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Nuclear speckles (NS) are membraneless nuclear organelles that act as critical hubs for pre-messenger RNA splicing. Defects in splicing are linked to several human diseases, including cancer, Alzheimer's disease, and dystrophies. While CLK kinases regulate the mobilization of splicing factors from NS, the molecular mechanisms underlying NS assembly and dissolution remain unclear. Using an adaptation of the Biotinylation by Antibody Recognition technique, we identified polyphosphate (polyP) as a...

Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33) in villi from unexplained recurrent pregnancy loss (URPL) patients, concomitant with elevated trophoblast senescence. More importantly, il33 knockout mice exhibited placental senescence and impaired trophoblast invasion. Mechanistically, senescent trophoblasts displayed metabolic...

Activation of RAS oncogenes in normal cells triggers a stable cell cycle arrest known as RAS-induced senescence (RIS), marked by persistent DNA damage and extensive epigenetic remodeling. Although bypassing RIS promotes tumorigenesis, the molecular mechanisms underlying this transition remain poorly defined. Here, we demonstrate that RIS cells accumulate high levels of R-loops-three-stranded DNA-RNA hybrids-that frequently co-localize with DNA G-quadruplexes formed on the non-template DNA...

Telomere healing seals the broken ends of DNA double-strand breaks by adding de novo telomeres. In the ciliate Paramecium, telomere healing results in chromosome fragmentation, which ultimately leads to clonal ageing. Despite its importance, where and how chromosomes fragment and undergo telomere healing, and to what extent sequence preferences exist, remain poorly understood. To investigate chromosome fragmentation, we enriched for telomere-containing sequences from the complex, highly...

Some organisms exhibit a remarkable ability to adapt their life history strategies within a single lifespan in response to dynamic biotic and abiotic cues, such as Caenorhabditis elegans larval facultative diapause. However, the molecular basis of how conspecific and prey cues are processed to conditionally alter the time to reproductive maturation remains largely unexplored. Here we discover that the longest transcript of the forkhead transcription factor FKH-7/FOXP is expressed and acts in C....

In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β, respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality. Here, we investigate the biological basis of α and β using the nematode...

The retina provides a unique window into systemic health, yet molecular mechanisms linking retinal features (oculomics) to clinical traits in aging remain unclear. In this study, we leveraged the homogeneous Canton 70 s Alumni Cohort (N = 258 females aged ~70 years) to minimize socio-demographic confounders and extracted oculomic features from fundus images using AutoMorph. Linear mixed-effects models identified 129 significant associations between oculomic and clinical features (p < 0.05)....

Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing...

Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch...

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