People with type 2 diabetes face a higher likelihood of heart attacks and strokes, and that risk increases with each passing year of the disease. Earlier research has shown that red blood cells can influence how well blood vessels function in diabetes. The new study adds an important insight by showing that the length of time someone has diabetes strongly affects when these blood cell changes begin and how they develop. After many years, red blood cells may start to directly damage blood vessels.

Evidence From Patients and Animal Studies

To better understand these effects, the research team examined both animal models and people with type 2 diabetes. Red blood cells taken from mice and from patients who had lived with diabetes for a long time disrupted normal blood vessel function. In contrast, red blood cells from newly diagnosed patients showed no harmful impact. However, after seven years of follow up, those same patients developed red blood cells with similar damaging properties. When scientists restored levels of microRNA-210 in the red blood cells, blood vessel function improved.

“What really stands out in our study is that it is not only the presence of type 2 diabetes that matters, but how long you have had the disease. It is only after several years that red blood cells develop a harmful effect on blood vessels,” says Zhichao Zhou, associate professor at the Department of Medicine, Solna, Karolinska Institutet, and lead author of the study.

A Possible Early Warning Marker

The findings suggest that microRNA-210 in red blood cells could be used as a biomarker to help detect the risk of cardiovascular complications at an earlier stage. Researchers are now exploring whether this approach can be applied in larger population studies.

“If we can identify which patients are at greatest risk before vascular damage has already occurred, we can also become better at preventing complications,” says Eftychia Kontidou, doctoral student from the same group and the first author of the study.

The blood test focuses on how the immune system reacts to flagellin, a protein found on certain gut bacteria. According to a research team led by Dr. Ken Croitoru, a clinician scientist at the Lunenfeld-Tanenbaum Research Institute at Sinai Health, people who later develop Crohn’s disease often show higher immune responses to this protein long in advance. The study team also included gastrointestinal medical resident Dr. Richard Wu and clinician scientist and staff gastroenterologist Dr. Sun-Ho Lee.

Drs. Croitoru and Lee are also members of Mount Sinai Hospital’s Centre for Inflammatory Bowel Disease (IBD), an internationally recognized center dedicated to inflammatory bowel disease research.

The findings were published in Clinical Gastroenterology and Hepatology and emphasize how interactions between gut bacteria and the immune system play a crucial role in the early development of Crohn’s disease.

A Disease on the Rise

Crohn’s disease is a chronic inflammatory disorder of the digestive tract that can lead to ongoing digestive problems, pain, and fatigue. These symptoms often have a major impact on daily life. Since 1995, rates of Crohn’s disease in children have doubled, and overall cases continue to increase. Crohn’s and Colitis Canada, a non profit organization focused on curing inflammatory bowel disease, estimates that about 470,000 Canadians will be living with IBD by 2035.

Why Early Antibodies Matter

Detecting antibodies to flagellin years before symptoms appear suggests that this immune response may help trigger the disease rather than simply result from it, Dr. Croitoru said. He believes that understanding these early immune changes could lead to new ways to predict who is at risk, prevent the disease from developing, and improve treatment.

“With all of the advanced biologic therapy we have today, patients’ responses are partial at best. We haven’t cured anybody yet, and we need to do better,” said Dr. Croitoru, who hold Canada Research Chair in Inflammatory Bowel Diseases.

Tracking Risk Through the GEM Project

The study is part of the Genetic, Environmental and Microbial (GEM) Project, a large international effort led by Dr. Croitoru. The project follows more than 5,000 healthy first degree relatives of people with Crohn’s disease. Since 2008, researchers have collected genetic, biological, and environmental information to better understand how the disease begins. So far, 130 participants have gone on to develop Crohn’s disease, allowing scientists to examine the condition before symptoms emerge.

Earlier work from the team showed that an inflammatory immune response aimed at gut bacteria can appear well before Crohn’s disease is diagnosed. In healthy individuals, gut bacteria normally live in balance with the body and support digestion. In people with Crohn’s disease, the immune system appears to react abnormally to microbes that are usually beneficial.

Building on Earlier Discoveries

Previous research by collaborators at the University of Alabama, led by Dr. Charles Elson, resulted in a test that detects antibodies against flagellin. That work showed that people with Crohn’s disease often have higher antibody levels directed at flagellin from Lachnospiraceae bacteria.

Drs. Croitoru and Lee then asked whether the same immune response could be found in healthy people who were at increased risk of developing Crohn’s disease.

“We wanted to know: do people who are at risk, who are healthy now, have these antibodies against flagellin?” said Dr. Croitoru. “We looked, we measured, and yes indeed, at least some of them did.”

Study Results and What Comes Next

The study followed 381 first degree relatives of people with Crohn’s disease. During the study period, 77 participants developed the condition. Among them, 28 individuals had elevated antibody levels, accounting for more than a third of those who became ill. The strongest immune responses were seen in siblings, underscoring the importance of shared environmental exposure, as shown previously by Dr. Croitoru.

Researchers also confirmed that this early immune response to Lachnospiraceae flagellin was linked to intestinal inflammation and problems with the gut barrier, both key features of Crohn’s disease. On average, participants were diagnosed nearly two and a half years after their blood samples were collected.

“Confirming our previous study immune response against bacterial flagellins show strong associations with future risk of Crohn’s in healthy first-degree relatives,” said Dr. Lee. “We found that this immune response is driven by a conserved domain of the flagellin protein. This raises the potential for designing a flagellin-directed vaccine in selected high-risk individuals for prevention of disease. Further validation and mechanistic studies are underway.”

A large study published Jan. 16 in Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association, set out to examine how often these two gene variants appear in a rare group known as super agers. Super agers are people age 80 or older whose memory and thinking abilities closely resemble those of adults who are 20 or 30 years younger. The research was led by investigators at Vanderbilt University Medical Center.

Lower Frequency of Alzheimer’s Risk Gene

The results showed a striking difference in genetic risk. Super agers were 68% less likely to carry APOE-ε4 when compared with individuals age 80 and older who had Alzheimer’s dementia.

What stood out even more was the comparison with cognitively healthy peers. Super agers were still 19% less likely to carry APOE-ε4 than other adults in the same age group who showed normal cognitive aging.

“This was our most striking finding — although all adults who reach the age of 80 without receiving a diagnosis of clinical dementia exhibit exceptional aging, our study suggests that the super-ager phenotype can be used to identify a particularly exceptional group of oldest-old adults with a reduced genetic risk for Alzheimer’s disease,” said Leslie Gaynor, PhD, assistant professor of Medicine in the Division of Geriatric Medicine. She led the study together with Alaina Durant, BS, a statistical genetic analyst in the Vanderbilt Memory and Alzheimer’s Center.

Higher Levels of a Protective Gene Variant

Researchers also discovered another important genetic distinction. For the first time, super agers were shown to have a higher frequency of APOE-ε2, the gene variant linked to reduced Alzheimer’s risk.

Compared with cognitively normal adults age 80 and older, super agers were 28% more likely to carry APOE-ε2. When compared with participants age 80 or older who had Alzheimer’s dementia, super agers were 103% more likely to have this protective variant.

Largest Study of Super Agers to Date

This observational study included the largest number of super agers examined so far. The analysis drew on data from the Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC), which is led by study co-author Timothy Hohman, PhD, professor of Neurology.

Altogether, the study evaluated genetic and clinical data from 18,080 participants across eight national aging cohorts.

How Super Agers Were Defined

Super ager status was partly determined by memory performance. Participants age 80 or older qualified if their memory scores were higher than the average score among cognitively normal adults ages 50 to 64.

The study population included participants from several race and ethnicity groups. Among them were 1,412 non-Hispanic white super agers and 211 non-Hispanic Black super agers. The dataset also included 8,829 individuals with AD dementia and 7,628 cognitively normal controls.

Worldwide, the APOE-ε4 variant is found in about 13.7% of people. Within this study population, the frequency was much higher at 43.9%.

Why Super Agers Matter for Alzheimer’s Research

“With interest in super agers growing,” Gaynor said, “our findings notably encourage the view that the super-ager phenotype will prove useful in the continued search for mechanisms conferring resilience to AD.

“This is by far the largest study to date to identify differences in APOE-ε4 allele frequency based on super-ager status, and the first study to find a relationship between APOE-ε2 allele frequency and super-ager status. We would expect these findings to lend continued interest to questions of how these variants may influence development of clinical dementia due to Alzheimer’s disease, as well as to the super-ager phenotype more generally.”

Research Team and Funding

Additional contributors from Vanderbilt University Medical Center included Angela Jefferson, PhD, Logan Dumitrescu, MS, PhD, and Derek Archer, PhD. They worked alongside 32 researchers from 15 universities.

The study was supported in part by National Institutes of Health awards U24 AG074855, U01 AG068057, and R01 AG059716.

“As the number one cause of common colds and a major cause of breathing problems in people with asthma and other chronic lung conditions, rhinoviruses are very important in human health,” says senior author Ellen Foxman of Yale School of Medicine. “This research allowed us to peer into the human nasal lining and see what is happening during rhinovirus infections at both the cellular and molecular levels.”

Creating Lab Grown Human Nasal Tissue

To closely observe how nasal cells respond to infection, the research team built a lab grown model of human nasal tissue. They grew nasal stem cells for four weeks while exposing the upper surface of the tissue to air. This setup encouraged the cells to mature into a structure that closely resembles the lining of the nasal passages and lung airways.

The resulting tissue contained multiple cell types found in the human airway, including mucus producing cells and cells with cilia. Cilia are tiny hair like structures that help move mucus and trapped particles out of the lungs.

“This model reflects the responses of the human body much more accurately than the conventional cell lines used for virology research,” Foxman says. “Since rhinovirus causes illness in humans but not other animals, organotypic models of human tissues are particularly valuable for studying this virus.”

Interferons and Early Antiviral Protection

Using this model, the researchers were able to monitor how thousands of individual cells respond together during infection. They also examined what happened when the cellular sensors responsible for detecting rhinovirus were blocked. These experiments revealed a powerful defense system coordinated by interferons, which are proteins that interfere with viral entry and replication.

When nasal cells detect rhinovirus, they release interferons that activate antiviral defenses not only in infected cells but also in nearby healthy cells. This coordinated response makes it difficult for the virus to reproduce and spread. If interferon activity begins quickly, the infection can be contained early. When the researchers blocked this response, the virus spread rapidly, infecting many more cells and causing significant damage. In some cases, the infected organoids did not survive.

“Our experiments show how critical and effective a rapid interferon response is in controlling rhinovirus infection, even without any cells of the immune system present,” says first author Bao Wang of Yale School of Medicine.

When Viral Growth Triggers Harmful Responses

The study also uncovered additional responses that occur when viral replication increases. Under these conditions, rhinovirus can activate a separate sensing system that leads both infected and uninfected cells to produce large amounts of mucus and inflammatory signals. This reaction can contribute to airway inflammation and breathing difficulties in the lungs.

According to the researchers, these pathways may offer useful targets for treatments aimed at reducing harmful symptoms while supporting effective antiviral defenses.

Limits of the Model and Future Research

The team notes that their organoid model includes fewer cell types than are present in the human body. During real infections, additional cells, including immune cells, are drawn to the site to help fight the virus. The researchers say that understanding how these additional cell types and environmental factors in the nasal passages and airways influence the body’s response to rhinovirus will be an important focus of future work.

“Our study advances the paradigm that the body’s responses to a virus, rather than the properties inherent to the virus itself, are hugely important in determining whether or not a virus will cause illness and how severe the illness will be,” Foxman says. “Targeting defense mechanisms is an exciting avenue for novel therapeutics.”

The study was carried out by an international research team led by Mauro D’Amato, Professor of Medical Genetics at LUM University and Ikerbasque Research Professor at CIC bioGUNE, member of BRTA. The researchers used a large-scale genetic strategy to look for common DNA differences linked to how often people have bowel movements, referred to in the study as stool frequency. To do this, they analyzed genetic data and health questionnaires from 268,606 individuals of European and East Asian ancestry. Advanced computational methods helped identify which genes and biological processes were most strongly connected to gut movement.

Known Gut Pathways Confirm the Findings

The analysis uncovered 21 regions of the human genome that influence bowel movement frequency, including 10 regions that had not been identified before. Many of the genetic signals pointed to biological systems already known to regulate gut motion, offering reassurance that the results fit with established biology. These included bile-acid regulation (bile acids help digest fats and also act as signaling molecules in the gut) and nerve signaling involved in intestinal muscle contractions (including acetylcholine-related signaling, which helps nerves communicate with muscle). Together, these findings reinforce existing knowledge about how the gut functions.

Vitamin B1 Stands Out as a Surprise Signal

The most notable discovery emerged when researchers focused on two high-priority genes connected to vitamin B1 biology. These genes, SLC35F3 and XPR1, play a role in how thiamine is transported and activated in the body. To see whether this genetic signal was reflected in everyday life, the team analyzed dietary data from the UK Biobank. Among 98,449 participants, higher intake of dietary thiamine was linked to more frequent bowel movements.

This relationship was not uniform across all individuals. The effect of thiamine intake on bowel movement frequency depended on genetic variation in the SLC35F3 and XPR1 genes (analysed together as a combined genetic score). These results suggest that inherited differences in how the body handles thiamine may shape how vitamin B1 intake influences bowel habits in the general population.

Links to IBS and Future Research

Dr. Cristian Diaz-Muñoz, the study’s first author, said “We used genetics to build a roadmap of biological pathways that set the gut’s pace. What stood out was how strongly the data pointed to vitamin B1 metabolism, alongside established mechanisms like bile acids and nerve signaling.”

The findings also suggest a meaningful biological connection between bowel movement frequency and IBS, a condition that affects millions of people worldwide. “Gut motility problems sit at the heart of IBS, constipation and other common gut-motility disorders” says Prof Mauro D’Amato, “but the underlying biology is very hard to pin down. These genetic results highlight specific pathways, especially vitamin B1, as testable leads for the next stage of research, including lab experiments and carefully designed clinical studies.”

The study was led by Mauro D’Amato’s Gastrointestinal Genetics Research Group and involved investigators from CIC bioGUNE in Spain, LUM University, Institute for Genetics and Biomedical Research – CNR, CEINGE and University of Naples Federico II in Italy, University of Groningen in The Netherlands, University of Oxford in UK, Concordia University and Ontario Institute for Cancer Research in Canada, and Monash University in Australia. The research was supported by grants from MCIU/AEI/10.13039/501100011033 and ERDF/EU (PID2023-148957OB-I00); PRIN2022/NextGenerationEU (2022PMZKEC; CUP E53D23004910008 and CUP B53D23008300006); ERC Starting Grant (101075624); PNRR/NextGenerationEU (PE00000015/Age-it); NWO-VICI (VI.C.232.074); NWO Gravitation ExposomeNL (024.004.017); EU Horizon DarkMatter program (101136582).