Day: January 9, 2023

Categories : Ageing ExerciseTags : Leave a comment

How to Stop Losing Exercise Recovery Capacity as We Age

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Old man jogging
Photo by Barbra Olsen on Pexels

Although exercise is well-known to protect against many ageing-related diseases, it is not known the beneficial effects of exercise diminish with age. Now, in a paper published in the Proceedings of the National Academy of Sciences, researchers investigated how a mitochondrial mechanism improves physical fitness by exercise training and identified one anti-ageing intervention that delayed the declines that occur with ageing in the model organism. These findings may lead to new strategies for promoting muscle function during ageing.

“Exercise has been widely employed to improve quality of life and to protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said co-corresponding author T. Keith Blackwell, MD, PhD, a senior investigator at Joslin. “Our data identify an essential mediator of exercise responsiveness and an entry point for interventions to maintain muscle function during ageing.”

That essential mediator is the cycle of fragmentation and repair of the mitochondria. Disruption of mitochondrial dynamics the cycle of repairing dysfunctional mitochondria and restoring the connectivity among the energy-producing organelles has been linked to the development and progression of chronic, age-related diseases, such as heart disease and type 2 diabetes.

“As we perceive that our muscles undergo a pattern of fatigue and restoration after an exercise session, they are undergoing this mitochondrial dynamic cycle,” said Blackwell. “In this process, muscles manage the aftermath of the metabolic demand of exercise and restore their functional capability.”

Blackwell and colleagues investigated the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm species frequently used in metabolic and aging research.

Recording wild type C. elegans worms as they swam or crawled, the investigators observed a typical age-related decline in physical fitness over the animals’ 15 days of adulthood. The scientists also showed a significant and progressive shift toward fragmented and/or disorganised mitochondria in the ageing animals. For example, they observed in young worms on day 1 of adulthood, a single bout of exercise induced fatigue after one hour. The 60-minute session also caused an increase in mitochondrial fragmentation in the animals’ muscle cells, but a period of 24 hours was sufficient to restore both performance and mitochondrial function.

In older (day 5 and day 10) worms, the animals’ performance did not return to baseline within 24 hours. Likewise, the older animals’ mitochondria underwent a cycle of fragmentation and repair, but the network reorganization that occurred was reduced compared to that of the younger animals.

“We determined that a single exercise session induces a cycle of fatigue and physical fitness recovery that is paralleled by a cycle of the mitochondrial network rebuilding,” said first author Juliane Cruz Campos, a postdoctoral fellow at Joslin Diabetes Center. “Ageing dampened the extent to which this occurred and induced a parallel decline in physical fitness. That suggested that mitochondrial dynamics might be important for maintaining physical fitness and possibly for physical fitness to be enhanced by a bout of exercise.”

In a second set of experiments, the scientists allowed wild type worms to swim for one hour per day for 10 consecutive days, starting at the onset of adulthood. As in humans, the long-term training programme significantly improved the animals’ middle-aged fitness at day 10, and mitigated the impairment of mitochondrial dynamics typically seen during ageing.

Finally, the researchers tested known, lifespan-extending interventions for their ability to improve exercise capacity during ageing. Worms with increased AMPK – a “guardian” of metabolism and mitochondrial homeostasis – exhibited improved physical fitness. They also demonstrated maintenance of exercise performance during ageing – but not enhancement. Worms engineered to lack AMPK exhibited reduced physical fitness during ageing as well as impairment of the recovery cycle. They also did not receive the age-delaying benefits of exercise over the course of the lifespan.

“An important goal of the ageing field is to identify interventions that not only extend lifespan but also enhance health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School. “In ageing humans, a decline in muscle function and exercise tolerance is a major concern that leads to substantial morbidity. Our data point towards potentially fruitful intervention points for forestalling this decline – most likely along with other aspects of ageing. It will be of great interest to determine how mitochondrial network plasticity influences physical fitness along with longevity and ageing-associated diseases in humans.”

Source: Joslin Diabetes Center

Categories : GeneticsTags : Leave a comment

Genetic Radiation Damage Passed down Through Fathers

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Chromosomes. Source: NIH

Whether radiation exposure of fathers can have consequences on their children is one of the most long-standing questions in radiation biology. Using the nematode Caenorhabditis elegans as a model, University of Cologne researchers reported in the journal Nature that radiation damage to mature sperm cannot be repaired but is instead passed on to the offspring.

Female eggs with radiation damage either accurately repair it or, if the damage is too severe, are eliminated and no damage is passed on. However, when the egg is fertilised with a radiation-damaged sperm, the maternal repair proteins that are provided by the egg try to repair the paternal DNA.

For this purpose, a highly error-prone repair mechanism is used and fuses the broken DNA pieces randomly. These random fusions of the breaks then lead to structural changes in the paternal chromosomes. The resulting offspring now carry the chromosome damage and in turn their offspring show severe developmental defects. The work done on C. elegans lays the foundation for a better understanding of the mechanisms for the heritable effects of paternal radiation exposure.

This work has now been published under the title ‘Inheritance of paternal DNA damage by histone-mediated repair restriction’ in 

The offspring that results from male animals that have been exposed to radiation and healthy female worms carry on the so-called structural variations – random connections of chromosome parts. In the offspring, these aberrations lead to recurrent breaks but this damage can no longer be repaired. Instead, the damaged chromosomes are shielded from accurate repair by proteins, so-called histones, that densely pack the long strands of DNA. In the densely packed DNA, the breaks can no longer be reached by the repair proteins. The packed DNA structures are held tightly together by the specific histone proteins, HIS-24 and HPL-1. When those histone proteins are removed, the paternally inherited damage is completely eliminated and viable offspring can be produced. The finding that histone proteins govern the accessibility of DNA for repairs could provide effective therapeutic targets for treating radiation damage.

Adding to the work on nematodes, the team detected the same structural variants, or randomly assembled chromosomes, in humans. Also here, the chromosome aberrations were specifically passed on from the fathers but not the mothers. For this, the scientists analysed various data sets from the 1000 Genome Project that contains genetic data from more than a thousand people and the Islandic deCODE project with genetic data from the respective mothers, fathers and children.

“Genome aberrations, especially structural variations in chromosomes, which develop in the paternal germline, are thought to increase the risk of disorders like autism and schizophrenia,” study leader Professor Dr Björn Schumacher said. This means that also in humans, mature sperm needs to be especially protected from radiation damage, and damaged mature sperm should not be used for conception. He added, “Such damage could potentially be inflicted during radiotherapy or chemotherapy and thus pose a risk in the two months that it takes to generate new sperm to replace the damaged one.” This is because in contrast to mature sperm, newly generated sperm have the capacity to accurately repair the damage.

Interestingly, the scientists found those structural variations in the chromosomes also in nematodes in the wild and in the human population. These results suggest that damage to mature sperm and the inaccurate repair of paternal DNA in the zygote could be major drivers for genetic diversity during evolution and might be responsible for genetic diseases in humans.

Source: University of Cologne

Categories : NeurologyTags : Leave a comment

Recognising a Voice is Easier with a Face

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To recognise a famous voice, human brains use the same centre that is activated when the speaker’s face is presented, according to the results of an innovative neuroscience study which asked participants to identify US presidents.

The new study, published in the Journal of Neurophysiology, suggests that voice and face recognition are linked even more intimately than previously thought. It offers an intriguing possibility that visual and auditory information relevant to identifying someone feeds into a common brain centre, allowing for more robust, well-rounded recognition by integrating separate modes of sensation.

“From behavioural research, we know that people can identify a familiar voice faster and more accurately when they can associate it with the speaker’s face, but we never had a good explanation of why that happens,” said senior author Taylor Abel, MD, associate professor of neurological surgery at the University of Pittsburgh School of Medicine. “In the visual cortex, specifically in the part that typically processes faces, we also see electrical activity in response to famous people’s voices, highlighting how deeply the two systems are interlinked.”

Even though the interplay between the auditory and the visual brain processing systems has been widely acknowledged and investigated by various teams of neuroscientists all over the world, those systems were traditionally thought to be structurally and spatially distinct.

Few studies have attempted to directly measure activity from the brain centre – which primarily consolidates and processes visual information – to determine whether this centre is also engaged when participants are exposed to famous voice stimuli.

Researchers recruited epilepsy patients who had been implanted with electrodes measuring brain activity to determine the source of their seizures.

Abel and his team showed five participants photographs of three US presidents – Bill Clinton, George W. Bush and Barack Obama – or played short recordings of their voices, and asked participants to identify them.

Recordings of the electrical activity from the region of the brain responsible for processing visual cues (the fusiform gyri) showed that the same region became active when participants heard familiar voices, though that response was lower in magnitude and slightly delayed.

“This is important because it shows that auditory and visual areas interact very early when we identify people, and that they don’t work in isolation,” said Abel. “In addition to enriching our understanding of the basic functioning of the brain, our study explains the mechanisms behind disorders where voice or face recognition is compromised, such as in some dementias or related disorders.”

Source: University of Pittsburgh

Categories : Antibiotics Environmental EffectsTags : Leave a comment

Antibiotics Residues in Water Threaten Human Health

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Photo by Nathan Dumlao on Unsplash

In Asia, researchers found that antibiotic residues in wastewater and wastewater treatment plants risk contributing to antibiotic resistance, and the drinking water may pose a threat to human health. Published in The Lancet Planetary Health, their comprehensive analysis also determined the relative contribution of various sources of antibiotic contamination in waterways, such as hospitals, municipals, livestock, and pharmaceutical manufacturing.

“Our results can help decision-makers to target risk reduction measures against environmental residues of priority antibiotics and in high-risk sites, to protect human health and the environment,” says first author Nada Hanna, researcher at the Department of Global Public Health at Karolinska Institutet. “Allocating these resources efficiently is especially vital for resource-poor countries that produce large amounts of antibiotics.”

Antibiotics can enter the environment during their production, consumption and disposal. Antibiotic residues in the environment, such as in wastewater and drinking water, can contribute to the emergence and spread of resistance.

Major antibiotics producers and users

The researchers looked for levels of antibiotic residues that are likely to contribute to antibiotic resistance from different aquatic sources in the Western Pacific Region (WPR) and the South-East Asia Region (SEAR), regions as defined by the World Health Organization. China and India, among the world’s largest producers and consumers of antibiotics, fall within these regions.

To find the data, researchers made a systematic review of the literature published between 2006 and 2019, including 218 relevant reports from the WPR and 22 from the SEAR. They also employed a method called Probabilistic Environmental Hazard Assessment to determine where the concentration of antibiotics is high enough to likely contribute to antibiotic resistance.

Ninety-two antibiotics were detected in the WPR, and forty five in the SEAR. Antibiotic concentrations exceeding the level considered safe for resistance development (Predicted No Effect Concentrations, PNECs) were observed in wastewater, influents and effluents of wastewater treatment plants and in receiving aquatic environments. Wastewater and influent of wastewater treatment plants had the highest risks. The relative impact of various contributors, such as hospital, municipal, livestock, and pharmaceutical manufacturing was also determined.

Potential threat to human health

In receiving aquatic environments, the highest likelihood of levels exceeding the threshold considered safe for resistance development was observed for the antibiotic ciprofloxacin in drinking water in China and the WPR.

“Antibiotic residues in wastewater and wastewater treatment plants may serve as hot spots for the development of antibiotic resistance in these regions and pose a potential threat to human health through exposure to different sources of water, including drinking water,” says Nada Hanna.

Limitations to be considered when interpreting the results are the lack of data on the environmental occurrence of antibiotics from many of the countries in the regions and the fact that only studies written in English were included.

Source: Karolinska Institutet

Categories : Medical Research & Technology NeurologyTags : Leave a comment

Newly Discovered Subarachnoidal Layer Protects the Brain

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Advances in neuro-imaging and molecular biology have unearthed a subtle, previously unknown layer in the brain. As described in the journal Science, the newly discovered layer forms a previously unknown component of brain anatomy that acts as both a protective barrier and platform from which immune cells monitor the brain for infection and inflammation.

“The discovery of a new anatomic structure that segregates and helps control the flow of cerebrospinal fluid (CSF) in and around the brain now provides us much greater appreciation of the sophisticated role that CSF plays not only in transporting and removing waste from the brain, but also in supporting its immune defenses,” said Maiken Nedergaard, co-director of the Center for Translational Neuromedicine at University of Rochester and the University of Copenhagen. Nedergaard and her colleagues have made significant findings in the field of neuroscience, including detailing the many critical functions of previously overlooked cells in the brain called glia and the brain’s unique process of waste removal, which the lab named the glymphatic system.

The study focuses on the series of membranes that encase the brain, creating a barrier from the rest of the body and keeping the brain bathed in CSF.  The traditional understanding of what is collectively called the meningeal layer identifies the three individual layers as dura, arachnoid, and pia matter.

 This new layer discovered by the international research team further divides the space between the arachnoid and pia layers, the subarachnoid space, into two compartments, separated by the newly described layer, which the researchers name SLYM (Subarachnoidal LYmphatic-like Membrane).  While the paper mostly describes the function of SLYM in mice, it also reports its presence in the adult human brain as well.

SLYM is a type of membrane that lines other organs in the body, including the lungs and heart, called mesothelium. These membranes typically surround and protect organs, and harbour immune cells.

The new membrane is very thin and delicate, consisting of only a few cells in thickness.  Yet SLYM is a tight barrier, allowing only very small molecules to transit and it also seems to separate “clean” and “dirty” CSF.  This last observation hints at the likely role played by SLYM in the glymphatic system, which requires a controlled flow and exchange of CSF, allowing the influx of fresh CSF while flushing the toxic proteins associated with Alzheimer’s and other neurological diseases from the central nervous system.  This discovery will help researchers more precisely understand the mechanics of the glymphatic system.

Central nervous system immune cells (indicated here expressing CD45) use SLYM as a platform close to the brain’s surface to monitor cerebrospinal fluid for signs of infection and inflammation.

The SLYM also appears important to the brain’s defences.  The central nervous system has its own native population of immune cells, and the membrane’s integrity prevents outside immune cells from entering.  In addition, the membrane appears to host its own population of central nervous system immune cells that use SLYM as an observation point close to the surface of the brain from which to scan passing CSF for signs of infection or inflammation. 

Discovery of the SLYM opens the door for further study of its role in brain disease.  For example, the researchers note that larger and more diverse concentrations of immune cells congregate on the membrane during inflammation and aging.  Furthermore, when the membrane was ruptured during traumatic brain injury, the resulting disruption in the flow of CSF impaired the glymphatic system and allowed non-central nervous system immune cells to enter the brain. 

These and similar observations suggest that diseases as diverse as multiple sclerosis, central nervous system infections, and Alzheimer’s might be triggered or worsened by abnormalities in SLYM function. They also suggest that the delivery of drugs and gene therapeutics to the brain may be impacted by SLYM, which will need to be considered as new generations of biologic therapies are being developed.

Source: University of Rochester Medical Center