Aged Gut Microbiota Contributes to Cognitive Impairment and Hippocampal Synapse Loss in Mice

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

Gut microbiota alteration during the aging process serves as a causative factor for aging-related cognitive decline, which is characterized by early hallmark, hippocampal synaptic loss. However, impact and mechanistic role of gut in synapse loss remains unclear. Here, we observed that fecal naturally aged mice successfully transferred impairment to young recipients. Multi-omics analysis revealed was with obvious change Bifidobacterium pseudolongum (B.p) metabolite tryptophan, indoleacetic acid (IAA) periphery brain. These features were also reproduced recipients transplanted microbiota. Fecal B.p abundance reduced patients compared healthy subjects showed positive correlation scores. Microbiota transplantation from who had fewer abundances yielded worse behavior than those higher abundances. Meanwhile, supplementation capable producing IAA enhancing peripheral brain bioavailability, well improving behaviors microglia-mediated 5 × FAD transgenic mice. produced shown prevent microglia engulfment synapses an aryl hydrocarbon receptor-dependent manner. This study reveals -induced decline is, at least partially, due deficiency its metabolite, IAA. It provides proof-of-concept strategy preventing neurodegenerative diseases modulating probionts their tryptophan metabolites.

Language: Английский

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Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3744 - 3744

Published: April 16, 2025

Transcription-coupled repair (TCR) and R-loops are two interrelated processes critical to the maintenance of genome stability during transcription. TCR, a specialized sub-pathway nucleotide excision repair, rapidly removes transcription-blocking lesions from transcribed strand active genes, thereby safeguarding transcription fidelity cellular homeostasis. In contrast, R-loops, RNA–DNA hybrid structures formed co-transcriptionally, play not only regulatory roles in gene expression replication but can also contribute instability when persistently accumulated. Recent experimental evidence has revealed dynamic crosstalk between TCR R-loop resolution pathways. This review highlights current molecular insights into biology, discusses impact their crosstalk, explores emerging therapeutic strategies aimed at optimizing DNA reducing disease risk conditions such as cancer neurodegenerative disorders.

Language: Английский

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Metabolic Dysfunction‐Associated Steatotic Liver Disease Is Associated With Accelerated Brain Ageing: A Population‐Based Study

Liver International, Journal Year: 2025, Volume and Issue: 45(6)

Published: April 29, 2025

ABSTRACT Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) is linked to cognitive decline and dementia risk. We aimed investigate the association between MASLD brain ageing explore role of low‐grade inflammation. Methods Within UK Biobank, 30 386 chronic neurological disorders‐free participants who underwent magnetic resonance imaging (MRI) scans were included. Individuals categorised into no MASLD/related SLD (including subtypes MASLD, with increased alcohol intake [MetALD] other combined aetiology). Brain age was estimated using machine learning by 1079 MRI phenotypes. gap (BAG) calculated as difference chronological age. Low‐grade inflammation (INFLA) based on white blood cell count, platelet, neutrophil granulocyte lymphocyte ratio C‐reactive protein. Data analysed linear regression structural equation models. Results At baseline, 7360 (24.2%) had SLD. Compared SLD, those significantly larger BAG ( β = 0.86, 95% CI 0.70, 1.02), well 0.59, 0.41, 0.77) or MetALD 1.57, 1.31, 1.83). The significant across middle‐aged (< 60) older (≥ adults, males females, APOE ɛ4 carriers non‐carriers. INFLA mediated 13.53% p < 0.001). Conclusion MetALD, associated accelerated ageing, even among adults systemic may partially mediate this association.

Language: Английский

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Cognitive synaptopathy: synaptic and dendritic spine dysfunction in age-related cognitive disorders

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Oct. 3, 2024

Cognitive impairment is a leading component of several neurodegenerative and neurodevelopmental diseases, profoundly impacting on the individual, family, society at large. pathologies are driven by multiplicity factors, from genetic mutations risk neurotransmitter-associated dysfunction, abnormal connectomics level local neuronal circuits broader brain networks, to environmental influences able modulate some endogenous factors. Otherwise healthy older adults can be expected experience degree mild cognitive impairment, which fall into category subjective deficits in clinical practice, while many diseases course with more profound alterations cognition, particularly within spectrum dementias. Our knowledge underlying neuropathological mechanisms root this ample palette entities far complete. This review looks current synaptic modifications context function along ageing dysfunction disease, providing insight differential diagnostic elements wide range synapse alterations, those associated changes physiological senescence abnormalities occurring advanced stages dementia. I propose term "cognitive synaptopathy" encompass higher disorders.

Language: Английский

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Cellular senescence as a key contributor to secondary neurodegeneration in traumatic brain injury and stroke

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Dec. 12, 2024

Abstract Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies counteract their devastating consequences still lacking. Cellular senescence, marked by irreversible cell-cycle arrest, is emerging a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be potential driver for secondary neurodegeneration following injury. Herein, we synthesize evidence TBI drive the accumulation senescent cells brain. The rationale targeting therapeutic approach combat TBI/stroke outlined. From translational perspective, emphasize current knowledge future directions senolytic therapy conditions.

Language: Английский

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The Hidden Dangers of Sedentary Living: Insights into Molecular, Cellular, and Systemic Mechanisms

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10757 - 10757

Published: Oct. 6, 2024

With the aging of global population, neurodegenerative diseases are emerging as a major public health issue. The adoption less sedentary lifestyle has been shown to have beneficial effect on cognitive decline, but molecular mechanisms responsible clear. Here we provide detailed analysis complex molecular, cellular, and systemic underlying age-related decline how choices influence these processes. A review evidence from animal models, human studies, postmortem analyses emphasizes importance integrating physical exercise with cognitive, multisensory, motor stimulation part multifaceted approach mitigating decline. We highlight potential non-pharmacological interventions address key hallmarks, such genomic instability, telomere attrition, neuroinflammation, underscore need for comprehensive personalized strategies promote resilience healthy aging.

Language: Английский

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Novel Techniques for Mapping DNA Damage and Repair in the Brain

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7021 - 7021

Published: June 27, 2024

DNA damage in the brain is influenced by endogenous processes and metabolism along with exogenous exposures. Accumulation of can contribute to various neurological disorders, including neurodegenerative diseases neuropsychiatric disorders. Traditional methods for assessing brain, such as immunohistochemistry mass spectrometry, have provided valuable insights but are limited their inability map specific adducts regional distributions within or genome. Recent advancements detection offer new opportunities address these limitations further our understanding repair brain. Here, we review emerging techniques offering more precise sensitive ways detect quantify lesions neural cells. We highlight applications discuss potential determining role disease.

Language: Английский

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Bursts of brain erosion: seizures and age-dependent neurological vulnerability

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

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The Impact of HIV on Early Brain Aging—A Pathophysiological (Re)View

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(23), P. 7031 - 7031

Published: Nov. 21, 2024

: This review aims to provide a comprehensive understanding of how HIV alters normal aging trajectories in the brain, presenting HIV-related molecular mechanisms and pathophysiological pathways involved brain aging. The explores roles inflammation, oxidative stress, viral persistence highlighting these factors contribute neuronal damage cognitive impairment accelerate Additionally, it also addresses impact antiretroviral therapy on biological markers associated with its occurrence.

Language: Английский

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When do the pathological signs become evident? Study of human mesenchymal stem cells in MDPL syndrome

Aging, Journal Year: 2024, Volume and Issue: 16(22), P. 13505 - 13525

Published: Nov. 26, 2024

Aging syndromes are rare genetic disorders sharing the features of accelerated senescence. Among these, Mandibular hypoplasia, Deafness and Progeroid with concomitant Lipodystrophy (MDPL; OMIM #615381) is a autosomal dominant disease due to

Language: Английский

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