This Review discusses the effects of three age-associated stressors—loss of proteostasis, oxidative damage and dysregulated nutrient sensing—on global protein synthesis and highlights how altered translation is used by the cell as a stress sensor.

In this Review, Lusk et al. discuss emerging insights into nuclear pore complex variability with regard to composition and dilation state, and propose nuclear mechanics as a key determinant of driving such plasticity and any associated diseases.

As biomedical research prioritizes human models and translational promise, classic model organisms are increasingly dismissed. Here we argue that they have a lasting value, both in enabling discovery and in cultivating scientific thinking, by training researchers in systems reasoning, integrative thinking and independent inquiry.

Watt, Dauber, Szkop and colleagues find that H3K4me3 remodels 5′UTR selection in hypoxia and that this process is independent of HIF-1 transcriptional mechanisms.

The authors identify a chemical cocktail to generate totipotent-like cells, which they then use to build an embryo model. This model captures a developmental spectrum from early embryogenesis to post-implantation events.

Khawaja et al. show sex-specific differences in neuronal-activity regulation by chaperone-mediated autophagy and that loss of chaperone-mediated autophagy leads to defective neuronal physiology and increased seizure susceptibility, linking chaperone-mediated autophagy to neuronal excitability.

Nguyen, Collier et al. find a mitochondria–lysosome inflammatory pathway regulated by the SUMO E3 ligase MAPL, which promotes vesicular mtDNA transport to lysosomes and subsequent gasdermin-dependent lysosomal permeabilization to activate pyroptosis.

Wu, Zhang and colleagues introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive learning-based method for spatial transcriptomics analysis that detects low-variance structures.

The authors show that the endoplasmic reticulum-phagy receptor FAM134B interacts with SCAP to regulate cholesterol biosynthesis, sequestering SCAP when endoplasmic reticulum cholesterol is high but dissociating upon low cholesterol levels, allowing SCAP to activate cholesterol synthesis.

As biomedical research prioritizes human models and translational promise, classic model organisms are increasingly dismissed. Here we argue that they have a lasting value, both in enabling discovery and in cultivating scientific thinking, by training researchers in systems reasoning, integrative thinking and independent inquiry.

We hypothesize that stress-induced RNA structural changes, stabilized by RNA-binding proteins in biomolecular condensates, propagate via conformational catalysis in a prion-like manner across generations. Our model suggests that RNA structure encodes heritable memory, and its roles should be explored in epigenetic inheritance, evolutionary adaptation and disease.