The maternal X chromosome affects cognition and brain ageing in female mice

Nature, Год журнала: 2025, Номер 638(8049), С. 152 - 159

Опубликована: Янв. 22, 2025

Abstract Female mammalian cells have two X chromosomes, one of maternal origin and paternal origin. During development, chromosome randomly becomes inactivated 1–4 . This renders either the (X m ) or p inactive, causing mosaicism that varies between female individuals, with some showing considerable complete skew remains active 5–7 Parent-of-X can modify epigenetics through DNA methylation 8,9 possibly gene expression; thus, could buffer dysregulated processes in ageing disease. However, whether its alters functions individuals is largely unknown. Here we tested towards an influences brain body—and then delineated unique features neurons neurons. An impaired cognition mice throughout lifespan led to worsened age. Cognitive deficits were accompanied by -mediated acceleration biological epigenetic hippocampus, a key centre for learning memory, mice. Several genes imprinted on hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation -imprinted improved Thus, cognition, accelerated contribute ageing. Understanding how impairs function lead understanding heterogeneity health X-chromosome-derived pathways protect against

Язык: Английский

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Molecular insights of exercise therapy in disease prevention and treatment

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 29, 2024

Despite substantial evidence emphasizing the pleiotropic benefits of exercise for prevention and treatment various diseases, underlying biological mechanisms have not been fully elucidated. Several attributed to signaling molecules that are released in response by different tissues such as skeletal muscle, cardiac adipose, liver tissue. These molecules, which collectively termed exerkines, form a heterogenous group bioactive substances, mediating inter-organ crosstalk well structural functional tissue adaption. Numerous scientific endeavors focused on identifying characterizing new mediators with properties. Additionally, some investigations molecular targets exerkines cellular cascades trigger adaption processes. A detailed understanding tissue-specific downstream effects is crucial harness health-related mediated improve targeted programs health disease. Herein, we review current vivo exerkine-induced signal transduction across multiple target highlight preventive therapeutic value exerkine diseases. By aspects research, provide comprehensive overview (i) underpinnings secretion, (ii) receptor-dependent receptor-independent adaption, (iii) clinical implications these disease treatment.

Язык: Английский

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Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 9, 2025

ABSTRACT Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging‐related diseases. It has long been speculated that “rejuvenation molecules” exist in their blood promote extended lifespan. We unexpectedly discovered longevity exhibit erythrocyte oxygen release function similar young individuals, whereas most elderly show reduced capacity. Untargeted metabolomics profiling revealed are characterized by youth‐like metabolic reprogramming these metabolites effectively differentiate the from elderly. Quantification analyses led us identify multiple novel longevity‐related within erythrocytes including adenosine, sphingosine‐1‐phosphate (S1P), glutathione (GSH) related amino acids. Mechanistically, we increased bisphosphoglycerate mutase (BPGM) MFSD2B protein levels of collaboratively work together induce elevation intracellular S1P, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) membrane cytosol, thereby orchestrate glucose toward Rapoport–Luebering Shunt 2,3‐BPG production trigger delivery. Furthermore, glutamine glutamate transporter expression coupled with enhanced metabolism underlie elevated GSH higher anti‐oxidative stress capacity individuals. As such, displayed less systemic hypoxia‐related more antioxidative anti‐inflammatory plasma, healthier clinical outcomes inflammation parameters as well better glucose–lipid metabolism, liver kidney function. Overall, identified youthful enable counteract peripheral tissue thus maintaining healthspan.

Язык: Английский

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Aging activates escape of the silent X chromosome in the female mouse hippocampus

Science Advances, Год журнала: 2025, Номер 11(10)

Опубликована: Март 5, 2025

Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive (Xi) active (Xa), in contrast males with only Xa. Thus, reactivation of silent Xi genes may contribute differences. We use allele-specific, single-nucleus RNA sequencing show that aging remodels transcription the Xa across hippocampal cell types. Aging preferentially changed gene expression on X's relative autosomes. Select underwent activation, new escape cells including dentate gyrus, critical learning memory. Expression escapee Plp1, a myelin component, was increased hippocampus female mice parahippocampus women. AAV-mediated Plp1 elevation gyrus male improved cognition. Understanding how confer advantage could lead novel targets counter brain disease both sexes.

Язык: Английский

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Genetically supported targets and drug repurposing for brain aging: A systematic study in the UK Biobank

Science Advances, Год журнала: 2025, Номер 11(11)

Опубликована: Март 12, 2025

Brain age gap (BAG), the deviation between estimated brain and chronological age, is a promising marker of health. However, genetic architecture reliable targets for aging remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)–based using deep learning models trained on UK Biobank validated with three external datasets. A genome-wide association study BAG identified two unreported loci seven previously reported loci. By integrating Mendelian Randomization (MR) colocalization analysis eQTL pQTL data, prioritized genetically supported druggable genes, including MAPT , TNFSF12 GZMB SIRPB1 GNLY NMB C1RL as aging. We rediscovered 13 potential drugs evidence from clinical trials several strong support. Our provides insights into basis aging, potentially facilitating drug development to extend health span.

Язык: Английский

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Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease—a comprehensive review from the ERA CKD-MBD working group

Clinical Kidney Journal, Год журнала: 2023, Номер 17(1)

Опубликована: Ноя. 3, 2023

Klotho, a multifunctional protein, acts as co-receptor in fibroblast growth factor 23 and exerts its impact through various molecular pathways, including Wnt, hypoxia-inducible insulin-like 1 pathways. The physiological significance of Klotho is the regulation vitamin D phosphate metabolism well serving vital component aging neurodegeneration. role neurodegeneration particular has gained considerable attention. In this narrative review we highlight several key insights into basis function synthesize current research on aging. deficiency was associated with cognitive impairment, reduced growth, diminished longevity development age-related diseases vivo. Serum levels showed decline individuals advanced age those affected by chronic kidney disease, establishing potential diagnostic significance. Additionally, multiple medications have been demonstrated to influence levels. Therefore, comprehensive suggests that could open door novel interventions aimed at addressing challenges neurodegenerative disorders.

Язык: Английский

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Plasma proteomic signature of human longevity

Aging Cell, Год журнала: 2024, Номер 23(6)

Опубликована: Март 5, 2024

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead longevity. We leveraged two large population-based prospective cohorts with long follow-ups evaluate proteomic signature longevity defined by survival 90 years age. Plasma was measured using a SOMAscan assay in 3067 participants from Cardiovascular Health Study (discovery cohort) and 4690 Age Gene/Environment Susceptibility-Reykjavik (replication cohort). Logistic regression identified 211 significant proteins CHS cohort Bonferroni-adjusted threshold, which 168 were available replication 105 replicated (corrected p value <0.05). most GDF-15 N-terminal pro-BNP both cohorts. A parsimonious protein-based prediction model built 33 selected LASSO 10-fold cross-validation validated 27 validation cohort. This outperformed basic traditional factors (demographics, height, weight, smoking) improving AUC 0.658 0.748 discovery 0.755 0.802 also found associations 169 out partially mediated physical and/or cognitive function. These findings contribute biomarkers pathways aging therapeutic delay age-related diseases.

Язык: Английский

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Aging and comprehensive molecular profiling in acute myeloid leukemia

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(10)

Опубликована: Фев. 29, 2024

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, targeted or whole exome obtained in 94% cases. The correlation factors including age clonal hematopoiesis (CH), gender, genomic/transcriptomic profiles (gene fusions, genetic mutations, gene expression networks pathways) was systematically analyzed. Overall, aged 60 y older showed apparently dismal prognosis. Alongside age, the frequency fusions defined World Health Organization classification decreased, while positive rate especially CH-related ones, increased. Additionally, number mutations higher fusion–negative (GF-) than those GF. Based on status CH- myelodysplastic syndromes (MDS)-related three mutant subgroups identified among GF- cohort, namely, CH-AML, CH-MDS-AML, other AML. Notably, CH-MDS-AML demonstrated predominance elderly male cases, cytopenia, significantly adverse clinical outcomes. Besides, HOXA / B , platelet factors, inflammatory responses most striking features associated aging poor prognosis Our work has thus unraveled intricate regulatory circuitry interactions different molecular groups

Язык: Английский

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Neuroprotective effects of intranasal extracellular vesicles from human platelet concentrates supernatants in traumatic brain injury and Parkinson’s disease models

Journal of Biomedical Science, Год журнала: 2024, Номер 31(1)

Опубликована: Сен. 5, 2024

The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic injury (TBI) and Parkinson's disease (PD) warrants further exploration. We aimed here characterize composition a PEV preparation isolated concentrate (PC) supernatant, determine its neurorestorative cellular animal models TBI PD.

Язык: Английский

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Peripheral to brain and hippocampus crosstalk induced by exercise mediates cognitive and structural hippocampal adaptations

Life Sciences, Год журнала: 2024, Номер 352, С. 122799 - 122799

Опубликована: Июнь 7, 2024

Язык: Английский

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