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The traditional pathological framework of Alzheimer's disease (AD) primarily focuses on the accumulation of β-amyloid (Aβ) and tau proteins. However, therapeutic strategies targeting these molecules have repeatedly encountered setbacks in clinical translation. Recent studies have progressively revealed that the dynamic interaction network among intracellular organelles plays a central role in the pathogenesis of AD. This systematic review examines the independent dysfunctions of three key...

The aberrant aggregation of tau leads to loss of its physiological functions and gain of toxic functions, and plays a crucial role in the pathogenesis of tauopathies including Alzheimer's disease (AD). Targeting tau aggregation is considered a promising strategy for treating tauopathies. The BRICHOS family consists of a variety of proteins containing the BRICHOS domain. Certain endogenous BRICHOS domains may inhibit the pathological aggregation of disease-associated proteins. However, the...

Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease...

The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical...

GM2 gangliosidoses, including Tay-Sachs (TSD) and Sandhoff (SD) diseases, are lysosomal storage disorders with neurological manifestations caused by the excessive accumulation of GM2 ganglioside due to the deficiency of the β-hexosaminidase A (HexA). Although gene therapy approaches are underway, concerns regarding efficacy and safety remain. Here, we evaluate a tyrosine-mutant adeno-associated virus serotype 9 (AAV9/3) vector encoding modified HEXB (modHEXB) wherein nine amino acid residues are...

Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in...

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Intratumoral heterogeneity in metastatic cancers complicates effective treatment, as distinct tumor subclones display varying drug sensitivities and metastatic capabilities, interacting through mechanisms that remain poorly understood. In this study, we utilized an isogenic ovarian cancer cell pair distinguished by differential β-catenin signaling: non-metastatic (NM) cells with low β-catenin and highly metastatic (HM) cells with elevated β-catenin signaling. Co-engrafting NM and HM cells...

Advanced glycation end products (AGEs) drive metabolic dysfunction, inflammation, and age-related disease, and their accumulation accelerates after menopause. Preclinical studies show that GLYLO, a five-compound glycation-lowering formulation (alpha-lipoic acid, nicotinamide, pyridoxine, benfotiamine, and piperine), reduces AGE burden and improves metabolic health, but its translational relevance in humans is unknown. The Glycation Reduction and Aging: a Clinical Evaluation (GRACE) trial is a...

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and...

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....