Telomere dysfunction in ageing and age-related diseases

Rossiello, Francesca; Jurk, Diana; Passos, João F.; Fagagna, Fabrizio d’Adda di

doi:10.1038/s41556-022-00842-x

Cited by 364 publications

(251 citation statements)

References 210 publications

(255 reference statements)

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“…The classical TBD is dyskeratosis congenita (DC), which presents with mucocutaneous triad of reticular skin pigmentation, nail dysplasia, and oral leukoplakia, and is predominantly a pediatric disease. TBDs, especially in adults, have a broad phenotypic variability and can present with hematological (cytopenias), pulmonary (idiopathic pulmonary fibrosis), gastrointestinal (cirrhosis), or immunodeficiency phenotypes, and present with a variable constellation of symptoms, penetrance, inheritance, and age of onsets (genetic anticipation) [ 3 , 4 ]. Currently, the clinical approach to identify TBD patients includes telomere length measurement by flowFISH and/or identification of a pathogenic variant in one of the genes affecting telomere structural integrity and maintenance specifically, DKC1 , TERC , TERT , NOP10 , NHP2 , ACD , TINF2 , POT1 , CTC1 , STN1 , WRAP53 , RTEL1 , PARN , NAF1 , and ZCCHC8 [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Clonal Hematopoiesis and Myeloid Neoplasms in the Context of Telomere Biology Disorders

Ferrer

Mangaonkar

Patnaik

2022

Curr Hematol Malig Rep

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Purpose of Review Telomere biology disorders (TBDs) are cancer-predisposing multisystemic diseases that portend a higher risk of transforming into myeloid neoplasms (MNs). Due to the rarity and high variability of clinical presentations, TBD-specific characteristics of MN and the mechanisms behind this predisposition are not well defined. Herein, we review recent studies on TBD patient cohorts describing myeloid transformation events and summarize efforts to develop screening and treatment guidelines for these patients. Recent Findings Preliminary studies have indicated that TBD patients have a higher prevalence of somatic genetic alterations in hematopoietic cells, an age-related phenomenon, also known as clonal hematopoiesis; increasing predisposition to MN. The CH mutational landscape in TBD differs from that observed in non-TBD patients and preliminary data suggest a higher frequency of somatic mutations in the DNA repair mechanism pathway. Although initial studies did not observe specific features of MN in TBD patients, certain events are common in TBD, such as hypocellular bone marrows. The mechanisms of MN development need further elucidation. Summary Current management options for MN-TBD patients need to be individualized and tailored as per the clinical context. Because of the high sensitivity to alkylator chemotherapy and radiation conferred by short telomeres, non-cytotoxic targeted therapies and immunotherapy are ideal therapeutic options, but these therapies are still being tested in clinical trials. Defining the mechanisms of CH evolution in TBD and identifying risk factors leading to MN evolution will allow for the development of screening and treatment guidelines for these patients.

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Section: Introductionmentioning

confidence: 99%

Clonal Hematopoiesis and Myeloid Neoplasms in the Context of Telomere Biology Disorders

Ferrer

Mangaonkar

Patnaik

2022

Curr Hematol Malig Rep

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“…The key finding from our study that a small, nondistorting oxidative base lesion within telomeres is sufficient to induce premature senescence in the absence of telomere shortening is surprising, but provides a mechanistic explanation for telomere dysfunction foci arising in vivo in various contexts 27 . Mouse cardiomyocytes and baboon hepatocytes in vivo, show increased DDR+ telomeres with age, with no appreciable shortening despite the presence of senescence markers 20 , 76 .…”

Section: Discussionmentioning

confidence: 69%

“…Dysfunctional telomeres are recognized by γH2AX and 53BP1 localization at telomeres, which are downstream effectors of DDR kinases ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3‑related) 25 , 26 . These foci are called TIFs (telomere dysfunction induced foci), TAFs (telomere associated DDR foci), or DDR+ telomeres 27 . Whereas telomere deprotection upon shelterin disruption activates the DDR 26 , evidence is lacking that ROS-induced telomere damage is extensive enough to completely displace shelterin.…”

Section: Mainmentioning

confidence: 99%

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening

Barnes

Rosa

Thosar

et al. 2022

Nat Struct Mol Biol

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Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening. Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

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“…Conversely, switch genes obtained from subjects engaged in high physical activity were predominantly associated with DNA repair mechanisms and telomerase maintenance. Telomerase maintenance positively influences longevity [ 20 ], and telomeric dysfunction is associated with developing a wide range of diseases, including cancer, metabolic disorders, and neurodegeneration [ 21 ]. Increased DNA double-strand breaks and altered levels of DNA repair proteins have been reported in the hippocampus of AD subjects [ 22 ] and neuronal and glial cells in the early stages of the disease [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Physical Activity Rewires the Human Brain against Neurodegeneration

Santiago¹,

Quinn

Potashkin

2022

IJMS

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Physical activity may offset cognitive decline and dementia, but the molecular mechanisms by which it promotes neuroprotection remain elusive. In the absence of disease-modifying therapies, understanding the molecular effects of physical activity in the brain may be useful for identifying novel targets for disease management. Here we employed several bioinformatic methods to dissect the molecular underpinnings of physical activity in brain health. Network analysis identified ‘switch genes’ associated with drastic hippocampal transcriptional changes in aged cognitively intact individuals. Switch genes are key genes associated with dramatic transcriptional changes and thus may play a fundamental role in disease pathogenesis. Switch genes are associated with protein processing pathways and the metabolic control of glucose, lipids, and fatty acids. Correlation analysis showed that transcriptional patterns associated with physical activity significantly overlapped and negatively correlated with those of neurodegenerative diseases. Functional analysis revealed that physical activity might confer neuroprotection in Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD) diseases via the upregulation of synaptic signaling pathways. In contrast, in frontotemporal dementia (FTD) its effects are mediated by restoring mitochondrial function and energy precursors. Additionally, physical activity is associated with the downregulation of genes involved in inflammation in AD, neurogenesis in FTD, regulation of growth and transcriptional repression in PD, and glial cell differentiation in HD. Collectively, these findings suggest that physical activity directs transcriptional changes in the brain through different pathways across the broad spectrum of neurodegenerative diseases. These results provide new evidence on the unique and shared mechanisms between physical activity and neurodegenerative diseases.

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Telomere dysfunction in ageing and age-related diseases

Cited by 364 publications

References 210 publications

Clonal Hematopoiesis and Myeloid Neoplasms in the Context of Telomere Biology Disorders

Clonal Hematopoiesis and Myeloid Neoplasms in the Context of Telomere Biology Disorders

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening

Physical Activity Rewires the Human Brain against Neurodegeneration

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