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Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons

2 weeks ago
Parkinson's disease (PD) is defined pathologically by loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). Yet synaptic dysfunction emerges much earlier, making it essential to define the mechanisms that drive early nigrostriatal deregulation. In the SNc, molecularly distinct dopamine neuron subtypes show differential susceptibility to PD. Here, we used intersectional genetic mouse models to determine how the PD-linked kinase LRRK2 affects vulnerable dopamine subtypes....
Chuyu Chen

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations

2 weeks ago
Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated...
Nuzulul Kurniansyah

Traumatic brain injury: Multi-omics insights into brain aging, neurodegeneration, and precision therapeutics

2 weeks ago
Traumatic brain injury (TBI) is a major cause of mortality and persistent neurological disability and is increasingly recognized as a potential contributor to accelerated brain aging and long-term neurodegenerative processes. Beyond the immediate mechanical insult, TBI initiates dynamic secondary injury cascades involving chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic and axonal degeneration, metabolic disturbances, and blood-brain barrier disruption. The...
Alaa Shafie

Intracranial aneurysms as a manifestation of premature vascular aging: Cellular senescence, inflammaging, and wall degeneration

2 weeks ago
Aging is a major risk factor for the formation, growth, and rupture of intracranial aneurysms, but the underlying biological mechanisms remain incompletely understood. Beyond chronological aging, accumulating evidence suggests that vascular aging is driven by cellular senescence, chronic inflammation, and hemodynamic stress, which together contribute to aneurysm wall degeneration. In this review, we synthesize current evidence on the role of aging in intracranial aneurysm biology, with a...
Takuma Maeda

Artificial Intelligence and Health Care for Older Adults, a Future for All of Us

2 weeks ago
We are racing towards a time wherein the largest demographic of the population will be comprised of older adults and where it is now also possible to measure, monitor, and diagnose long term risk factors and provide effective and valuable preventative interventions. Thanks to the achievements of modern health care, we have reached a tipping point in the need for a robust geriatric workforce. Through the implementation of thoughtful, deliberate, and collaborative processes, Artificial...
Peter M Abadir

Low-burden AI approach for cross-national early identification of cognitive impairment using real-world questionnaire response behaviours

2 weeks ago
Under-recognition of cognitive impairment remains a major global public health challenge, particularly in low- and middle-income countries. Many cases go unrecognised because conventional cognitive assessment is resource-intensive and difficult to scale across diverse populations. Here we show that easily captured indicators of reduced survey response quality, derived from how older adults answer routine psychosocial questionnaires, can identify cognitive impairment risk across countries. Using...
Hongxin Gao

Nanopore sequencing identifies parent-of-origin specific age-associated methylation changes at imprinted loci in the human genome

2 weeks ago
Aging is accompanied by widespread DNA methylation changes, yet their full genomic scope and parent-of-origin dynamics remain poorly understood. Here, we apply nanopore long-read sequencing to 7,284 whole blood samples enabling methylation measurements of 17,959,684 high-quality CpG units. Over 20% of the measured high quality CpG units undergo age-associated changes, predominantly hypomethylation. From these data, we construct a methylation aging clock from 1,373 high-quality CpG units, with...
Brynja Sigurpalsdottir

Whole-brain cholinergic modulation following computerized cognitive training in healthy older adults: a [18F]FEOBV PET study

2 weeks ago
The cholinergic system is central to attention, learning, and neuroplasticity and undergoes progressive degeneration with aging. Neuroplasticity-based computerized cognitive training is a scalable, non-pharmacological strategy to support cognitive health in older adults, yet its neurobiological mechanisms remain unclear. [18F]Fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET) quantifies presynaptic cholinergic terminals via vesicular acetylcholine transporter (VACht) binding,...
Ana de Figueiredo Pelegrino

Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease

2 weeks ago
Microtubules are well-researched components of the cytoskeleton, yet we lack a holistic understanding that bridges molecular and cellular details with the broader functions of the microtubule cytoskeleton in development, ageing and disease. For example, how microtubule properties and functions are affected by tubulin post-translational modifications, disease-related mutations or variation of the microtubule lattice remains unexplored. In this Roadmap, we argue that integrating various...
Carsten Janke

Lifelong dietary interventions selectively reverse age-associated circulating microRNA upregulation in a time-dependent manner in female MMTV-TGF-α mice

2 weeks ago
Breast cancer is among the leading causes of cancer mortality worldwide, with aging as a major risk factor. Caloric restriction (CR) is a well-established non-pharmaceutical intervention that extends healthspan and delays tumorigenesis, yet the systemic molecular mechanisms remain elusive. Both chronic and intermittent CR influence metabolic homeostasis, but their long-term effects on circulating miRNAs in breast cancer predisposition are unclear. Here, we examined how chronic and intermittent...
Bilge Guvenc Tuna

An in vivo resource of age-regulated C. elegans intestinal secretory-pathway proteins highlights secreted enzymes associated with lifespan regulation

2 weeks ago
Secreted proteins are essential to modulate homeostasis in the extracellular space and facilitate communication to distal cells or tissues. Yet, the identity and functional importance of extracellular proteins in aging have been understudied. Here we use proximity labeling followed by quantitative proteomics to systematically characterize proteins along the intestinal secretory pathway in C. elegans, focusing on secreted proteins. We identify intestine-secreted proteins that are modulated with...
Jason W Miklas

Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture

2 weeks ago
Endolysosomal dysfunction is a hallmark of Alzheimer's disease and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity in Caenorhabditis elegans and human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal...
Jessica Tittelmeier