Retrotransposons shape species-specific embryonic stem cell gene expression.

Over half of our genome is composed of retrotransposons, which are mobile elements that can readily amplify their copy number by replicating through an RNA intermediate. Most of these elements are no longer mobile but still contain regulatory sequences that can serve as promoters, enhancers or repressors for cellular genes. Despite dominating our genetic content, little is known about the precise functions of retrotransposons, which include both endogenous retroviruses (ERVs) and non-LTR elements like long interspersed nuclear element 1 (LINE-1). However, a few recent cutting-edge publications have illustrated how retrotransposons shape species-specific stem cell gene expression by two opposing mechanisms, involving their recruitment of stem cell-enriched transcription factors (TFs): firstly, they can activate expression of genes linked to naïve pluripotency, and secondly, they can induce repression of proximal genes. The paradox that different retrotransposons are active or silent in embryonic stem cells (ESCs) can be explained by differences between retrotransposon families, between individual copies within the same family, and between subpopulations of ESCs. Since they have coevolved with their host genomes, some of them have been co-opted to perform species-specific beneficial functions, while others have been implicated in genetic disease. In this review, we will discuss retrotransposon functions in ESCs, focusing on recent mechanistic advances of how HERV-H has been adopted to preserve human naïve pluripotency and how particular LINE-1, SVA and ERV family members recruit species-specific transcriptional repressors. This review highlights the fine balance between activation and repression of retrotransposons that exists to harness their ability to drive evolution, while minimizing the risk they pose to genome integrity

The quest to slow ageing through drug discovery

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life