Tag Archives: #aging

Scientists Discover New Regulators Of The Aging Process (Biology)

The attachment of the small protein ubiquitin to other proteins (ubiquitination) regulates numerous biological processes, including signal transduction and metabolism / Scientists at the University of Cologne discover the link to aging and longevity / Publication in ‘Nature’.

Scientists have discovered that the protein ubiquitin plays an important role in the regulation of the aging process. Ubiquitin was previously known to control numerous processes, such as signal transduction and metabolism. Prof. Dr. David Vilchez and his colleagues at the CECAD Cluster of Excellence for Aging Research at the University of Cologne performed a comprehensive quantitative analysis of ubiquitin signatures during aging in the model organism Caenorhabditis elegans, a nematode worm which is broadly used for aging research. This method – called ubiquitin proteomics – measures all changes in ubiquitination of proteins in the cell. The resulting data provide site-specific information and define quantitative changes in ubiquitin changes across all proteins in a cell during aging. A comparison with the total protein content of a cell (proteome) showed which changes have functional consequences in protein turnover and actual protein content during aging. The scientists thus discovered new regulators of lifespan and provide a comprehensive data set that helps to understand aging and longevity. The article, ‘Rewiring of the ubiquitinated proteome determines aging in C. elegans,‘ has now been published in Nature.

‘Our study of ubiquitin changes led us to a number of exciting conclusions with important insights for understanding the aging process,” said Dr Seda Koyuncu, lead author of the study. “We discovered that aging leads to changes in the ubiquitination of thousands of proteins in the cell, whereas longevity measures such as reduced food intake and reduced insulin signaling prevent these changes.’ Specifically, the researchers found that aging causes a general loss of ubiquitination. This is caused by the enzymes that remove ubiquitin from proteins become more active during aging. Normally, ubiquitinated proteins are recognized and destroyed by the proteasome, the cell’s garbage truck. The scientists showed that the longevity of organisms is determined by age-related changes in the degradation of structural and regulatory proteins by the proteasome. “We studied animals with a defective proteasome to identify proteins that become less ubiquitinated with age and thus are not cleaned up by the proteasome and accumulate in the cell. The resulting protein accumulation leads to cell death,” Koyuncu says. “Remarkably, we saw that reducing the protein levels of these untagged proteins was sufficient to prolong longevity, while preventing their degradation by the proteasome shortened lifespan.”

In addition to providing a comprehensive data set, the investigators showed that defining changes in the ubiquitin-modified proteome can lead to the discovery of new regulators of lifespan and aging traits. They focused their follow-up analyses on two specific proteins that lacked ubiquitin labeling during aging. IFB-2, a protein important for cell structure, and EPS-8, a modulator of a signaling pathway that regulates a variety of cellular processes. These proteins, which are no longer adequately labeled in aged organisms, affect longevity in a variety of tissues. Increased protein levels of IFB-2, for example, cause the intestine to fail to digest properly or absorb nutrients and also make it more susceptible to bacterial infections, which is a characteristic of aging animals. “Remarkably, knockdown of IFB-2 in adult C. elegans was enough to restore normal gut function,” Koyuncu says. Too much amounts of EPS-8 in cells over activate a specific signaling pathway (RAC) in muscle and brain cells. The team discovered here that the RAC signaling pathway determines longevity, muscle integrity and motility.

“Our findings may point to new ways to delay the aging process and improve quality of life in old age. In particular, we have established a novel link between aging and general changes in the ubiquitin-modified proteome, a process that actively influences longevity,” said study coordinator David Vilchez, research group leader at CECAD and the Center for Molecular Medicine Cologne (CMMC). “Our results and rich datasets may have important implications for several research priorities, including aging, ubiquitination and other cellular processes.”

Featured image: Left: Muscle actin cytoskeleton in young animals. Middle: Muscle actin cytoskeleton in old animals with destabilization of muscle cytoskeleton due to aging Right: Prevention of destabilization of muscle cytoskeleton in old animals by lowering the age-dysregulated high levels of EPS-8, a regulator of actin cytoskeleton. © David Vilchez

Koyuncu S, Loureiro R, Lee HJ, Wagle P, Krueger M, Vilchez D. Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature 2021

Provided by University of Cologne

New Insights Into the Relationship Between How We Feel And Our Views On Aging (Psychology)

A new study finds that the disconnect between how old we feel and how old we want to be can offer insights into the relationship between our views on aging and our health.

Subjective age discordance (SAD) – the difference between how old you feel and how old you would like to be—is a fairly new concept in the psychology of aging. However, the work to this point has used SAD to look at longitudinal data and how people’s views on aging evolve over months or years.

“We wanted to see whether SAD could help us assess day-to-day changes in our views on aging, and how that may relate to our physical health and well-being,” says Shevaun Neupert, co-author of the study and a professor of psychology at North Carolina State University.

SAD is determined by taking how old you feel, subtracting how old you would like to be and then dividing it by your actual age. The higher the score, the more you feel older than you want to be.

For this study, researchers enrolled 116 adults aged 60-90 and 107 adults aged 18-36. Study participants filled out an online survey every day for eight days. The survey was designed to assess how old participants felt each day, their ideal age, their positive and negative mood over the course of the day, any stresses they experienced, and any physical complaints, such as backaches or cold symptoms.

“We found that both older adults and younger adults experienced SAD,” Neupert says. “It was more pronounced in older adults, which makes sense. However, it fluctuated more from day to day in younger adults, which was interesting.”

“We think younger adults are getting pushed and pulled more,” says Jennifer Bellingtier, first author of the paper, and a researcher at Friedrich Schiller University Jena. “Younger adults are concerned about negative stereotypes associated with aging, but may also be dealing with negative stereotypes associated with younger generations and wishing they had some of the privileges and status associated with being older.”

Two additional findings stood out.

“On days when the age you feel is closer to your ideal age, people tend to have a more positive mood,” Bellingtier says. “And, on average, people who have more health complaints also had higher SAD scores.”

Neither finding was surprising, but both show the value of the SAD concept as a tool for understanding people’s views on age and aging. It may also offer a new approach for the way we think about aging and its impacts on health.

“Previous research has found that how old you feel can affect your physical and mental well-being, and interventions to address that have focused on trying to make people feel younger,” Neupert says.

“That approach is problematic, in that it effectively encourages ageism,” says Bellingtier. “Our findings in this study suggest that another approach to improving well-being would be to find ways to reduce this subjective age discordance. In other words, instead of telling people to feel young, we could help people by encouraging them to raise their ‘ideal’ age.”

The paper, “Daily Experiences of Subjective Age Discordance and Well-Being,” is published in the journal Psychology and Aging.

Reference: Jennifer A. Bellingtier et al, Daily experiences of subjective age discordance and well-being., Psychology and Aging (2021). DOI: 10.1037/pag0000621

Provided by North Carolina State University

Research Identifies Potential Role Of ‘Junk DNA’ Sequence In Aging, Cancer (Medicine)

The human body is essentially made up of trillions of living cells. It ages as its cells age, which happens when those cells eventually stop replicating and dividing. Scientists have long known that genes influence how cells age and how long humans live, but how that works exactly remains unclear. Findings from a new study led by researchers at Washington State University have solved a small piece of that puzzle, bringing scientists one step closer to solving the mystery of aging.

A research team headed by Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, recently identified a DNA region known as VNTR2-1 that appears to drive the activity of the telomerase gene, which has been shown to prevent aging in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells. In normal cells, the length of telomeres gets a little bit shorter every time cells duplicate their DNA before they divide. When telomeres get too short, cells can no longer reproduce, causing them to age and die. However, in certain cell types–including reproductive cells and cancer cells–the activity of the telomerase gene ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.

Knowing how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.

Zhu said that his team’s latest finding that VNTR2-1 helps to drive the activity of the telomerase gene is especially notable because of the type of DNA sequence it represents.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” Zhu said. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matters in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

Their finding is based on a series of experiments that found that deleting the DNA sequence from cancer cells–both in a human cell line and in mice–caused telomeres to shorten, cells to age, and tumors to stop growing. Subsequently, they conducted a study that looked at the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats–or copies–of the DNA to as long as 160 repeats.

“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Zhu said.

Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Zhu said it was worth noting that having a shorter sequence does not necessarily mean your lifespan will be shorter, because it means the telomerase gene is less active and your telomere length may be shorter, which could make you less likely to develop cancer.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Zhu noted that since African Americans have been in the United States for generations, many of them have Caucasian ancestors from whom they may have inherited some of this sequence. So as a next step, he and his team hope to be able to study the sequence in an African population.

In addition to Zhu, authors on the paper include co-first authors Tao Xu and De Cheng and others at Washington State University, as well as their collaborators at Northeast Forestry University in China; Pennsylvania State University; and North Carolina State University.

Funding for this study came from the National Institutes of Health’s National Institute of General Medical Sciences, the Melanoma Research Alliance, and the Health Sciences and Services Authority of Spokane County.

Featured image: Jiyue Zhu (second from left) talks to members of his research team inside his laboratory on the WSU Health Sciences Spokane campus, including Ken Porter (far left), Sean Mcgranaghan (center), Fan Zhang (second from right), and Jinlong Zhang (far right). © Photo by Cori Kogan, WSU Health Sciences Spokane

Reference: Tao Xu, De Cheng et al., “Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene”, PNAS June 29, 2021 118 (26) e2019043118; https://doi.org/10.1073/pnas.2019043118

Provided by Washington State University

New Study Shows How To Boost Muscle Regeneration and Rebuild Tissue (Biology)

Salk research reveals clues about molecular changes underlying muscle loss tied to aging

One of the many effects of aging is loss of muscle mass, which contributes to disability in older people. To counter this loss, scientists at the Salk Institute are studying ways to accelerate the regeneration of muscle tissue, using a combination of molecular compounds that are commonly used in stem-cell research.

In a study published on May 25, 2021, in Nature Communications, the investigators showed that using these compounds increased the regeneration of muscle cells in mice by activating the precursors of muscle cells, called myogenic progenitors. Although more work is needed before this approach can be applied in humans, the research provides insight into the underlying mechanisms related to muscle regeneration and growth and could one day help athletes as well as aging adults regenerate tissue more effectively.

“Loss of these progenitors has been connected to age-related muscle degeneration,” says Salk Professor Juan Carlos Izpisua Belmonte, the paper’s senior author. “Our study uncovers specific factors that are able to accelerate muscle regeneration, as well as revealing the mechanism by which this occurred.”Induction of Yamanaka factors (OKSM) in muscle fibers increases the number of myogenic progenitors. Top, control; bottom, treatment. Red-pink color is Pax7, a muscle stem-cell marker. Blue indicates muscle nuclei.
Click here for a high-resolution image.
Credit: Salk Institute

The compounds used in the study are often called Yamanaka factors after the Japanese scientist who discovered them. Yamanaka factors are a combination of proteins (called transcription factors) that control how DNA is copied for translation into other proteins. In lab research, they are used to convert specialized cells, like skin cells, into more stem-cell-like cells that are pluripotent, which means they have the ability to become many different types of cells.

“Our laboratory previously showed that these factors can rejuvenate cells and promote tissue regeneration in live animals,” says first author Chao Wang, a postdoctoral fellow in the Izpisua Belmonte lab. “But how this happens was not previously known.”

Muscle regeneration is mediated by muscle stem cells, also called satellite cells. Satellite cells are located in a niche between a layer of connective tissue (basal lamina) and muscle fibers (myofibers). In this study, the team used two different mouse models to pinpoint the muscle stem-cell-specific or niche-specific changes following addition of Yamanaka factors. They focused on younger mice to study the effects of the factors independent of age.

In the myofiber-specific model, they found that adding the Yamanaka factors accelerated muscle regeneration in mice by reducing the levels of a protein called Wnt4 in the niche, which in turn activated the satellite cells. By contrast, in the satellite-cell-specific model, Yamanaka factors did not activate satellite cells and did not improve muscle regeneration, suggesting that Wnt4 plays a vital role in muscle regeneration.

According to Izpisua Belmonte, who holds the Roger Guillemin Chair, the observations from this study could eventually lead to new treatments by targeting Wnt4.

“Our laboratory has recently developed novel gene-editing technologies that could be used to accelerate muscle recovery after injury and improve muscle function,” he says. “We could potentially use this technology to either directly reduce Wnt4 levels in skeletal muscle or to block the communication between Wnt4 and muscle stem cells.”

The investigators are also studying other ways to rejuvenate cells, including using mRNA and genetic engineering. These techniques could eventually lead to new approaches to boost tissue and organ regeneration.

Other authors included: Ruben Rabadan Ros, Paloma Martinez Redondo, Zaijun Ma, Lei Shi, Yuan Xue, Isabel Guillen-Guillen, Ling Huang, Tomoaki Hishida, Hsin-Kai Liao, Concepcion Rodriguez Esteban, and Pradeep Reddy of Salk; Estrella Nuñez Delicado of Universidad Católica San Antonio de Murcia in Spain; and Pedro Guillen Garcia of Clinica CEMTRO in Spain.

The work was funded by NIH-NCI CCSG: P30 014195, the Helmsley Trust, Fundacion Ramon Areces, Asociación de Futbolistas Españoles (AFE), Fundacion Pedro Guillen, Universidad Católica San Antonio de Murcia (UCAM), the Moxie Foundation and CIRM (GC1R-06673-B).

DOI: 10.1038/s41467-021-23353-z

Featured image: Induction of Yamanaka factors (OKSM) in muscle fibers increases the number of myogenic progenitors. Top, control; bottom, treatment. Red-pink color is Pax7, a muscle stem-cell marker. Blue indicates muscle nuclei. © Salk Institute


Provided by Salk Institute

Cancer Treatments May Accelerate Cellular Aging (Medicine)

Epigenetic changes associated with greater inflammation and fatigue

New research indicates that certain anti-cancer therapies may hasten cellular aging, where changes in the DNA of patients may contribute to greater inflammation and fatigue. The findings are published by Wiley early online in CANCER, a peer-reviewed journal of the American Cancer Society.

Gene activity is often adjusted during life through epigenetic changes, or physical modifications to DNA that do not involve altering the underlying DNA sequence. Some individuals may experience epigenetic age acceleration (EAA) that puts them at a higher risk of age-related conditions than other individuals of the same chronological age. Investigators recently examined EAA changes during and following cancer treatment, and they looked for a potential link between these changes and fatigue in patients with head and neck cancer (HNC).

In the study of 133 patients with HNC, half of the patients experienced severe fatigue at some point. EAA was most prominent immediately after radiation therapy, when the average epigenetic age was accelerated by 4.9 years. Increased EAA was associated with elevated fatigue, and patients with severe fatigue experienced 3.1 years higher EAA than those with low fatigue. Also, patients with high levels of markers of inflammation exhibited approximately 5 years higher EAA, and inflammation appeared to account for most of the effects of EAA on fatigue.

“Our findings add to the body of evidence suggesting that long-term toxicity and possibly increased mortality incurred from anti-cancer treatments for patients with HNC may be related to increased EAA and its association with inflammation,” said lead author Canhua Xiao, PhD, RN, FAAN, of the Emory University School of Nursing, in Atlanta. “Future studies could examine the vulnerabilities that may account for sustained high EAA, fatigue, and inflammation among patients.”

The authors noted that interventions to reduce inflammation, including prior to cancer treatment, might benefit patients by decelerating the aging process and subsequently reducing age-related chronic health problems such as fatigue.

An accompanying editorial stresses that chronic fatigue in patients receiving treatment for cancer is not just a symptom; it may also play an important role in influencing patients’ health.

References: (1) “Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: a longitudinal study.” Canhua Xiao, Jonathan J. Beitler, Gang Peng, Morgan E. Levine, Karen N Conneely, Hongyu Zhao, Jennifer C. Felger, Evanthia C Wommack, Cynthia E. Chico, Sangchoon Jeon, Kristin A. Higgins, Dong M. Shin, Nabil F. Saba, Barbara A. Burtness, Deborah W. Bruner, and Andrew H. Miller, MD. CANCER; Published Online: May 24, 2021 (DOI: 10.1002/cncr.33641). URL Upon Publication: http://doi.wiley.com/10.1002/cncr.33641 (2) “Doc, I Feel Tired … Oh Really, So How’s Your Mucositis?” Kord M. Kober and Sue S. Yom. CANCER; Published Online: May 24, 2021 (DOI: 10.1002/cncr.33640). URL Upon Publication: http://doi.wiley.com/10.1002/cncr.33640

Provided by Wiley

Researchers Reveal Novel Aging Markers and Regulators (Biology)

Researchers from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Science (CAS) and Peking University have found lncRNAs as novel aging markers and regulators, and aging associated lncRNAs carry the signature of evolutionary constraint and participate the NFκB signaling. The study was published in the journal Nature Aging.

Aging is an inevitable process in organism. It causes human tissue and organ degeneration and increases the risk of mortality and diseases. Compared to a century ago, humans are now enjoying greatly improved life quality, medical resources and much more extended lifespan expectancy. However, longer lifespan also increases the risk of chronic disease, reduce perception, motor and cognitive function in old age.

The research team led by Prof. Jing-Dong Jackie HAN from SINH in this study analyzed aging associated transcriptome data of 11 species through bioinformatics methods, and found that aging associated lncRNAs have strong evolutionary conservation and are enriched in functional features documented in various databases. 

From transcription factor binding enrichment and functional prediction, they found that aging associated lncRNAs are predominantly related to NFkB signaling.

By using CRISPR screening, they found 13 of them modulate the reporter of NFkB signaling, and named them NFkB modulating aging-related lncRNAs (NFKBMARL).  

The researchers further studied the molecular mechanisms by which NFKBMARL-1 regulates NFkB signaling.

They found that NFKBMARL-1 binds to the enhancer of its neighboring gene NFKBIZ, a known NFkB mediator and effector, and recruits RELA to the promoter of NFKBIZ within same topological associated domain to amplify NFkB signaling. Inhibiting NFKBMARL-1 inhibits the NFkB signaling and suppresses the expression of aging-related inflammatory factors.

The researchers hope that many more aging-associated lncRNAs can be uncovered as regulators of inflammation, aging and senescence in the future, which highlights them as a previously overlooked key player driving the vicious cycle of ‘inflammaging’ and underlying the etiology of many aging-associated diseases.

Featured image credit: authors

Reference: Cai, D., Han, JD.J. Aging-associated lncRNAs are evolutionarily conserved and participate in NFκB signaling. Nat Aging 1, 438–453 (2021). https://doi.org/10.1038/s43587-021-00056-0

Provided by Chinese Academy of Sciences

USC Stem Cell Study Reveals Neural Stem Cells Age Rapidly (Biology)

Researchers at Keck School of Medicine of USC conduct first-ever study of Abl1 gene’s role in neural stem cell biology and the implications for cognitive decline

In a new study published in Cell Stem Cell, a team led by USC Stem Cell scientist Michael Bonaguidi, PhD, demonstrates that neural stem cells – the stem cells of the nervous system – age rapidly.

“There is chronological aging, and there is biological aging, and they are not the same thing,” said Bonaguidi, an Assistant Professor of Stem Cell Biology and Regenerative Medicine, Gerontology and Biomedical Engineering at the Keck School of Medicine of USC. “We’re interested in the biological aging of neural stem cells, which are particularly vulnerable to the ravages of time. This has implications for the normal cognitive decline that most of us experience as we grow older, as well as for dementia, Alzheimer’s disease, epilepsy and brain injury.”

In the study, first author Albina Ibrayeva, a PhD candidate in the Bonaguidi Lab in the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, joined her colleagues in looking at the brains of young, middle-aged and old mice.

By tracing individual neural stem cells, or NSCs, over the course of several months, they identified “short-term NSCs” that quickly differentiate into more specialized neurons, and “long-term NSCs” that continually divide and replicate themselves to maintain an ongoing reserve of stem cells with the ability to generate many different cell types in the brain. This key population of long-term NSCs divided less often and failed to maintain their numbers as the mice aged.

The scientists next examined thousands of genes in the long-term NSCs, which were dividing less often and had slipped into an inactive state known as quiescence. The gene activity of the quiescent NSCs varied greatly in young versus middle-aged animals. As expected, there were changes in genes that control how long-term NSCs divide, as well as generate new neurons and other brain cells. Remarkably, there were many important changes in gene activity related to biological aging at younger ages than anticipated. These pro-aging genes make it more difficult for cells to repair damage to their DNA, regulate their genetic activity, control inflammation and handle other stresses.

Among the pro-aging genes, the scientists were most intrigued by Abl1, which formed the hub of a network of interrelated genes.

“We were interested in the gene Abl1, because no one has ever studied its role in neural stem cell biology–whether in development or in aging,” said Ibrayeva.

Using an existing, FDA-approved chemotherapy drug called Imatinib, scientists could easily inhibit the activity of the gene Abl1. The scientists gave older mice doses of Imatinib for six days. After the drug blocked the activity of the gene Abl1, the NSCs began to divide more and proliferate in the hippocampus, the part of the brain responsible for learning and memory.

“We’ve succeeded in getting neural stem cells to divide more without depleting, and that’s step one,” said Bonaguidi. “Step two will be to induce these stem cells to make more neurons. Step three will be to demonstrate that these additional neurons actually improve learning and memory. Much work remains to be done, but this study marks exciting progress towards our goal of identifying prescription drugs that could rejuvenate our brains as we grow older.”

Additional co-authors include: Maxwell Bay, Elbert Pu, Lei Peng, Naibo Zhang, Daniel Aaron, Congrui Lin, Galen Resler, and Axel Hidalgo from USC; David Jorg and Benjamin D. Simons from the University of Cambridge; and Heechul Jun and Mi-Hyeon Jang from the Mayo Clinic College of Medicine.

Seventy percent of the research was supported by federal funding from the National Institutes of Health (R00NS080913, R56AG064077, R01AG0585560, and T32HD060549-08), and the remainder was supported by non-federal funding from the Donald E. and Delia B. Baxter Foundation, the L.K. Whittier Foundation, The Eli and Edythe Broad Foundation, the Children’s Hospital Los Angeles TSRI pilot program, a Royal Society E P Abraham Professorship (RP\R1\180165), the Wellcome Trust (098357/Z/12/Z), the American Federation for Aging Research Scholarship for Research in Biology of Aging and the USC Provost’s Research Enhancement Fellowship.

Featured image: Neural stem cell clones in young (green) and old (red) mouse brains. © Albina Ibrayeva/Bonaguidi Lab

Reference: Albina Ibrayeva, Maxwell Bay, Elbert Pu, David J. Jörg, Lei Peng, Heechul Jun, Naibo Zhang, Daniel Aaron, Congrui Lin, Galen Resler, Axel Hidalgo, Mi-Hyeon Jang, Benjamin D. Simons, Michael A. Bonaguidi, Early stem cell aging in the mature brain, Cell Stem Cell, 2021, , ISSN 1934-5909, https://doi.org/10.1016/j.stem.2021.03.018. (https://www.sciencedirect.com/science/article/pii/S1934590921001247)

Provided by Keck School of Medicine of USC

Researchers Reveal New DNA-sensing Pathway in CD4+ T Cells and Regulatory Mechanism Mediating Aging-related Autoimmune Diseases (Medicine)

In a study published online in Immunity, Dr. XIAO Yichuan’s group at the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS), collaborating with Dr. ZHENG Mingyue’s group at the Shanghai Institute of Materia Medica of CAS, revealed that the KU complex mediated-DNA sensing in CD4+ T cells potentiates T cell activation and aging-related autoimmune diseases.   

For the elderly, although thymus atrophy causes a decrease in naive T cell output, the number of peripheral T cells does not decrease because of its homeostatic proliferation and activation under the aging state. However, the mechanism by which aging enhances homeostatic proliferation of T cells and thus promotes the development of autoimmune inflammation remains unknown. 

As expected, there is a huge accumulation of DNA in the cytoplasm of CD4+ T cells of aged mice and humans. The accumulated DNA enhances the proliferation and activation of TCR induced CD4+ T cells, suggesting DNA sensing can promote T cell functional activation. The researchers screened the proteins that bind to T cell cytoplasmic DNA by mass spectrometry and immunoblotting, and found that DNA in T cells does not bind to cGAS, but to KU complex (KU70/KU80).

Besides, they revealed that the KU complex was abundantly expressed in the cytoplasm of T cells and its recognition of DNA in CD4+ T cells promoted the activation of DNA-PKcs. This process in turn mediated the phosphorylation of ZAK at T169. The phosphorylated ZAK then activated the downstream AKT/mTOR pathway, enhancing the proliferation and activation of CD4+ T cells. Thus, activation of the KU complex-mediated DNA-sensing pathway in CD4+ T cells is a key mechanism leading to the development of autoimmune inflammation in aged mice. 

The discovery of the newly identified DNA-sensing pathway inspires the researchers to explore potential therapeutic strategies of aging-associated autoimmune inflammation.  

By using the Caloric Restriction (CR) or Fast-Mimicking Diet (FMD) mouse models, the researchers found that both modes of dieting significantly reduced DNA damage and cytoplasmic DNA accumulation in aged mouse CD4+ T cells, thereby inhibiting ZAK-T169 phosphorylation and activation of downstream AKT/mTOR signaling. The process ultimately suppressed CD4+ T cell activation and aging-associated autoimmune disease.   

Based on the identified key protein kinase ZAK in the DNA sensing pathway, the researchers applied deep learning combined with molecular simulation to screen a library of approximately 130,000 compounds and obtained iZAK2, a small molecule compound that specifically inhibits ZAK kinase activity. iZAK2 was found to effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune disease in aged mice.  

The findings of this study reveal a novel DNA-sensing pathway in aged CD4+ T cells that is independent on cGAS/STING, which promotes T cell activation and proliferation and leads to the development of aging-associated autoimmune diseases. Further investigation and development of inhibitors that block DNA-sensing signaling in T cells may be beneficial for clinical treatment of aging-related autoimmune diseases. 

Aging of the immune system is a leading cause of chronic inflammation and autoimmune diseases of the elderly.  

Featured image: Schematic representation of the cartoon and mechanism of DNA sensing in aged CD4+ T cells promoting its activation and autoimmune inflammation. (Image by Dr. XIAO’s group)

Reference: Yan Wang, Zunyun Fu, Xutong Li et al., “Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation”, 2021. DOI: https://doi.org/10.1016/j.immuni.2021.02.003

Provided by Chinese Academy of Sciences

New Study Shows 24-72 Hours of Poor Oral Hygiene Impacts Oral Health (Medicine)

Poor oral hygiene produces gum-disease bacteria and accelerates oral microbiome aging faster than previously thought. 

A new study shows that within 24-72 hours of the interruption of oral hygiene, there was a steep decrease in the presence of ‘good oral bacteria’ and the beneficial anti-inflammatory chemicals they are associated with. An increase of ‘bad bacteria’ typically present in the mouths of patients with periodontitis, a severe gum disease which can lead to tooth damage or loss, was also discovered. 

The research team, led by scientists from Single-Cell Center, Qingdao Institute of BioEnergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences (CAS) and Procter & Gamble Company (P&G), published their findings in the journal mBio on Mar. 9, 2021. 

The researchers asked 40 study participants with different levels of naturally occurring gingivitis to perform optimal oral hygiene for three weeks. This led to reduced gingivitis and a healthy baseline for the study. Gingivitis was then induced when their oral hygiene routine was interrupted over the course of four weeks. Restart of oral hygiene leads to recovery due to the reversible nature of gingivitis.

The researchers performed genetic analyses on the population of bacteria in the participants’ gum as it changed. Chemical analyses of the molecules produced by the bacteria were performed and immune responses of the study participants were recorded. 

Within just 24-72 hours of the cessation of oral hygiene, the researchers found there was a steep decrease in the presence of multiple Rothia species as well as the chemical betaine, which was reported to play an anti-inflammatory role in several inflammatory diseases.

In addition, there was a swift, full activation of multiple salivary cytokines – proteins and other molecules produced by immune system cells associated with inflammation. And just as the presence of the ‘good bacteria’ had declined, there was a sharp increase in the presence of the types of bacteria typically present in the mouths of patients with periodontitis even though there weren’t any symptoms of the illness yet.  

Taken together, the positive association with betaine and the negative association with gingivitis suggest that Rothia may be ‘good bacteria’ beneficial to gum health, contributing to the production of betaine in some way. 

“We also found a sudden ‘aging’ of the bacteria in the mouth,” said XU Jian, Director of Single-Cell Center at QIBEBT and senior author of the study. “Their oral microbiome had aged the equivalent of about a year in less than a month.” 

Previous studies have demonstrated that the composition of the population of oral bacteria (the oral microbiome) is a good predictor of the age of a patient. As one ages, one sees less of some species of bacteria and more of others. Older people, for example, tend to have far fewer Rothia species of bacteria.

“After only 28 days of gingivitis, we found the study participants had the ‘oral microbial age’ of those a year older,” said HUANG Shi, one investigator leading this study. 

The researchers now want to continue to study the link between Rothia, betaine and inflammation to see if they can come up with better early-stage responses to gingivitis.  

Featured image: Longitudinal multi-omics and microbiome meta-analysis identify an asymptomatic gingival state that links gingivitis, periodontitis and aging. (Image by LIU Yang)

Reference: Huang S, He T, Yue F, Xu X, Wang L, Zhu P, Teng F, Sun Z, Liu X, Jing G, Su X, Jin L, Liu J, Xu J. 2021. Longitudinal multi-omics and microbiome meta-analysis identify an asymptomatic gingival state that links gingivitis, periodontitis, and aging. mBio 12:e03281-20. https://doi.org/10.1128/mBio.03281-20.

Provided by Chinese Academy of Sciences