Obesity and ageing predispose to numerous, yet overlapping chronic diseases. For example, metabolic abnormalities, including insulin resistance (IR) and type 2 diabetes (T2D) are important causes of morbidity and mortality. Low‐grade chronic inflammation of tissues, such as the liver, visceral adipose tissue and neurological tissues, is considered a significant contributor to these chronic diseases. Thus, it is becoming increasingly important to understand what drives this inflammation in affected tissues. Recent evidence, especially in the context of obesity, suggests that the intestine plays an important role as the gatekeeper of inflammatory stimuli that ultimately fuels low‐grade chronic tissue inflammation. In addition to metabolic diseases, abnormalities in the intestinal mucosal barrier have been linked to a range of other chronic inflammatory conditions, such as neurodegeneration and ageing. The flow of inflammatory stimuli from the gut is in part controlled by local immunological inputs impacting the intestinal barrier. Here, we will review the impact of obesity and ageing on the intestinal immune system and its downstream consequences on gut barrier function, which is strongly implicated in the pathogenesis of obesity and age‐related diseases. In particular, we will discuss the effects of age‐related intestinal dysfunction on neurodegenerative diseases.

Accurate transcription is required for the faithful expression of genetic information. However, relatively little is known about the molecular mechanisms that control the fidelity of transcription, or the conservation of these mechanisms across the tree of life. To address these issues, we measured the error rate of transcription in five organisms of increasing complexity and found that the error rate of RNA polymerase II ranges from 2.9 × 10−6 ± 1.9 × 10−7/bp in yeast to 4.0 × 10−6 ± 5.2 × 10−7/bp in worms, 5.69 × 10−6 ± 8.2 × 10−7/bp in flies, 4.9 × 10−6 ± 3.6 × 10−7/bp in mouse cells and 4.7 × 10−6 ± 9.9 × 10−8/bp in human cells. These error rates were modified by various factors including aging, mutagen treatment and gene modifications. For example, the deletion or modification of several related genes increased the error rate substantially in both yeast and human cells. This research highlights the evolutionary conservation of factors that control the fidelity of transcription. Additionally, these experiments provide a reasonable estimate of the error rate of transcription in human cells and identify disease alleles in a subunit of RNA polymerase II that display error-prone transcription. Finally, we provide evidence suggesting that the error rate and spectrum of transcription co-evolved with our genetic code.

Accurate transcription is required for the faithful expression of genetic information. Surprisingly though, little is known about the molecular mechanisms that control the fidelity of transcription, or the conservation of these mechanisms across the tree of life. To address this issue, we measured the error rate of transcription in five organisms of increasing complexity and identified various genes, alleles and processes that control transcriptional fidelity in multicellular organisms. In doing so, they highlight the evolutionary conservation of fidelity factors and open up new opportunities to probe the impact of transcription errors on intact organisms and human physiology. Finally, our experiments provide the first reasonable estimate of the error rate of transcription in human cells, identify the first disease associated with error-prone RNA polymerases and suggest that transcription errors may have contributed to the evolution of our genetic code.