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Aging and age-related disorders pose a complex challenge to the biomedical research community. To better understand how senescence is regulated is of high significance to promote healthy aging and treat age-associated disorders. In a research paper published today in Nature Cell Biology, Rugang Zhang, Ph.D., deputy director of the Ellen and Ronald Caplan Cancer Center, Christopher M. Davis Endowed Professor, and program leader of the Immunology, Microenvironment & Metastasis Program, at The Wistar Institute, and his team revealed a novel ADAR1-SIRT1-p16INK4a axis in regulating cellular senescence and its potential implications in tissue aging.
“Understanding the basic mechanism underlying tissue aging is challenging and cellular senescence offers an angle into the complex biology that drives tissue aging. These mechanistic insights gained by studying senescence regulation during tissue aging can in turn be used to promote healthy aging and combat age-associated disorders.” states Zhang.
Central to this quest is a protein called p16INK4a because its expression both increases during tissue aging and it drives senescence. Prior studies established that depletion of p16INK4a expressing cells is sufficient to delay age-associated disorders. Thus, approaches that prevent age-associated increase in p16INK4a expression may have important implications in designing intervention strategies to promote healthy aging.
The research team’s findings center around a protein called ADAR1. ADAR1 is a specialized enzyme involved in RNA editing and is now revealed in senescence. Postdoctoral researcher in the Zhang lab and first author on the paper Xue Hao, Ph.D., explains that this research was largely inspired by prior independent research carried out in model organisms such as fruit flies and worms showing that depletion of the equivalent of human ADAR1 in these organisms reduces lifespan and causes age-dependent changes such as neurodegeneration.
This story also benefits from a highly collaborative Wistar Institute culture. In fact, the previous work of Kazuko Nishikura, Ph.D., professor in the Gene Expression & Regulation Program at Wistar’s Ellen and Ronald Caplan Cancer Center — and a pioneer in ADAR1 biology — showed that stressed cells utilize ADAR1 as protection from apoptosis, programmed cell death. “As senescent cells are stressed cells and are resistant to apoptosis, the first question we set out to ask was whether ADAR1 is related to cellular senescence and secondly, how does it regulate senescence and what is its’ potential implication in tissue aging.” Hao explains.
The team first examined the expression of ADAR1 in vitro in human fibroblasts and in vivo in multiple tissues from young and aged mice. Then, they experimentally altered ADAR1 expression in multiple cell types in petri-dish and mouse tissues to establish ADAR1 as a critical regulator of p16INK4a expression. Intriguingly, the team discovered that ADAR1 loss promotes p16INK4a expression through SIRT1, another protein known to regulate both senescence and tissue aging. Interestingly, this function of ADAR1 does not depend on its biological role in RNA editing.
They also found that downregulation of ADAR1 by a process called autophagy (the degradation and recycling of damaged or unneeded cell components) during senescence decreased the stability of SIRT1 mRNA, which in turn upregulated the translation of p16INK4a to induce senescence. Hao elaborates, “Our study revealed a novel ADAR1-SIRT1- p16 INK4a axis that plays an important role in cellular senescence at translational level, and this newly defined function of ADAR1 is independent of its RNA editing function.”
Zhang says, “Our study starts to reveal the missing link between ADAR1 and tissue aging through p16INK4a expression during senescence. In addition, these findings provided a scientific rational to explore whether this newly discovered mechanism can be leveraged for therapeutic development regarding age-associated disorders.”
“One of the ways to potentially restore ADAR1 expression as a means to suppress p16INK4a and senescence observed during tissue aging is by inhibiting autophagy.” Hao details. She adds about next research steps, “Our study raises some interesting questions. For example, what is the relative contribution of this mechanism to p16INK4a expression during aging of different tissues? In addition, it would be interesting to determine whether intervention of this pathway can alleviate the age-associated disorders that are linked to p16INK4a expression in previous published animal models.”
Co-authors: Xue Hao, Yusuke Shiromoto, Masayuki Sakurai, Martina Towers, Qiang Zhang, Shuai Wu, Bin Tian, Andrew Kossenkov, Kazuko Nishikura, Pingyu Liu from The Wistar Institute; Aaron Havas, Peter D. Adams from Sanford Burnham Prebys Medical Discovery Institute; Lu Wang, Shelley Berger from the University of Pennsylvania.
Work supported by: This work was supported by US National Institutes of Health grants (R01CA160331 to R.Z., P01AG031862 to P.D.A., S.L.B and R.Z., R01GM040536 and R01GM130716 to K.N., and R50CA211199 to A.V.K.). K.N. was supported by a grant from Emerson Collective. Support of Core Facilities was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute.

Since June, the number of COVID-19 infections started rising again, as the most transmissible omicron variant started picking up delta variant mutations leading to new subvariants BA.4/BA.5 and Deltacron variants. Out of all the five known variants of concern, which have been shown to evade therapeutic antibodies and vaccines developed against unmutated, original SARS-CoV-2 virus, delta is the most virulent leading to severe symptoms and increased mortality among infected people. A new peer-reviewed study provides answers to why delta is the most lethal variant of SARS-CoV-2.
To answer this critical question, researchers at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences performed robust biophysical analyses on the delta variant and individual mutations that comprise the delta variant.
The study was published in today’s issue of the Journal of Molecular Biology and featured on the journal’s cover.
“Our findings help explain why patients who have been vaccinated are still able to be infected by the new variants and why patients who have contracted the delta variant are more likely to be hospitalized,” said author Krishna Mallela, PhD, professor in the department of pharmaceutical sciences at the CU Skaggs School of Pharmacy and Pharmaceutical Sciences located on the University of Colorado Anschutz Medical Campus.
Researchers Casey Patrick, Vaibhav Upadhyay and Alexandra Lucas from Mallela’s lab identified the effect of mutated residues in the receptor binding domain (RBD) through which SARS-CoV-2 binds to ACE2 receptors that decrease the neutralization capacity of approved antibodies and polyclonal plasma from recovered patients.
“Due to the fact that we know vaccines are becoming less effective against emerging variants of SARS-CoV-2, it is important to understand what mutations are causing this decrease in neutralization capacity,” Mallela said.
The scientists outline crucial information on mutated residues that are now frequently occurring in variants of SARS-CoV-2.
Graduate Student Casey Patrick discusses his results on SARS-CoV-2 variants with Mallela.
“Since we have performed individual analyses on these mutations, we have a foundational understanding of how some residues are affecting immune escape and infectivity of SARS-CoV-2,” Mallela said.
The researchers found delta displayed unique biophysical characteristics unlike the previous variants alpha, beta and gamma. The human immune system generates antibodies to neutralize the virus in response to virus infection. These neutralizing antibodies have been classified into different classes, depending on their epitope location on the RBD, and some of these antibodies have previously been approved for emergency use by the FDA. Results from Mallela’s lab indicated the delta variant has evolved towards escape from Class 2 and Class 3 antibodies, rather than enhancing the receptor binding or escape from Class 1 antibodies. Class 1 antibodies bind to RBD only in up conformation where RBD is accessible to ACE2 binding, whereas Class 2 and Class 3 antibodies bind to RBD irrespective of whether it is in up conformation (accessible to ACE2) or down conformation (inaccessible to ACE2). Delta also shows higher protein expression. One mutation in the delta variant, T478K, is believed to have evolved from patients who were infected with earlier variants of SARS-CoV-2. This mutation has been shown to escape antibodies generated from previous COVID-19 infections.
The results indicate that the immune escape from neutralizing antibodies is the main biophysical parameter that is determining the fitness landscape of the emerging variants.
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Materials provided by University of Colorado Anschutz Medical Campus. Original written by Julia Milzer. Note: Content may be edited for style and length.

UCF researchers have found a new way to track metastatic cancer cells in the body, which in the future could help identify cancer earlier and give patients more treatment options.
In the latest issue of PLOS ONE, Dr. Annette Khaled’s research lab reported using a protein complex called a chaperonin as a new marker for cancer cells in blood — that provides a clearer indication of spreading cancer. By using the new marker, UCF scientists were able to detect more cancer cells in the blood, a procedure called liquid biopsy, which could help patients suffering from breast and lung cancers better monitor their disease.
Cancer cells need a lot of proteins to survive and travel through the body. The chaperonin complex lets proteins fold into functional, three-dimensional shapes. Without the complex, important proteins needed by cancer cells can’t form. All cells contain the chaperonin complex. But cancer cells have significantly higher levels because as Dr. Khaled explains, “cancer cells are hungry for protein.” In the past few years, Dr. Khaled identified the chaperonin complex as a significant indicator of a cancer’s severity and has developed nanoparticle-based therapies to seek out the chaperonin complex in cancer cells and destroy it. Without this protein-folding mechanism, cancer cells starve and die.
“The more chaperonin complex, the more advanced the cancer,” Dr. Khaled said. “By using the chaperonin complex to detect cancer cells in blood, we get a warning that the cancer may be spreading. Using the chaperonin complex to detect cancer cells in blood is a unique solution for a non-invasive diagnosis.”
Markers to identify cancer cells in blood are commonly based on epithelial features in cells that line surfaces of the body from which cancers arise. But such markers to detect cancer cells in blood are fairly “generic,” Dr. Khaled explained “and provide little information about the cancer itself.” Cancer cells that are shed into blood can come from any part of the tumor and don’t survive past a few hours. So, using a marker like the chaperonin complex that identifies dangerous cancer cells circulating in blood could alert doctors that a patient is relapsing or not responding to treatments.
Dr. Khaled is head of the College of Medicine’s Division of Cancer Research. Her study began by using blood and tissues from metastatic breast cancer patients being treated at Orlando Health’s UF Cancer Center to test if the chaperonin complex was better than traditional markers to identify cancer cells in blood. Then with blood from lung cancer patients, she validated this idea and found that using the chaperonin complex detected more lung cancer cells compared to standard methods for liquid biopsy.
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Materials provided by University of Central Florida. Original written by Wendy Sarubbi. Note: Content may be edited for style and length.

Since first discovered in the 1980s, retrons have puzzled researchers who simply wanted to know what these bacterial DNA sequences actually did. Now, EMBL scientists have identified that some retrons encode toxin proteins, which they keep inactive with the help of a small DNA fragment. When a bacterial virus (phage) attacks bacteria, the small DNA can sense the attack and unleash the toxin.
“Bacterial chromosomes contain hundreds of different toxin/antitoxin systems of unknown function that might be leveraged to inhibit phages, and our findings provide an approach to understand how they could do that,” said Nassos Typas, a group leader in the Genome Biology Unit and a co-chair of EMBL’s Microbial Ecosystems and Infection Biology transversal themes. His group has just reported its latest findings in Nature.
Simply put, retrons contain an enzyme called reverse transcriptase that uses small RNA as a template to produce multicopy single-stranded DNA (msDNA). Although scientists knew how this msDNA is produced across many bacteria, its function and role in the cell had remained enigmatic until June 2020, when the Typas group, as well as the Sorek group from the Weizmann Institute of Science in Israel, posted their independent studies in an open-access preprint repository.
“For more than 30 years, we’d had no clue why bacteria have retrons because no phenotypes had been associated with cells lacking retrons or msDNA,” said Jacob Bobonis, the paper’s lead author, who completed his PhD in the Typas group.
But new information came to light when a previous member of the Typas group found an important clue — a phenotype. They discovered that a pathogenic bacterium Salmonella cannot grow in colder temperatures without making msDNA. The group then teamed up with the lab of Helene Andrews-Polymenis at Texas A&M University and her then postdoc, Johanna Elfenbein, now PI at the University of Madison. Together, they identified that Salmonella cells unable to make msDNA were also sensitive to a lack of oxygen, preventing them from colonising a cow’s gut.
While these phenotypes alone didn’t show the retrons’ special immune defence capabilities, they gave the scientists a starting point to study the retrons further.

In one of the first investigations of the effectiveness of a second mRNA booster against COVID-19 Omicron variants, a study from the U.S. Centers for Disease Control and Prevention (CDC) has found that a second booster shot significantly improved effectiveness against widespread variants Omicron BA.1 and BA.2/BA.2.12.1.
With the first booster, vaccine effectiveness against these variants was only 68 percent (lower than against previous variants) and declined to 52 percent effectiveness after six months. With the second vaccine, effectiveness against these variants climbed to 80 percent within the first six months. Data is not yet available for effectiveness after six months.
The study looked at effectiveness of the second booster in reducing COVID Omicron BA.1 and BA.2/BA.2.12.1 related hospitalizations and emergency department (ED) visits and found the shot protected against both hospitalizations and ED visits.
“The findings of this study are important because they provide an answer to a question that many people are asking: Should I get the second booster shot? The data clearly show that a second booster significantly increases vaccine effectiveness against these variants — which while no longer dominant in many areas, are still present,” said study co-author Shaun Grannis, M.D., M.S., vice president for data and analytics at Regenstrief Institute and professor of family medicine at Indiana University School of Medicine. “As we go into the fall, when viruses typically pick up, we want to encourage people who are eligible for a second booster to be proactive and to strongly consider getting one because it will provide greater protection. It will reduce the need for COVID-19-related emergency department visits and hospitalizations.
“From a population health perspective, the protection supplied by the second booster helps ensure that healthcare resources are capable of responding to the full spectrum of medical needs, reducing the chance of overwhelming health systems with COVID-19-related disease.”
Current CDC recommendations for a second booster (fourth shot of the vaccine) are for people 50 and older as well as for moderately or severely immunocompromised individuals who are 12 and older.
“Effectiveness of 2, 3, and 4 COVID-19 mRNA vaccine doses among immunocompetent adults during SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 sublineage periods — VISION Network, 10 states, December 2021-June 2022” is published in the CDC’s Morbidity and Mortality Weekly Report.
The U.S. Centers for Disease Control and Prevention (CDC) collaborated with seven U.S. healthcare systems plus the Regenstrief Institute, to create the VISION network to assess COVID-19 vaccine effectiveness. In addition to Regenstrief Institute, other members are Columbia University Irving Medical Center, HealthPartners, Intermountain Healthcare, Kaiser Permanente Northern California, Kaiser Permanente Northwest, University of Colorado and Paso Del Norte Health Information Exchange (PHIX). Regenstrief contributes data and expertise to the VISION Network.
Authors of this VISION Network study are from 10 states and 19 institutions, including the public sector, research, clinical and academia. Regenstrief Institute authors, in addition to Dr. Grannis, are Brian E. Dixon, PhD, MPA, Regenstrief Institute and IU Richard M. Fairbanks School of Public Health; William F. Fadel, PhD, and Nimish Ramesh Valvi, DrPH, MBBS, both Regenstrief fellows.
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Materials provided by Regenstrief Institute. Note: Content may be edited for style and length.

In some homes, summer may mean more screen time for kids.
And among concerns that come with children spending more hours on digital devices, video games and televisions — and less time outdoors — harm to their eyes.
But just half of parents recognize that screen time has a major impact their child’s eye health, suggests the C.S. Mott Children’s Hospital National Poll on Children’s Health at University of Michigan Health.
“Many parents may not be aware of both the short and long-term health issues linked to excessive screen time, including its effect on children’s eyes,” said Mott Poll co-director Sarah Clark.
“Our findings suggest that some parents may have inaccurate perceptions of activities that affect their child’s eye health and vision and how to minimize risks.”
The nationally-representative report was based on responses from 2,002 parents of children ages 3-18 surveyed in April.

Rutgers scientists have found more clear-cut evidence of how the destructive proteins linked to Alzheimer’s disease attack human brain cells and destroy surrounding tissue.
In one of the first studies of its kind examining human brain cells grown in a mouse brain, researchers identified a pivotal mechanism that could be a potential therapeutic target for a disease that afflicts millions and has no known cure.
Writing in the journal Cell Stem Cell, the researchers described experiments studying human brain immune cells injected into the brains of specially bred immunodeficient mice, creating what they called a human-mouse chimera. They detailed what happened to specialized immune brain cells known as microglia after those cells were exposed to tau proteins — destructive substances believed to be involved in Alzheimer’s and other severe human brain diseases.
“In this study, we used our newly developed chimeric mouse brain model — where human cells are injected and allowed to grow, develop and mature with appropriate functions in a live mouse brain,” said Peng Jiang, an associate professor in the Department of Cell Biology and Neuroscience at the Rutgers School of Arts and Sciences. “This provided an unprecedented opportunity to investigate the role of human microglia in brains as well as the cognitive impairment seen in Alzheimer’s Disease and Down syndrome, a genetic disorder with a high risk of developing Alzheimer’s disease.”
By studying the processin the human-mouse brain chimera, the scientists were able to witness and analyze — through samples extracted at different stages — a cellular brain attack that has been largely elusive up to this point.
In autopsies, scientists have been able to study the brains of people who died from Alzheimer’s and have seen residues of tau proteins, cellular changes, and some other possible causative factors. The human-mouse brain chimera has allowed the Rutgers team to extract and see human cells in the actual process of deterioration.
The mice in the study were specially bred to be immunodeficient so that they could receive implanted human cells without rejecting them due to normal immune defenses. The immunodeficient mice were injected with human microglial cells and, later, with tau proteins, which are linked to the development of the brain disease.
“Since microglial cells are one of the first cell responders when something goes wrong in the brain, we believe the changes we saw to be significant,” said Mengmeng Jin, a postdoctoral researcher in the Department of Cell Biology and Neuroscience at Rutgers and first author on the study.
A genetic analysis also showed genes involved in interferon signaling turning on during the attack, indicating an important area to target for future therapies.
Other Rutgers scientists involved in the study include Professor Ronald Hart, associate professors Kelvin Kwan and Ping Xie, postdoctoral fellows Ranjie Xu, and Azadeh Jadali, doctoral students Mahabub Maraj Alam, Ziyuan Ma and Sining Zhu, all of the Department of Cell Biology and Neuroscience; and Associate Professor Zhiping Pang, postdoctoral fellow Matteo Bernabucci and doctoral student Le Wang of the Department of Cell Biology and Neuroscience and the Child Health Institute of New Jersey at Rutgers Robert Wood Johnson Medical School. Scientists at the University of California, Irvine and Florida International University contributed to the study.
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Materials provided by Rutgers University. Original written by Kitta MacPherson. Note: Content may be edited for style and length.

Prostate cancer is the most common form of cancer in male in Sweden. Researchers at Umeå University in Sweden have now discovered a faster and easier way to determine who has an aggressive form of cancer, and who has not. “This may have great implications on precision medicine when treating prostate cancer, and on more cancer groups alike,” says Maréne Landström, Professor of Pathology at Umeå University.
Over 10,000 men are annually diagnosed with prostate cancer in Sweden. Out of those, 2,300 of these lives cannot be saved, whereas many others can be cured or actually carry harmless tumours. The medical services are struggling with a balancing act between detecting as many cancers as possible in good time to start treatments early, and avoiding to diagnose men with cancer when the tumour is harmless as this causes unnecessary anxiety and negatively impacts the quality of life.
Consequently, intense work is carried out at research institutes to improve the methods distinguishing cancers that require treatment from cancers that should be left untouched, or preferably should not even be detected.
The research group of Professor Maréne Landström at the Department of Medical Biosciences is busy studying just that. In this project, they have also collaborated with a research group at Uppsala University.
The Umeå researchers have now discovered a new function in specific proteins in the transforming growth factor beta (TGF-β) signalling pathway, which is a significant path that affects how cancer cells grow and spread. This may have huge implications on the treatment of cancer since the discovery makes it possible to identify the men who are at risk of developing aggressive and life-threatening prostate cancer more easily, faster and early in the course of disease.
“We have found a new, previously unknown, function of the TGF-β type I receptor (TbRI), which is an important signalling protein in cancer cells. Previous studies have shown that TGF-β signalling is important in the development of several cancer forms,” says Maréne Landström, Professor of Pathology at the Department of Medical Biosciences at Umeå University, continuing: “But with the use of this new discovery, we can put the men with prostate cancer whose prognosis is promising at ease, and those with high-risk prostate cancer can be offered treatment sooner. Our findings and the publication is significant for a large group of patients with prostate cancer, and there is reason to believe that further patient groups will benefit from this.

Air pollution remains a silent killer in Massachusetts, responsible for an estimated 2,780 deaths a year and for measurable cognitive loss in Bay State children exposed to fine particulate pollutants in the air they breathe, according to a new study by researchers at Boston College’s Global Observatory on Planetary Health.
The study was supported by the Barr Foundation and is the first to examine far-reaching public health consequences of air pollution in the state on a town-by-town basis. The study found air-pollution-related disease, death and IQ loss occur in every city and town regardless of demographics or income level. Highest rates were in the most economically disadvantaged and socially underserved cities and towns.
The Boston College team estimates the cumulative impact on childhood cognitive development in Massachusetts in 2019 was a loss of almost 2 million Performance IQ points, or more than 2 IQ points for the average child, according to the report, published today in the journal Environmental Health. IQ loss impairs children’s school performance and reduces graduation rates, the team noted.
“We are talking about the impacts of air pollution at a very local level in Massachusetts — not just statewide,” said lead author Boston College Professor of Biology Philip J. Landrigan, MD, director of the Observatory. “This report gives the people in every city and town the opportunity to see for themselves the quality of the air they and their families are breathing and the dangerous health implications for both adults and children as a consequence of air pollution.”
“All of these health effects occurred at pollution levels below current EPA standards,” Landrigan noted.
The average level of fine particulate pollution across Massachusetts in 2019 was 6.3 micrograms per cubic meter, and levels ranged from a low of 2.77 micrograms per cubic meter in Worcester County to a high of 8.26 in Suffolk County. The U.S. Environmental Protection Agency standard is 12 micrograms per cubic meter, and the World Health Organization’s recommended guideline is 5.

Adding immunotherapy to standard anti-rejection medication could change the lives of thousands of kidney transplant patients with incurable cancer, as new research shows it can reduce this risk of organ rejection and eliminate cancer in a quarter of patients.
Conducted by researchers at the Royal Adelaide Hospital and the University of South Australia, the world-first study showed that a dual combination of transplant anti-rejection drugs and immune checkpoint inhibitors* not only reduced organ rejection rates to 12 per cent (from 40-50 per cent) but also eradicated cancer cells in 25 per cent of patients.
Immune checkpoint inhibitors are drugs that block proteins called checkpoints. These checkpoints help keep immune responses from being too strong but can also keep T-cells from killing cancer cells. When these checkpoints are blocked, the T-cells can kill cancer cells more effectively.
UniSA researcher and renal specialist at the Royal Adelaide Hospital, Associate Professor Rob Carroll, says these findings are a gamechanger for kidney transplant patients with incurable cancer.
“Cancer is a leading cause of death in kidney transplant recipients with the rate of cancer being three-times higher in this group, than in the general population,” Assoc Prof Carroll says.
“The terrible irony is that the immunosuppressants that patients must always take to stop their immune systems attacking their transplants, are also the medicines that stops the immune system getting rid of pre-cancer cells.
“To correct this imbalance, our study tested the efficacy of maintaining baseline anti-rejection drugs (to protect the transplant) and adding immune checkpoint inhibitors (to attack the cancer).
“The patients responded well with lower rates of organ rejection to 12 per cent, compared to previous reports and eliminating cancers cells in 25 per cent of patients.
“It’s a massive advancement for kidney transplant patients; a whole new lease on life.”
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Materials provided by University of South Australia. Note: Content may be edited for style and length.