Aging clocks based on accumulating stochastic variation

Nature Aging, Год журнала: 2024, Номер 4(6), С. 871 - 885

Опубликована: Май 9, 2024

Abstract Aging clocks have provided one of the most important recent breakthroughs in biology aging, and may provide indicators for effectiveness interventions aging process preventive treatments age-related diseases. The reproducibility accurate has reinvigorated debate on whether a programmed underlies aging. Here we show that accumulating stochastic variation purely simulated data is sufficient to build clocks, first-generation second-generation are compatible with accumulation DNA methylation or transcriptomic data. We find predict chronological biological age, indicated by significant prediction differences smoking, calorie restriction, heterochronic parabiosis partial reprogramming. Although our simulations not explicitly rule out process, results suggest stochastically changes any set ground state at age zero generating clocks.

Язык: Английский

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Transcription-coupled DNA–protein crosslink repair by CSB and CRL4CSA-mediated degradation

Nature Cell Biology, Год журнала: 2024, Номер 26(5), С. 770 - 783

Опубликована: Апрель 10, 2024

DNA-protein crosslinks (DPCs) arise from enzymatic intermediates, metabolism or chemicals like chemotherapeutics. DPCs are highly cytotoxic as they impede DNA-based processes such replication, which is counteracted through proteolysis-mediated DPC removal by spartan (SPRTN) the proteasome. However, whether affect transcription and how transcription-blocking repaired remains largely unknown. Here we show that severely RNA polymerase II-mediated preferentially in active genes transcription-coupled (TC-DPC) repair. TC-DPC repair initiated recruiting nucleotide excision (TC-NER) factors CSB CSA to DPC-stalled II. indispensable for repair; however, downstream TC-NER UVSSA XPA not, a result indicative of non-canonical mechanism. functions independently SPRTN but mediated ubiquitin ligase CRL4

Язык: Английский

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Transcriptional elongation control in developmental gene expression, aging, and disease

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 3972 - 3999

Опубликована: Ноя. 1, 2023

Язык: Английский

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G-quadruplexes and associated proteins in aging and Alzheimer’s disease

Frontiers in Aging, Год журнала: 2023, Номер 4

Опубликована: Июнь 1, 2023

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer’s disease (AD). characterized by progressive cognitive decline, memory loss, and neuropsychiatric behavioral symptoms, accounting most of the reported dementia cases. This now becoming major challenge burden on modern society, especially with aging population. Over last few decades, significant understanding pathophysiology AD has been gained studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, neuroinflammation. review focuses role non-canonical secondary structures DNA/RNA G-quadruplexes (G4s, G4-DNA, G4-RNA), G4-binding proteins (G4BPs), helicases, their roles in AD. Being critically important cellular function, G4s are involved regulation DNA RNA processes, replication, transcription, translation, localization, degradation. Recent studies have also highlighted G4-DNA’s inducing double-strand breaks that cause genomic instability G4-RNA’s participation regulating stress granule formation. emphasizes significance processes how homeostatic imbalance may contribute to

Язык: Английский

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Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Март 2, 2024

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, spinal cord. Unfortunately, there are few effective treatments, thus remains critical need to find novel interventions that can mitigate against its effects. Whilst aetiology of ALS unclear, ageing major risk factor. Ageing slowly progressive process marked by functional decline an organism over lifespan. However, it unclear how promotes ALS. At molecular cellular level specific hallmarks characteristic normal ageing. These highly inter-related overlap significantly with each other. Moreover, whilst process, striking similarities at between these factors neurodegeneration Nine were originally proposed: genomic instability, loss telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, proteostasis, mitochondrial dysfunction, stem cell exhaustion, altered inter-cellular communication. recently (2023) expanded include dysregulation autophagy, inflammation dysbiosis. Hence, given latest updates hallmarks, their close association disease processes ALS, new examination relationship pathophysiology warranted. In this review, we describe possible mechanisms which impacts on neurodegenerative implicated therapeutic may arise from this.

Язык: Английский

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Time is ticking faster for long genes in aging

Trends in Genetics, Год журнала: 2024, Номер 40(4), С. 299 - 312

Опубликована: Март 21, 2024

Recent studies of aging organisms have identified a systematic phenomenon, characterized by negative correlation between gene length and their expression in various cell types, species, diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) suggest that it may represent bottleneck the machinery thereby significantly contribute to as an etiological factor. review potential links GLTD key processes such DNA damage explore identifying disease modification targets. Notably, Alzheimer's disease, spotlights extremely long synaptic genes at chromosomal fragile sites (CFSs) vulnerability postmitotic damage. is integral element biological aging.

Язык: Английский

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DNA Damage and Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4187 - 4187

Опубликована: Апрель 10, 2024

The etiology underlying most sporadic Parkinson's' disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, mechanisms how these cause death neurons not understood. Several agents are mitochondrial toxins that inhibit complex I electron transport chain. Familial PD genes also encode proteins with important functions mitochondria. Mitochondrial dysfunction respiratory chain, combination presence redox active dopamine molecules cells, will lead to accumulation reactive oxygen species (ROS) Here, propose a mechanism regarding ROS may killing specificity for One rarely considered hypothesis produced by defective mitochondria formation oxidative DNA damage nuclear DNA. Many neuron-specific extraordinary long, ranging size from several hundred kilobases well over megabase. It predictable such long contain large numbers damaged bases, example form 8-oxoguanine (8-oxoG), which major type ROS. These lesions slow down or stall progression RNA polymerase II, term referred transcription stress. Furthermore, ROS-induced mutations, even postmitotic cells impaired mutagenesis loss neuronal integrity, eventually leading during human lifetime.

Язык: Английский

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A synthetic methylotroph achieves accelerated cell growth by alleviating transcription-replication conflicts

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 2, 2025

Microbial utilization of methanol for valorization is an effective way to advance green bio-manufacturing technology. Although synthetic methylotrophs have been developed, strategies enhance their cell growth rate and internal regulatory mechanism remain underexplored. In this study, we design a assimilation (SMA) pathway containing only six enzymes linked central carbon metabolism, which does not require energy emissions. Through rational laboratory evolution, E. coli harboring with the SMA converted into methylotroph. By self-adjusting expression TOPAI (topoisomerase I inhibitor) alleviate transcriptional-replication conflicts (TRCs), doubling time methylotrophic reduced 4.5 h, approaching that natural methylotrophs. This work has potential overcome limitation C1-assimilating microbes development circular economy. Slow affects valorization. Here, strains self-adjust topoisomerase inhibitor transcription-replication in reduce its

Язык: Английский

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Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Abstract Aging of the brain vasculature plays a key role in development neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, genomic instability endothelial cells (EC) its potential effect on homeostasis is still largely unclear. We here investigated how aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human ECs an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, higher sprouting capacities due underlying dysregulation Dll4-Notch pathway. line, EC-KO mice showed more P21 + cells, augmented expression angiogenic markers, concomitant increase number pericytes. Moreover, leakage enhanced cell adhesion molecule accompanied peripheral immune infiltration into brain. These findings were confined white matter, suggesting regional susceptibility. Collectively, our results underline as driver impaired function, sprouting, migration brain, observed during process.

Язык: Английский

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Genome Instability and DNA Repair in Somatic and Reproductive Aging

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2023, Номер 19(1), С. 261 - 290

Опубликована: Окт. 13, 2023

Genetic material is constantly subjected to genotoxic insults and critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic germ cells as the soma only requires during an individual's lifespan, while germline indefinitely perpetuates its genetic information. lesions are recognized repaired by mechanistically highly diverse repair machineries. The damage response impinges a vast array of homeostatic processes can ultimately result cell fate changes such apoptosis or cellular senescence. causally contributes aging process aging-associated diseases, most prominently cancer. By causing mutations, lead diseases impact evolutionary trajectory species. ensuring tight control could be instructive defining strategies for improved They may provide future interventions maintain health prevent disease aging.

Язык: Английский

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