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An in vivo approach combining high-throughput screening with cell type-specific readouts could enable elucidation of genotype-phenotype relationships in complex tissues. We developed an in vivo gain-of-function Perturb-seq platform, termed iGOF-Perturb-seq, to build a functional atlas of ~1000 transcription factors (TFs) in astrocytes, a cell type essential to many brain functions. We then identified cofunctional modules, annotated uncharacterized TFs, and predicted disease-associated TF...

CONCLUSION: Validity and reliability are established for this ability-based QoL scale, within a sample of mostly cognitively unimpaired, community-dwelling older adults. The QFS-5 aligns with EQ-5D, demonstrating potential clinical and research utility to measure relevant patient-reported QoL outcomes.

The Greenland shark (Somniosus microcephalus), with a lifespan estimated around 300 years, represents a unique model for studying vertebrate longevity. Here, we characterize its cardiac aging profile and compare it with two other species: the deep-sea shark Etmopterus spinax and the short-lived teleost Nothobranchius furzeri. Histological analysis revealed extensive interstitial and perivascular fibrosis throughout the ventricular myocardium of S. microcephalus, affecting both compact and spongy...

Successful embryo development, acquisition of uterine receptivity, implantation, and decidualization during the peri-implantation window are essential events that ensure a healthy pregnancy. While ovarian aging has long been considered the primary cause of age-related decline in fertility, emerging evidence demonstrates that uterine aging also compromises the ability to support pregnancy. The chromosomal passenger complex, composed of pIncenp, Aurora B, Survivin, and Borealin, is a critical...

Thymic negative selection is characterized by the apoptosis of autoreactive thymocytes and plays a critical role in maintaining self-tolerance. Numerous apoptosis-related genes influence cell fate during T-cell development. The PERP protein functions in apoptosis induction and as a tumor suppressor; however, p53 targets the Perp promoter, leading to its downregulation in various cancers. We investigated the specific role of Perp by studying conditional knock-out mice exhibiting partial thymic...

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The steroid hormone 5-androstene-3β,17β-diol (ADIOL) was discovered nearly a century ago in humans, yet its physiological functions have remained poorly understood. Using C. elegans, we identify ADIOL as essential for several pro-healthspan effects of fasting and caloric restriction (CR). These dietary restriction regimens activate an ADIOL-NHR-91-kynurenic acid signaling axis, partly through transcriptional programs associated with ADIOL biosynthesis. Within this axis, ADIOL acts through...

Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells (ECs) and their role in endothelial dysfunction with aging...

Mental and nervous system disorders often co-occur with cardiovascular diseases in aging populations, yet the biological relationships underlying these associations remain incompletely understood. Using heart and brain imaging data from 33,573 UK Biobank (UKB) participants, we developed a brain age prediction model to estimate the brain age gap (BAG), an imaging-based marker of brain aging. We then examined BAG as a mediator between 82 cardiac imaging-derived phenotypes (IDPs) and 11 disorders....

Aging research has traditionally focused on lifespan and healthspan as primary outcome domains, implicitly treating chronological time as a uniform container of value. The memory-structured reconstruction of extended chronological intervals has not been systematically examined as an aging-related variable. I introduce experienced longevity, defined as the amount of lived time subjectively contained within a fixed chronological interval. Drawing on established distinctions between retrospective...

Science, Volume 392, Issue 6796, April 2026.