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On 29–30 November 2023, the inaugural Global Healthspan Summit, convened in Riyadh by the nonprofit Hevolution Foundation, provided a dynamic platform that united experts from diverse sectors to foster collaborative discussions on aging research, innovative healthcare strategies and the healthspan ecosystem. This Meeting Report encapsulates the multifaceted insights that were garnered from the perspectives of science, economics and society.

Proto-oncogenic pathways, including the insulin-like growth factor-I (IGF-I), Ras and AKT/PKB pathways, have recently been implicated in the ageing process. In simple organisms, proto-oncogene homologues increase DNA damage, whereas in mice they increase cancer incidence. So, can we prevent cancer by chronic downregulation of pro-ageing pathways?

Sequencing the nuclear genomes of Guillardia theta and Bigelowiella natans, transitional forms in the endosymbiotic acquisition of photosynthesis by engulfment of certain eukaryotic algae, reveals unprecedented alternative splicing for a single-celled organism (B. natans) and extensive genetic and biochemical mosaicism, shedding light on why nucleomorphs persist in these species but not other algae.

Genome sequencing and phylogenomic analysis show that the lungfish, not the coelacanth, is the closest living relative of tetrapods, that coelacanth protein-coding genes are more slowly evolving than those of tetrapods and lungfish, and that the genes and regulatory elements that underwent changes during the vertebrate transition to land reflect adaptation to a new environment.

The biological role of 2′-O-methylation of host and viral mRNA has remained elusive. Thiel and co-workers show that this modification modulates the induction of type I interferon and sensitivity to interferon.

High salt intake changed the gut microbiome and increased T_H17 cell numbers in mice, and reduced intestinal survival of Lactobacillus species, increased the number of T_H17 cells and increased blood pressure in humans.

Cortical thickness has high heritability estimates and is known to be influenced by genetic factors. Here, Freytag and colleagues show that DNA methylation patterns of peripheral blood monocytes are also correlated with cortical thickness and memory performance in human.

Here, the authors map chromatin conformation at high resolution after rapid Mediator depletion to show that its loss reduces the frequency of enhancer-promoter interactions and associated gene expression, with a corresponding redistribution of Cohesin.

Sequencing of newly synthesised RNA can reveal the transcriptional dynamics in a population of cells. Here the authors develop NASC-seq to bring this sensitivity and temporal resolution to single-cell analysis.

A number of disease-causing human transthyretin (TTR) mutations are known to lead to amyloid formation. Here the authors combine neutron crystallography, native mass spectrometry and modelling studies to characterize the T119M and S52P-TTR mutants, providing mechanistic insights into TTR amyloidosis.

An anatomical study of the structure, distribution and use of whiskers on the elephant trunk reveal unique characteristics that may facilitate its manipulative capabilities.

Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.

The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.

New methods and larger sample groups are used to precisely determine the alleles in the HLA complex which contribute susceptibility to type 1 diabetes.

Ingo Braasch, John Postlethwait and colleagues report the genome of the spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before genome duplication. Their data provide insights into the evolution of genes involved in immunity, mineralization and development and facilitate the comparison of cis-regulatory elements between teleosts and humans.

Philippe Amouyel, Julie Williams, Gerard Schellenberg, Sudha Seshadri and colleagues report a meta-analysis of genome-wide association studies for late-onset Alzheimer's disease in 17,008 cases and 37,154 controls with replication in an additional 8,572 cases and 11,312 controls. They identify 11 loci newly associated with Alzheimer's disease.

Julie Williams and colleagues report a genome-wide association study for Alzheimer's disease. They identify variants at the CLU and PICALM loci associated with susceptibility to late-onset Alzheimer's disease.

Multi-protein kinetochore complexes bind to the centromeric region of chromosomes to ensure accurate spindle attachment and chromosome segregation, although centromere organization differs widely between species. Westermann and colleagues now identify the budding yeast protein Cnn1 as the orthologue of mammalian CENP-T. They show that it binds to the Ndc80 kinetochore complex and functions in chromosome segregation, illustrating a conserved role for this protein.

The authors here look into the phase transitions in Li-/Mn-rich layered cathode materials during synthesis and cycling. It is revealed that the Li-rich layered structure tends to transform to a Li-poor spinel phase via an intermediate Li-containing rock salt phase, with release of lithium/oxygen.

Oxygen vacancies can impart interesting properties in complex oxides, but specific architectures designed to create high-density oxygen vacancies are largely unknown. Here the authors report a fluorite-bixbyite nanobrush platform to tune interfacial oxygen and show that an atomically well-defined heterointerface can induce charge modulation.

In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.

Polanía et al. show that, similarly to sensory signals, subjective preferences guiding choice are represented by the brain in a manner that accounts for regularities of the environment, thereby optimizing use of limited neural processing resources.

Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.

A large meta-analysis combining genome-wide and custom high-density genotyping array data identifies 63 new susceptibility loci for prostate cancer, enhancing fine-mapping efforts and providing insights into the underlying biology.

Nature Immunology’s 20^th anniversary is a good opportunity to reminisce about the ImmGen collective endeavor — its goals, successes and horror stories — and the group’s exploration of various modes of scientific publishing.

Transcription of eukaryotic protein-coding genes is initiated by RNA polymerase II (Pol II) in a complex with transcription factors including the transcription factor IIB (B). The crystal structure of the complete Pol II–B complex is now presented with complementary functional data. The results shed light on the mechanism of transcription initiation, including the transition to RNA elongation.

A non-coding polymorphism at a locus associated with myocardial infarction in humans creates a CCAAT/enhancer binding protein transcription factor binding site and alters the hepatic expression of the SORT1 gene. These authors show that modulating Sort1 levels in mouse liver alters levels of plasma low-density lipoprotein cholesterol and very low-density lipoprotein, potentially explaining why polymorphisms at this locus are associated with heart disease.

Naomi Wray and colleagues report an analysis of genome-wide association data sets from the Psychiatric Genomics Consortium for five psychiatric disorders. They find that common variation explains 17–29% of the variance in liability and provide further support for a shared genetic etiology for these related psychiatric disorders.

Turbulence in pipe flows causes substantial friction (and therefore economic) losses. An experimental and numerical study now shows a solution might be to initially enhance turbulent mixing, which subsequently leads to a collapse of turbulence.

Rosalind Eeles, Christopher Haiman and colleagues report genome-wide association and meta-analyses of prostate cancer in populations of European, African, Japanese and Latino ancestry. They identify 23 new susceptibility loci, including one associated with early-onset prostate cancer.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.