Mechanisms of astrocyte aging in reactivity and disease

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Фев. 21, 2025

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor they contribute to neuronal dysfunction disease risk as organisms age. Here, we examine the transcriptional, cell biology, functional differences in across normal aging. Astrocytes at baseline heterogenous, responsive their environments, critical regulators of microenvironments function. With increasing age, adopt different immune-related senescence-associated states, which relate organelle loss homeostasis maintenance, both autonomously non-cell autonomously. These perturbed states increasingly associated with age-related onset neurodegeneration, suggesting that astrocyte a compelling target for future manipulation prevention disease.

Язык: Английский

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An MRI-informed histo-molecular analysis implicates ependymal cells in the pathogenesis of periventricular pathology in multiple sclerosis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Abstract It is now widely recognized that the cerebrospinal fluid (CSF)-adjacent brain surfaces – namely subpial cortical region and ependyma-adjacent periventricular are uniquely susceptible to a distinct, diffuse form of pathology in multiple sclerosis. So-called surface-in gradients predict future disease relapses independent classical white matter lesions thought occur as result cytotoxic factors CSF. Given underlying mechanisms driving appear be they represent novel treatment target. However, exactly how factor entry into regulated at these CSF-facing borders not understood, particularly ventricular interface. Indeed, although studies have indicated ependymal cells may damaged MS, there has yet comprehensive assessment cell health disease. We employed ultra-high-field MRI-guided immunohistochemistry, electron microscopy, multiomic single nucleus RNA/ATAC sequencing deeply phenotype human MS. Our data revealed direct correlate immune-responsive, reactive state assumed by associated with widespread transporter junctional protein gene dysregulation. then further defined regulatory networks underpinning MS state, predicted ligands known enriched CSF could drive emergence this tested one candidate vivo . found IFNγ increased murine permeability conditional knockout interferon gamma receptor 1 (Ifngr1) was sufficient reverse effect. directly implicate dysregulation More widely, we denote modulatory capacity on function influence inflammatory status region.

Язык: Английский

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Single-cell Transcriptomics Unravel Stereocilia Degeneration as a Key Contributor to Age-related Vestibular Dysfunction in Mice and Humans

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract Age-related vestibular dysfunction (ARVD) is a prevalent, debilitating condition in the elderly. The etiology and molecular mechanisms are poorly understood. We focused on mechanosensitive hair cells (HCs) as they particularly vulnerable to aging. Using single-cell RNA-seq transcriptomes of young old mouse HCs, we show that aging HCs display both universal blueprints, such genomic instability, mitochondrial dysfunction, impaired proteostasis, cell type-specific signatures associated with deterioration bundles mechanotransduction. These also observed aged human suggesting shared mechanisms. Importantly, morphological functional analysis revealed bundle degeneration decline precede HC loss, highlighting mechanotransduction key contributor ARVD. Furthermore, cellular changes less pronounced than cochlear underscoring different pace between two mammalian inner ear sensory epithelia.

Язык: Английский

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Intermittent fasting attenuates CNS inflammaging - rebalancing the transposonome

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 12, 2025

A hallmark of CNS aging is sterile, chronic, low-grade neuroinflammation. Understanding how the develops chronic inflammation necessary to achieve extended healthspan. Characterisation neuroinflammatory molecular triggers remains limited. Interventions that reduce neuroinflammation and extend health lifespan could be useful in this regard. One such intervention intermittent fasting (IF), but IF impacts insufficiently understood. To address this, we performed deep RNA-sequencing on young, middle-aged, old, mouse regions. Additionally, sequenced spinal cord animals subject adult lifelong IF. We found most differentially expressed genes (DEGs) at middle age were region specific (~ 50–84%), whilst effect weakened 18–72%) old age, suggesting emergence a more general global profile. DEGs from all regions enriched for inflammatory immune ontologies. Surprisingly, SC was aging- neuroinflammation-impacted both ages, with by far highest number DEGs, largest net increase expression transposable elements (TEs), greatest enrichment immune-related ontologies, generally larger increases gene expression. Overall, normal upregulation sensors non-self, DNA/RNA, activation inflammasomes, cGAS-STING1 interferon response genes, across CNS. Whilst still developed an profile SC, average lower ~ 50% compared age-matched controls. IF-specific apparent, also acts separate, potentially targetable, pathways those impacted aging. Expression disease associated microglia, phagocytic exhaustion, STING1, inflammasome decreased Significantly, TE reversed decrease. In summary, find hotspot, attenuates neuroinflammaging rebalancing transposonome.

Язык: Английский

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Age-related brain changes in mice strike hypothalamus ‘hot spot’

The Transmitter, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Berberine Extends Lifespan in C. elegans Through Multi-Target Synergistic Antioxidant Effects

Antioxidants, Год журнала: 2025, Номер 14(4), С. 450 - 450

Опубликована: Апрель 9, 2025

Aging is a process of gradual functional decline in complex physiological systems and closely related to the occurrence various diseases. Berberine, bioactive alkaloid derived from Coptis chinensis (Huanglian), has emerged as promising candidate for anti-aging interventions. This study comprehensively investigated lifespan-extending effects molecular mechanisms berberine C. elegans through integrated approaches including lifespan assays, locomotor activity analysis, oxidative stress challenges, transcriptomic profiling. Furthermore, genetic models mutant transgenic worms were employed delineate their interactions with insulin/IGF-1 signaling (IIS) pathway. Our results demonstrate that extended mean wild-type by 27%. By activating transcription factors such DAF-16/FOXO, HSF-1, SKN-1/NRF2, upregulated antioxidant enzyme expression, reduced lipofuscin accumulation, improved resistance. Transcriptomic analysis revealed significant changes lipid metabolism-related genes, particularly pathways involving fatty acid synthesis, degradation, sphingolipid metabolism. These findings establish exerts multi-target coordinated activation stress-responsive metabolic optimization, providing mechanistic insights developing natural product-based geroprotective strategies.

Язык: Английский

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Cell-Type-Specific Transposable Element Demethylation and TAD Remodeling in the Aging Mouse Brain

Опубликована: Янв. 1, 2025

Язык: Английский

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