healthy aging. Among such changes, he suggests that bingo halls could transition from their sedentary entertainment function to become active and stimulating learning centers.

As well as napping to refresh our memories and other brain and body functions, he also outlines a series of practical tips to boost brain power and enhance our RI (Real Intelligence).

These include building up ‘associative’ memory – the brain’s ‘dictionary of meaning’ where it attaches new information to what it already knows. Try reading a book aloud, using all of your senses instead of going on autopilot and turning daily encounters into fully-lived experiences.

Other techniques include integrating a day for true rest into the week, reviewing your lifestyle as early as your 20s or 30s, adopting a healthy diet, and eliminating or radically moderating alcohol consumption to reduce the risk of dementia.

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Study reveals strong links between the quality of diet and cognitive ability

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Eating a high-quality diet in youth and middle age could help keep your brain functioning well in your senior years, according to new preliminary findings from a study that used data collected from over 3,000 people followed for nearly seven decades.

The research adds to a growing body of evidence that a healthy diet could help ward off Alzheimer’s disease and age-related cognitive decline. Whereas most previous research on the topic has focused on eating habits of people in their 60s and 70s, the new study is the first to track diet and cognitive ability throughout the lifespan — from age 4 to 70 — and suggests the links may start much earlier than previously recognized.

“These initial findings generally support current public health guidance that it is important to establish healthy dietary patterns early in life in order to support and maintain health throughout life,” said Kelly Cara, PhD, a recent graduate of the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University.

“Our findings also provide new evidence suggesting that improvements to dietary patterns up to midlife may influence cognitive performance and help mitigate, or lessen, cognitive decline in later years.”

Cognitive performance, or thinking ability, can keep improving well into middle age, but typically begins to decline after age 65. More severe conditions such as dementia can also develop alongside aging-related declines. Researchers say that eating a healthy diet — in particular, a diet rich in plant-based foods that contain high levels of antioxidants and mono- and polyunsaturated fats — can support brain health by reducing oxidative stress and improving blood flow to the brain.

For the new research, scientists used data from 3,059 U.K. adults who were enrolled as children in a study called National Survey of Health and Development. Members of the cohort, called the 1946 British Birth Cohort, have provided data on dietary intakes, cognitive outcomes and other factors via questionnaires and tests over the course of more than 75 years.

Analysing participants’ dietary intakes at five timepoints in relation to their cognitive ability at seven timepoints, researchers found that dietary quality was closely linked with trends in general, or “global,” cognitive ability. For example, only about 8% of people with low-quality diets sustained high cognitive ability and only about 7% of people with high-quality diets sustained low cognitive ability over time compared with their peers.

Cognitive ability can have important impacts on quality of life and independence as we age. For example, at age 68-70, participants in the highest cognitive group showed a much higher retention of working memory, processing speed and general cognitive performance compared to those in the lowest cognitive group. In addition, nearly one-quarter of participants in the lowest cognitive group showed signs of dementia at this timepoint while none of those in the highest cognitive group showed signs of dementia.

While most people saw steady improvements in their dietary quality throughout adulthood, the researchers noted that slight differences in diet quality in childhood seemed to set the tone for later life dietary patterns, for better or worse. “This suggests that early life dietary intakes may influence our dietary decisions later in life, and the cumulative effects of diet over time are linked with the progression of our global cognitive abilities,” said Cara.

To assess diet quality, the researchers used the 2020 Healthy Eating Index, which measures how closely one’s diet aligns with the 2020-2025 Dietary Guidelines for Americans. Study participants who sustained the highest cognitive abilities over time relative to their peers tended to eat more recommended foods such as vegetables, fruits, legumes and whole grains and less sodium, added sugars and refined grains.

“Dietary patterns that are high in whole or less processed plant-food groups including leafy green vegetables, beans, whole fruits and whole grains may be most protective,” said Cara. “Adjusting one’s dietary intake at any age to incorporate more of these foods and to align more closely with current dietary recommendations is likely to improve our health in many ways, including our cognitive health.”

Since the study participants were predominantly Caucasian individuals from across the U.K., the researchers said that further research would be needed to determine whether the results would apply to populations with greater racial, ethnic and dietary diversity. They also noted that changes in study focus and protocols over the course of the long-running study created some gaps and inconsistencies in data collection. Despite these limitations, however, the researchers were able to create global cognitive ability percentile rank scores using data from multiple cognitive domains to evaluate how participants compared to their peers at each age and over time.

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Research unveils new insights into osteoporosis development

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Researchers from Osaka University have identified a gene underlying the development of osteoporosis, and have developed a new mouse model, pointing the way for future treatments and a greater understanding of this disease.

Osteoporosis — weakening of the bones with age — affects millions worldwide, and this figure is increasing annually as the global population ages.

It is associated with the ageing, or ‘senescence’, of bone cells, but the underlying cell types and mechanisms were unclear. Now, however, a research team from Osaka University has identified a key osteoporosis-related gene, Men1, and developed a new animal model of this disease.

Bones contain cells called osteoblasts and osteoclasts. Osteoclasts break down old bone tissue in a process called ‘resorption’, allowing it to be replaced with new healthy bone made by osteoblasts. Osteoporosis can result when the breakdown of the old bone occurs at a rate faster than formation of the new bone. Cellular senescence of osteoblasts, reducing their efficiency, might be a reason underlying this imbalance.

A gene called Men1 is linked to a genetic condition known as MEN1, causing benign tumors and associated with both cellular senescence and the development of osteoporosis early in life. The team investigated the role of Men1 in age-related osteoporosis and found that elderly mice showed both reduced levels of Men1 and increased activity of senescence-related genes in osteoblasts.

They then generated a mouse model where Men1 could be inactivated specifically in osteoblasts. The bones of these mice resembled the fragile bones seen in elderly humans. “The osteoblasts showed reduced bone formation activity, and accelerated cellular senescence through a pathway called mTORC1,” explains lead author Yuichiro Ukon, “while the numbers of osteoclasts were increased, increasing bone resorption.”

Inactivation of Men1 thus upset the balance between bone breakdown and formation, leading to the development of osteoporosis.

This new mouse model is particularly important because most studies of osteoporosis use elderly mice to mimic the human symptoms. However, natural aging involves multiple factors that influence the onset of osteoporosis, including reduced activity with increasing age and menopause-related hormonal changes.

“This model is the first time that the cellular senescence underlying osteoporosis has been modeled without the confounding factors present in elderly mice,” explains corresponding author Takashi Kaito, “and is therefore a key step forward in our understanding of the biological mechanisms behind this disease.”

The team also showed that the use of a drug called metformin, known to suppress the mTORC1 cellular senescence pathway, was able to suppress this senescence in osteoblast cells in vitro, and to partially restore the bone structure in Men1-deficient mice, indicating the potential effectiveness of osteoporosis treatments targeting cellular senescence.

This study is therefore highly significant in advancing our understanding of osteoporosis and potential treatments, as well as identifying biomarkers of the disease for evaluating the efficiency of prospective therapies. The mice developed here also provide a novel model of osteoporosis, which is key for ongoing research. Because cellular senescence has been linked to other age-related diseases and cancers, this work may provide insights into many other diseases.

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