Using the model organism Caenorhabditis elegans, researchers at the University of Cologne have developed an ‘aging clock’ that reads the biological age of an organism directly from its gene expression, the transcriptome. Bioinformatician David Meyer and geneticist Professor Dr Björn Schumacher, director of the Institute for Genome Stability in Aging and Disease at the CECAD Cluster of Excellence in Aging Research and the Center for Molecular Medicine Cologne (CMMC), describe their so-called BiT age (binarized transcriptomic aging clock) in the article ‘BiT age: A transcriptome based aging clock near the theoretical limit of accuracy’ in Aging Cell.
We are all familiar with chronological age — our age since birth. But biological age can differ from it, at times significantly. Everyone ages differently. Scientists can use aging clocks to determine an organism’s biological age. Until now, aging clocks such as Horvath’s epigenetic clock have been based on the pattern of methylations, small chemical groups that attach to DNA and change with age. Using the transcriptome, the new clock takes into consideration the set of genes that are read from DNA (messenger RNA) to make proteins for the cell.
Until now, the transcriptome was considered too complex to indicate age. Sometimes genes transcribe a particularly large amount of mRNA, sometimes less. Hence, so far it has not been possible to develop precise aging clocks based on gene activity. Meyer and Schumacher’s new approach uses a mathematical trick to eliminate the differences in gene activity. The binarized transcriptome aging clock divides genes into two groups — ‘on’ or ‘off’ — thus minimizing high variation. This makes aging predictable from the transcriptome. ‘Surprisingly, this simple procedure allows very accurate prediction of biological age, close to the theoretical limit of accuracy. Most importantly, this aging clock also works at high ages, which were previously difficult to measure because the variation in gene activity is particularly high then,’ said Meyer.
BiT age is based exclusively on approximately 1,000 different transcriptomes of C. elegans, for which the lifespan is precisely known. Model organisms such as the nematode provide a controllable view of the aging process, allowing biomarkers to be discovered and the effects of external influences such as UV radiation or nutrition on longevity to be studied.
The new aging clock allows researchers to accurately predict the pro- and anti-aging effects of gene variants and various external factors in the nematode at a young age. The aging clock also showed that genes of the immune response as well as signalling in neurons are significant for the aging process. ‘BiT age can also be applied to predict human age quickly and with very high accuracy. Measuring biological age is important to determine the influence of environment, diet or therapies on the aging process and the development of age-related diseases. This clock could therefore find wide application in aging research. Since BiT age is based purely on gene activity, it can basically be applied to any organism,’ Schumacher explained.

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Imagine seeing the world in muted shades — gray sky, gray grass. Some people with color blindness see everything this way, though most can’t see specific colors. Tinted glasses can help, but they can’t be used to correct blurry vision. And dyed contact lenses currently in development for the condition are potentially harmful and unstable. Now, in ACS Nano, researchers report infusing contact lenses with gold nanoparticles to create a safer way to see colors.
Some daily activities, such as determining if a banana is ripe, selecting matching clothes or stopping at a red light, can be difficult for those with color blindness. Most people with this genetic disorder have trouble discriminating red and green shades, and red-tinted glasses can make those colors more prominent and easier to see. However, these lenses are bulky and the lens material cannot be made to fix vision problems. Thus, researchers have shifted to the development of special tinted contact lenses. Although the prototype hot-pink dyed lenses improved red-green color perception in clinical trials, they leached dye, which led to concerns about their safety. Gold nanocomposites are nontoxic and have been used for centuries to produce “cranberry glass” because of the way they scatter light. So, Ahmed Salih, Haider Butt and colleagues wanted to see whether incorporating gold nanoparticles into contact lens material instead of dye could improve red-green contrast safely and effectively.
To make the contact lenses, the researchers evenly mixed gold nanoparticles into a hydrogel polymer, producing rose-tinted gels that filtered light within 520-580 nm, the wavelengths where red and green overlap. The most effective contact lenses were those with 40 nm-wide gold nanoparticles, because in tests, these particles did not clump or filter more color than necessary. In addition, these lenses had water-retention properties similar to those of commercial ones and were not toxic to cells growing in petri dishes in the lab. Finally, the researchers directly compared their new material to two commercially available pairs of tinted glasses, and their previously developed hot-pink dyed contact lens. The gold nanocomposite lenses were more selective in the wavelengths they blocked than the glasses. The new lenses matched the wavelength range of the dyed contact lenses, suggesting the gold nanocomposite ones would be suitable for people with red-green color issues without the potential safety concerns. The researchers say that the next step is to conduct clinical trials with human patients to assess comfort.

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At the beginning of an immune response, a molecule known to mobilize immune cells into the bloodstream, where they home in on infection sites, rapidly shifts position, a new study shows. Researchers say this indirectly amplifies the attack on foreign microbes or the body’s own tissues.
Past studies had shown that the immune system regulates the concentration of the molecule, sphingosine 1 phosphate (S1P), in order to draw cells to the right locations. The targeted cells have proteins on their surface that are sensitive to levels of this molecule, enabling them to follow the molecule’s “trail,” researchers say. S1P concentration gradients, for instance, can guide immune T cells to either stay in lymph nodes, connected glands in which these cells mature, or move into blood vessels.
For the first time, researchers at NYU Grossman School of Medicine showed in mice experiments that S1P levels in lymph nodes increase as the immune response mounts. Such activation of immune cells can cause inflammation, swelling, and/or death of targeted cells.
While past work had shown that S1P is produced by cells attached to lymph nodes, the new study found that monocytes, circulating immune cells, also produced it when mice were infected with a virus. This in turn may influence the migration of T cells, a set of white blood cells that expands rapidly in response to infection, say the study authors.
Publishing in the journal Nature online March 3, study results showed that T cells left mouse lymph nodes less than half as fast when S1P levels rose, while mostly immature cells escaped when S1P levels were not spiking.
“Our research shows a larger role for sphingosine 1 phosphate in coordinating immune defenses in response to infection and inflammation,” says study lead investigator Audrey Baeyens, PhD, a postdoctoral fellow at NYU Langone and its Skirball Institute of Biomolecular Medicine. “While further testing is needed, our findings raise the prospect of controlling levels of S1P to either boost or diminish the body’s immune response, as needed.”
Moreover, the researchers found that when lymph node levels of S1P went up, it signaled T cells to remain in lymph nodes. Such “trapped” T cells, with longer time to mature and become fully armed in the node, increase in their toxicity. These mature T cells can attack cells infected by viruses, or healthy cells as part of autoimmune diseases.
Indeed, medications that block S1P, preventing immune cells from leaving the lymph nodes, are used to curb unwanted and autoimmune inflammation related to inflammatory bowel disease, psoriasis, and multiple sclerosis, a disease for which fingolimod (Gilenya) is one of the few approved treatments.
Researchers say their findings could also explain why multiple sclerosis patients can experience severe disease relapse immediately after ceasing fingolimod treatment, as T cells held long in lymph nodes are then freed to attack the body’s nerves, a key trait of the disease.
“Now that we have a better understanding of sphingosine 1 phosphate inhibition, we can work on finding new uses for this class of medications, perhaps by manipulating the time T cells spend in the lymph nodes,” says study senior investigator Susan Schwab, PhD. Schwab is an associate professor in the Department of Pathology at NYU Langone and Skirball.
For the study, S1P levels were measured in mice bred to develop symptoms of multiple sclerosis, a disease involving severe inflammation of the brain and spine. They also measured S1P levels in mice exposed to viral genetic material to mimic the inflammation that occurs in infection.
Schwab says the team next plans to study how different S1P levels affect T cell maturation, and how these different maturation times strengthen or weaken the overall immune response to infection.

Care homes are at high risk of experiencing outbreaks of COVID-19, the disease caused by SARS-CoV-2. Older people and those affected by heart disease, respiratory disease and type 2 diabetes — all of which increase with age — are at greatest risk of severe disease and even death, making the care home population especially vulnerable.
Care homes are known to be high-risk settings for infectious diseases, owing to a combination of the underlying vulnerability of residents who are often frail and elderly, the shared living environment with multiple communal spaces, and the high number of contacts between residents, staff and visitors in an enclosed space.
In research published in eLife, a team led by scientists at the University of Cambridge and Wellcome Sanger Institute used a combination of genome sequencing and detailed epidemiological information to examine the impact of COVID-19 on care homes and to look at how the virus spreads in these settings.
SARS-CoV-2 is an RNA virus and as such its genetic code is prone to errors each time it replicates. It is currently estimated that the virus mutates at a rate of 2.5 nucleotides (the A, C, G and U of its genetic code) per month. Reading — or ‘sequencing’ — the genetic code of the virus can provide valuable information on its biology and transmission. It allows researchers to create ‘family trees’ — known as phylogenetic trees — that show how samples relate to each other.
Scientists and clinicians in Cambridge have pioneered the use of genome sequencing and epidemiological information to trace outbreaks and transmission networks in hospitals and community-based healthcare settings, helping inform infection control measures and break the chains of transmission. Since March 2020, they have been applying this method to SARS-CoV-2 as part of the COVID-19 Genomics UK (COG-UK) Consortium.
In this new study, researchers analysed samples collected from 6,600 patients between 26 February and 10 May 2020 and tested at the Public Health England (PHE) Laboratory in Cambridge. Out of all the cases, 1,167 (18%) were care home residents from 337 care homes, 193 of which were residential homes and 144 nursing homes, the majority in the East of England. The median age of care home residents was 86 years.

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While the median number of cases per care home was two, the ten care homes with the largest number of cases accounted for 164 cases. There was a slight trend for nursing homes to have more cases per home than residential homes, with a median of three cases.
Compared with non-care home residents admitted to hospital with COVID-19, hospitalised care home residents were less likely to be admitted to intensive care units (less than 7% versus 21%) and more likely to die (47% versus 20%).
The researchers also explored links between care homes and hospitals. 68% of care home residents were admitted to hospital during the study period. 57% were admitted with COVID-19, 6% of cases had suspected hospital-acquired infection, and 33% were discharged from hospital within 7 days of a positive test. These findings highlight the ample opportunities for SARS-CoV-2 transmission between hospital and care home settings.
When the researchers examined the viral sequences, they found that for several of the care homes with the highest number of cases, all of the cases clustered closely together on a phylogenetic tree with either identical genomes or just one base pair difference. This was consistent with a single outbreak spreading within the care home.
By contrast, for several other care homes, cases were distributed across the phylogenetic tree, with more widespread genetic differences, suggesting that each of these cases was independent and not related to a shared transmission source.

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“Older people, particularly those in care homes who may be frail, are at particular risk from COVID-19, so it’s essential we do all that we can to protect them,” said Dr Estée Török, an Honorary Consultant at Addenbrooke’s Hospital, Cambridge University Hospitals (CUH), and an Honorary Senior Visiting Fellow at the University of Cambridge.
“Preventing the introduction of new infections into care homes should be a key priority to limit outbreaks, alongside infection control efforts to limit transmission within care homes, including once an outbreak has been identified.”
The team found two clusters that were linked to healthcare workers. One of these involved care home residents, a carer from that home and another from an unknown care home, paramedics and people living with them. The second involved several care home residents and acute medical staff at Cambridge University Hospitals NHS Foundation Trust who cared for at least one of the residents. It was not possible to say where these clusters originated from and how the virus spread.
“Using this technique of ‘genomic surveillance’ can help institutions such as care homes and hospitals better understand the transmission networks that allow the spread of COVID-19,” added Dr William Hamilton from the University of Cambridge and CUH. “This can then inform infection control measures, helping ensure that these places are as safe as possible for residents, patients, staff and visitors.”
The absolute number of diagnosed COVID-19 cases from care home residents declined more slowly in April than for non-care home residents, increasing the proportion of cases from care homes and contributing to the slow rate of decline in total case numbers during April and early May 2020.
“Our data suggest that care home transmission was more resistant to lockdown measures than non-care home settings. This may reflect the underlying vulnerability of the care home population, and the infection control challenges of nursing multiple residents who may also share communal living spaces,” said Gerry Tonkin-Hill from the Wellcome Sanger Institute.
The team found no new viral lineages from outside the UK, which may reflect the success of travel restrictions in limiting new viral introductions into the general population during the first epidemic wave and lockdown period.
This work was funded by COG-UK, Wellcome, the Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre.

An international research group led by the University of Basel has developed a promising strategy for therapeutic cancer vaccines. Using two different viruses as vehicles, they administered specific tumor components in experiments on mice with cancer in order to stimulate their immune system to attack the tumor. The approach is now being tested in clinical studies.
Making use of the immune system as an ally in the fight against cancer forms the basis of a wide range of modern cancer therapies. One of these is therapeutic cancer vaccination: following diagnosis, specialists set about determining which components of the tumor could function as an identifying feature for the immune system. The patient is then administered exactly these components by means of vaccination, with a view to triggering the strongest possible immune response against the tumor.
Viruses that have been rendered harmless are used as vehicles for delivering the characteristic tumor molecules into the body. In the past, however, many attempts at creating this kind of cancer therapy failed due to an insufficient immune response. One of the hurdles is that the tumor is made up of the body’s own cells, and the immune system takes safety precautions in order to avoid attacking such cells. In addition, the immune cells often end up attacking the “foreign” virus vehicle more aggressively than the body’s own cargo. With almost all cancer therapies of this kind developed so far, therefore, the desired effect on the tumor has failed to materialize. Finding the appropriate vehicle is just as relevant in terms of effectiveness as the choice of tumor component as the point of attack.
Arenaviruses as vehicles
The research group led by Professor Daniel Pinschewer of the University of Basel had already discovered in previous studies that viruses from the arenavirus family are highly suitable as vehicles for triggering a strong immune response. The group now reports in the journal Cell Reports Medicine that the combination of two different arenaviruses produced promising results in animal experiments.
The researchers focused on two distantly related viruses called Pichinde virus and Lymphocytic choriomeningitis virus, which they adapted via molecular biological methods for use as vaccine vectors. When they took the approach of administering the selected tumor component first with the one virus and then, at a later point, with the other, the immune system shifted its attack away from the vehicle and more towards the cargo. “By using two different viruses, one after the other, we focus the triggered immune response on the actual target, the tumor molecule,” explains Pinschewer.
Tumor eliminated or slowed down
In experiments with mice, the researchers were able to measure a potent activation of killer T cells that eliminated the cancer cells. In 20% to 40% of the animals — depending on the type of cancer — the tumor disappeared, while in other cases the rate of tumor growth was at least temporary slowed.
“We can’t say anything about the efficacy of our approach in humans as yet,” Pinschewer points out. However, ongoing studies with a cancer therapy based on a single arenavirus have already shown promising results. The effects on tumors in animal experiments cannot be assumed to translate directly into the effect on corresponding cancer types in humans. “However, since the therapy with two different viruses works better in mice than the therapy with only one virus, our research results make me optimistic,” Pinschewer adds.
The biotech company Hookipa Pharma, of which Pinschewer is one of the founders, is now investigating the efficacy of this novel approach to cancer therapy in humans. “We are currently exploring what our approach by itself can actually achieve,” the researcher says. “If it proves successful, a wide range of combinations with existing therapies could be envisaged, in which the respective mechanisms would join forces to eliminate tumors even better.”

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Women who experience an accelerated accumulation of abdominal fat during menopause are at greater risk of heart disease, even if their weight stays steady, according to a University of Pittsburgh Graduate School of Public Health-led analysis published today in the journal Menopause.
The study — based on a quarter century of data collected on hundreds of women — suggests that measuring waist circumference during preventive health care appointments for midlife women could be an early indicator of heart disease risk beyond the widely used body mass index (BMI) — which is a calculation of weight vs. height.
“We need to shift gears on how we think about heart disease risk in women, particularly as they approach and go through menopause,” said senior author Samar El Khoudary, Ph.D., M.P.H., associate professor of epidemiology at Pitt Public Health. “Our research is increasingly showing that it isn’t so important how much fat a woman is carrying, which doctors typically measure using weight and BMI, as it is where she is carrying that fat.”
El Khoudary and her colleagues looked at data on 362 women from Pittsburgh and Chicago who participated in the Study of Women’s Health Across the Nation (SWAN) Heart study. The women, who were an average age of 51, had their visceral adipose tissue — fat surrounding the abdominal organs — measured by CT scan and the thickness of the internal carotid artery lining in their neck measured by ultrasound, at a few points during the study. Carotid artery thickness is an early indicator of heart disease.
The team found that for every 20% increase in abdominal fat, the thickness of the carotid artery lining grew by 2% independent of overall weight, BMI and other traditional risk factors for heart disease.
They also found that abdominal fat started a steep acceleration, on average, within two years before the participants’ last period and continued a more gradual growth after the menopausal transition.
Saad Samargandy, Ph.D., M.P.H., who was a doctoral student at Pitt Public Health at the time of the research, explained that fat that hugs the abdominal organs is related to greater secretion of toxic molecules that can be harmful to cardiovascular health.
“Almost 70% of post-menopausal women have central obesity — or excessive weight in their mid-section,” said Samargandy, also the first author of the journal article. “Our analysis showed an accelerated increase of visceral abdominal fat during the menopausal transition of 8% per year, independent of chronological aging.”
Measuring abdominal fat by CT scan is expensive, inconvenient and could unnecessarily expose women to radiation — so El Khoudary suggests that regularly measuring and tracking waist circumference would be a good proxy to monitor for accelerating increases in abdominal fat. Measuring weight and BMI alone could miss abdominal fat growth because two women of the same age may have the same BMI but different distribution of fat in their body, she added.
“Historically, there’s been a disproportionate emphasis on BMI and cardiovascular disease,” said El Khoudary. “Through this long-running study, we’ve found a clear link between growth in abdominal fat and risk of cardiovascular disease that can be tracked with a measuring tape but could be missed by calculating BMI. If you can identify women at risk, you can help them modify their lifestyle and diet early to hopefully lower that risk.”
Late last year, El Khoudary led a team in publishing a new scientific statement for the American Heart Association that calls for increased awareness of the cardiovascular and metabolic changes unique to the menopausal transition and the importance of counseling women on early interventions to reduce cardiovascular disease risk factors.
El Khoudary noted that more research is needed to determine if certain diet, exercise or lifestyle interventions are more effective than others, as well as whether there is a clear cut-off point for when growth in waist circumference becomes concerning for heart disease risk.

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Utah researchers report significant new insights into the development of blood cancers. In work published today in Blood Cancer Discovery, a journal of the American Association for Cancer Research, scientists describe an analysis of published data from more than 7,000 patients diagnosed with leukemia and other blood disorders. Their findings provide new clues about mutations that may initiate cancer development and those that may help cancer to progress.
The researchers sought to identify mutation hotspots, or frequent changes in specific locations of the cancer patients’ genetic information. The researchers then used these hotspots to look for whether the same mutations were present in the DNA data of more than 4,500 people who were not known to have a cancer diagnosis. They found that approximately 2 percent of these presumably healthy participants had, at low levels, mutations identical to those frequently observed in the cancer patients.
“Understanding how a disease develops is greatly benefited by studying persons who are currently healthy but are on a trajectory for disease onset,” said Clint Mason, PhD, assistant professor of pediatrics at the U of U, who specializes in cancer genomics and bioinformatics and led the study.
Mutations occur throughout the 3 billion bases of DNA that are present in human cells. Many will have no impact on health, yet certain mutations may cause or support development of diseases, including cancer. Therefore, scientists are working to discern which mutations have a significant impact on health. In this study, the researchers sought to understand which mutations are most frequently present in adults and children both with and without blood cancers. They hope this information may illuminate an understanding of these cancers, and further, may potentially be used to identify people who are progressing towards cancer.
The team of researchers consisted nearly entirely of University of Utah (U of U) faculty and students. Mason was joined by co-first authors Julie Feusier, PhD, a trainee in the department of human genetics and now a postdoctoral fellow at Huntsman Cancer Institute, and Sasi Arunachalam, PhD, a postdoctoral fellow at Huntsman Cancer Institute and now a research associate at St. Jude Children’s Research Hospital, in performing analyses along with other co-authors.
For the first part of the study, the researchers completed a large data mining analysis to examine published data from 48 cancer studies that reported mutations present in persons who were being diagnosed with leukemia or other hematologic malignancies. Across the 7,430 pediatric and adult cancer patients of those studies, 434 DNA locations were identified as frequently mutated. Then, in a subsequent analysis of many terabytes of publicly available genetic data, the researchers identified these same cancer-relevant mutations at low levels among 83 of the 4,538 persons who were presumably free from cancer.
“When identical mutations are found to be present in a small percentage of blood cells of a healthy person, it may indicate that something abnormal has begun to occur,” explained Mason.
This abnormal process (known as clonal hematopoiesis) has previously been found to be increasingly common as people age. As a result, researchers generally focus on the study of adults when investigating this phenomenon. Yet in this study, in addition to adults, the researchers analyzed data from 400 children who were likely to be free from cancer. They found preliminary evidence that early cancer mutations could be detected in this age group.
In an accompanying commentary, to be published by Blood Cancer Discovery in its “In the Spotlight” section, Barbara Spitzer, MD, and Ross Levine, MD, of the Memorial Sloan Kettering Cancer Center, wrote, “This work demonstrates the first evidence that [clonal hematopoiesis] is observed in children outside of those with advanced malignancies.” They further commented, “This expansion of the range of hematologic malignancy hotspot mutations goes beyond an improved understanding of the molecular repertoire of hematologic malignancies… More complete knowledge of relevant mutations may increase our detection of patients at highest risk for malignant transformation.”
Finding a low-level mutation identical to one that is frequently present at cancer diagnoses could be alarming to a currently healthy person screened for such events. But fortunately, because cancer frequently requires multiple mutations to be present in a sizeable fraction of cells, most persons with a single low-level mutation are not likely to develop cancer for many years or decades — if they develop cancer at all. Large longitudinal studies are needed to identify the timeframe over which specific mutations or combinations of mutations accelerate progression to cancer.
The Utah researchers next hope to determine the stability of mutations identified at younger ages. This will give a preliminary glimpse into their potential to serve as biomarkers for those having greatest risk of cancer. Future intervention studies will require such an identification.
“Our goal has been to help fill in gaps in the understanding of cancer development so that future prevention work can take place more quickly and effectively,” said Mason. “We are grateful to have been able to contribute a few puzzle pieces to that monumental effort.”