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Chronic inflammation occurs when the immune system is stuck in attack-mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health-and experts anticipate their incidence is on the rise. A new study by investigators from Mass General Brigham identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as viral or bacterial infection. Results are published in Nature.

Chronic inflammatory diseases cause a great deal of suffering and death, but we still have much to learn about what drives chronic inflammation and how to treat it. Our findings help us separate chronic and acute inflammation, as well as identify a new target for stopping chronic inflammation that results from aging and disease.”

Zhixun Dou, PhD, senior author of the Center for Regenerative Medicine and Krantz Family Center for Cancer Research at Massachusetts General Hospital

Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. They confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.

The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.

Further research is needed to validate the therapeutic potential of WSTF restoration in broader settings and to develop specific strategies to target WSTF. Additionally, the findings suggest other similar proteins may be involved in chronic inflammation, opening a promising new avenue for studying and treating inflammation in the future.

A study published in Cell Stem Cell reveals that some mutations in blood stem cells might help protect against late-onset Alzheimer’s disease.

A team led by researchers at Baylor College of Medicine discovered that both a mouse model and people carrying blood stem cells with mutations in the gene TET2, but not in the gene DNMT3A, had a lower risk for developing Alzheimer’s disease. Their study proposes a mechanism that can protect against the disease and opens new avenues for potential strategies to control the emergence and progression of this devastating condition.

“Our lab has long been studying blood stem cells, also called hematopoietic stem cells,” said lead author Dr. Katherine King, professor of pediatrics – infectious diseases and a member of the Center for Cell and Gene Therapy and the Dan L Duncan Comprehensive Cancer Center at Baylor. She also is part of Texas Children’s Hospital.

Hematopoietic stem cells live in the bone marrow and generate all the different types of blood cells the body needs to stay alive and healthy – red blood cells, immune cells and platelets. As people get older, blood stem cells can develop mutations, and this occurs in about 20% of 70-year-olds. Most of the time, these mutations don’t cause problems, but sometimes, a mutation drives the cells to divide more than others, forming a clone. This process is called clonal hematopoiesis and it has been linked to a higher risk for conditions such as cardiovascular disease, stroke, blood cancers like leukemia and chronic obstructive pulmonary disease. However, many questions remain regarding the connection between clonal hematopoiesis and Alzheimer’s disease.

“In the current study, we investigated the effect of the two genes most commonly mutated in clonal hematopoiesis, TET2 and DNMT3A, on Alzheimer’s disease,” said first author Dr. Katie A. Matatall, instructor in the King lab. “We also selected these mutations because they are involved in inflammation, which is known to be increased in Alzheimer’s disease.”

The team discovered that the two mutations do not behave the same way. Clonal hematopoiesis with the TET2-mutant was associated with a 47% reduced risk of late-onset Alzheimer’s disease in humans, whereas other mutations of clonal hematopoiesis did not confer protection. In a mouse model, transplantation of Tet2-mutant bone marrow reduced cognitive decline and beta-amyloid plaque formation, effects not observed with Dnmt3a-mutant cells.

Adults with poor Life’s Essential 8 scores faced significantly higher atrial fibrillation risk, suggesting that heart-healthy habits could be key to preventing this common arrhythmia.

Study: Association of life’s essential 8 score with incidence of atrial fibrillation: The Framingham heart study. Image Credit: Magic mine / Shutterstock

In a recent study published in the American Journal of Preventive Cardiology, researchers in Boston, USA, investigated the relationship between the Life’s Essential 8 (LE8) score and the risk of atrial fibrillation (AF).

AF is the most common arrhythmia, whose prevalence and incidence are increasing worldwide. Thirty years ago, the Framingham Heart Study (FHS) established age, type 2 diabetes, hypertension, valvular heart disease, heart failure, and coronary heart disease as risk factors for AF. Since then, obesity, metabolic syndrome, excess alcohol intake, and obstructive sleep apnea have been identified as modifiable risk factors for AF pathogenesis.

LE8 is based on the Life’s Simple 7 (LS7), which was developed to define and measure cardiovascular health and promote positive health outcomes. LE8 is an update to LS7 that additionally includes a sleep health metric. Recent studies indicate an inverse relation between the LE8 score and health outcomes, such as fatty liver disease, cardiovascular disease (CVD), kidney disease, dementia, and CVD mortality.

About the study

The present study evaluated the associations between the LE8 score and AF risk. The study population included subjects from the FHS Omni 1 and Offspring cohorts. Individuals aged 45 years or older attending one or more index exam cycles were included in the current analyses. Participants were assigned a composite cardiovascular health score at their index exams based on their adherence to eight healthy lifestyle components.

These lifestyle components included diet, smoking habits, sleep duration, body mass index (BMI), fasting blood glucose, physical activity, cholesterol levels, and blood pressure. The LE8 score was the mean of the scores assigned to each component. The study’s outcome was incident AF, ascertained from electrocardiograms. Subjects were followed up from the date of the index exam until the next index exam, incident AF, death, or for 10 years.

Fine-Gray hazard models, which account for competing mortality risks, were used to evaluate the associations between LE8 and AF risk, adjusted for sex and age. In secondary analyses, separate models were developed for each LE8 component. In addition, the team investigated whether age modified the association between incident AF and LE8. The association between the LE8 score and the risk of all-cause mortality was also assessed.

Findings

The study included 3,161 participants aged 65 years, on average, who contributed 4,628 index exam cycles. Most participants were female (57%) and from the Offspring cohort (93%). The average LE8 score was 67.6 at the index exams. The LE8 score was ≥80 (ideal), <50 (poor), and 50–79 (intermediate) for 16%, 7%, and 76% of participants, respectively. Overall, 410 individuals had incident AF, and 424 deaths occurred over the follow-up.

The risk of incident AF was higher for individuals with poor LE8 scores compared to those with ideal scores. The incidence rate of AF per 1,000 person-years of follow-up was 17.2 for participants with poor LE8 scores, 7.9 for those with ideal scores, and 10.3 for those with intermediate scores. Notably, intermediate cardiovascular health showed no significant difference in AF risk compared to ideal health (sHR=0.95). Moreover, higher continuous scores were associated with a reduced risk of AF.

Subjects with poor scores on the BMI, blood pressure, and glucose components had a greater risk of AF than those with ideal scores on the respective components. There was no evidence that age modified the association between incident AF and LE8. Furthermore, participants with poor LE8 scores had an elevated risk of all-cause mortality relative to those with ideal scores. A more favorable score for physical activity, glucose, and smoking was associated with lower mortality risk.

Conclusions

In sum, the study assessed the risk of incident AF in two FHS cohorts using LE8 scores. AF incidence was 10.4 cases per 1,000 person-years, comparable to estimates from other studies. A poor LE8 score was associated with an increased risk of AF compared to an ideal score. Moreover, higher continuous scores were associated with lower risk of AF and all-cause mortality. Poor blood pressure, glucose, and BMI scores were also associated with a higher AF risk.

An intermediate LE8 score was not associated with the risk of AF. The analysis accounted for repeated participant contributions across exam cycles using statistical clustering methods. Notably, the sample predominantly comprised middle-aged and older adults of European descent (the Offspring cohort), which limits generalizability to younger individuals and other ethnic or racial groups. Recall or misclassification bias was also likely, as several LE8 components were assessed using self-reported data. Future analyses should focus on whether specific interventions or behaviors would augment CVD outcomes.