Genomic Instability and Epigenetic Changes during Aging

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14279 - 14279

Published: Sept. 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.

Language: Английский

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Cellular reprogramming as a tool to model human aging in a dish

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 28, 2024

Abstract The design of human model systems is highly relevant to unveil the underlying mechanisms aging and provide insights on potential interventions extend health life span. In this perspective, we explore 2D or 3D culture models comprising induced pluripotent stem cells transdifferentiated obtained from aged age-related disorder-affected donors enhance our understanding catalyze discovery anti-aging interventions.

Language: Английский

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Ageing as an Important Risk Factor for Cancer

Anticancer Research, Journal Year: 2016, Volume and Issue: 36(10), P. 5009 - 5018

Published: Oct. 10, 2016

An ageing population is a typical feature of many developed countries across the world. Analyzed from biomedical and philosophical point view, this phenomenon also potential risk factor for social sustainability communities. The association between cancer seems to be more than apparent. Therefore, further increase epidemic-like incidence malignant tumors in can expected near future. Elderly people usually suffer age-dependent diseases, such polymorbidity seriously affect treatment tumors. Such an impending situation may associated with multiple medical, economic issues. This article summarizes data about possible molecular mechanism influencing rapid spreading elderly population. Reduction activity DNA repair machinery likely genetic cause. Besides this, even epigenetic mechanisms influence process. In context, role stroma controlling biological properties prospective target translational research therapeutic outcomes.

Language: Английский

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POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies

Gene, Journal Year: 2016, Volume and Issue: 590(1), P. 128 - 141

Published: June 21, 2016

Language: Английский

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Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

eLife, Journal Year: 2019, Volume and Issue: 8

Published: March 25, 2019

Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability microsatellite instability-high (MSI-H) MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability MSI-H but not stable (MSS) colorectal lines. In cells, loss results severe genome integrity defects. ATP-binding deficient variants fail to rescue phenotype WRN-depleted Reconstitution depletion studies indicate dependence attributable acute MMR gene function might arise during sustained MMR-deficiency. Our study suggests pharmacological inhibition represents an opportunity develop targeted for

Language: Английский

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WRNMutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Human Mutation, Journal Year: 2016, Volume and Issue: 38(1), P. 7 - 15

Published: Sept. 26, 2016

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by constellation of adult onset phenotypes consistent with an acceleration intrinsic biological aging. It caused pathogenic variants in the WRN gene, which encodes multifunctional nuclear protein exonuclease and helicase activities. thought to be involved optimization various aspects DNA metabolism, including repair, recombination, replication, transcription. In this update, we summarize total 83 different mutations, eight previously unpublished mutations identified International Registry Syndrome (Seattle, WA) Japanese Consortium (Chiba, Japan), as well 75 already reported literature. The Seattle recruits patients from all over world investigate genetic causes wide variety progeroid syndromes order contribute knowledge basic mechanisms human Given unusually high prevalence WS heterozygous carriers Japan, major goal develop effective therapies establish management guidelines for Japan elsewhere. This review will also discuss potential translational approaches disorder, those currently under investigation.

Language: Английский

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WRN regulates pathway choice between classical and alternative non-homologous end joining

Nature Communications, Journal Year: 2016, Volume and Issue: 7(1)

Published: Dec. 6, 2016

Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained the diverse functions of DNA metabolism. However, origin large deletions and telomere fusions are not yet understood. Here, we report that regulates pathway choice between classical (c)- alternative (alt)-nonhomologous end joining (NHEJ) during double-strand break (DSB) repair. It promotes c-NHEJ via helicase exonuclease activities inhibits alt-NHEJ using non-enzymatic functions. When recruited to DSBs it suppresses recruitment MRE11 CtIP, protects from 5' resection. Moreover, knockdown Wrn, alone or combination Trf2 mouse embryonic fibroblasts results increased fusions, which were ablated Ctip knockdown. We show shields MRE11/CtIP-mediated resection prevent fusions.

Language: Английский

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History of DNA Helicases

Genes, Journal Year: 2020, Volume and Issue: 11(3), P. 255 - 255

Published: Feb. 27, 2020

Since the discovery of DNA double helix, there has been a fascination in understanding molecular mechanisms and cellular processes that account for: (i) transmission genetic information from one generation to next (ii) remarkable stability genome. Nucleic acid biologists have endeavored unravel mysteries not only understand replication, repair, recombination, transcription but also characterize underlying basis diseases characterized by chromosomal instability. Perhaps unexpectedly at first, helicases arisen as key class enzymes study this latter capacity. From first ATP-dependent unwinding mid 1970’s burgeoning helicase-dependent pathways found be prevalent all kingdoms life, story scientific helicase research is rich informative. Over four decades after their discovery, we take opportunity provide history helicases. No doubt, many chapters are left written. Nonetheless, juncture privileged share our perspective on field – where it been, its current state, headed.

Language: Английский

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Recent advances in biomarkers for senescence: Bridging basic research to clinic

Geriatrics and gerontology international/Geriatrics & gerontology international, Journal Year: 2025, Volume and Issue: 25(2), P. 139 - 147

Published: Jan. 3, 2025

In this review, we review the current status of biomarkers for aging and possible perspectives on anti‐aging or rejuvenation from standpoint biomarkers. Aging is observed in all cells organs, focused research into senescence skin, musculoskeletal system, immune cardiovascular system. Commonly used include SA‐βgal, cell‐cycle markers, senescence‐associated secretory phenotype (SASP) factors, damage‐associated molecular patterns (DAMPs), DNA‐damage‐related markers. addition, each organ cell has its specific Generally speaking, a combination required to define age‐related changes. When considering translation basic research, that are highly sensitive, specific, with validation reliability as well being non‐invasive optimal; however, currently reported markers do not fulfill prerequisite rodent models necessarily represent human aging, applicable clinical settings. The clinically they provide useful information decision‐making, such predicting disease risk, diagnosing disease, monitoring progression, guiding treatment decisions. Therefore, development robust, reliable, humans necessary develop therapy humans. Geriatr Gerontol Int 2025; 25: 139–147 .

Language: Английский

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Hereditary and familial thyroid tumours

Histopathology, Journal Year: 2017, Volume and Issue: 72(1), P. 70 - 81

Published: Dec. 14, 2017

The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection lesions have made cancers the most rapidly in USA 2017 (SEER Cancer Facts, 2017). Clinical awareness potential risk factors, such as inherited cancers, allowed earlier recognition more vulnerable population clusters. Hereditary neoplasms arising from calcitonin‐producing C cells are known familial medullary carcinomas (FMTCs), include well‐documented syndromes multiple endocrine neoplasia IIA or IIB, pure carcinoma syndrome. Familial follicular referred to non‐medullary (FNMTC), cell‐derived carcinoma. Clinicopathological correlations resulted further subclassification FNMTCs into two groups. Among first group found characterised by a predominance non‐thyroidal tumours, including adenomatous polyposis, Cowden syndrome, Werner Carney complex, Pendred second encompasses spectrum papillary with without oxyphilia, renal cell carcinoma, multinodular goitre. Most described being aggressive than sporadic predisposition for lymph node metastasis, extrathyroidal invasion, younger age onset. distinct pathology some these should alert pathologist possible cancer

Language: Английский

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