Cellular senescence and senolytics: the path to the clinic

Nature Medicine, Год журнала: 2022, Номер 28(8), С. 1556 - 1568

Опубликована: Авг. 1, 2022

Язык: Английский

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Multimorbidity

Nature Reviews Disease Primers, Год журнала: 2022, Номер 8(1)

Опубликована: Июль 14, 2022

Язык: Английский

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Reactive Oxygen Species Signaling and Oxidative Stress: Transcriptional Regulation and Evolution

Antioxidants, Год журнала: 2024, Номер 13(3), С. 312 - 312

Опубликована: Март 1, 2024

Since the evolution of aerobic metabolism, reactive oxygen species (ROS) have represented significant challenges to diverse life forms. In recent decades, increasing knowledge has revealed a dual role for ROS in cell physiology, showing they serve as major source cellular damage while also functioning important signaling molecules various biological processes. Our understanding homeostasis and ROS-mediated pathways presumed that are ancient highly conserved mechanisms shared by most organisms. However, emerging evidence highlights complexity plasticity signaling, particularly animals evolved extreme environments. this review, we focus on generation, antioxidative systems main influenced ROS. addition, discuss ROS’s responsive transcription regulation how it may been shaped over course evolution.

Язык: Английский

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BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside

Cancers, Год журнала: 2022, Номер 14(16), С. 3888 - 3888

Опубликована: Авг. 11, 2022

DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian (EOC) is among the tumours with highest percentage of hereditary cases. BRCA1 BRCA2 predisposing pathogenic variants (PVs) were first to associated EOC, whereas additional genes comprising homologous recombination (HR) pathway have been discovered sequencing technologies. The incidence DDR patients metastatic prostate much higher compared those localized disease. Genetic testing playing an increasingly important role treatment cancer. development poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for EOC. One mechanisms PARP exploits concept synthetic lethality. Tumours or mutations highly sensitive inhibitors. Moreover, lethal interaction may beyond germline BRCA context HR deficiency, this area ongoing research. advanced stages as castration-resistant However, there major concern regarding need identify reliable biomarkers predictive response. In review, we explore DDR, potential genomic analysis cancer, therapeutics inhibitors, along biomarkers.

Язык: Английский

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Genome-wide RNA polymerase stalling shapes the transcriptome during aging

Nature Genetics, Год журнала: 2023, Номер 55(2), С. 268 - 279

Опубликована: Янв. 19, 2023

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and polymerase II chromatin immunoprecipitation followed by to elucidate the underlying mechanisms triggering gene wild-type aged mice. We found that 2-year-old liver, 40% of elongating polymerases are stalled, lowering productive transcription skewing transcriptional output a gene-length-dependent fashion. demonstrate this stress caused endogenous DNA damage explains majority aging most mainly postmitotic organs, specifically affecting hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function cellular resilience. Age-related evolutionary conserved from nematodes humans. Thus, accumulation stochastic during deteriorates basal transcription, which establishes age-related transcriptome causes dysfunction key pathways, disclosing functionally underlies major aspects normal aging.

Язык: Английский

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Epigenetics, DNA damage, and aging

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(16)

Опубликована: Авг. 14, 2022

Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance several types chromatin changes. The DNA lesions (chemical perturbations nucleotides) increases with age, as does number genomic mutations and transcriptional disruptions caused by replication or transcription those lesions, respectively. At epigenetic level, precise methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, tight regulation histone modifications begins unravel. instability these mechanisms allows transposon element reactivation remobilization, further mutations, dysregulation, cytoplasmic fragments. This cumulative promotes cell signaling events that drive fate decisions extracellular communications known disrupt tissue homeostasis regeneration. In this Review, we focus on age-related changes their interactions instigate events.

Язык: Английский

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Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Апрель 14, 2023

Abstract Redox homeostasis refers to the balance between production of reactive oxygen species (ROS) as well nitrogen (RNS), and their elimination by antioxidants. It is linked all important cellular activities oxidative stress a result imbalance pro-oxidants antioxidant species. Oxidative perturbs many activities, including processes that maintain integrity DNA. Nucleic acids are highly therefore particularly susceptible damage. The DNA damage response detects repairs these lesions. Efficient repair essential for maintaining viability, but they decline considerably during aging. deficiencies in increasingly described age-related neurodegenerative diseases, such Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis Huntington’s disease. Furthermore, has long been associated with conditions. Moreover, both redox dysregulation increase significantly aging, which biggest risk factor diseases. However, links dysfunction damage, joint contributions pathophysiology conditions, only just emerging. This review will discuss associations address increasing evidence an major source disorders. Understanding connections may facilitate better understanding disease mechanisms, ultimately lead design therapeutic strategies based on preventing

Язык: Английский

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Chemically induced reprogramming to reverse cellular aging

Aging, Год журнала: 2023, Номер 15(13), С. 5966 - 5989

Опубликована: Июль 12, 2023

A hallmark of eukaryotic aging is a loss epigenetic information, process that can be reversed. We have previously shown the ectopic induction Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals restore youthful DNA methylation patterns, transcript profiles, tissue function, without erasing cellular identity, requires active demethylation. To screen for molecules reverse rejuvenate human cells altering genome, we developed high-throughput cell-based assays distinguish young from old senescent cells, including transcription-based clocks real-time nucleocytoplasmic compartmentalization (NCC) assay. identify six chemical cocktails, which, less than week compromising genome-wide profile transcriptomic age. Thus, rejuvenation by age reversal achieved, not only genetic, but also means.

Язык: Английский

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Endometrial receptivity in women of advanced age: an underrated factor in infertility

Human Reproduction Update, Год журнала: 2023, Номер 29(6), С. 773 - 793

Опубликована: Июль 19, 2023

Abstract BACKGROUND Modern lifestyle has led to an increase in the age at conception. Advanced is one of critical risk factors for female-related infertility. It well known that maternal positively correlates with deterioration oocyte quality and chromosomal abnormalities oocytes embryos. The effect on endometrial function may be equally important factor influencing implantation rate, pregnancy overall female fertility. However, there are only a few published studies this topic, suggesting area been under-explored. Improving our knowledge aging from biological (cellular, molecular, histological) clinical perspectives would broaden understanding risks age-related OBJECTIVE AND RATIONALE objective narrative review critically evaluate existing literature focus synthesizing evidence impact conception success. This provide insights into gaps application research findings promote development treatment options field. SEARCH METHODS was prepared using PubMed (Medline) until February 2023 keywords such as ‘endometrial aging’, ‘receptivity’, ‘decidualization’, ‘hormone’, ‘senescence’, ‘cellular’, ‘molecular’, ‘methylation’, ‘biological age’, ‘epigenetic’, ‘oocyte recipient’, donation’, ‘embryo transfer’, ‘pregnancy rate’. Articles language other than English were excluded. OUTCOMES In endometrium, alterations occur cellular, histological levels negative biology impair receptivity. Additionally, advanced influences cellular senescence, which plays role during initial phase major obstacle suitable senolytic agents aging. Aging also accountable chronic conditions associated inflammaging, eventually can lead increased pro-inflammation tissue fibrosis. Furthermore, epigenetic regulation thus altering relation between its chronological age. donation cycles determine receptivity respect rates implantation, pregnancy, miscarriage, live birth have revealed contradictory inferences indicating need future mechanisms corresponding causal effects women’s WIDER IMPLICATIONS Increasing infertility IVF failures. Based complied observations synthesized conclusions review, shown functioning. information recommendations focusing molecular composition, transcriptomic changes further prospective needed explore newly emerging therapeutic options, target without affecting decidualization. Moreover, trial protocols, cycles, beneficial direct implications outcomes.

Язык: Английский

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Genomic Instability and Epigenetic Changes during Aging

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(18), С. 14279 - 14279

Опубликована: Сен. 19, 2023

Aging is considered the deterioration of physiological functions along with an increased mortality rate. This scientific review focuses on central importance genomic instability during aging process, encompassing a range cellular and molecular changes that occur advancing age. In particular, this revision addresses genetic epigenetic alterations contribute to instability, such as telomere shortening, DNA damage accumulation, decreased repair capacity. Furthermore, explores aging, including modifications histones, methylation patterns, role non-coding RNAs. Finally, discusses organization chromatin its contribution heterochromatin loss, remodeling, in nucleosome histone abundance. conclusion, highlights fundamental plays process underscores need for continued research into these complex biological mechanisms.

Язык: Английский

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