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Nuclear receptors (NRs), a superfamily of ligand-activated transcription factors, serve as master regulators linking signaling molecules to the genome, coordinating a variety of essential physiological processes in development, homeostasis, metabolism, and reproduction. As the central biological sensors, NRs respond to a wide range of endogenous substances and xenobiotics, thereby orchestrating critical processes such as metabolic homeostasis, inflammatory and immune responses, cellular...

Extracellular matrix (ECM), once regarded as a passive structural scaffold, is now recognized as a key hallmark of aging. In the context of female reproductive aging, ECM remodeling acts as a pivotal driver of functional deterioration. This review outlines how age-associated ECM alterations, including collagen cross-linking, elastin degradation, and perturbed biomechanics, orchestrate ovarian aging through the mechanical activation of Hippo signaling, compromise endometrial receptivity via...

Aging clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneities remain underdeveloped. This study introduces scAgeClock, a novel gated multi-head attention neural network-based single-cell aging clock model. Leveraging a large-scale dataset of over 16 million single-cell...

The muscle-tendon junction (MTJ) is a specialised interface between muscle and tendon and transmits muscle-generated force to the tendon. The MTJ is particularly vulnerable to injuries compared to muscle and tendon and becomes more injury prone with age. Despite its clinical importance, the mechanisms driving MTJ ageing and age-related functional deterioration remain poorly understood. In this study, young (3-month-old) and old (23-month-old) male mice were used to provide the first...

CONCLUSION: Findings suggest a substantial burden of multimorbidity in NORC residents and reinforce the importance of designing programs in NORCs to help older adults with multimorbidity age in place.

The aging of the vasculature is a primary determinant of cardiovascular disease risk and a key contributor to organismal decline. While our understanding of its molecular underpinnings has grown exponentially, the translation of these discoveries into effective clinical interventions remains a major hurdle. This review provides a critical appraisal of the current state of vascular aging pharmacology. We first dissect the core pathogenic mechanisms, including epigenetic drift, chronic low-grade...

CONCLUSION: A highly efficient and cost-effective PND model was successfully established in 4-month-old SAMP8 mice. This model stably recapitulates core PND pathologies and serves as a valuable tool for investigating pathogenesis and screening therapeutic strategies for PND.

Motor dysfunction in different subtypes of mild cognitive impairment (MCI) and dementia have been widely reported. Whether motor profiles could differentiate between MCI subtypes such as amnestic MCI (aMCI) and non-amnestic MCI (naMCI) has not been systematically studied, but could augment the diagnostic process to improve diagnostic accuracy early on in the disease process. Here, we compare motor function across the motor domain between cognitively unimpaired (CU; n = 878), aMCI (n = 89) and...

The ERROR project tried enticing reviewers with payments. Now, it’s launching a journal—and promising papers as rewards

The core pathological hallmark of Parkinson's disease (PD) is the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), driven by misfolding and aggregation of a-synuclein (aSyn) into Lewy bodies. This triggers severe cellular dysfunction, including endoplasmic reticulum (ER) stress and the dysregulation of the unfolded protein response (UPR). TMBIM6, an anti-apoptotic ER protein, inhibits the UPR sensor IRE1a. Although TMBIM6 exhibits...

The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and their associations with brain aging. In this study, we characterized the associations between 73 country-level physical and social exposomal factors and multimodal brain age in 18,701 participants from 34 countries (healthy individuals and those with Alzheimer's disease,...

Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data...

The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease. Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by...

Stroke remains a leading cause of mortality and long-term disability worldwide, and secondary injury mechanisms-particularly neuroinflammation-continue to limit functional recovery despite advances in reperfusion therapies. Post-stroke neuroinflammation is not a static or uniformly deleterious process but a temporally evolving and spatially heterogeneous continuum shaped by cellular transcriptional plasticity, metabolic reprogramming, and systemic modifiers such as aging and comorbidities....

Chronic neuroinflammation is a hallmark of neurodegenerative and cerebrovascular diseases and is largely driven by dysfunctional activation of microglia and astrocytes. Recent advances in single-cell transcriptomics and metabolic profiling have revealed the remarkable heterogeneity and plasticity of these glial cells, highlighting their dual roles in neuroprotection and neurotoxicity. Upon activation, microglia adopt pro-inflammatory phenotypes and undergo metabolic reprogramming characterized...

CONCLUSION: These findings reveal a novel pulse-derived harmonic signature as a biomarker for prefrailty, indicating that subtle arterial functional alterations detectable via spectral analysis are associated with early physical vulnerability and may help bridge vascular pathology with geriatric decline. The discriminative performance (AUC = 0.70) is competitive with existing tools, while the 1-minute, noninvasive protocol establishes a favorable balance between accuracy and clinical...

CONCLUSIONS: Our study identifies CISD2 and MST1 as high-confidence proteins implicated in frailty pathogenesis through brain and plasma mechanisms, respectively. These findings provide crucial molecular insights into aging and highlight promising targets for therapeutic intervention to mitigate frailty.

CONCLUSIONS: Blood neurodegeneration biomarkers show complex associations with cognition that involve direct and physical performance-related pathways. Our findings suggest that physical performance may serve as an early marker and therapeutic target in neurodegenerative aging, particularly in vulnerable populations, though longitudinal studies are needed to establish temporal relationships.

Aging is a complex, multifactorial process, influencing disease risk and overall health. While chronological age (CA) is widely used in clinical practice, it fails to capture individual aging trajectories. Current approaches to estimate biological age (BA) often focus on single organs or predefined clinical biomarkers, limiting comprehensive assessment. We introduce a novel, purely imaging-driven deep learning framework for organ-specific BA estimation across seven organ systems. Our...