Publisher Health

Older adults with depression are actually aging faster than their peers, UConn Center on Aging researchers report.
“These patients show evidence of accelerated biological aging, and poor physical and brain health,” which are the main drivers of this association, says Breno Diniz, a UConn School of Medicine geriatric psychiatrist and author of the study, which appears in Nature Mental Health on March 22.
Diniz and colleagues from several other institutions looked at 426 people with late-in-life depression. They measured the levels of proteins associated with aging in each person’s blood. When a cell gets old, it begins to function differently, less efficiently, than a “young” cell. It often produces proteins that promote inflammation or other unhealthy conditions, and those proteins can be measured in the blood. Diniz and the other researchers compared the levels of these proteins with measures of the participants’ physical health, medical problems, brain function, and the severity of their depression.
To their surprise, the severity of a person’s depression seemed unrelated to their level of accelerated aging. However, they did find that accelerated aging was associated with worse cardiovascular health overall. People with higher levels of aging-associated proteins were more likely to have high blood pressure, high cholesterol, and multiple medical problems. The accelerated aging was also associated with worse performance on tests of brain health such as working memory and other cognitive skills.
“Those two findings open up opportunities for preventive strategies to reduce the disability associated with major depression in older adults, and to prevent their acceleration of biological aging,” Diniz says.
The researchers are now looking at whether therapies to reduce the number of aged, “senescent” cells in a person’s body can improve late in life depression. They are also looking at specific sources and patterns of proteins associated with aging, to see if this might lead to personalized treatments in the future.

Mpox — previously known as “monkeypox” — is currently spreading worldwide. An international research team from Goethe University and the University of Kent has now identified a compound that could help fight the disease. Their study has been published in the Journal of Medical Virology.
Nitroxoline is the name of the new drug candidate that could potentially be used to treat mpox. It was identified by scientists at Goethe University and the University of Kent as part of a multi-site study. The results of their research will now allow clinical trials to begin soon.
The current mpox outbreak is the first of this size to occur outside of Africa and also the first mpox outbreak caused by human-to-human transmission. People with immunodeficiencies are particularly at risk from the disease. Although antiviral agents have already been shown to inhibit the replication of the mpox virus in experimental models, the efficacy of these substances has not yet been confirmed in humans and some may have significant side effects. In addition, there are insufficient stocks to treat all mpox patients. Moreover, resistance formation against tecovirimat, the most promising mpox drug candidate to date, has already been reported.
In the present study, the international team led by Professor Jindrich Cinatl (of Goethe University Frankfurt and the Dr. Petra Joh-Research Institute) and Professor Martin Michaelis (School of Biosciences, University of Kent) has identified nitroxoline, a well-tolerated antibiotic, as a potential treatment alternative for the mpox virus based on experiments using cell culture and skin explant models.
Nitroxoline is also effective against a tecovirimat-resistant strain of the mpox virus, as well as other bacterial and viral pathogens that are frequently co-transmitted with mpox viruses, meaning it simultaneously suppresses multiple pathogens that are often involved in severe courses of mpox. Since nitroxoline is a well-tolerated antibiotic that has long been used to treat humans, it can be tested directly against mpox in clinical trials.
“The emergence of resistant virus strains is a cause of great concern,” says Professor Jindrich Cinatl of Goethe University and the Dr. Petra Joh-Research Institute. “It is very reassuring that nitroxoline is effective against a tecovirimat-resistant virus.”
Professor Martin Michaelis of the University of Kent adds: “The more different drugs become available to treat viral diseases, the better. We hope that nitroxoline will turn out to be an effective treatment for mpox patients.”

Scientists at St. Jude Children’s Research Hospital and Rockefeller University have combined their expertise to gain a better understanding of the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations in CFTR cause cystic fibrosis, a fatal disease with no cure. Current therapies using a drug called a potentiator can enhance CFTR functions in some patients; but how the potentiators work is not well understood. The new findings reveal how CFTR functions mechanistically and how disease mutations and potentiators affect those functions. With this information, researchers may be able to design more effective therapies for cystic fibrosis. The study was published today in Nature.
Cystic fibrosis is a genetic disorder that causes people to produce mucus that is too thick and sticky. This can block airways and lead to lung damage as well as cause problems with digestion. The disease affects about 35,000 people in the United States. CFTR is an anion channel, a passageway that maintains the right balance of salts and fluid across epithelial and other membranes. Mutations in CFTR are what cause cystic fibrosis, but these mutations can affect CFTR function differently. Therefore, some drugs used to treat the disease can only partially restore function of specific mutant forms of CFTR.
Structures of CFTR, previously captured in the laboratory of Jue Chen, Ph.D., and colleagues at Rockefeller University, revealed two distinct conformations (shapes). Those static images allowed researchers to see the channel when it is open or when it is closed, but the transition between states has been incompletely understood. Conformational changes were thus inferred to be important for opening and closing the channel, accounting for the electrophysiological properties of CFTR, which have been analyzed for decades. Those findings fueled interest in directly visualizing the structural transitions of CFTR in real time and examining how conformational changes are affected by disease mutations and by drugs used to enhance CFTR function in patients.
“Through this collaboration, we had the opportunity to really dial into the relationship between structure and function,” said co-corresponding author Scott Blanchard, Ph.D., St. Jude Department of Structural Biology. “Our lab’s prior work on ribosomes and G-protein coupled receptors had shown this is possible, but there are very few single proteins that are more relevant for the treatment of disease than CFTR because treatments for cystic fibrosis are aimed at ameliorating the defects in the mutant forms of this protein.”
“The ability to make biophysical measurements and get these types of quantitative insights is one of the advances of single-molecular imaging that never ceases to amaze me.”
Collaboration leads to a breakthrough
The complementary expertise of the research groups was key to making their discoveries. Through electrophysiology and structural studies, the Rockefeller team was able to guide the placement of single-molecule probes by the St. Jude team. By deploying single-molecule fluorescence resonance energy transfer (smFRET) the St. Jude team was able to provide new insights into the moving pieces of the CFTR machinery. Through the integration of cryo-electron microscopy, electrophysiology and smFRET, the research group was able to draw the connections needed to better understand how CFTR works.

“There is potential here to help cystic fibrosis patients by learning about the structure and behavior of CFTR,” said first author Jesper Levring, Rockefeller University. “Looking at these molecules one at a time using these methods — single-channel electrophysiology and smFRET — we could correlate the function of the channel with the conformational changes and relate it back to the underlying structural biology.”
What the researchers found is that CFTR exhibits a hierarchical gating mechanism. The two nucleotide-binding domains of the CFTR dimerize (combine) prior to channel opening. Conformational changes within the dimerized channel, related to ATP hydrolysis (a reaction where energy is released), regulate chloride conductance. The significance of this mechanistic insight was further revealed by the finding that the potentiator drugs Ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while the nucleotide-binding domains are dimerized. Mutations that cause cystic fibrosis can reduce the efficiency of the dimerization. These insights will be useful for informing the search for more effective clinical therapies.
“The most satisfying thing about this work is that we have answered a question about how CFTR works that has been a subject of debate in the field for many years,” said Chen, who is co-corresponding author of the study. “Every individual method has limitations, so you can have good data but still not have the answers. By combining approaches, we have gotten to a unified mechanism that gives us insight into how this molecule works. With this understanding we can then test how mutations or drugs affect the function, which is ultimately how we’ll get to better therapeutics.”
Authors and funding
The study’s other authors are Gabriel Fitzgerald, Weill Cornell Medicine; and Daniel Terry and Zeliha Kilic of St. Jude.
The study was supported by the National Institutes of Health (GM079238), the Howard Hughes Medical Institute and ALSAC, the fundraising and awareness organization of St. Jude.

Changes in the brain caused by Alzheimer’s disease are associated with shortening of the telomeres — the protective caps on the ends of chromosomes that shorten as cells age — according to a new study led by Anya Topiwala of Oxford Population Health, part of the University of Oxford, UK, published March 22 in the open-access journal PLOS ONE.
Telomeres on chromosomes protect DNA from degrading, but every time a cell divides, the telomeres lose some of their length. Short telomeres are a sign of stress and cellular aging, and are also associated with a higher risk of neurological and psychiatric disorders. Currently, little is known about the links between telomere length and changes that occur in the brains of people with neurological conditions. Understanding those relationships could offer insights into the biological mechanisms that cause neurodegenerative disorders.
In the new study, researchers compared telomere length in white blood cells to results from brain MRIs and electronic health records from more than 31,000 participants in the UK Biobank, a large-scale biomedical database and research resource containing anonymized genetic, lifestyle and health information from half a million UK participants. The analysis revealed that patients with longer telomeres also tended to have better brain health. They had a larger volume of grey matter in their brains overall and a larger hippocampus, both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex — the outer, folded layer of grey matter — which thins as Alzheimer’s disease progresses. The researchers speculate that longer telomeres might therefore help protect patients from developing dementia, though there was no association with stroke or Parkinson’s disease.
Overall, the findings show that shorter telomeres can be linked to multiple changes in the brain associated with dementia. To date, this is the largest and richest study of the relationships between telomere length and MRI markers in the brain. The associations suggest that accelerated aging in the brain, as indicated by telomere length, could represent a biological pathway that leads to neurodegenerative disease.
The authors add: “We found associations between telomere length, a marker of biological ageing, and multiple aspects of brain structure. This may explain why individuals with longer telomeres have a lower risk of dementia.”

If you live near a busy road you might feel like the constant sound of roaring engines, honking horns and wailing sirens makes your blood pressure rise. Now a new study published today in JACC: Advances confirms it can do exactly that.
Previous studies have shown a connection between noisy road traffic and increased risk of hypertension. However, strong evidence was lacking, and it was unclear whether noise or air pollution played a bigger role. The new research shows that it is exposure to road traffic noise itself that can elevate hypertension risk.
“We were a little surprised that the association between road traffic noise and hypertension was robust even after adjustment for air pollution,” said Jing Huang, assistant professor in the Department of Occupational and Environmental Health Sciences in the School of Public Health at Peking University in Beijing, China, and lead author of the study.
Previous studies of the issue were cross-sectional, meaning they showed that traffic noise and hypertension were linked, but failed to show a causal relationship. For the new paper, researchers conducted a prospective study using UK Biobank data that looked at health outcomes over time.
Researchers analyzed data from more than 240,000 people (aged 40 to 69 years) who started out without hypertension. They estimated road traffic noise based on residential address and the Common Noise Assessment Method, a European modeling tool.
Using follow-up data over a median 8.1 years, they looked at how many people developed hypertension. Not only did they find that people living near road traffic noise were more likely to develop hypertension, they also found that risk increased in tandem with the noise “dose.”
These associations held true even when researchers adjusted for exposure to fine particles and nitrogen dioxide. However, people who had high exposure to both traffic noise and air pollution had the highest hypertension risk, showing that air pollution plays a role as well.
“Road traffic noise and traffic-related air pollution coexist around us,” Huang said. “It is essential to explore the independent effects of road traffic noise, rather than the total environment.”
The findings can support public health measures because they confirm that exposure to road traffic noise is harmful to our blood pressure, she said. Policymaking may alleviate the adverse impacts of road traffic noise as a societal effort, such as setting stricter noise guideline and enforcement, improving road conditions and urban design, and investing advanced technology on quieter vehicles.
“To date, this is the first large-sized prospective study directly addressing the effect of road traffic noise on the incidence of newly-diagnosed hypertension,” said Jiandong Zhang, cardiovascular disease fellow in the division of cardiology at the University of North Carolina at Chapel Hill, and author of the accompanying editorial comment. “The data demonstrated in this article provides a higher quality of evidence to justify the potential to modify road traffic noise and air pollution from both individual and societal levels in improving cardiovascular health.”
As a follow-up, Huang said field studies are underway to better understand the pathophysiological mechanisms through which road noise affects hypertension.
The study was supervised by Kazem Rahimi, lead of the Deep Medicine program at the Nuffield Department of Women’s and Reproductive Health at the University of Oxford, and Samuel Cai, lecturer in environmental epidemiology at the Centre for Environmental Health and Sustainability at the University of Leicester.

Researchers have developed a new type of neural implant that could restore limb function to amputees and others who have lost the use of their arms or legs.
In a study carried out in rats, researchers from the University of Cambridge used the device to improve the connection between the brain and paralysed limbs. The device combines flexible electronics and human stem cells — the body’s ‘reprogrammable’ master cells — to better integrate with the nerve and drive limb function.
Previous attempts at using neural implants to restore limb function have mostly failed, as scar tissue tends to form around the electrodes over time, impeding the connection between the device and the nerve. By sandwiching a layer of muscle cells reprogrammed from stem cells between the electrodes and the living tissue, the researchers found that the device integrated with the host’s body and the formation of scar tissue was prevented. The cells survived on the electrode for the duration of the 28-day experiment, the first time this has been monitored over such a long period.
The researchers say that by combining two advanced therapies for nerve regeneration — cell therapy and bioelectronics — into a single device, they can overcome the shortcomings of both approaches, improving functionality and sensitivity.
While extensive research and testing will be needed before it can be used in humans, the device is a promising development for amputees or those who have lost function of a limb or limbs. The results are reported in the journal Science Advances.
A huge challenge when attempting to reverse injuries that result in the loss of a limb or the loss of function of a limb is the inability of neurons to regenerate and rebuild disrupted neural circuits.

“If someone has an arm or a leg amputated, for example, all the signals in the nervous system are still there, even though the physical limb is gone,” said Dr Damiano Barone from Cambridge’s Department of Clinical Neurosciences, who co-led the research. “The challenge with integrating artificial limbs, or restoring function to arms or legs, is extracting the information from the nerve and getting it to the limb so that function is restored.”
One way of addressing this problem is implanting a nerve in the large muscles of the shoulder and attaching electrodes to it. The problem with this approach is scar tissue forms around the electrode, plus it is only possible to extract surface-level information from the electrode.
To get better resolution, any implant for restoring function would need to extract much more information from the electrodes. And to improve sensitivity, the researchers wanted to design something that could work on the scale of a single nerve fibre, or axon.
“An axon itself has a tiny voltage,” said Barone. “But once it connects with a muscle cell, which has a much higher voltage, the signal from the muscle cell is easier to extract. That’s where you can increase the sensitivity of the implant.”
The researchers designed a biocompatible flexible electronic device that is thin enough to be attached to the end of a nerve. A layer of stem cells, reprogrammed into muscle cells, was then placed on the electrode. This is the first time that this type of stem cell, called an induced pluripotent stem cell, has been used in a living organism in this way.

“These cells give us an enormous degree of control,” said Barone. “We can tell them how to behave and check on them throughout the experiment. By putting cells in between the electronics and the living body, the body doesn’t see the electrodes, it just sees the cells, so scar tissue isn’t generated.”
The Cambridge biohybrid device was implanted into the paralysed forearm of the rats. The stem cells, which had been transformed into muscle cells prior to implantation, integrated with the nerves in the rat’s forearm. While the rats did not have movement restored to their forearms, the device was able to pick up the signals from the brain that control movement. If connected to the rest of the nerve or a prosthetic limb, the device could help restore movement.
The cell layer also improved the function of the device, by improving resolution and allowing long-term monitoring inside a living organism. The cells survived through the 28-day experiment: the first time that cells have been shown to survive an extended experiment of this kind.
The researchers say that their approach has multiple advantages over other attempts to restore function in amputees. In addition to its easier integration and long-term stability, the device is small enough that its implantation would only require keyhole surgery. Other neural interfacing technologies for the restoration of function in amputees require complex patient-specific interpretations of cortical activity to be associated with muscle movements, while the Cambridge-developed device is a highly scalable solution since it uses ‘off the shelf’ cells.
In addition to its potential for the restoration of function in people who have lost the use of a limb or limbs, the researchers say their device could also be used to control prosthetic limbs by interacting with specific axons responsible for motor control.
“This interface could revolutionise the way we interact with technology,” said co-first author Amy Rochford, from the Department of Engineering. “By combining living human cells with bioelectronic materials, we’ve created a system that can communicate with the brain in a more natural and intuitive way, opening up new possibilities for prosthetics, brain-machine interfaces, and even enhancing cognitive abilities.”
“This technology represents an exciting new approach to neural implants, which we hope will unlock new treatments for patients in need,” said co-first author Dr Alejandro Carnicer-Lombarte, also from the Department of Engineering.
“This was a high-risk endeavour, and I’m so pleased that it worked,” said Professor George Malliaras from Cambridge’s Department of Engineering, who co-led the research. “It’s one of those things that you don’t know whether it will take two years or ten before it works, and it ended up happening very efficiently.”
The researchers are now working to further optimise the devices and improve their scalability. The team have filed a patent application on the technology with the support of Cambridge Enterprise, the University’s technology transfer arm.
The technology relies on opti-oxTM enabled muscle cells. opti-ox is a precision cellular reprogramming technology that enables faithful execution of genetic programmes in cells allowing them to be manufactured consistently at scale. The opti-ox enabled muscle iPSC cell lines used in the experiment were supplied by the Kotter lab from the University of Cambridge. The opti-ox reprogramming technology is owned by synthetic biology company bit.bio.
The research was supported in part by the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI), Wellcome, and the European Union’s Horizon 2020 Research and Innovation Programme.

Mutations in genes that form the desmosome are the most common cause of the cardiac disease arrhythmogenic cardiomyopathy (ACM), which affects one in 2000 to 5000 people worldwide. Researchers from the group of Eva van Rooij now discovered how a mutation in the desmosomal gene plakophilin-2 leads to ACM. They found that the structural and functional changes in ACM hearts caused by a plakophilin-2 mutation are the result of increased desmosomal protein degradation. The results of this study, published in Science Translational Medicine on March 22nd 2023, further our understanding of ACM and could contribute to the development of new therapies for this disease.
ACM is a progressive and inheritable cardiac disease for which currently no treatments exist to halt its progression. Although patients initially do not experience any symptoms, they are at a higher risk of arrhythmias and resulting sudden cardiac arrest. As the disease progresses, patches of fibrotic and fat tissue form in the heart which can lead to heart failure. At this stage, patients require a heart transplantation as treatment.
Plakophilin-2
Over 50% of all ACM cases are caused by a mutation in one of the desmosomal genes, which together form complex protein structures known as desmosomes. Desmosomes form “bridges” between individual heart muscle cells, allowing the cells to contract in a coordinated manner. Most of the desmosomal mutations that cause ACM occur in a gene called plakophilin-2. Nevertheless, very little is known on how mutations in this gene lead to the disease. To change this, the Van Rooij lab first studied human heart samples from ACM patients carrying mutations in the plakophilin-2 gene. “We saw lower levels of all desmosomal proteins and disorganized desmosomal proteins in fibrotic areas of the ACM hearts,” says Jenny (Hoyee) Tsui, first author on the paper. Tsui: “In addition, cultured 3D heart muscle tissue originating from a patient with a plakophilin-2 mutation, was unable to continue beating at higher pacing rates, which resembles arrhythmias seen in the clinic.”
ACM in mice
The researchers then used a genetic tool called CRISPR/Cas9 to introduce the human plakophilin-2 mutation in mice to mimic ACM. This allowed them to study progression of the disease in more detail. They observed that old ACM mice carrying this mutation had lower levels of desmosomal proteins and heart relaxation issues, similar to ACM patients. Strikingly, the researchers discovered that the mutation lowered levels of desmosomal proteins even in young, healthy mice of which the heart contracted normally. From this they concluded that a loss of desmosomal proteins could underlie the onset of ACM caused by a plakophilin-2 mutation.
Protein degradation
The researchers then moved on to explain the loss of desmosomal proteins. For this they studied both RNA and protein levels in their ACM mice. “The levels of desmosomal proteins were lower in our ACM mice compared to healthy control mice. However, the RNA levels of these genes were unchanged. We discovered that these surprising findings are the result of increased protein degradation in ACM hearts,” explains Sebastiaan van Kampen, co-first author of the paper. Tsui adds: “When we treated our ACM mice with a drug that prevents protein degradation, the levels of desmosomal proteins were restored. More importantly, the restored levels of desmosomal proteins improved calcium handling of heart muscle cells, which is vital for their normal function.”
Towards new therapies
The results of this study, published in Science Translational Medicine, raise new insights into ACM development and indicate that protein degradation could be an interesting target for future therapies. “Protein degradation occurs in every cell of our body and is crucial for the function of these cells. To overcome side-effects of future therapies we will need to develop drugs that prevent degradation of desmosomal proteins in heart muscle cells specifically,” explains Eva van Rooij, group leader at the Hubrecht Institute and last author of the study. More research is thus needed to realize this. In the future, these new specific drugs could potentially be used to halt the onset and prevent progression of ACM.

Mechanotherapy, the concept of using mechanical forces to stimulate tissue healing, has been used for decades as a form of physical therapy to help heal injured muscles. However, the biological basis and optimal settings for mechanotherapies are still poorly understood, especially with respect to elderly patients. Given the well-known decline in healing ability that occurs with age, elderly patients stand to benefit greatly from an effective, non-invasive musculoskeletal treatment approach.
A new multidisciplinary study helps close this knowledge gap of mechanotherapies’ effectiveness in aged muscle. The study was performed by researchers at the Wyss Institute for Biologically Inspired Engineering and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) led by Wyss Core Faculty member David Mooney, Ph.D. in collaboration with Associate Faculty member and Paul A. Maeder Professor of Engineering and Applied Sciences, Conor Walsh, Ph.D. In previous work, the collaborators used Walsh’s Lab’s expertise in wearable robotic systems to develop a robotic mechanotherapy device that functions like a highly advanced massage gun. This technology enabled precise delivery of non-invasive mechanotherapy to injured muscles of mice, allowing the team to measure its biological effects. The researchers had used this device to optimize the magnitude, duration, and frequency of force applied to the muscles of young animals to accelerate healing, and found that mechanotherapy accelerated muscle healing by mitigating inflammation after injury.
Now, using this device on aged muscle, the researchers found that the same mechanotherapy treatment that helps young muscle heal faster after injury actually has the opposite effect with aging — the settings that promoted healing in young muscle exacerbated injury in old muscle. In search for an explanation for these results, the team found that mechanotherapy amplified rather than alleviated inflammation in aged muscle, ultimately hindering the normal healing process by disrupting the behavior of muscle stem cells, a subset of cells responsible for replacing damaged muscle tissue.
Prompted by these findings, the researchers next asked if controlling inflammation along with delivering mechanotherapy could help achieve healing effects in aged muscles. They found that this was indeed the case: combining mechanotherapy with anti-inflammatory treatment significantly improved healing in aged muscles and was superior to anti-inflammatory treatment alone. This work, published in Science Robotics, opens an exciting non-invasive therapeutic avenue for healing muscle injuries in elderly patients.
“Our study highlights critical differences in how muscle stem cells and immune cells respond to mechanical forces in the context of age, and how upregulated inflammation additionally compromises the function of aged stem cells needed for the regeneration of old muscles,” said Mooney who also is the Robert P. Pinkas Family Professor of Bioengineering at SEAS. “Muscle mechanotherapies likely thus won’t be a ‘one-size-fits-all.’ To realize their benefits, they will have to be tailored to patient populations, and specifically for aged individuals, it will be key to modulate inflammation.”
From surprise to solution
Following their surprising discovery that mechanotherapy alone actually hinders the normal regeneration process of aged muscles by interacting with the immune system, the team took a deeper look at the muscles’ stem cells. Applying a mechanical load to muscle, as is done during mechanotherapy treatment, influences muscle cell behavior via several molecular “mechanotransduction pathways” that also affect stem cells. “We showed that although aged stem cell behavior was disrupted by the elevated inflammation, they were still able to ‘feel’ the mechanical forces of loading as we demonstrated by the activation of these pathways,” said first-author Stephanie McNamara, who is a graduate student on Mooney’s team and currently enrolled in the joint Harvard/MIT MD-PhD program. “This actually was what prompted us to ask whether controlling inflammation might enable these cells to respond to the mechanical stimuli — and indeed it did.”
The team found that administering anti-inflammatory therapy in the form of glucocorticoids alongside mechanotherapy suppressed key pro-inflammatory pathways and reduced overall inflammation levels in injured aged muscle to those seen in injured young muscle. Yet at a cellular level the muscle cells continued to experience mechanotransduction, and by removing the negative impacts of inflammation, injured aged muscles could positively respond to the robot-delivered mechanical loading.
“It is well-known that, with age, many of the normal processes of muscle healing and inflammation change. It’s important to question whether the same mechanisms seen in studies performed in young animals stay the same as the body ages,” McNamara says. “By leveraging what we learned in this study and our previous work and combining it with growing expertise in wearable soft robotic systems, we believe that in the future personalized mechanotherapeutic approaches can be developed to heal injuries across all ages.”
“This discovery that a non-invasive mechanotherapy can stimulate muscle repair in the elderly when combined with anti-inflammatory therapy opens an entirely new path for regeneration and repair in older populations. Mechanotherapies clearly have immense potential to change the lives of patients, but it is truly cross-disciplinary collaborations, such as the one between Dave Mooney’s and Conor Walsh’s groups at the Wyss Institute, that set the stage for advancing them into clinical realities,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.
Other authors on the study are additional members of Mooney’s and Walsh’s groups, including Bo Ri Seo, Benjamin Freedman, Emily Roloson, Jonathan Alvarez, C. T. O’Neill; and Herman Vandenburgh, Professor Emeritus at Brown University, Providence, RI. The study was funded by the National Institute of Dental and Craniofacial Research (under grant #R01DE013349), National Science Foundation (under grant #DMR-1420570), National Institute of Arthritis and Musculoskeletal and Skin Disease (under grant #F31AR075367), National Institutes of Health (under grant #K99AG065495), National Institute of General Medical Sciences (under award #T32GM007753 and T32GM144273), as well as an AR3T Regenerative Rehabilitation Pilot grant.

Exercise has many benefits — strengthening muscles and bones, preventing disease and extending lifespan. It is also known to change the composition and activity of the trillions of microbes in our guts known as the microbiome.
It is well known that the microbiomes of athletes are different from those who are sedentary. This is not overly surprising according to the author and PhD student Shrushti Shah. “Athletes are often lean and follow strict diet and training schedules — these factors alone can explain the different microbiomes of athletes,” says Shah, a Kinesiology PhD student specializing in Nutrition, Metabolism and Genetics.
To investigate how exercise shapes the gut microbiota in non-athletes, the study assessed information on the type, time and intensity of exercise in relation to microbiomes in a large cohort of middle-aged adults. Information on body weight, diet and hand-grip strength were also collected.
“Encouragingly, the study found that physical activity of moderate duration (greater than 150 minutes per week) increased both the richness and diversity of the gut microbiomes compared to study participants that exercised less,” says Jane Shearer, PhD, a professor in the Faculty of Kinesiology and the Cumming School Medicine. “Given this, more exercise appears to be important in improving microbiome health and individuals should aim to meet the Health Canada recommended 150 min of moderate-intensity physical activity per week.”
When exercise intensity was examined, results showed that how long a person exercised was more important than how hard they exercised during each workout in improving microbes in the gut. Reasons for this are not known and are a topic of future work in the laboratory.
The study also showed that changes in the microbiome were not the same between different groups of individuals. The most beneficial changes were seen in those individuals of normal weight compared to those who were overweight. According to study investigator Dr. Chunlong Mu, PhD, a postdoctoral associate in Kinesiology, this is because “being overweight exerts its own influences on the gut microbiome independently of exercise. In this case, poor dietary habits outweigh some of the beneficial influences of exercise on the gut microbes.”
With this in mind, the best advice appears not only to exercise more, but also take steps to maintain a healthy weight to achieve a healthy and optimally functioning gut microbiome.
Jane Shearer, PhD, is a professor at the Faculty of Kinesiology and in the Department of Biochemistry & Molecular Biology at the Cumming School of Medicine (CSM). She is a member of the Alberta Children’s Hospital Research Institute, Owerko Centre, Snyder Institute for Chronic Diseases, and Hotchkiss Brain Institute at the CSM.

Memory B cells play a critical role to provide long-term immunity after a vaccination or infection. In a study published in the journal Immunity, researchers describe a distinct and novel subset of memory B cells that predict long-lived antibody responses to influenza vaccination in humans.
These effector memory B cells appear to be poised for a rapid serum antibody response upon secondary challenge one year later, Anoma Nellore, M.D., Fran Lund, Ph.D., and colleagues at the University of Alabama at Birmingham and Emory University report. Evidence from transcriptional and epigenetic profiling shows that the cells in this subset differ from all previously described memory B cell subsets.
The UAB researchers identified the novel subset by the presence of FcRL5 receptor protein on the cell surface. In immunology, a profusion of different cell-surface markers is used to identify and separate immune-cell types. In the novel memory B cell subset, FcRL5 acts as a surrogate marker for positive expression of the T-bet transcription factor inside the cells. Various transcription factors act as master regulators to orchestrate the expression of many different gene sets as various cell types grow and differentiate.
Nellore, Lund and colleagues found that the FcRL5+ T-bet+ memory B cells can be detected seven days after immunization, and the presence of these cells correlates with vaccine antibody responses months later. Thus, these cells may represent an early, easily monitored cellular compartment that can predict the development of a long-lived antibody response to vaccines.
This could be a boon to the development of a more effective yearly influenza vaccine. “New annual influenza vaccines must be tested, and then manufactured, months in advance of the winter flu season,” Lund said. “This means we must make an educated guess as to which flu strain will be circulating the next winter.”
Why are vaccine candidates made so far in advance? Pharmaceutical companies, Lund says, need to wait many weeks after vaccinating volunteers to learn whether the new vaccine elicits a durable immune response that will last for months. “One potential outcome of the current study is we may have identified a new way to predict influenza vaccine durability that would give us an answer in days, rather than weeks or months,” Lund said. “If so, this type of early ‘biomarker’ could be used to test flu vaccines closer to flu season — and moving that timeline might give us a better shot at predicting the right flu strain for the new annual vaccine.”
Seasonal flu kills 290,000 to 650,000 people each year, according to World Health Organization estimates. The global flu vaccine market was more than $5 billion in 2020.

To understand the Immunity study, it is useful to remember what happens when a vaccinated person subsequently encounters a flu virus.
Following exposure to previously encountered antigens, such as the hemagglutinin on inactivated influenza in flu vaccines, the immune system launches a recall response dominated by pre-existing memory B cells that can either produce new daughter cells or cells that can rapidly proliferate and differentiate into short-lived plasmablasts that produce antibodies to decrease morbidity and mortality. These latter B cells are called “effector” memory B cells.
“The best vaccines induce the formation of long-lived plasma cells and memory B cells,” said Lund, the Charles H. McCauley Professor in the UAB Department of Microbiology and director of the Immunology Institute. “Plasma cells live in your bone marrow and make protective antibodies that can be found in your blood, while memory B cells live for many years in your lymph nodes and in tissues like your lungs.
“Although plasma cells can survive for decades after vaccines like the measles vaccine, other plasma cells wane much more quickly after vaccination, as is seen with COVID-19,” Lund said. “If that happens, memory B cells become very important because these long-lived cells can rapidly respond to infection and can quickly begin making antibody.”
In the study, the UAB researchers looked at B cells isolated from blood of human volunteers who received flu vaccines over a span of three years, as well as B cells from tonsil tissue obtained after tonsillectomies.

They compared naïve B cells, FcRL5+ T-bet+ hemagglutinin-specific memory B cells, FcRL5neg T-betneg hemagglutinin-specific memory B cells and antibody secreting B cells, using standard phenotype profiling and single-cell RNA sequencing. They found that the FcRL5+ T-bet+ hemagglutinin-specific memory B cells were transcriptionally similar to effector-like memory cells, while the FcRL5neg T-betneg hemagglutinin-specific memory B cells exhibited stem-like central memory properties.
Antibody-secreting B cells need to produce a lot of energy to churn out antibody production, and they also must turn on processes that protect the cells from some of the detrimental side effects of that intense metabolism, including controlling the dangerous reactive oxygen species and boosting the unfolded protein response.
The FcRL5+ T-bet+ hemagglutinin-specific memory B cells did not express the plasma cell commitment factor, but did express transcriptional, epigenetic and metabolic functional programs that poised these cells for antibody production. These included upregulated genes for energy-intensive metabolic processes and cellular stress responses.
Accordingly, FcRL5+ T-bet+ hemagglutinin-specific memory B cells at Day 7 post-vaccination expressed intracellular immunoglobulin, a sign of early transition to antibody-secreting cells. Furthermore, human tonsil-derived FcRL5+ T-bet+ memory B differentiated more rapidly into antibody-secreting cells in vitro than did FcRL5neg T-betneg hemagglutinin-specific memory B cells.
Lund and Nellore, an associate professor in the UAB Department of Medicine Division of Infectious Diseases, are co-corresponding authors of the study, “A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.”
Co-authors with Lund and Nellore are Esther Zumaquero, R. Glenn King, Betty Mousseau, Fen Zhou and Alexander F. Rosenberg, UAB Department of Microbiology; Christopher D. Scharer, Tian Mi, Jeremy M. Boss, Christopher M. Tipton and Ignacio Sanz, Emory University School of Medicine, Atlanta, Georgia; Christopher F. Fucile, UAB Informatics Institute; John E. Bradley and Troy D. Randall, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Stuti Mutneja and Paul A. Goepfert, UAB Department of Medicine Division of Infectious Diseases.
Funding for the work came from National Institutes of Health grants AI125180, AI109962 and AI142737 and from the UAB Center for Clinical and Translational Science.