Medical Bulletin 14/ August/ 2024

A study published in the journal Frontiers in molecular neuroscience states that Everyone has moments of forgetfulness from time to time, especially as we get older. But older adults don’t just have difficulty remembering new information. They also have a harder time modifying those memories when new details emerge. Yet, little is known about the mechanisms behind memory updating and how those mechanisms go awry with age.

A team of researchers from Penn State has identified an enzyme that contributes to age-related impairments in memory updating. When blocked, older mice were better able to incorporate new information and performed similarly to their younger counterparts. The researchers said that the findings may lead to the development of potential therapeutic targets for improving cognitive flexibility in old age.

When a memory forms, the brain rewires itself to keep that memory in place through a process called consolidation. Cells express proteins at the synapse, the gap between neurons that allows communication between nerve cells, linking together the cells activated when the memory formed. When the memory is recalled, those cells then fire together at the same time

In this study, the research team wanted to understand why it’s harder to update memories with normal ageing. To test this, they blocked histone deacetylase 3 (HDAC3), an enzyme that regulates gene transcription, the process of copying information from a DNA segment into RNA that will ultimately make a functional protein. HDAC3 has been shown to negatively affect memory formation and gene expression during consolidation but the researchers said its role in memory reconsolidation wasn’t previously studied.

HDAC3 typically tightens up the chromatin, a complex of DNA and proteins, and makes it hard for transcription to happen. If this enzymatic activity is blocked from happening, it may help maintain a more open chromatin state and improve gene expression. When HDAC3 was blocked during the memory reconsolidation phase, it prevented the typical age-related deficits in memory updating. Older mice performed as well as their younger counterparts during a memory update task.

The team used a methodology called the objects in updated locations paradigm, which Kwapis developed specifically to test memory updating. It includes three phases: a training session where mice learn two locations of identical objects; an update session where one of the objects is moved to a new location; and a test session where the objects are placed in four separate locations — the original two training locations, the updated location and a completely novel location.

The study found that alterations in this enzyme's activity could contribute to cognitive decline in older age. The research highlights the potential of targeting this enzyme as a therapeutic strategy to mitigate memory loss and other cognitive impairments associated with ageing. However, further studies in humans are needed to confirm these findings and develop effective treatments.

References: Alaghband, Y., Kwapis, J. L., López, A. J., White, A. O., Aimiuwu, O. V., Al-Kachak, A., et al. (2017). Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory. Neurobiol. Learn. Mem. 145, 94–104. doi: 10.1016/j.nlm.2017.09.001

Eating a low-fat vegan diet reduces harmful inflammatory dietary compounds called advanced glycation end-products (AGEs) by 73%, compared to no reduction on a Mediterranean diet, according to new research by the Physicians Committee for Responsible Medicine published in the journal Frontiers in Nutrition. The decrease in AGEs on the vegan diet was associated with an average weight loss of 13 pounds, compared with no change on the Mediterranean diet.

The reduction of dietary AGEs on the low-fat vegan diet came mainly from excluding the consumption of meat (41%), minimising the consumption of added fats (27%), and avoiding dairy products (14%).

AGEs may be ingested through the diet, and animal products are generally higher in AGEs than plant foods. Cooking with high heat under dry conditions, such as grilling, leads to significant formation of AGEs, especially in animal-derived foods, which are also rich in fats. High amounts of AGEs circulating in the body can contribute to insulin resistance, which can lead to weight gain. AGEs are also linked to inflammation and oxidative stress, which contribute to chronic diseases like heart disease and type 2 diabetes.

The new research is a secondary analysis of a previous Physicians Committee study comparing a low-fat vegan diet to a Mediterranean diet. The study randomly assigned participants to either a low-fat vegan diet, which consisted of fruits, vegetables, grains, and beans, or a Mediterranean diet, which focused on fruits, vegetables, legumes, fish, low-fat dairy, and extra virgin olive oil, for 16 weeks. Neither group had a calorie limit. Participants then went back to their baseline diets for a four-week washout period before switching to the opposite group for an additional 16 weeks. Dietary AGEs were calculated based on self-reported dietary intake records. AGE scores were assigned to each food item, using a published database of AGE content.

This study indicated that a vegan diet may be more effective than a Mediterranean diet for weight loss and reduced harmful inflammatory dietary compounds. The findings suggested that a vegan diet's emphasis on plant-based foods and exclusion of animal products might lead to greater reductions in body weight and markers of inflammation. This could be attributed to the higher intake of fibre, lower caloric density, and avoidance of certain inflammatory compounds found in animal products. This study highlights the potential benefits of a vegan diet in promoting overall health and reducing inflammation.

References: National Institute of Diabetes and Digestive, and Kidney Diseases.Overweight & obesity statistics. Bethesda, MD: National Institute of Diabetes and Digestive, and Kidney Diseases (2018).

Multiple biological pathways involving organs and the brain play a key part in physical and mental health, according to a new study published in the journal Nature Mental Health.

It is analysed that out of 18,000 individuals, 7,749 people had no major clinically-diagnosed medical or mental health conditions, while 10,334 had reported a diagnosis of either schizophrenia, bipolar disorder, depression or anxiety.Using advanced statistical models, the researchers found a significant association between poorer organ health and higher depressive symptoms, and that the brain plays an important role in linking body health and depression.

The organ systems studied included the lungs, muscles and bones, kidneys, liver, heart, and the metabolic and immune systems.

By integrating clinical data, brain imaging and a wide array of organ-specific biomarkers in a large population-based cohort, for the first time it established multiple pathways involving the brain as a mediating factor and through which poor physical health of body organ systems may lead to poor mental health.

Physical health was also taken into account, as well as lifestyle factors such as sleep quality, diet, exercise, smoking, and alcohol consumption.

Professor Andrew Zalesky, an author of the study from the Departments of Psychiatry and Biomedical Engineering at the University of Melbourne, said. "This is a significant body of work because we have shown the link between physical health and depression and anxiety, and how that is partially influenced by individual changes in brain structure.

It is concluded that maintaining good physical health can positively influence brain function, leading to better mental well-being. Conversely, poor physical health may disrupt these brain pathways, contributing to mental health issues such as anxiety, depression, or cognitive decline. The findings underscored the importance of a holistic approach to health, where physical and mental well-being are closely intertwined, and suggest that interventions aimed at improving physical health could also have beneficial effects on mental health.

References: Tian, Y. E., et al. (2024). Brain, lifestyle and environmental pathways linking physical and mental health. Nature Mental Health. doi.org/10.1038/s44220-024-00303-4.

In a new paper published today in the journal Gastroenterology, People with celiac disease must navigate everyday life by avoiding gluten, a protein in wheat, rye and barley which can trigger painful symptoms in the gut, impede the absorption of nutrients and raise the risk of other serious long-term issues.

Celiac disease, an autoimmune disorder affecting around 1% of the population, has roughly doubled in prevalence over the past 25 years, yet no treatment is available.

An interdisciplinary team from McMaster University in Canada, along with researchers from the US, Australia, and Argentina, has spent six years uncovering a crucial piece of the puzzle, the initiation and location of the gluten response.

They found that the inner lining of the upper intestine, called the "epithelium" composed of a variety of cells that are not classically part of the immune system – also plays an active role in directing the inflammatory response to gluten.

Using microscopic biomaterials in the laboratory, the team created a biologically functioning model of the intestinal epithelium which allowed the researchers to isolate the effects of specific molecules in the epithelial cells of people with celiac disease. The model allowed the researchers to generate and observe the reactions under controlled conditions, an option that is simply not available in extremely complex gut environments of living beings.

In conclusion, the breakthrough study elucidated the critical role of the intestinal epithelium in the pathophysiology of celiac disease. By demonstrating how epithelial cells contribute to the immune response against gluten, the research provided new insights into the mechanisms underlying the disease. These findings underscore the importance of targeting the intestinal epithelium in developing novel therapeutic strategies for celiac disease. The study's results mark a significant advancement in our understanding of gluten sensitivity and open avenues for more effective treatments.

References: Rahmani, S., et al. (2024) Gluten-Dependent Activation of CD4+ T Cells by MHC Class II–Expressing Epithelium. Gastroenterology. doi.org/10.1053/j.gastro.2024.07.008.