Deciphering cell states and genealogies of human haematopoiesis.

The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems2-5, simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging. Here we introduce an improved, single-cell lineage-tracing system based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as both differences in total HSC output and biases towards the production of different mature cell types. We also find that the diversity of HSC clones decreases markedly with age, leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides a clonally resolved and cell-state-aware atlas of human haematopoiesis at single-cell resolution, showing an unappreciated functional diversity of human HSC clones and, more broadly, paving the way for refined studies of clonal dynamics across a range of tissues in human health and disease.

Extensive age-dependent loss of antibody diversity in naturally short-lived turquoise killifish.

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.

Continuous Glucose Monitoring Use in Clinical Trials for On-Market Diabetes Drugs.

To the best of our knowledge, there are no published data on the historical and recent use of CGM in clinical trials of pharmacological agents used in the treatment of diabetes. We analyzed 2,032 clinical trials of 40 antihyperglycemic therapies currently on the market with a study start date between 1 January 2000 and 31 December 2019. According to ClinicalTrials.gov, 119 (5.9%) of these trials used CGM. CGM usage in clinical trials has increased over time, rising from <5% before 2005 to 12.5% in 2019. However, it is still low given its inclusion in the American Diabetes Association's latest guidelines and known limitations of A1C for assessing ongoing diabetes care.

The turquoise killifish: a genetically tractable model for the study of aging.

Lifespan is a remarkably diverse trait in nature, ranging from just hours in adult mayflies to hundreds of years in the Greenland shark and quahog clam. Great disparities in lifespan are often observed even among somewhat closely related species; for example, in the laboratory, wild-derived strains of the common house mouse have a maximum observed lifespan of approximately 6 years, while a similarly sized rodent, the naked mole rat, can live for over 30 years. Comparative biology of aging across the tree of life provides a tremendous opportunity for understanding the molecular and genetic basis underlying lifespan and aging. However, a lack of molecular and laboratory tools has limited the ability of researchers to take full advantage of the incredible diversity of aging phenotypes in nature. Recent developments in genomic technology have made it increasingly possible to study non-canonical model organisms for aging. One promising new genetic model organism amenable to a range of experimental interventions is the turquoise killifish (Nothobranchius furzeri). This fish species has a naturally short lifespan and undergoes a wide range of aging-related transformations. These fish have a fully sequenced genome and transcriptome, and killifish embryos are accessible to transgenesis and genome editing. Furthermore, different killifish species and populations show striking differences in lifespan, providing the opportunity for comparative analysis of aging. This Review introduces the natural life history of the turquoise killifish, its emerging applicability as an aging model system, the genetic tools that have been developed to study aging for this species and a summary of recent studies facilitated by these new tools.