Could therapies that remove senescent cells — called senotherapeutics — also improve the health of humans as we age? Answering this question and more has the potential to significantly advance human health, and the National Institutes of Health (NIH) has launched an extensive research initiative for this very purpose.

The SenNet Consortium, a collaboration of institutions from throughout the United States, was initially launched in 2021 with centers established to gather and analyze human data. The researchers will collect and analyze 18 tissues from healthy humans across lifespan to discern the full scope of senescent cells and how they may contribute to the aging process. The work of the SenNet Consortium was recently presented in a paper published in Nature Aging.

Along with colleagues from Mayo Clinic, University of Texas Health Science center at San Antonio, and UConn Health, JAX Professor Paul Robson, Ph.D. is taking part in the mapping of four human tissue types (kidney, adipose, pancreas, and placenta) within the KAPP-Sen Tissue Mapping Center. The Robson Lab also leads the Biological Analysis Core, and the Data Analysis Core of KAPP-Sen TMC is led by JAX Associate Professor Duygu Ucar, Ph.D., and JAX Professor Jeff Chuang, Ph.D.

SenNet has also grown over the past year to add mouse-focused investigators, and JAX was designated as a Tissue Mapping Center (TMC) for SenNet in August 2022, supported by a four-year, $10.7 million grant from the National Institute on Aging. JAX-Sen is led by Professor and Maxine Groffsky Endowed Chair Nadia Rosenthal, Ph.D., FMedSci with co-principal investigators Robson, JAX Associate Professor Ron Korstanje, Ph.D., and UConn Health’s Ming Xu, Ph.D. Associate Professor Sheng Li and Principal Computational Scientist Matt Mahoney lead the Data Analysis Core of the JAX-Sen TMC.

JAX is poised to make substantial contributions to SenNet by profiling senescent cells in kidney, placenta, pancreas, and heart, all tissues that are relevant to chronic diseases of aging. The team will draw upon its genetically diverse mouse resources, including Diversity Outbred mouse populations, to model a range of molecular senescence traits, as well as inbred mice specifically engineered to help visualize senescent cell subsets.

As three of the tissues (kidney, pancreas, and placenta) in the mouse JAX-Sen TMC are shared with the human KAPP-Sen TMC, these efforts align well with the JAX institutional initiative to continue to build the human-mouse interface. The goal of SenNet goes beyond building an atlas of senescent cells in the body and knowing more about senescent cell biology. The potential benefits of senotherapeutics for healthy human aging are exciting, as are other possible clinical advances, such as identifying individuals at higher risk for age-related disease.

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Materials provided by Jackson Laboratory. Original written by Mark Wanner. Note: Content may be edited for style and length.

These biofilms aren’t just unpleasant and unappealing however, they can be seriously troublesome. For example, in the medical field, the formation of biofilm can reduce the effectiveness of antibiotic treatments. The key to understanding biomass formation lies in understanding how bacteria behave en masse.

A new paper in EPJE by Heinrich-Heine-Universität, Düsseldorf, Germany, researcher Davide Breoni and his co-authors presents a mathematical model for the motion of bacteria that includes cell division and death, the basic ingredients of the cell cycle.

The team developed a mathematical model of bacterial movement in process creating a link between statistical physics and biophysics.

“Our new model belongs to a class of models for ‘active matter’ that currently encounter a lot of interest in statistical physics,” Breoni says. “This field studies the collective properties of particle systems that have their own energy source — bacteria are an exemplary case.”

The model devised by the team delivered a surprise by suggesting that when it comes to movement bacteria can act as a unit.

“In the course of our investigation, we found out that the model predicts that the formation of bacterial colonies can occur through the build-up of travelling waves, concentrated ‘packages’ of bacteria,” Breoni adds. “We did not expect this to arise from such a simple model as ours.”

He believes that the results should be interesting to the general public who may be aware of bacterial colonies, but not know how they move in a collective way.

Breoni concludes by pointing out this is a very simple model suggesting how the research could proceed from here. “We could try to make the model more realistic and confront the results to experiment to test its predictions,” he says. “On the other hand, this research is very much curiosity-driven and results from intense discussions among the researchers — an approach we’d like to maintain so we can continue to surprise ourselves with our findings.”

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Materials provided by Springer. Note: Content may be edited for style and length.

Building tissues and organs is one of the most complex and essential tasks that cells must accomplish during embryogenesis. In this collective task, cells communicate through a variety of communication methods, including biochemical signals — similar to a cell’s sense of smell — and mechanical cues — the cell’s sense of touch. Researchers in a variety of disciplines have been fascinated by cell communication for decades. Professor Otger Campàs together with his colleagues from the Physics of Life (PoL) Cluster of Excellence at Technische Universität Dresden and from the University of California Santa Barbara (UCSB) have now been able to unravel another mystery surrounding the question of how cells use their sense of touch to make vital decisions during embryogenesis. Their paper has now been published in the journal Nature Materials.

Testing the surroundings In their paper, the researchers report how cells within a living embryo mechanically test their environment and what mechanical parameters and structures they perceive. “We know a lot about how cells sense and respond to mechanical cues in a dish. However, their microenvironment is quite different within an embryo and we did not know what mechanical cues they perceive in a living tissue,” said Campàs, Chair of Tissue Dynamics and PoL Managing Director.

The mechanical cures helps cells make important decisions, such as whether or not to divide, move or even differentiate, the differentiation process by which stem cells turn into more specialized cells able to perform specific functions. Previous works revealed that stem cells placed on a synthetic substrate rely heavily on mechanical cues to make decisions: Cells on surfaces with a stiffness similar to bones became osteoblasts (bone cells), whereas cells on surfaces with a stiffness similar to brain tissue became neurons. The findings greatly advanced the field of tissue engineering as researchers used these mechanical cues to create synthetic scaffolds to coax stem cells to develop into desired outcomes. These scaffolds are used today in a variety of biomedical applications.

From a dish to the living embryo

However, a dish is not the cell’s natural habitat. While building an organism, cells are not in contact with synthetic scaffolds in a flat dish, but rather with complex living materials in three dimensions.

Over the last decade, Prof. Campàs’ research group uncovered the mechanical cues that guide cells in the complex tissues of an embryo. Using a unique technique developed in his lab, the researchers could probe the living tissue in a similar way as cells do and find out what mechanical structures the cells sense. “We first studied how cells mechanically test their micro-environment as they differentiate and build the body axis of a vertebrate, as they differentiate,” Campàs said. “Cells used different protrusions to push and pull on their environment. So we quantified how fast and strong they were pushing.” Using a ferromagnetic oil droplet that they inserted between developing cells and subjecting it to a controlled magnetic field, they were able to mimic these tiny forces and measure the mechanical response of the cells surroundings.

Sensing the tissue architecture and cells change fate

Critical to these embryonic cells’ actions is their collective physical state, which Campàs and his research group described in a previous paper to be that of an active foam, similar in consistency to soap suds or beer froth, with cells clumped together by cell adhesion and tugging of each other. What the cells are mechanically probing, Campàs and team found out, is the collective state of this “living foam” — how stiff it is and how confined the assemblage is. “And right at the moment that cells differentiate and decide to change their fate, there is a change in the material properties of the tissue that they perceive.” According to him, at the moment the cells within the tissue decide on their fate, the tissue falls its stiffness.

Going forward

What’s not yet proven in this study is the complex question of whether — and if so, how — the change in the stiffness in the embryonic environment drives the change in the cell state. “There is an interplay between the mechanical characteristics of the structures that cells collectively build, such as tissues or organs, and the decisions they make individually, as these depend on the mechanics cues that cells sense in the tissue. This interplay is at the core of how nature builds organisms.”

The findings from this study might also have important implications for tissue engineering. Potential materials that mimic the foam-like characteristics of the embryonic tissue, as opposed to the widely used synthetic polymer or gel scaffolds, may allow researchers to create more robust and sophisticated synthetic tissues, organs and implants in the lab, with the appropriate geometries and mechanical characteristics for the desired functions.

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Materials provided by Technische Universität Dresden. Original written by Magdalena Selbig. Note: Content may be edited for style and length.

In a new study published December 28, 2022 in Immunity, scientists at University of California San Diego School of Medicine revealed a previously unappreciated complexity of T_RM cell biology in the gut, which may inspire a new generation of precision therapeutics against infection, cancer and auto-immune disease.

After experiencing an infection, the immune system leaves behind memory T cells, which maintain a long-lasting molecular memory of the pathogen and are ready to sound the alarm if it ever returns. While some memory T cells are designed to circulate through the bloodstream and provide whole-body protection, others reside in specific organs and are specialized to fight the pathogens that target that part of the body. These T_RM cells can provide life-long immunity at the target tissue, but can also contribute to autoimmune diseases if overactivated.

“T_RM cells are the first responders, right at the front lines of infection,” said senior author John T. Chang, MD, professor at UC San Diego School of Medicine. “Most of our vaccines are designed to provide systemic immunity, but we may be able to get even better protection by instead focusing on boosting the tissue-specific cells that encounter the pathogen first.”

For example, a respiratory virus may be best fought by strengthening T_RM cells in the nose and lungs, and a pathogenic gut microbe best treated by enhancing T_RM cells in the intestines. Thus the goal is to develop therapeutics that could boost the formation and maintenance of T_RM cells, or in the case of autoimmune disease, remove the immune cells by disrupting these same pathways.

The issue is, scientists still have a lot to learn about what helps T_RM cells form and survive, and these rules may be quite different in each tissue type.

To explore this, the researchers performed a series of experiments to characterize T_RM cells in mice from four different compartments of the gut: two organs (the small intestine and the colon) and two different tissue layers in each (the intraepithelial and lamina propria layers).

The experiments revealed that T_RM cells in each tissue type exhibited distinct patterns of cytokine and granzyme expression, along with substantial transcriptional, epigenetic and functional heterogeneity. In other words, the same type of immune cells in each part of the gut appeared to be very different in their molecular makeup, function and the chemical signals they depend on.

Reinforcing this further, each population of cells also showed differential dependence on Eomesodermin (Eomes), a transcriptional factor known to affect T_RM cell development. Eomes was canonically thought to repress T_RM cells based on previous data collected from the skin, liver and kidney, but the new experiments revealed the opposite was true in the small intestine. There, Eomes proved to be surprisingly important in the survival of T_RM cells. However, this was not the case in the colon, highlighting the high context-specificity even within the gut.

Future research will continue to define the rules of T_RM cell formation and maintenance in other tissues and explore what drives their specificity. For example, the authors suggest that differences in the microbiome of the small intestine and the colon may contribute to the unique needs of their T_RM cells, so manipulating the microbiome may be another approach to regulating immune cells in the gut.

“In the future, we want to be thinking about vaccines and other therapeutics that are tailored to the specific needs of each organ,” said Chang. “By knowing what each tissue type needs to support the formation and maintenance of T_RM cells, we can provide the most efficient immune defenses against disease.”

Co-authors of the study include: Yun Hsuan Lin, Han G. Duong, Abigail E. Limary, Eleanor S. Kim, Paul Hsu, Shefali A. Patel, William H. Wong, Cynthia S. Indralingam, Yi Chia Liu, Priscilla Yao, Natalie R. Chiang, Sara A. Vandenburgh, Taylor R. Anderson, Jocelyn G. Olvera, Amir Ferry, Kennidy K. Takehara, Wenhao Jin, Matthew S. Tsai, Gene W. Yeo and Ananda W. Goldrath, all at UC San Diego.

In a study published in Cell Reports, researchers from Nara Institute of Science and Technology (NAIST) have revealed that antigen-specific killer T cells (CD8⁺ T cells) rapidly expand in the lungs when they encounter antigen-presenting alveolar macrophages (AMs) to protect against viral infection.

CD8⁺ T cells confer protective immunity against infection with respiratory viruses, such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by killing infected cells. In order to target the correct cells for killing, naive CD8⁺ T cells must be primed by contact with antigen-presenting cells (APCs), which mediate the uptake of virus-infected cells and present their antigens, in a process known as cross-presentation. The primed CD8⁺ T cells then clonally expand and differentiate into effector or long-lived antigen-specific memory T cells.

“Multiple cell types can present antigen to CD8⁺ T cells in the lungs, although the role of tissue-resident macrophages in this process is unclear,” explains Takumi Kawasaki, lead author of the study. “AMs are the first cells in the lungs that encounter infectious materials, environmental particles, surfactants, and dying cells, and they are important for the host defense against bacterial and fungal infection, so we suspected that they were also important in protecting against respiratory virus infection.”

To test this, the researchers explored the mechanisms by which APCs instruct antigen-specific CD8⁺ T cells in the lungs. First, mice were primed by vaccination with a specific antigen or infection with IAV, and then they were subjected to secondary immunization or re-infection.

“We determined that antigen-presenting AMs present inhaled antigen to memory CD8⁺ T cells,” says senior author of the study, Taro Kawai, “and that this resulted in a rapid expansion of antigen-specific CD8⁺ T cells in the lungs.”

Furthermore, the researchers found that AMs help to develop resident memory-type cell population by producing interleukin 18. Importantly, administration of antigen-loaded AMs to mice induced the proliferation of resident memory-type CD8⁺ T cells.

“This strategy may improve the efficacy of CD8⁺ T cell-dependent cellular immunity,” says Kawai.

Given that the lung is a major tissue for IAV and SARS-CoV-2 infection, the findings from this study regarding the mechanism of lung-resident memory CD8+ cell expansion are expected to lead to the development of new vaccines that induce cellular immunity. Virus-specific antigen-presenting AMs could be delivered as a type of “cell transplant vaccine” in the future.

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Materials provided by Nara Institute of Science and Technology. Note: Content may be edited for style and length.

Now, an international team of scientists from Japan, Canada and Germany have discovered a new situation from our everyday environment where this ability is compromised — when our body pitches (body pitch) and moves at the same time (body motion).

The scientists’ observations, which were published in the journal Multisensory Research, were based on real-world scenarios, revealing factors long overlooked by past laboratory studies.

“Unlike typical studies of this kind, which happen in well-controlled laboratories, our team traveled to Hong Kong to conduct field research on the world-renowned Peak Tram,” said Dr Chia-huei Tseng, who led the research and is associate professor at Tohoku University’s Research Institute of Electrical Communication (RIEC). “We performed experiments on hundreds of commuters making their way up Hong Kong’s highest hill, Victoria Peak.”

Although body pitch and body motion have been studied in previous studies, the phenomena were isolated. This study combined both aspects to determine a new situation where verticality becomes distorted.

The team enlisted the help of an architect to build a device that participants could hold to indicate their perceived verticality (i.e., subjective haptic vertical or SHV).

In most laboratory setting, humans are capable of perceiving SHV with an error of less than 1 degree. However, when measurements were taken on the moving Peak Tram, a misjudgment of 10 degrees was observed, something never previously reported.

To investigate the possible sources of errors, the researchers devised additional experiments. First, they had participants close their eyes to rule out visual influences. Then, to eliminate the effects of the vestibular system — the sensory system that creates a sense of balance and spatial orientation — they inserted a back wedge between the participants and their chairs. None of these alternations had much bearing on diminishing the SHV error, ruling out visual and vestibular systems as the primary cause.

Additionally, they ran their tests on Hong Kong’s Ding Ding Tram, which runs at similar speeds to the Peak Tram but on a relatively flat surface. In both situations, no bias was detected.

Psychology Professor Kenzo Sakurai from Tohoku Gakuin University, an expert on self-motion and co-author of the study, points out what a major discovery their findings are. “The failure to accurately sense our body orientation relative to gravity may result in inappropriate movements or falls, as well as impair daily functions such as walking, climbing a staircase, and carrying a tray. In specialized tasks such as driving a car or piloting a plane, this failure could be disastrous.”

Dr Tseng thinks that their study demonstrates a great example of scientific inquiry generalizing the actual world we live in. “On top of its pure scientific contribution, this study challenges the misconception that research is limited to scientific cubicles indoors. In this case, the natural environment provided a well-designed puzzle for scientists to solve.”

With international travel restriction gradually lifting, the paper’s authors encourage those to take a ride on Hong Kong’s Peak Tram to feel this fascinating perceptual phenomenon. But maybe wait until after the ride to get your coffee.

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Materials provided by Tohoku University. Note: Content may be edited for style and length.

Scientists in Japan have identified a nerve pathway involved in the processing of rewarding and distressing stimuli and situations in mice.

The new pathway, originating in a bundle of brain stem nerve fibres called the median raphe nucleus, acts in opposition to a previously identified reward/aversion pathway that originates in the nearby dorsal raphe nucleus. The findings, published by scientists at Hokkaido University and Kyoto University with their colleagues in the journal Nature Communications, could have implications for developing drug treatments for various mental disorders, including addictions and major depression.

Previous studies had already revealed that activating serotonin-producing nerve fibres from the dorsal raphe nucleus in the brain stem of mice leads to the pleasurable feeling associated with reward. However, selective serotonin reuptake inhibitors (SSRIs), antidepressant drugs that increase serotonin levels in the brain, fail to exert clear feelings of reward and to treat the loss of ability to feel pleasure associated with depression. This suggests that there are other serotonin-producing nerve pathways in the brain associated with the feelings of reward and aversion.

To further study the reward and aversion nerve pathways of the brain, Hokkaido University neuropharmacologist Yu Ohmura and Kyoto University pharmacologist Kazuki Nagayasu, together with colleagues at several universities in Japan, focused their attention on the median raphe nucleus. This region has not received as much research attention as its brain stem neighbour, the dorsal raphe nucleus, even though it also is a source of serotonergic nerve fibres.

The scientists conducted a wide variety of tests to measure activity of serotonin neurons in mice, in response to stimulating and inhibiting the median raphe, by using fluorescent proteins that detect entry of calcium ions, a proxy of neuronal activation in a cell-type specific manner.

They found that, for example, pinching a mouse’s tail — an unpleasant stimulus — increased calcium-dependent fluorescence in the serotonin neurons of the median raphe. Giving mice a treat such as sugar, on the other hand, reduced median raphe serotonin fluorescence. Also, directly stimulating or inhibiting the median raphe nucleus, using a genetic technique involving light, led to aversive or reward-seeking behaviours, such as avoiding or wanting to stay in a chamber — depending on the type of stimulus applied.

The team also conducted tests to discover where the switched-on serotonergic nerve fibres of the median raphe were sending signals to and found an important connection with the brain stem’s interpenduncular nucleus. They also identified serotonin receptors within this nucleus that were involved in the aversive properties associated with median raphe serotonergic activity.

Further research is needed to fully elucidate this pathway and others related to rewarding and aversive feelings and behaviours. “These new insights could lead to a better understanding of the biological basis of mental disorders where aberrant processing of rewards and aversive information occur, such as in drug addiction and major depressive disorder,” says Ohmura.

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Materials provided by Hokkaido University. Note: Content may be edited for style and length.

In the new study, published Dec. 8 in Cancer Research, scientists used a preclinical model of bladder cancer to investigate the role of the enzyme called APOBEC3G in promoting the disease and found that it significantly increased the number of mutations in tumor cells, boosting the genetic diversity of bladder tumors and hastening mortality.

“Our findings suggest that APOBEC3G is a big contributor to bladder cancer evolution and should be considered as a target for future treatment strategies,” said study senior author Dr. Bishoy M. Faltas, assistant professor of cell and developmental biology at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.

The APOBEC3 family of enzymes is capable of mutating RNA or DNA — by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an erroneous nucleotide at that position. The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV — they attempt to hobble viral replication by mutating the cytosines in the viral genome.

The inherent hazardousness of these enzymes suggests that mechanisms must be in place to prevent them from harming cellular DNA. However, starting about a decade ago, researchers using new DNA-sequencing techniques began to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the mutations in these tumors were APOBEC3-related — and that these mutations appeared to have a role in helping tumors evade the effects of chemotherapy.

Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations needed for cancerous growth but also boost their ability to diversify and “evolve” thereafter — enabling further growth and spread despite immune defenses, drug treatments, and other adverse factors.

In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all the knockout-only mice survived, whereas nearly a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in the mouse cells was present in the nucleus, where cellular DNA is kept using an ‘optical sectioning’ microscopy technique. Previously, this protein had been thought to reside only outside the nucleus. They also found that the bladder tumors of the APOBEC3G mice had about twice the number of mutations compared to the tumors in knockout-only mice.

Identifying the specific mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had caused a greater mutational burden and genomic diversity in the tumors, likely accounting for the greater malignancy and mortality in the APOBEC3G mice. “We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from signatures caused by other members of the APOBEC3 family” said Dr. Liu.

Lastly, the researchers looked for APOBEC3G’s mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are linked to worse outcomes.

“These findings will inform future efforts to restrict or steer tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.