Category Archives: Physiology

People With Stroke Who Walk 30 Minutes Per Day May Have 54% Lower Risk Of Death (Medicine)

A new study shows that people who walk or garden at least three to four hours per week, or bike at least two to three hours per week, or the equivalent after having a stroke may have a 54% lower risk of death from any cause. The research is published in the August 11, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study found the most benefit for younger stroke survivors. When people under the age of 75 exercised at least that amount, their risk of death was reduced by 80%.

“A better understanding of the role of physical activity in the health of people who survive stroke is needed to design better exercise therapies and public health campaigns so we can help these individuals live longer,” said study author Raed A. Joundi, MD, DPhil, of the University of Calgary in Canada and a member of the American Academy of Neurology. “Our results are exciting, because just three to four hours a week of walking was associated with big reductions in mortality, and that may be attainable for many community members with prior stroke. In addition, we found people achieved even greater benefit with walking six to seven hours per week. These results might have implications for guidelines for stroke survivors in the future.”

The study looked at 895 people with an average age of 72 who had a prior stroke and 97,805 people with an average age of 63 who had never had a stroke.

Average weekly physical activity was evaluated from questions about activities such as walking, running, gardening, weight training, bicycling and swimming. For example, people were asked, “In the past three months, how many times did you walk for exercise? About how much time did you spend on each occasion?” Researchers used the frequency and duration of each type of physical activity to calculate the amount of exercise.

Researchers followed participants for an average of about four and a half years. After accounting for other factors that could affect risk of death, like age and smoking, researchers found that 25% of the people who had previous strokes died from any cause, compared to 6% of the people who had never had a stroke.

In the stroke group, 15% of the people who exercised at least the equivalent of three to four hours of walking each week died during follow up, compared to 33%, who did not exercise that minimum amount. In the group of people who had never had strokes, 4% of the people who exercised that amount died, compared to 8% who did not.

Researchers found the largest reduction in death rate among people who had a previous stroke but were under 75 years of age. In that group, 11% of those who exercised at least the minimum amount died, compared to 29% who did not. People with previous stroke who were under 75 years of age and met the minimum level of physical activity were about 80% less likely to die during study follow-up than those who did not. People over 75 years of age who exercised the minimum experienced less of a benefit, but were still 32% less likely to die.

“Our results suggest that getting a minimum amount of physical activity may reduce long-term mortality from any cause in stroke survivors,” Joundi said. “We should particularly emphasize this to stroke survivors who are younger in age, as they may gain the greatest health benefits from walking just thirty minutes each day.”

A limitation of the study is that people may not have accurately reported their amount of exercise.


Reference: Raed A. Joundi, Scott B. Patten, Aysha Lukmanji, Jeanne VA Williams, Eric E. Smith. Association Between Physical Activity and Mortality Among Community-Dwelling Stroke Survivors. Neurology, 2021; 10.1212/WNL.0000000000012535 DOI: 10.1212/WNL.0000000000012535


Provided by American Academy of Neurology

Researchers Discovered A Type of Blood Vessel Cell in Muscles That Multiplies Rapidly Upon Exercise (Physiology)

ETH Zurich Professor Katrien De Bock and her team have discovered a certain type of blood vessel cell in muscles that multiplies rapidly upon exercise, thereby forming new blood vessels. Researchers can use this to find novel therapies for vascular disorders of the muscle.

“In industrialised countries, the leading cause of surgeons having to amputate a foot or leg is impaired vascular supply to the muscles of diabetic patients,” Katrien De Bock says. As Professor for Exercise and Health at ETH Zurich, she and her team study how to treat vascular disorders of the muscles and how new blood vessels form. It’s common knowledge that exercise and sport stimulate the formation of blood vessels. By contrast, very little is known about the underlying molecular and cellular mechanisms. “Once we understand these mechanisms, we can work towards systematically improving the blood supply of patients’ muscles,” De Bock says.

In mice and using cultured human cells, De Bock and her colleagues have now investigated how exercise promotes the formation of thin blood capillaries in the muscle in healthy subjects. Turning the spotlight onto the cells of the vascular wall (known as endothelial cells), they discovered that there are two capillary endothelial cell types, which can be distinguished by the molecular marker ATF4. It turns out that cells with very little ATF4 are mainly found in the capillaries supplying the white muscle fibres, while cells with high levels of ATF4 primarily form part of the blood vessels close to red muscle fibres.

Ready to go

Moreover, the scientists demonstrated that exercise predominantly stimulates cell division of endothelial cells with high levels of ATF4 (those near red muscle fibres), leading to the formation of new capillaries. By contrast, exercise does not elicit a direct response in cells with very little ATF4. “Endothelial cells with high levels of ATF4 are on ‘metabolic standby mode’, always ready to start forming new vessels,” De Bock says. ATF4 is a regulatory protein inside the cell. Cells with this protein are primed to quickly respond to the appropriate stimulus. As soon as a person – or, in this case, a mouse – starts exercising, these cells increase their amino acid intake and accelerate the formation of DNA and proteins, encouraging rapid cell proliferation. This ultimately leads to the formation of new blood vessels.

Why these ‘ready to go’ endothelial cells are mainly found near red muscle fibres is not yet known. The researchers intend to unravel this mystery next. In addition, the scientists hope to use these findings to develop therapies that stimulate the growth of muscular blood vessels in patients suffering from diabetes or arterial occlusions and in organ transplant recipients.

Featured image: Microscopically fine blood capillaries carry oxygen and nutrients to the muscles. The picture shows several fascicles, composed of numerous muscle fibres. (Visualisations: Science Photo Library / Mikkel Juul Jensen)


Reference

Fan Z, Turiel G, Ardicoglu R, Ghobrial M, Masschelein E, Kocijan T, Zhang J, Tan G, Fitzgerald G, Gorski T, Alvarado-Diaz A, Gilardoni P, Adams CM, Ghesquière B, De Bock K: Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells. Cell Metabolism, 5 August 2021, doi: 10.1016/j.cmet.2021.07.015


Provided by ETH Zurich

Study Identifies Molecule That Stimulates Muscle-Building (Physiology)

In a randomized control study of 10 healthy young men, researchers compared how consuming the single amino acid leucine or its two-molecule equivalent, dileucine, influenced muscle-building and breakdown. They found that dileucine boosts the metabolic processes that drive muscle growth 42% more than free leucine does.

They report their findings in the Journal of Applied Physiology. 

Leucine, isoleucine and valine all are branched-chain amino acids, famous among body builders and health enthusiasts for their purported muscle-enhancing benefits. Like other amino acids, they are the building blocks of proteins. But leucine also acts as a signaling molecule that triggers muscle-building pathways in cells, said University of Illinois Urbana-Champaign kinesiology and community health professor Nicholas Burd, who led the new research with kinesiology graduate student Kevin Paulussen.

Digestion breaks the chemical bonds between the amino acids that make up proteins, resulting in a stew of shorter molecules, including free amino acids and dipeptides. Previous studies have suggested that the small intestine absorbs dipeptides like dileucine more rapidly than their single-molecule counterparts, Burd said.

“But few studies have examined whether dileucine in the diet makes it into the blood as a dipeptide or is first broken down into two leucine molecules,” he said. “And no studies have examined its effects on acute muscle-building and breakdown.” Burd’s laboratory is one of a small number of research facilities set up to study muscle protein metabolism in human participants.

Graphic by Diana Yates

For the new study, participants came to the lab after a 12-hour fast and were infused with stable isotopes, chemical probes that allow researchers to track the process of muscle protein synthesis and breakdown. Then biopsies of muscle tissue were taken from the upper leg.

“After that, we fed them either 2 grams of leucine or 2 grams of dileucine,” Burd said. “And we studied their muscle-remodeling response for three hours.” This was a double-blind study, meaning that the data were coded to prevent participants and researchers from knowing who received leucine or dileucine in the initial phases of the study. Three more muscle biopsies were taken, at 30, 60 and 180 minutes after participants ingested the leucine or dileucine.

“We found that leucine got into the blood more quickly when participants consumed dileucine than if they had just free leucine,” Burd said. “That means that some of that dileucine is getting hydrolyzed, or cut up, before it gets into the bloodstream. But we also saw that dileucine was getting into the bloodstream intact.”

The next question was whether dileucine had any effect on muscle-building processes, he said.

“So, we looked at pathways that signal the muscle-building process, including protein breakdown as part of the remodeling process. And we found no difference in protein breakdown between the leucine alone and the dileucine condition,” Burd said. “But on the protein synthesis side, we saw that dileucine turns up the muscle-building process more than leucine does.”

Those who consumed dileucine had 42% more synthesis of new muscle proteins than those who ingested only leucine.

“To put that in perspective, exercise alone can cause a 100-150% increase in the muscle-building response,” Burd said.

The researchers also showed that animal-based proteins are the best source of dileucine in the diet. But Burd does not think people should start ingesting large amounts of animal protein or taking dileucine supplements to enhance their muscle metabolism. The study is only a first step toward understanding how the body uses dipeptides, “and focusing on a single nutrient doesn’t provide a perspective on how the overall diet and eating pattern impacts muscle growth,” he said.

“We don’t yet know the mechanism by which dileucine works,” Burd said. “This is just a first attempt to understand how these types of peptides are playing a role in human physiology.”

Editor’s notes

The paper Dileucine ingestion is more effective than leucine in stimulating muscle protein turnover in young males: a double blind randomized controlled trial is available online and from the U. of I. News Bureau.

DOI: 10.1152/japplphysiol.00295.2021


Featured image:U. of I. kinesiology graduate student Kevin Paulussen, left, kinesiology and community health professor Nicholas Burd and their colleagues found that dileucine – a peptide consisting of two leucines chemically bonded to one another – boosts the metabolic processes that promote muscle-building more than free leucine does.Photo by L. Brian Stauffer.


Produced by Illinois News Bureau

Fight-or-flight Response Is Altered in Healthy Young People Who Had COVID-19 (Physiology)

New research published in the Journal of Physiology found that otherwise healthy young people diagnosed with COVID-19, regardless of their symptom severity, have problems with their nervous system when compared with healthy control subjects.

Specifically, the system that oversees the fight-or-flight response, the sympathetic nervous system, seems to be abnormal (overactive in some instances and underactive in others) in those recently diagnosed with COVID-19.

These results are especially important given the emerging evidence of symptoms like racing hearts being reported in conjunction with “long-COVID.”

The impact of this alteration in fight-or-flight response, especially if prolonged, means that many processes within the body could be disrupted or affected. This research team has specifically been looking at the impact on the cardiovascular system—including blood pressure and blood flow—but the sympathetic nervous system is also important in exercise responses, the digestive system, the immune function, and more.

Understanding what happens in the body shortly following diagnosis of COVID-19 is an important first step towards understanding the potential long-term consequences of contracting the disease.

Importantly, if similar disruption of the flight-or-fight response, like that found here in young individuals, is present in older adults following COVID-19 infection, there may be substantial adverse implications for cardiovascular health.

The researchers studied lung function, exercise capacity, vascular function, and neural cardiovascular control (the control of heartbeat by the brain).

They used a technique called microneurography, wherein the researchers inserted a tiny needle with an electrode into a nerve behind the knee, which records the electrical impulses of that nerve and measures how many bursts of electrical activity are happening and how big the bursts are.

From this nerve activity, they can assess the function of the sympathetic nervous system through a series of tests. For all the tests, the subject was lying on their back on a bed. First, the researchers looked at the baseline resting activity of the nerves, heart rate, and blood pressure. Resting sympathetic nerve activity was higher in the COVID-19 participants than healthy people used as controls in the experiment.

Then, the subject did a “cold pressor test,” where they stick their hand in an ice-water mixture (~0° C) for two minutes. In healthy individuals, this causes a profound increase in that sympathetic nerve (fight-or-flight) activity and blood pressure. The COVID-19 subjects rated their pain substantially lower than healthy subjects typically do.

Finally, the participant was moved to an upright position (the bed they’re lying on can tilt up and down) to see how well their body can respond to a change in position. The COVID-19 subjects had a pretty large increase in heart rate during this test; they also had higher sympathetic nerve activity throughout the tilt test compared with other healthy young adults.

As with all research on humans, there are limitations to this study. However, the biggest limitation in the present study is its cross-sectional nature—in other words, we do not know what the COVID-19 subjects’ nervous system activity “looked like” before they were diagnosed with COVID-19.

These findings are consistent with the increasing reports of long-COVID symptoms pertaining to problems with the fight-or-flight response.

Abigail Stickford, senior author on this study said, “Through our collaborative project, we have been following this cohort of COVID-19 subjects for six months following their positive test results. This work was representative of short-term data, so the next steps for us are to wrap up data collection and interpret how the subjects have changed over this time.”


Reference: Nina L. Stute et al, COVID‐19 is getting on our nerves: Sympathetic neural activity and hemodynamics in young adults recovering from SARS‐CoV‐2, The Journal of Physiology (2021). DOI: 10.1113/JP281888


Provided by The Journal of Physiology

Exercise Improves Health Through Changes On DNA (Physiology)

Six weeks of physical exercise led to changes in the epigenetic information of skeletal muscle cells in young men. These changes took place in areas of the genome that have been linked to disease. Scientists at the University of Copenhagen say their research shows, for the first time, how exercise remodels DNA in skeletal muscle, so that new signals are established to keep the body healthy.

While it is widely known that regular physical exercise decreases the risk of virtually all chronic illnesses, the mechanisms at play are not fully known. Now scientists at the University of Copenhagen have discovered that the beneficial effects of physical exercise may in part result from changes to the structure of our DNA. These changes are referred as ‘epigenetic’.

DNA is the molecular instruction manual found in all our cells. Some sections of our DNA are genes, which are instructions for building proteins – the body’s building blocks – while other sections are called enhancers that regulate which genes are switched on or off, when, and in which tissue. The scientists found, for the first time, that exercise rewires the enhancers in regions of our DNA that are known to be associated with the risk to develop disease.

“Our findings provide a mechanism for the known beneficial effects of exercise. By connecting each enhancer with a gene, we further provide a list of direct targets that could mediate this effect,” says Professor Romain Barrès from the Novo Nordisk Foundation Center for Basic Metabolic Research, the senior author of the research, which was published in Molecular Metabolism.

Exercise improves health of organs including the brain

The team of scientists hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle. They recruited healthy young men and put them through a six-week endurance exercise program. The scientists collected a biopsy of their thigh muscle before and after the exercise intervention and examined if changes in the epigenetic signature of their DNA occurred after training.

The scientists discovered that after completing the endurance training program, the structure of many enhancers in the skeletal muscle of the young men had been altered. By connecting the enhancers to genetic databases, they discovered that many of the regulated enhancers have already been identified as hotspots of genetic variation between individuals – hotspots that have been associated with human disease.

The scientists found that exercise benefited organs that are distant from muscle, like the brain. They speculate that these benefits might result from signals released by muscles into the bloodstream. In particular, they found that exercise remodels enhancer activity in skeletal muscle that are linked to cognitive abilities, which opens for the identification of exercise training-induced secreted muscle factors targeting the brain.

“Our data provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans,” says Assistant Professor Kristine Williams, the lead author of this study.

Read the original article in Molecular Metabolism here: Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health


Provided by University of Copenhagen

Daily Practice Of Three-step Breathing Exercise Associated With A Lower Percentage of COVID-19 (Physiology)

Apurvakumar Pandya and colleagues in their recent paper, assess the prevalence of Covid-19 infection among people practicing threestep rhythmic breathing (3SRB) exercise and those who were not practising. Their study indicated that the prevalence of Covid-19 is lower among people practicing 3SRB compared to those who are not practicing 3SRB. Their study recently appeared in medRxiv.

Three-Step Breathing exercise is a breathing pattern that aids an individual breathe in rhythm with nature. It is a slow and deep breathing technique founded by Yogi Sri Soli Tavaria. It is also known as refining exercises and is believed to cleanse impurities from the mind and the body. Studies on the effect of Three Step Rhythmic Breathing (3SRB) on COVID-19 remain unknown. There are many claims that breathing exercises can strengthen the lungs and may be beneficial for reducing the impact of COVID-19 before, during, and after it strikes. Now, Apurvakumar Pandya and colleagues attempted to determine the prevalence of COVID-19 among people practicing 3SRB exercise and those who are not practicing 3SRB exercise in India.

They conducted a community-based cross-sectional observational study and collected data using a self-constructed online google survey tool from July 2020 to August 2020.

Out of a total 1083 sample, a higher proportion of the participants (41.3%) belonged to the 34-49 years age group, followed by the age group of 50-65 (32.5%). The sample was almost equally distributed; about 51.9% of the population was male, and 48.4% were female.

They found that, COVID-19 positivity was recorded almost double (3.1%) in groups not practicing 3SRB exercises compared to a group (1.3%) practicing 3SRB exercises. Furthermore, the practice of 3SRB was significantly associated with a lower percentage of COVID-19 infection (p=0.046).

Their study is the first to show that the daily practice of 3SRB, associated with a lower percentage of COVID-19 infection. However, future study with a robust methodology is required to validate the findings of this study and determine the effects of 3SRB on physiological and biological markers.


Reference: Apurvakumar Pandya, Dileep Mavalankar, Pravin Maithia, “Three-step rhythmic breathing exercise and COVID-19: A cross-sectional study”, medRxiv 2021.07.07.21259527; doi: https://doi.org/10.1101/2021.07.07.21259527


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How Childhood Exercise Could Maintain And Promote Cognitive Function in Later Life? (Physiology)

Illuminating changes in brain networks and cortical structure

A research group including Professor MATSUDA Tetsuya of Tamagawa University’s Brain Science Institute (Machida City, Tokyo; Director: SAKAGAMI Masamichi) and Assistant Professor ISHIHARA Toru from Kobe University’s Graduate School of Human Development and Environment has illuminated the changes in the brain’s neural network and cortex structure that underlie the positive association between childhood exercise and the maintenance and promotion of cognitive function in later life.

These results were published in the academic journal NeuroImage on May 23, 2021 (CET).

Main points

  • The researchers showed that people who are physically active during childhood (up to 12 years of age) have higher cognitive functions in later life.
  • However, they could not find a correlation between cognitive function and post-childhood physical activity.
  • The positive association between childhood exercise and cognitive function was evident in the modular*1 segregation of brain networks, strengthened inter-hemispheric connectivity, greater cortical thickness, lower levels of dendritic arborization and decreased density.
  • During childhood, the formation of the brain’s network is susceptible to environmental and experience-related factors. It is thought that exercise during this period optimizes brain network development and is linked to the maintenance and promotion of cognitive function in later life.

Research Background

Research over the previous decade has shown that exercise during childhood affects the development of cognitive functions. Recent findings have indicated that these benefits of childhood exercise extend to the maintenance and promotion of cognitive functions in middle age and later life. However, the changes in brain functionality and structure related to this positive association have yet to be illuminated. This research study investigated the relationship between physical activity in childhood and cognitive function in later life, using MRI (magnetic resonance imaging) to illuminate the structural and functional changes in the brain that are behind this relationship.

Experiment Method

The research group conducted a study on 214 participants ranging in age from 26 to 69 in order to investigate the relationship between childhood exercise and cognitive function, and the underlying functional and structural neural networks and cortical structure. Childhood exercise was assessed via questionnaire. One aspect of cognitive function, response inhibition (the ability to suppress inappropriate behaviors), was measured using a Go/No-go task. The image data from the MRI was analysed and the following were calculated: structural and functional connectivity*2, cortical thickness, myelination, the degree of neurite orientation dispersion and density index. The brain was divided into 360 areas in accordance with the Human Connectome Project*3, and functional and structural parameters were obtained for each area. In the statistical analysis, information obtained through the questionnaire was used as confounders. This included each participant’s educational background, parents’ educational background, number of siblings and exercise during adulthood.

Experiment Results

Firstly, the researchers analyzed the relationship between whether participants exercised during childhood and Go/No-go task performance (false alarm rate). They found that participants who exercised during childhood (up until age 12) had a lower false alarm rate than those who didn’t (Figure 1). Furthermore, this correlation was found regardless of the age of the participant. However, no such relationship was found between task performance and post-childhood exercise.

Figure 1: Box plots to show the relationship between childhood exercise and the false alarm rate in the Go/No-go task. © Kobe University

Next, the research group investigated structural and functional connectivity in the brain relating to Go/No-go task performance in participants who exercised during childhood. From these results, they confirmed that in terms of structural connectivity in the brain, there were positive associations (Figure 2A: connections indicated in red) and negative associations (Figure 2A:  connections indicated in blue) between exercise during childhood and the false alarm rate in the Go/No-go task. Large-scale network connectivity was found in over half (73%) of structurally connected areas that were positively associated with the Go/No-go task false alarm rate (Figure 2B, left portion). On the other hand, inter-hemispheric connectivity was found in the majority (88%) of structurally connected areas that were negatively associated with the task’s false alarm rate (Figure 2B, right portion). In terms of connections between functional areas, connections showing positive associations (Figure 3A: connections indicated in red) with the Go/No-go task false alarm rate were identified in participants who exercised during childhood but no negatively associated connections were found. Furthermore, large-scale network connectivity was found in the majority (91%) of connected areas that were positively associated with the task’s false alarm rate (Figure 3B, left portion).

Figure 2: Structural connections between areas of the brain in relation to the false alarm rate in the Go/No-go task were characteristic of participants who exercised during childhood. © Kobe University

In those participants who did not exercise during childhood, there was no structural or functional connectivity identified in relation to the false alarm rate in the Go/No-go task. Lastly, the researchers investigated cortical structure parameters in relation to the Go/No-go false alarm rate for participants who exercised as children. They found that task performance was negatively associated with cortical density, and positively associated with the degree of neurite orientation dispersion and density.

The above results demonstrate that modular segregation and strengthened inter-hemispheric connections in the brain networks of people who exercised during childhood reduced the number of mistakes that they made in the Go/No-go task.

Figure 3: Functional connections between areas of the brain in relation to the false alarm rate in the Go/No-go task were characteristic of participants who exercised during childhood. © Kobe University

Glossary

※1 ModuleA single unit that combines with others to form the entire structure of a system. The human brain has a clear modular structure: it is divided into a number of large-scale networks made up of multiple areas.※2 Structural and Functional ConnectivityThis refers to the structural and functional relationships between different areas of the brain. Structural connections between areas of the brain can be identified by anatomical nerve fiber connections, and functional connections are indicated by similarities in patterns of neural activity.※3 Human Connectome ProjectThis large scale research project began in North America in 2012 and aims to deepen understanding of brain connectivity.

Acknowledgements

This research received funding from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) research project ‘The science of personalized value development through adolescence: integration of brain, real-world, and life-course approaches’ (Scientific Research on Innovative Areas: Research in a proposed research area) and the Japan Agency for Medical Research and Development’s ‘Strategic Research Program for Brain Sciences’ (Principal Investigator: Kiyoto Kasai), and KAKENHI grants from the Japan Society for the Promotion of Science (JSPS).

Journal Information


Provided by Kobe University

We Cannot Cheat Ageing and Death (Physiology)

New study finds fresh evidence for our inevitable death

A study led by Fernando Colchero, University of Southern Denmark and Susan Alberts, Duke University, North Carolina, that included researchers from 42 institutions across 14 countries, provides new insights into the aging theory “the invariant rate of ageing hypothesis”, which states that every species has a relatively fixed rate of aging.

– Human death is inevitable. No matter how many vitamins we take, how healthy our environment is or how much we exercise, we will eventually age and die, said Fernando Colchero.

He is an expert in applying statistics and mathematics to population biology and an associate professor at Department of Mathematics and Computer Science, University of Southern Denmark.

“We were able to shed light on the invariant rate of ageing hypothesis by combining an unpresented wealth of data and comparing births and deaths patterns on nine human populations with information from 30 non-human primate populations, including gorillas, chimpanzees and baboons living in the wild and in zoos” said Fernando Colchero.

In order to explore this hypothesis, the researchers analyzed the relationship between life expectancy, this is the average age at which individuals die in a population, and lifespan equality, which measures how concentrated deaths are around older ages.

Their results show that, as life expectancy increases, so does lifespan equality. So, lifespan equality is very high when most of the individuals in a population tend to die at around the same age such as observed in modern Japan or Sweden – which is around their 70s or 80s. However, in the 1800s lifespan equality was very low in those same countries, since deaths were less concentrated at old ages, resulting also in lower life expectancy.

– Life expectancy has increased dramatically and still does in many parts of the world. But this is not because we have slowed our rate of aging; the reason is that more and more infants, children and young people survive and this brings up the average life expectancy, said Fernando Colchero.

Previous research from some of the authors of the study has unraveled the striking regularity between life expectancy and lifespan equality among human populations, from pre-industrial European countries, hunter gatherers, to modern industrialize countries.

However, by exploring these patterns among our closest relatives, this study shows that this pattern might be universal among primates, while it provides unique insights into the mechanisms that produce it.

“We observe that not only humans, but also other primate species exposed to different environments, succeed in living longer by reducing infant and juvenile mortality. However, this relationship only holds if we reduce early mortality, and not by reducing the rate of ageing” said Fernando Colchero.

Using statistics and mathematics the authors show that even small changes in the rate of ageing would make a population of, say, baboons, to demographically behave as a population of chimpanzees or even humans.

‘Not all is lost’, says Fernando Colchero, ‘medical science has advanced at an unprecedented pace, so maybe science might succeed in achieving what evolution could not: to reduce the rate of ageing’.

This work was supported by NIA P01AG031719, with additional support provided by the Max Planck Institute of Demographic Research and the Duke University Population Research Institute.


Reference: “The Long Lives of Primates and the ‘Invariant Rate of Ageing’ Hypothesis,” F. Colchero, J.M. Aburto, E.A. Archie, C. Boesch, T. Breuer, F.A. Campos, A. Collins, D.A. Conde, M. Cords, C. Crockford, M.E. Thompson, L.M. Fedigan, C. Fichtel, M. Groenenberg, C. Hobaiter, P.M. Kappeler, R.R. Lawler, R.J. Lewis, Z.P. Machanda, M.L. Manguette, M.N. Muller, C. Packer, R.J. Parnell, S. Perry, A.E. Pusey, M.M. Robbins, R.M. Seyfarth, J.B. Silk, J. Staerk, T.S. Stoinski, E.J. Stokes, K.B. Strier, S.C. Strum, J. Tung, F. Villavicencio, R.M. Wittig, R.W. Wrangham, K. Zuberbühler, J.W. Vaupel, S.C. Alberts. Nature Communications, DOI: 10.1038/s41467-021-23894-3.


Provided by University of Southern Denmark

Scientists Turn Up Calorie-burning in Brown Fat With A Unique ‘On’ Switch (Physiology)

An exceptional receptor on the surface of brown fat cells drives calorie-burning without the need for an external signaling molecule. Mice genetically engineered to overproduce this receptor, GPR3, in brown fat were completely protected from metabolic disease despite being continuously fed a high caloric diet. The scientists behind this discovery at the University of Copenhagen believe their findings upend the current dogma describing how cell surface receptors work, while opening the door to new approaches for treating obesity.

Cells receive messages from their surroundings using receptors located on their surfaces. These messages are molecules – or ligands – that physically bind to the receptors, This messaging system is responsible for an enormous variety of cell functions and behaviors and is the most common target for therapeutic drugs.

A small subset of receptors appear to function without requiring a ligand, but it is not understood how these ‘receptors function and, most critically, which biological role they play. Now, scientists at the University of Copenhagen have discovered that one such receptor, GPR3, has a ‘built-in’ ligand and does not need any external ligand in order to work.

The researchers made this finding while searching for a new way to stimulate brown fat’s unparalleled ability to take up and burn glucose and lipids from the bloodstream. They found that cues from within brown fat cells increased the levels of GPR3 receptors on the cell surface that resulted in continuous calorie-burning. These discoveries, which were published in the journal Cell, suggest that fat cells may have more control over their own trajectory than was previously understood, while also presenting a promising new approach to treating obesity.

“Given the global obesity crisis, a great deal of effort is being put into identifying novel ways to safely exploit the calorie-burning power of brown fat. Identifying a unique candidate like GPR3, with such untapped therapeutic potential for metabolic disease, is exciting in and of itself. But uncovering a new paradigm of receptor control in the process takes it to another level for us,” says Associate Professor Zach Gerhart-Hines from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

Safely unlocking brown fat calorie-burning has been a key hurdle

Brown fat’s profound calorie-burning ability makes it an appealing therapeutic target for metabolic diseases. This beneficial function of brown fat is naturally activated when mice and humans are exposed to cold temperatures. However, scientists have struggled to safely mimic this effect with drugs.

The cell surface receptors classically known to stimulate brown fat activity are the beta-adrenergic – or ‘fight or flight’ – receptors. While activation of these receptors can increase brown fat calorie-burning in humans, it also results in serious side effects, including increased heart rate and blood pressure.

GPR3 protected mice from obesity

The CBMR scientists went back to the drawing board to find a way to activate brown fat in the same, safe, way as cold exposure. They exposed mice to the cold, screened their cell surface receptors, and found that cold exposure dramatically increased the production of GPR3 receptors. They further discovered that the fat cells themselves were responsible for sending an internal molecular signal that triggered the profound production of GPR3 receptors.

The scientists went on to genetically engineer mice with elevated levels of GPR3 receptors in their brown fat cells. They found that these mice were resistant to developing obesity, despite being fed a high caloric diet. Compared to control animals, they burned more energy, gained less fat tissue, and were better able to control their blood glucose levels. Even more remarkably, increasing the number of GPR3 receptors in brown fat cells counteracted metabolic disease in older mice that already had developed obesity.

“By using genetic tools to increase GPR3 levels in obese mice, we could begin reversing weight gain and completely correct glucose control. GPR3 activated the brown fat cells to essentially act as a sink for carbohydrates and lipids from the blood,” says PhD Student Olivia Sveidahl Johansen, the first author.

A safer alternative to activate the health benefits of brown fat cells?

The findings suggest that increasing the production of GPR3 in human brown and white fat cells can boost calorie-burning. Current drugs, which exploit cell surface receptors like GPR3, largely act by mimicking the natural signaling molecule or ligand. This approach typically requires a patient to take the medication continually in order to maintain receptor activation.

GPR3, on the other hand, has an ‘built-in’ ligand, which keeps it constantly active. This opens up new therapeutic possibilities, such as gene therapy, as an alternative approach to treating obesity.

To explore this idea, the authors teamed up with collaborators at the University of Bonn and ETH Zurich to engineer viruses that could selectively increase the production of GPR3 in brown fat cells of mice. They found that a single administration of this virus significantly boosted the calorie-burning of the animals for over a month.

“With the help of our extraordinary collaborative team within Denmark and abroad, we will continue to explore potential strategies of therapeutically exploiting the unique activity of GPR3, specifically in the context of fat tissue and metabolic disease. However, from an even broader perspective, we hope that this work will inspire future investigations that branch out into the control of GPR3 and related receptors in other tissues throughout the body and the application to other disease states,” says Associate Professor Gerhart-Hines.

Acknowledgements

The primary funding for the project came from the European Research Council, the Independent Research Fund of Denmark, and the Novo Nordisk Foundation. The work involved several Danish universities, hospitals, and University of Copenhagen spinout, Embark Biotech ApS as well as numerous international collaborations with universities from Sweden, Germany, Austria, Switzerland, the Netherlands, the UK, and the United States.

Read the full article in Cell here: Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis


Provided by University of Copenhagen