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New math discovery provides method for studying cell ageing

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New mathematical tools revealing how quickly cell proteins break down are poised to uncover deeper insights into how we age, according to a recently published paper.

The paper, co-authored by researchers at Mississippi State, Harvard Medical School and the University of Cambridge, “Maximum entropy determination of mammalian proteome dynamics,” presents the new tools that quantify the degradation rates of cell proteins—how quickly they break down—helping us understand how cells grow and die and how we age.

Proteins—complex molecules made from various combinations of amino acids—carry the bulk of the workload within a cell, providing its structure, responding to messages from outside the cell and removing waste.

The results proved that not all proteins degrade at the same pace but instead fall into one of three categories, breaking down over the course of minutes, hours or days. While previous research has examined cell protein breakdown, this study was the first to quantify mathematically the degradation rates of all cell protein molecules, using a technique called maximum entropy.

Galen Collins, assistant professor in MSU’s Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, co-authored the paper published in the Proceedings of the National Academy of Sciences, or PNAS, in April.

“We already understand how quickly proteins are made, which can happen in a matter of minutes,” said Collins, who is also a scientist in the Mississippi Agricultural and Forestry Experiment Station.

“Until now, we’ve had a very poor understanding of how much time it takes them to break down.”

Lead author Alexander Dear, research fellow in applied mathematics at Harvard University, adds: “For certain kinds of scientific questions, experiments can often reveal infinitely many possible answers; however, they are not all equally plausible. The principle of maximum entropy is a mathematical law that shows us how to precisely calculate the plausibility of each answer—its ‘entropy’—so that we can choose the one that is the most likely.”

“This kind of math is sort of like a camera that zooms in on your license plate from far away and figures out what the numbers should be,” Collins said.

“Maximum entropy gives us a clear and precise picture of how protein degradation occurs in cells.”

In addition, the team used these tools to study some specific implications of protein degradation for humans and animals. For one, they examined how those rates change as muscles develop and adapt to starvation.

“We found that starvation had the greatest impact on the intermediate group of proteins in muscular cells, which have a half-life of a few hours, causing the breakdown to shift and accelerate,” Collins said.

“This discovery could have implications for cancer patients who experience cachexia, or muscle wasting due to the disease and its treatments.”

They also explored how a shift in the breakdown of certain cell proteins contributes to neurodegenerative disease.

“These diseases occur when waste proteins, which usually break down quickly, live longer than they should,” Collins said.

“The brain becomes like a teenager’s bedroom, accumulating trash, and when you don’t clean it up, it becomes uninhabitable.”

Dear affirmed the study’s value lies not only in what it revealed about cell protein degeneration, but also in giving scientists a new method to investigate cell activity with precision.

“Our work provides a powerful new experimental method for quantifying protein metabolism in cells,” he said. “Its simplicity and rapidity make it particularly well-suited for studying metabolic changes.”

Collins’s post-doctoral advisor at Harvard and a co-author of the article, the late Alfred Goldberg, was a pioneer in studying the life and death of proteins. Collins noted this study was built on nearly five decades of Goldberg’s research and his late-career collaboration with mathematicians from the University of Cambridge. After coming to MSU a year ago, Collins continued collaborating with his colleagues to complete the paper.

“It’s an incredible honour to be published in PNAS, but it was also a lot of fun being part of this team,” Collins said. “And it’s very meaningful to see my former mentor’s body of work wrapped up and published.”

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How older people explore new spaces could suggest dementia

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Results from a new study have shown an analogous shift in exploration behaviour in middle age for the first time in humans.

Spatial navigation – the ability to select and follow a route from one place to another – is a skill we use every day. Depending on practice, general cognitive ability, and childhood environment, some people are naturally better at this than others.

However, research has also shown that people’s skill in spatial navigation tends to decrease with increasing age.

This decline in navigation skill has been generally attributed to worsening spatial memory, due to changes in brain structure and function that naturally occur with age. But what if it isn’t just due to our spatial memory declining, but also to changes in how we explore a novel environment? Such a shift has been observed in aging animals, ranging from insects to rodents and fish.

An exploratory study

Results from this new study, published in Frontiers in Aging Neuroscience, could have clinical applications.

First author Dr Vaisakh Puthusseryppady, a postdoctoral researcher at the University of California at Irvine, stated: “Compared to younger individuals, middle-aged people exhibit overall less exploration when learning a novel maze environment, and seem to be prioritising learning specific important locations in the maze as opposed to the overall maze layout.”

Puthusseryppady and colleagues recruited 87 middle-aged (on average 50 years old) and 50 young (on average 19 years old) women and men as volunteers. None had a history of neurologic disease including dementia, or psychiatric illness.

The researchers tested how well the volunteers explored and learned to navigate a maze in virtual reality. The maze was composed of crossroads and corridors, separated by hedges. Distinctive objects were scattered around it at strategic locations as landmarks. In the first ‘exploration phase’, the volunteers were instructed to freely explore the maze and learn the locations of the objects.

In each of the 24 trials in the second ‘wayfinding phase’, the volunteers had to apply what they had learnt, navigating between two randomly chosen objects within 45 seconds.

As expected, young people on average had a greater success rate in finding their way. But importantly, further statistical analyses showed that this difference in success rate was partially driven by observed qualitative changes in how young vs middle-aged participants learned about the maze.

“Compared to younger individuals, middle-aged individuals explored the maze environment less, as they travelled less distance, paused for longer periods of time at decision points, and visited more objects than young individuals,” said Dr Mary Hegarty, a professor at the Department of Psychological and Brain Sciences of the University of California at Santa Barbara, and a joint corresponding author.

These differences were so notable, the authors were able to predict using artificial intelligence whether a participant was middle-aged or young.

Pointing the way for applications

Reduced exploration in middle-aged people may be due to age-related changes in the brain’s navigation network, for example the medial temporal and parietal lobes.

The authors speculated that these findings could inform training interventions that can help middle-aged adults to improve their navigation abilities and preserve cognitive ability.

Co-author Daniela Cossio, a PhD student at the University of California at Irvine, explained: “If we were to train middle-aged people to explore novel environments better – with a focus on traveling greater distances, visiting paths that connect the environment, in a more spread-out manner – this might lead to improvements in their spatial memory, helping to slow down their decline in cognitive ability.”

Dr Elizabeth Chrastil, one of the corresponding authors, and an associate professor at the same institute, looked ahead: “We are currently investigating whether these kinds of changes in exploration behaviour can be identified in people at risk of Alzheimer’s Disease, as well as in those who actually have Alzheimer’s.

“We anticipate that altered exploration behaviour could ultimately become a novel clinical marker for early cognitive decline related to Alzheimer’s.”

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Lung cancer screening prolongs lives in real-world study

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Among US veterans diagnosed with lung cancer through the Veterans Health Administration healthcare system, those who underwent screening before diagnosis were more likely to be diagnosed with earlier stage disease and had a higher cure rate than those who had not been screened.

Lung cancer is the leading cause of cancer deaths worldwide, and most patients are diagnosed at an advanced stage.

Early detection through screening could save lives, and current recommendations state that adults 50–80 years old with at least a 20-pack-year smoking history who currently smoke or have quit within the past 15 years should undergo annual imaging tests for lung cancer.

Such screening has been shown to be beneficial in clinical trials, but there are limited data on the real-world effectiveness of lung cancer screening. To investigate, researchers assessed the impact of screening among patients in the Veterans Health Administration healthcare system diagnosed with lung cancer from 2011–2018.

Among 57,919 individuals diagnosed with lung cancer, 2,167 (3.9%) underwent screening before diagnosis. Patients who underwent screening had higher rates of early (stage I) diagnoses compared with those who had no screening (52% versus 27%), lower rates of death from any cause (49.8% versus 72.1%), and death from cancer (41.0% versus 70.3%) over 5 years.

“It is incredible to witness how dedicated national efforts to increase lung cancer screening from the Lung Precision Oncology Program can lead to substantial improvements in lung cancer outcomes,” said co–corresponding author Michael Green, MD, PhD, of the University of Michigan and the Veterans Affairs Ann Arbor Healthcare System.

The findings come from an observational study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

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Pioneering therapy approach to combat age-related vision loss

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Cirrus Therapeutics, the University of Bristol, and London’s Global University Institute of Ophthalmology have discovered a revolutionary treatment for age-related macular degeneration (AMD), the leading cause of vision loss among older adults.

Featured on the cover of the journal Science Translational Medicine, this breakthrough research reveals that boosting a specific protein, IRAK-M, in retinal cells could offer a new and highly effective therapy for AMD.

AMD can severely impact a person’s vision. Patients suffering from AMD often start with blurred vision or seeing a black dot in their central vision, which can ultimately expand to the point where there is no useful central vision. Currently, AMD affects approximately 200 million people worldwide, a number projected to rise to 288 million by 2040 with graying populations.

The exact cause of AMD is complex and thought to involve a combination of aging, environmental, and lifestyle factors.

The team found that augmenting IRAK-M levels in retinal cells can significantly protect against retinal degeneration.

“This discovery represents the first pathway-agnostic approach toward AMD, offering a comprehensive treatment option for the millions of people who suffer from this debilitating condition,” said Dr. Andrew Dick, Head of the Academic Unit of Ophthalmology at the University of Bristol, Director of the UCL Institute of Ophthalmology, and co-founder and Chief Scientific Advisor of Cirrus Therapeutics.

Dr. Jian Liu, the first author and senior research scientist at the Academic Unit of Ophthalmology of the University of Bristol, added: “Since age stands as a primary risk factor for AMD, the gradual decrease of IRAK- M levels with age, which further declines in AMD, is a key way to identify the potential markers of early AMD progression and ultimately a new way of treatment.”

This discovery will build and improve upon current treatments for AMD, which are targeting single pathophysiology pathways. “Our novel approach not only addresses the multiple pathways involved in treating AMD but also offers the most compelling and evidence-based strategy available today,” said Cirrus Therapeutics co-founder and Chief Executive Officer Dr. Ying Kai Chan.

Cirrus Therapeutics recently spun out of the University of Bristol to develop therapies related to this discovery.

The research for this paper was funded by the Rosetrees Trust, Stoneygate Trust, Underwood Trust, Macular Society, Sight Research UK, Moran Eye Center at the University of Utah, Sharon Eccles Steele Center for Translation, and supported by the National Institute for Health and Care Research (NIHR) BRC Moorfields and UCL-Institute of Ophthalmology.

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