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Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing effective treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies. Gene-based association tests provide a more powerful alternative to traditional SNP-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate...

Alzheimer's disease (AD) has a strong genetic predisposition. Genome-wide association studies have identified multiple risk loci, yet many non-coding variants remain uncharacterized. Machine learning-based polygenic risk scores (PRS) enhance prediction by modeling genetic epistasis and sex-specific risks. This review summarizes AD genetic risk factors, PRS methodologies, and ML-based AD risk prediction. It also highlights challenges such as population bias, functional validation, and integrating...

CONCLUSIONS: Our framework establishes a powerful new paradigm for epigenetic research that can be extended to other complex diseases, offering both a valuable tool for variant effect interpretation and a promising strategy for uncovering novel disease mechanisms through epigenetic profiling.

In the context of cognitive neuroscience research on aging, older women are often overrepresented in observational research, whereas men are overrepresented in clinical trials. Factors underlying the selection bias between and across genders in research on aging are currently poorly understood. Addressing this knowledge gap is critical to provide guidance on how we might mitigate selection bias and improve the generalizability, robustness, and reproducibility of our findings. We aimed to...

Adiponectin is an adipose tissue-derived peptide hormone that exerts beneficial metabolic effects in many tissues throughout the body. It is most well-known for its ability to enhance insulin sensitivity and dampen chronic inflammation. The impact of age on adiponectin is controversial; levels of adiponectin in circulation in older individuals have been linked to both positive and negative effects. This review integrates genetic, mechanistic, and therapeutic perspectives on adiponectin in aging....

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation, where a pattern considered abnormal in one cell type may be normal in another, complicate the identification of early methylation changes that drive or signal disease development. This complexity can obscure early markers of increased disease risk, making it challenging to detect and intervene in disease processes at their inception. Here, we report 31,744 CpG loci exhibiting highly consistent methylation profiles...

Extracellular vesicles (EVs) are key mediators of intercellular communication and may reflect physiological changes during aging. We analyzed plasma-derived EVs from a healthy aging cohort stratified by age, using size exclusion chromatography, surface profiling, nanoparticle tracking, and small RNA sequencing. While EV size and concentration remained largely unchanged, older individuals showed shifts in EV immunophenotype consistent with immunosenescence and displayed distinct miRNA signatures...

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ObjectivesPhysical health often declines with age, yet subjective well-being (SWB) tends to remain stable. Stereotype Embodiment Theory proposes that internalized self-perceptions of aging (SPAs) shape how physical changes are interpreted. This study tested whether SPA buffered the affective impact of health decline. The role of SPA was tested in midlife and late adulthood.MethodsData came from the ILSE, a population-based study of 1,002 adults initially aged 40 or 60 and followed for 20 years....

This study examined hypothesized differences across males and females in the relationship between cognitive trajectories and mortality in older adults. Data were drawn from the ZARADEMP study on dementia and depression in adults aged 55 and older in Zaragoza, Spain. A total of 2403 cognitively healthy individuals who completed at least three of four waves over a 12-year follow-up were included. Cognitive trajectories were derived from Mini-Mental State Examination (MMSE) scores. Using growth...

Aging-associated sarcopenia is driven in part by the progressive loss of type II glycolytic fibers and the functional decline of their resident stem cells, the satellite cells (SCs). We show here that these defects result from attenuation of the hypoxia-inducible factor-1α (HIF-1α) signaling pathway and can be reversed by pharmacological HIF-1α reactivation. In the tibialis anterior muscle of 18-month-old C57BL/6J mice, HIF-1α protein abundance decreased by ≈46% and canonical targets (Vegfa,...

Glutamate accumulation linked to Parkinson's disease (PD) pathogenesis. While glutamate chemical exchange saturation transfer (GluCEST) imaging has been applied in various CNS disorders, its utility in PD remains underexplored. This study investigated the clinical relevance of dentate nucleus and cerebellar hemisphere glutamate levels across PD motor subtypes. We enrolled 36 resting-tremor predominant PD (PDRT), 33 akinetic-rigid predominant PD (PDAR), and 40 healthy controls (HCs). GluCEST data...

The current clinical diagnostic criteria for Parkinson disease (PD) have limitations and are inherently insensitive to the earliest stages of disease, when classical motor signs can be absent. Imaging and genetic tests are currently used to support or establish a diagnosis of PD, but no validated biomarker-based diagnostic framework currently exists. Substantial progress has been made in the field of molecular disease markers, most notably with the development and validation of seed...

Dementia diagnosis increasingly relies on blood-based biomarkers, yet their performance in diverse populations remains insufficiently characterized. Latin America, with substantial genetic and environmental heterogeneity, is particularly underrepresented in biomarker research. Here we show that plasma AT(N) biomarkers can distinguish Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) in a multinational Latin American cohort (N = 605). Aβ(42)/Aβ(40) amyloid-β ratios were...

Ageing entails a variety of cellular and physiological changes that increase susceptibility to disease and death. A significant contributor to ageing is cellular senescence, a state of irreversible cell cycle arrest triggered by stressors such as DNA damage, telomere shortening, and the senescence-associated secretory phenotype. It is challenging to understand the nonlinear interactions between these complex mechanisms using conventional laboratory approaches. Mathematical modelling is capable...

Ischemic stroke (IS) is a cerebrovascular disorder that, if left untreated, can lead to secondary neurodegeneration and Post Stroke Cognitive Impairment (PSCI). Current therapies offer a narrow time window, highlighting the need for alternative approaches. Flavonoids, known for their neuroprotective properties, are promising candidates. Chrysin, a flavone with multiple pharmacological activities, was investigated for its therapeutic role in IS and PSCI. Pharmacokinetic and toxicological profiles...

Copper (Cu)-based single-atom catalysts (SACs) enable electrocatalytic CO(2) reduction into methane (CH(4)) fuel for thermal power plant decarbonization, yet conventional Cu SACs face industrial deployment barriers like instability and sluggish kinetics caused by d - p orbital coupling. Herein, we develop a Cu-Ti(1)O(3) catalyst with localized Cu single-atom sites by oxygen vacancy (O(v))-involved orbital engineering, achieving industrial-level CH(4) production. Theoretical and in-situ studies...

The aging population experiences concurrent brain aging and deterioration of bone health. Imaging-derived brain age gap (BAG) demonstrates enhanced predictive capacity for age-related pathologies compared to chronological age. This study included 28,705 participants who underwent brain MRI at a mean age of 63.2 years, with brain age predicted from 1705 imaging-derived phenotypes using LASSO regression (mean predicted brain age: 63.2 years). We then assessed the associations of BAG with BMD at 4...

Arms races between parasites and hosts are key drivers of evolution. Selfishly replicating transposable elements (TEs) are thought to follow similar dynamics, but strong evidence is missing. We test this in termites, social insects in which TEs have been linked to ageing. Sequencing genomes and profiling DNA methylation across the termite phylogeny reveal corresponding phylogenetic signals in TEs and TE methylation, indicative of co-evolution. TE methylation reduces TE success, as both TE...

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