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Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or...

Trained immunity, an emerging treatment strategy, confers long-term anti-tumour memory by modulating epigenetic and metabolic reprogramming of innate immune cells, offering a novel pathway for immunotherapy of haematological malignancies. This article systematically outlines the mechanisms by which inducers such as β-glucan, Bacille Calmette-Guérin (BCG) and cytokines train key effector cells including macrophages and natural killer (NK) cells. It further analyses how ageing-encompassing both...

The human antiviral antibody reactome provides a cumulative molecular record of immune exposures. Using high-resolution VirScan profiling, we compared epitope-level antibody responses across early childhood and adulthood. Infants are born with maternal IgG antibodies, but these antibodies decay rapidly and are replaced by endogenous responses to ~22 new viral exposures within three years. Pediatric antibody reactivities remain highly dynamic until about age 7 and are broad in epitope specificity...

Nutrition shapes development, health and risk of disease over the life course and across generations. The predominant approaches to understanding these relationships have either been to consider the effects of single nutrients, one at a time, or to consider associations with food types and dietary patterns. Although, to date, the single-nutrient approach has defined much of the scientific enquiry and public debate on the macronutrients - carbohydrate, fat and protein - there is an emerging...

Biodiversity loss in the present era requires new tools for studying nonmodel organisms. Elephants are both an endangered species and excellent models for studying complex phenotypes including size, social behavior and longevity. Here we report the first derivation of elephant (Elephas maximus) induced pluripotent stem (emiPS) cells. We achieved emiPS cells using two approaches: (1) a two-step process of chemical media induction and colony selection followed by over-expression of elephant...

Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase...

Hepatic inflammation and immunosurveillance play major roles in the progression of liver cancer. A common trigger for hepatic inflammation is oxidative stress, which stems from mitochondrial dysfunction. Here, we demonstrate that deletion of the mitochondrial stress integrator OMA1 increases hepatic primary tumor incidence and impairs survival in mice. Persistent activation of the KEAP1-Nrf2 oxidative stress pathway in the absence of OMA1 promotes early liver injury, which progresses into...

Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline Ca^(2+) levels and impaired long-term...

APOE4, the major genetic risk factor for Alzheimer's disease (AD), and ATP-binding cassette-A1 (ABCA1), required for lipidation of APOE are gene products of the liver X receptor (LXR) receptor. LXR agonists have been validated in animal models as therapeutics for AD, atherosclerosis, and many other diseases. Clinical progress has been thwarted by unwanted hepatic lipogenesis. Structurally diverse LXR ligands were profiled in coregulator TR-FRET (CRT) assays analyzing ligand-induced coactivator...

The accumulation of aberrant proteins or their impaired clearance leads to neurodegenerative diseases (NDs). The protein amino terminus (Nt) and its modifications determine the fate of proteins and their cellular effects. Nt acetylation, Nt methylation, and Nt myristoylation are protein Nt modifications implicated in the pathogenesis of proteinopathies like Alzheimer's, Parkinson's, and Huntington's diseases by regulating the protein lifespan, folding, and interaction with protein/DNA. In...

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) represent a promising cell-free strategy for intervertebral disc degeneration (IDD). Here, we obtained oxidative stress-preconditioned exosomes (O-Exos) from BMSCs exposed to low-concentration hydrogen peroxide. Compared with exosomes from untreated cells (N-Exos), O-Exos more effectively delayed nucleus pulposus (NP) cell senescence and attenuated IDD in vitro and in vivo. The superior effects of O-Exos were associated with...

Aging-related metabolic dysregulation and vascular vulnerability contribute substantially to stroke susceptibility, yet subtype-specific metabolic signatures remain incompletely characterized. Employing a nested case-control design within the Taizhou Longitudinal Study, we quantified 296 lipoprotein parameters and 54 metabolites in 1208 stroke-control pairs using nuclear magnetic resonance. Logistic regression estimated subtype-specific associations, and machine learning constructed prediction...

Resting heart rate (RHR) is an accessible measure that may reflect age-related cardiovascular and autonomic dysregulation relevant to cognitive ageing. However, evidence linking RHR with cognitive outcomes is inconsistent, and most studies relied on single baseline measurements that may not capture cumulative exposure. This study examined the associations of baseline and longitudinally averaged RHR with cognitive decline and dementia in older adults. This was a secondary analysis of the ASPirin...