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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.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

By performing a CAR-adapted base-editing screen of phosphatidylinositol-3-kinase delta (PI3Kδ, PIK3CD), Bucher et al. identify mutations affecting endogenous PI3K–AKT signaling that enhances CAR T cell antitumor potency.

Antimicrobial resistance genes that have been mobilized between bacterial species represent a subset of the naturally occurring resistome. Here, the authors compare the abundance, diversity and geographical patterns of acquired resistance genes with latent resistance genes in global sewage metagenomes.

The neurophysiology of excessive daytime sleepiness in Parkinson’s disease (PD) remains unclear. Here, the authors found that beta oscillatory activity, a pathophysiological signature of PD motor signs, is also associated with daytime vigilance in parkinsonism

This study establishes the pig as a complementary model for studying human pancreas development. It shows pigs mimic human developmental tempo, gene regulation, and endocrine cell emergence, offering a valuable large-animal model for developmental biology.

Unprotected β-fluoroamines are important motifs in synthetic chemistry, offering versatility for the development of β-fluorinated nitrogen-containing compounds. Here, the authors disclose an iron-catalyzed three-component aminofluorination of alkenes using a hydroxylamine reagent and Et3N · 3HF, offering a direct entry to unprotected β-fluoroamines.

Ischemic heart disease causes irreversible damage due to poor cardiomyocyte renewal. Here, the authors show that PKM2 modRNA therapy in pigs drives cardiomyocyte proliferation, minimizes fibrosis, restores cardiac function and prevents heart failure after injury.

It is uncertain how much life expectancy of the Chinese population would improve under current and greater policy targets on lifestyle-based risk factors for chronic diseases and mortality behaviours. Here we report a simulation of how improvements in four risk factors, namely smoking, alcohol use, physical activity and diet, could affect mortality. We show that in the ideal scenario, that is, all people who currently smokers quit smoking, excessive alcohol userswas reduced to moderate intake, people under 65 increased moderate physical activity by one hour and those aged 65 and older increased by half an hour per day, and all participants ate 200 g more fresh fruits and 50 g more fish/seafood per day, life expectancy at age 30 would increase by 4.83 and 5.39 years for men and women, respectively. In a more moderate risk reduction scenario referred to as the practical scenario, where improvements in each lifestyle factor were approximately halved, the gains in life expectancy at age 30 could be half those of the ideal scenario. However, the validity of these estimates in practise may be influenced by population-wide adherence to lifestyle recommendations. Our findings suggest that the current policy targets set by the Healthy China Initiative could be adjusted dynamically, and a greater increase in life expectancy would be achieved.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Experiments under upper-tropospheric conditions map the chemical formation of isoprene oxygenated organic molecules (important molecules for new particle formation) and reveal that relative radical ratios control their composition

Experiments with untreated municipal wastewaters from 47 countries showed that some samples selected for resistant E. coli, whereas non-resistant bacteria were favored in most cases, providing a nuanced view on resistance evolution in sewage.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Designing single molecules capable of complex sensing functions is challenging. Now, using crowdsourced RNA designs from the online game Eterna, compact single-molecule sensors have been demonstrated for a variety of tasks, including a complex three-input tuberculosis diagnostic. The development of a Monte Carlo Tree Search algorithm enabled automated design of similarly sophisticated nucleic-acid sensors.

Monoclonal antibodies and ligands targeting CD40 exhibit diverse agonistic and antitumor activities that are influenced by their design. Here, the authors identify mechanistic differences between clinically relevant anti-CD40 subclasses and CD40L, focusing on the dynamics and strengths of multi-bond formation at the single-molecule level.

Tilt-corrected bright-field scanning transmission electron microscopy offers enhanced cryogenic electron microscopy contrast and substantial improvement in dose efficiency for thick samples such as bacterial cells and large organelles, while still being able to perform single-particle analysis.

Genome-wide analyses in over one million self-reported cases and controls identify genetic variants associated with stuttering and find genetic correlations with autism, depression and impaired musical rhythm, supporting a potential neurological basis for stuttering.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

Experiments performed in the CERN CLOUD chamber show that, under upper-tropospheric conditions, new atmospheric particle formation may be initiated by the reaction of hydroxyl radicals with isoprene emitted by rainforests.

Many recent proteomics studies use either Olink or SomaScan platforms to quantify proteins in high-throughput, but the consistency between the two is unclear. Here, the authors measure proteins in the same samples using both platforms, finding only modest correlation, and compare associations with genetic variants and disease.

Neuromuscular junctions (NMJs) are denervated in amyotrophic lateral sclerosis (ALS) through unknown mechanisms. Here, the authors show immune cells infiltrating muscle of ALS patients and mouse models, driven by CCL2-CCR2, which can be blocked to protect NMJs.

Passive immunisation for respiratory syncytial virus for infants is recommended by the World Health Organization but products currently available have limited duration of protection. Here, the authors investigate the age distribution of infant hospitalisation for respiratory syncytial virus to inform optimal timing of immunisation.

Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.

The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task in mice.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

Nickel(II) dihalide precatalysts with bidentate nitrogen ligands are widely used in cross-coupling reactions, notably in combination with photosensitizers, forming catalytic systems that currently drive major conceptual and synthetic thrusts within organic chemistry. Here the authors show a general mechanism by which these precatalysts are converted to the reduced, catalytically active species, using a range of characterization and spectroscopic techniques.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

A cross-reactive antibody and T cell response is identified in a large portion of patients with multisystem inflammatory syndrome in children.

A meta-analysis of genome-wide association study data from 77,418 individuals of East Asian ancestry with type 2 diabetes identifies novel variants associated with increased risk of type 2 diabetes.

Inter-areal connectivity within the prefrontal cortex remains poorly understood. Here the authors describe an inhibitory projection within the medial prefrontal cortex that exerts top-down control over local inhibitory neurons causing disinhibition of output neurons and ultimately modulating behavior governed by the target area.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Here, the authors suggest that nitric oxide (NO) is an endogenous epigenetic regulator of gene expression by inhibiting DNA demethylation enzymes (TET and ALKBH2) and increasing DNA methylation at gene regulatory loci throughout the genome.

Conventional protein oxidation pathways typically involve free diffusion of reactive oxygen species (ROS), which primarily attack the protein surface. Here, the authors report a pathway of protein damage, O₂-confined photooxidation, where O₂ is captured in protein cavities and subsequently converted into multiple ROS which attack the protein interior.

Precision nutrition requires accurate predictions of individual metabolic responses to diets. Here, authors show their deep-learning model, McMLP, outperforms existing methods in predicting metabolite responses to dietary interventions.

A standardized, realistic phantom dataset consisting of ground-truth annotations for six diverse molecular species is provided as a community resource for cryo-electron-tomography algorithm benchmarking.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk