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Extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau are the two main pathological hallmarks of Alzheimer's disease (AD). Although the co-occurrence and synergistic effects of Aβ and Tau are well established, the mechanisms underlying their interplay in a biomolecular condensate environment remain unclear. Here we show that Aβ40 does not undergo liquid-liquid phase separation (LLPS) but significantly enhances Tau phase...

Parkinson's disease (PD) and related familial Parkinsonism are defined by motor dysfunction, but the specific upstream molecular causes of these clinical symptoms can vary widely. We hypothesize that these causes converge onto a limited number of core cellular pathways. To investigate this, we created a collection of 24 genetically well-controlled Drosophila models of familial forms of PD and related mono-genic forms of Parkinsonism. Using unbiased behavioral screening and machine learning we...

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Cellular senescence, originally described as a finite proliferative arrest in cultured somatic cells, has since been recognized as a central mechanism underlying aging and the development of age-associated disorders. The progressive accumulation of senescent cells (SnCs) promotes chronic inflammation through the senescence-associated secretory phenotype (SASP) and circumvents immune-mediated clearance by upregulating pro-survival and immune checkpoint pathways. Early "first-generation"...

A growing body of evidence supports the role of nutrient sensing and metabolism pathways in regulating ageing rate and healthspan, but the diversity of human lifestyles challenges our ability to identify the mechanisms of this age acceleration. Here, we examine how the transition of wild King penguins to zoo husbandry can closely mimic the shift to a Western lifestyle in humans, and shed light on conserved epigenetic changes in responses to sedentary conditions. We show that, just like modern...

Cellular morphology is tightly linked to function, but how subcellular transcript localization contributes remains unclear. Using microglia, the brain's resident macrophages, as a model, we combined multiplexed error-robust fluorescence in situ hybridization with immunohistochemistry to map how morphology and subcellular mRNA localization interact with function in young and aged mouse brains. We show that mRNA spatial organization varies across microglial states and defines distinct localization...

The postmenopausal decrease in estrogen production contributes to a significant increase in the risk of age-related diseases. There is an identified gap in the field regarding the effectiveness of targeted interventions for specific groups of women at increased risk, and whether these interventions can support successful aging and reduce mortality. Data regarding 2239 Caucasian female participants of the PolSenior study aged 65 and over were analyzed. Based on strict criteria, participants were...

CONCLUSIONS: This work establishes a valuable transcriptomic resource for glial GABA-associated ASH neuronal aging and identifies candidate pathways, offering critical molecular insights to dissect age-related neurodegeneration mechanisms and inform potential therapeutic targets.

Pre-Inca elites wore headdresses made of feathers from Amazonian macaws

Insects must perform tricky internal calculations to travel in a straight line

Newly mapped brain circuitry in mice links tooth grinding to pleasure pathways

Intraocular pressure is tightly regulated by the conventional outflow tissues, preventing ocular hypertension that leads to neurodegeneration of the optic nerve, or glaucoma. Although macrophages reside throughout the conventional outflow tract, their role in regulating intraocular pressure remains unknown. Using macrophage lineage-tracing approaches, we uncovered a dual macrophage ontogeny with distinct spatial organization across the mouse lifespan. Long-lived resident tissue macrophages were...

Infraslow (<0.1 Hz) global brain activity, quantified by the global mean blood-oxygenation-level-dependent (gBOLD) signal in resting-state functional magnetic resonance imaging (fMRI), is elevated during sleep and coupled to cerebrospinal fluid (CSF) dynamics, a key pathway for the brain waste clearance implicated in neurodegenerative disorders such as Alzheimer's disease. However, the effect of sleep deprivation on gBOLD activity and its interaction with aging remain poorly understood. Using a...

Histone modifications represent an untapped resource for biological age prediction that overcomes limitations of traditional DNA methylation-based epigenetic clocks. Here, we developed and validated histone modification-based epigenetic clocks by systematically analyzing publicly available ChIP-seq datasets spanning six tissue types and six histone marks. We identified age-associated loci and constructed 36 tissue-specific epigenetic clocks that demonstrated strong resilience to technical and...

Infraslow (<0.1 Hz) global brain activity, quantified by the global mean blood-oxygenation-level-dependent (gBOLD) signal in resting-state functional magnetic resonance imaging (fMRI), is elevated during sleep and coupled to cerebrospinal fluid (CSF) dynamics, a key pathway for the brain waste clearance implicated in neurodegenerative disorders such as Alzheimer's disease. However, the effect of sleep deprivation on gBOLD activity and its interaction with aging remain poorly understood. Using a...

Parental age and inbreeding have both been shown to have substantial fitness effects in laboratory experiments and in observations of wild animals. These demographic effects are likely to be strongly impacted by habitat fragmentation and warming temperatures, so understanding them is a priority. In insects and other ectotherms, some processes implicated in senescence are dependent on temperature. Anticipated changes in climate may therefore have direct effects on senescence in insects, or...

Pharmacological modulation of ageing is viewed as a viable route to extending lifespan and healthspan, yet the efficacy of putative geroprotectors may depend strongly on physiological and environmental context. Lithium chloride (LiCl) has been reported to extend lifespan in several model organisms, but evidence remains inconsistent and the role of reproductive investment-an energetically costly and often lifespan-correlated process-has rarely been examined. We tested the effects of dietary LiCl...

Neurodegenerative diseases are a set of devastating medical conditions in which neuronal loss associated with the aggregation of toxic proteins leads to progressive cognitive impairment. These diseases are usually modeled in animals by mimicking late disease stages through genetic modifications that aggressively accumulate proteins that damage the brain. However, these diseases typically unfold over decades, and disease-associated genes are known to have important, but understudied, biological...

Neurodegenerative diseases are a set of devastating medical conditions in which neuronal loss associated with the aggregation of toxic proteins leads to progressive cognitive impairment. These diseases are usually modeled in animals by mimicking late disease stages through genetic modifications that aggressively accumulate proteins that damage the brain. However, these diseases typically unfold over decades, and disease-associated genes are known to have important, but understudied, biological...

Identifying biomarkers that precisely track the neurodegenerative component of Alzheimer's disease (AD) is essential for effective clinical management. Here we show that cerebrospinal fluid (CSF) levels of the synaptic proteins NPTX1 and NPTXR are robust indicators of disease severity and future clinical progression. In two independent, multi-ethnic cohorts spanning the AD continuum (n = 635), lower CSF NPTX levels correlate strongly with cognitive impairment and cortical thinning in...