Premature aging in genetic diseases: what conclusions can be drawn for physiological aging

Frontiers in Aging, Journal Year: 2024, Volume and Issue: 4

Published: Feb. 28, 2024

According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes cellular damage (genomic instability, telomere attrition, loss proteostasis, epigenetic alterations and compromised macroautophagy), antagonistic that represent response (deregulated nutrient sensing, senescence, mitochondrial dysfunction) integrative culprits phenotype (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). In contrast aging, premature diseases are driven by one or two distinct such as genomic instability in case Werner syndrome (WS), each displaying other a variable extent. this review we will focus on well-investigated Hutchinson-Gilford progeria (HGPS), WS, Cockayne (CS) for provide an overview reported elucidate resemblance mechanistic level context characteristic age-related diseases. Ubiquitous tissue specific animal models discussed useful tools decipher fundamental aging-related mechanisms develop intervention strategies combat

Language: Английский

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Targeting the DNA damage response in cancer

MedComm, Journal Year: 2024, Volume and Issue: 5(11)

Published: Oct. 31, 2024

DNA damage response (DDR) pathway is the coordinated cellular network dealing with identification, signaling, and repair of damage. It tightly regulates cell cycle progression promotes to minimize daughter cells. Key proteins involved in DDR are frequently mutated/inactivated human cancers promote genomic instability, a recognized hallmark cancer. Besides being an intrinsic property tumors, also represents unique therapeutic opportunity. Indeed, inhibition expected delay repair, causing persistent unrepaired breaks, interfere progression, sensitize cancer cells several DNA-damaging agents, such as radiotherapy chemotherapy. In addition, defects have been shown render these more dependent on remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over past two decades has led synthesis testing hundreds small inhibitors against key proteins, some antitumor activity cancers. parallel, search for synthetic lethality interaction broadening use inhibitors. this review, we discuss state-of-art ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 Polθ inhibitors, highlighting results obtained ongoing clinical trials both monotherapy combination chemotherapy radiotherapy.

Language: Английский

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Hemophagocytic lymphohistiocytosis as the initial manifestation of bone marrow failure in a child with a TERC variant telomere biology disorder

Therapeutic Advances in Rare Disease, Journal Year: 2025, Volume and Issue: 6

Published: Jan. 1, 2025

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome, rarely associated with bone marrow failure (BMF). Telomere biology disorders (TBD) are caused by inherited defects in telomerase processes and can have heterogeneous presentations including idiopathic pulmonary fibrosis, cirrhosis, BMF. We report case of 10-year-old male from Lima, Peru, who presented HLH as the initial manifestation TBD. He experienced fever, gastrointestinal symptoms, mucocutaneous involvement. Initial laboratory analyses revealed pancytopenia elevated inflammatory markers. Despite symptomatic antibiotic treatment, his clinical condition persisted leading to suspicion Kawasaki disease and, subsequently, HLH. Immunomodulatory treatment was initiated good response. Bone aspiration severe hypocellular cytophagocytosis. Genetic studies identified pathogenic variant TERC gene (n.110_113del), which also found patient’s mother brother. BMF rare. This highlights importance considering TBD children unclear etiology value genetic testing such cases.

Language: Английский

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TERT de novo mutation-associated dyskeratosis congenita and porto-sinusoidal vascular disease: a case report

Journal of Medical Case Reports, Journal Year: 2025, Volume and Issue: 19(1)

Published: Jan. 23, 2025

Abstract Background Dyskeratosis congenita is a rare genetic disease due to telomere biology disorder and characterized by heterogeneous clinical manifestations severe complications. “Porto-sinusoidal vascular disease” has been recently proposed, according new diagnostic criteria, replace the term “idiopathic non-cirrhotic portal hypertension.” TERT plays an important role in telomeric DNA repair replication. A c.2286 + 1G/A mutation splicing consensus site was identified patient with pulmonary fibrosis. Recently, pathogenic de novo c.280A > T variant associated diffuse lung infant. Case presentation 16-year-old Han male experienced unexplained black stool for 7 days, accompanied dizziness fatigue. On examination, there were mesh pigmentations on exposed areas of skin both hands feet. Laboratory testing revealed moderate hemorrhagic anemia mild elevation alanine aminotransferase. computed tomography scan showed hypertension, esophageal gastric varices, splenomegaly. The liver stiffness measurement FibroScan 6.0 kPa. Liver biopsy typical features porto-sinusoidal disease. Whole exome sequencing heterozygous 1G quantitative polymerase chain reaction very short telomeres (less than first percentile his age). diagnosed as mutation-related dyskeratosis He underwent variceal ligation treatment received carvedilol tablet (12.5 mg) every morning. After 6 months, he iron deficiency started receiving polysaccharide complex therapy. Conclusion When discovering reticular rash unknown it necessary perform whole chromosome length clarify possibility congenita/telomere

Language: Английский

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Founder Variants in the Mexican Population: A Systematic Review

Archives of Medical Research, Journal Year: 2025, Volume and Issue: 56(5), P. 103209 - 103209

Published: April 14, 2025

Language: Английский

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Telomere biology: from disorders to hematological diseases

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: May 19, 2023

Variations in the length of telomeres and pathogenic variants involved telomere maintenance have been correlated with several human diseases. Recent breakthroughs biology knowledge contributed to identification illnesses named “telomeropathies” revealed an association between disease outcome. This review emphasizes physiology aspects describes prototype diseases which are implicated their pathophysiology. We also provide information on role hematological ranging from bone marrow failure syndromes acute chronic leukemias.

Language: Английский

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The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis

Biomolecules, Journal Year: 2023, Volume and Issue: 13(8), P. 1249 - 1249

Published: Aug. 16, 2023

Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond–Blackfan Shwachman–Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond–Blackfan assembly (Shwachman–Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). pathogenetic mechanisms IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest apoptosis hematopoietic stem, progenitor, precursor cells. Here, we review the propose a role for pro-inflammatory cytokines, TGF-β, IL-1β, IFN-α, in mediating cytopenias. We suggest pathogenic cytokines transformation myeloid neoplasia hypothesize anti-inflammatory therapies.

Language: Английский

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A Nutrigenomic View on the Premature-Aging Disease Fanconi Anemia

Nutrients, Journal Year: 2024, Volume and Issue: 16(14), P. 2271 - 2271

Published: July 15, 2024

Fanconi anemia, a rare disorder with an incidence of 1 in 300,000, is caused by mutations FANC genes, which affect the repair DNA interstrand crosslinks. The disease characterized congenital malformations, bone marrow failure within first decade life, and recurrent squamous cell carcinomas oral cavity, esophagus, anogenital regions starting around age 20. In this review, we propose that anemia should be considered premature-aging syndrome. Interestingly, onset severity life-limiting clinical features can influenced lifestyle choices, such as healthy diet physical activity. These factors shape epigenetic status at-risk types enhance competence immune system through nutritional signaling. may serve model for understanding aging process general population, addressing research gaps its presentation suggesting prevention strategies. Additionally, will discuss how balance genetic environmental risk factors—affecting both cancer speed aging—is interlinked signal transduction dietary molecules. underlying nutrigenomic principles offer guidance individuals well population.

Language: Английский

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Analyzing the role of ferroptosis in ribosome‐related bone marrow failure disorders: From pathophysiology to potential pharmacological exploitation

IUBMB Life, Journal Year: 2024, Volume and Issue: 76(12), P. 1011 - 1034

Published: July 25, 2024

Abstract Within the last decade, scientific community has witnessed importance of ferroptosis as a novel cascade molecular events leading to cellular decisions death distinct from apoptosis and other known forms cell death. Notably, such non‐ apoptotic iron‐dependent regulated been found be intricately linked several physiological processes well pathogenesis various diseases. To this end, recent data support notion that potential connection between inherited bone marrow failure (IBMF) in individuals with ribosomopathies may exist. In review, we suggest ribosome‐related IBMFs identified mutations ribosomal proteins lead changes ribosome composition hematopoietic progenitors, seem affect function, thus enhancing expression some mRNAs subgroups while reducing others. These an imbalance inside pathways are promoted others inhibited. This disturbance is accompanied by ROS production lipid peroxidation, additional finding most them iron accumulation. Once peroxidation accumulation two main characteristics ferroptosis, it possible mechanism plays key role manifestation IBMF type disease. If further confirmed, new pharmacological targets inhibitors already exploited for treatment diseases, could utilized improve ribosomopathies.

Language: Английский

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Telomere biology disorders: from dyskeratosis congenita and beyond

Postgraduate Medical Journal, Journal Year: 2024, Volume and Issue: 100(1190), P. 879 - 889

Published: Aug. 28, 2024

Defective telomerase function or telomere maintenance causes genomic instability. Alterations in length and/or attrition are the primary features of rare diseases known as biology disorders telomeropathies. Recent advances molecular basis these and cutting-edge methods assessing have increased our understanding this topic. Multiorgan manifestations different phenotypes been reported even carriers within same family. In context, apart from dyskeratosis congenita, formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective mechanisms. Moreover, patients prone to developing specific cancer types exhibit exceptional sensitivity toxicity standard chemotherapy regimens. The current review describes diverse spectrum clinical pediatric adult patients, their correlation pathogenic variants, considerations during management increase awareness improve a multidisciplinary approach.

Language: Английский

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