Search

As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

McCreery, Stubb et al. show that mechano-osmotic changes in the nucleus induce general transcriptional repression and prime chromatin for cell fate transitions by relieving repression of specific differentiation genes.

Somatic instability plays a role in Huntington’s disease. Here, the authors show that lowering HTT levels by transcriptional repression suppresses somatic instability. This can also be done without affecting HTT levels by direct CAG repeat binding.

There are limited vaccines available for Ebola virus and none for broad protection from filoviruses. Here, the authors rationally design vaccines using nanoparticles and stabilized Ebola virus and other filovirus glycoproteins, characterize antibody epitopes and profile lymph node and antibody responses in mice.

This study presents an extensive molecular characterization of the reprograming process by analysis of transcriptomic, epigenomic and proteomic data sets describing the routes to pluripotency; it finds distinct routes towards two stable pluripotent states characterized by distinct epigenetic events.

Evading infection in Cellulophaga baltica comes with cellular changes that alter carbon cycling, metabolite secretion and sedimentation rates.

The JAK2^V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell-type-specific manner, influencing inflammation states and differentiation trajectories in patients with myeloproliferative neoplasms.

Preservation of oral microbiome ancient DNA from Oceania is much better than human ancient DNA. The authors leverage this to demonstrate that oral microbial community composition in Oceania is not only distinct from the rest of the world, but it may also be associated with patterns of ancient human migration in the region.

We developed PRINT, a computational method that identifies footprints of DNA–protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size.

MORC2, a chromatin remodeler involved in epigenetic silencing and DNA repair, is linked to cancer and neurological disorders when dysregulated. Here, the authors show that MORC2 binds DNA at multiple sites, clamps onto it, and induces compaction, a process regulated by its phosphorylation.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

In a phase 3 trial for Huntington’s disease, pridopidine did not meet its primary endpoints but was safe and favored in some prespecified subgroup analyses.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Parallel operation of two exchange-only qubits consisting of six quantum dots arranged linearly is shown to be achievable and maintains qubit control quality compared with sequential operation, with potential for use in scaled quantum computing.

The combination of JWST and ALMA data here unravel the history of the gas content of a quiescent galaxy, which became quenched through an act of self-sabotage. Black-hole accretion feedback heated the galaxy’s surrounding material, preventing its accretion.

Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

Deep learning reduces errors in sequences from PacBio HiFi reads.

An atlas study of adipose tissue in people with obesity undergoing weight loss and their lean counterparts reveals that weight loss reduces cell senescence but cannot reverse all the metabolic problems caused by obesity.

SCIFER detects clonal selection in whole-genome sequencing data using a population genetics model. Applied to a range of somatic tissues, SCIFER quantifies stem cell dynamics and infers clonal ages and sizes without requiring knowledge of driver events.

A pan-cancer epigenetic and transcriptomic atlas identifies epigenetic drivers associated with cancer transitions.

Cells must sense heat quickly to protect their proteins and membranes. Here, the authors show that membrane stretch detected by the membrane sensor Mid2 promotes rapid phosphorylation of the Hsp70 chaperone to coordinate gene activity, protein synthesis and resolution of stress-induced protein droplets during heat shock.

The causative agent of sea star wasting disease has been elusive. This study used genetic datasets and experimental exposures to demonstrate that a strain of the bacterium Vibrio pectenicida caused disease and mortality in sea stars.

Wang, Xiao and colleagues develop and validate organ-specific proteomic aging clocks across large population cohorts in the UK, the USA and China, which show strong performance in tracking organ aging and predicting the risk of morbidity and mortality.

An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

Defective DNA interstrand crosslink repair in Fanconi anaemia drives extensive genomic rearrangements, thereby substantially increasing the risk of cancer development.

Semiconductor-based, non-optical DNA sequencing technologies such as Ion Torrent sequencing offer speed and cost advantages compared with alternative techniques. Cheng et al. demonstrate a protocol allowing the use of Ion Torrent technology to sequence DNA from chromatin immunoprecipitation experiments.

Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

Longitudinal multi-omics reveals shifts to the human microbiome across multiple body sites and the associated immune responses during short-term spaceflight.

Claudin 18.2 (CLDN18.2) has emerged as a target for gastrointestinal cancer, however, on-target/off-tumor toxicities have been also reported. Here, after reporting evidence of erosive gastritis in patients treated with CLDN18.2 targeted immunotherapies, the authors develop and characterize CLDN18.2 fully-human VH-only single domain CARs, showing that a lower affinity CAR mitigates on-target/off-tumor toxicity while preserving anti-tumor efficacy in gastric cancer models.

Intracellular redox state orchestrates a self-reinforcing circuit connecting hypoxia inducible factor 1α-dependent signalling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1 to govern intestinal stem cell fate.

Single cell genome sequencing approaches have identified somatic copy number variants (CNVs) in human neurons, but small sample sizes (<100 neurons) have limited the power to find recurrent patterns such as CNV hotspots in a single individual. Here, the authors develop an approach to map CNVs in 2097 neurons from a neurotypical individual, finding that >10% neurons contain at least one somatic CNV, and enabling deeper investigation of these events.

Understanding of the immune microenvironment in pediatric acute T cell lymphoblastic leukemia is limited. By analyzing single-cell transcriptome, surface protein expression and immune repertoire data, the authors here identify non-malignant CD4^-CD8^- TCRαβ T cells that are present in a subset of patients with Rap1 signaling in leukemia cells and are associated with adverse clinical outcome in patients with low minimal residual disease.

The authors identify a Cys→Ser transformation (C19S) in insulin leading to neoepitope presentation and CD4⁺ T cell autoreactivity in type 1 diabetes. Inflammation and oxidative stress enhanced C19S transformation in β cells and antigen-presenting cells, resulting in C19S-specific CD4⁺ T cells with an activated memory phenotype linked to disease progression.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

Variable New Antigens Receptors (VNARs) from shark antibodies possess a unique molecular dexterity that allows them to access epitopes inaccessible to conventional antibodies. Here, the authors use crystallography to investigate how two VNARs selectively engage soluble TNF-alpha.

LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, is a receptor for tick-borne encephalitis virus.

Long-read chromatin assay reveals (1) a novel class of accessible chromatin regions, (2) accessibility within individual LTR retrotransposons and (3) the relationship between diffuse accessibility, gene body methylation and hAT transposon insertion.

Excised signal circles are circular DNA by-products of V(D)J recombination that form a complex with the V(D)J recombinase, and when increased in abundance, result in increased mutagenesis, causing adverse outcomes in cancer.

An analysis of prescription medications shows that several non-antibiotic drugs, such as the heart medication digoxin, can reduce the immune response to pathogens and increase the risk of gastrointestinal infections by altering the composition of the microbiome.

NIPBL perturbation activates long terminal repeat (LTR)-derived alternative promoters due to reorganization of chromatin’s hierarchical structure, leading to LTR co-option and oncogene activation in melanoma cell lines.

Liquid biopsy assays are important to prognosticate outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients treated with androgen receptor (AR) inhibitors. Here this group reports detecting circulating tumor DNA in limiting plasma cell-free DNA of mCRPC patients as prognostic marker of poor survival after AR treatment.