Features Of Premature Aging Research Articles

Obesity-related comorbidities as potential factors influencing features of premature ageing in severely obese patients

Obesity-related comorbidities as potential factors influencing features of premature ageing in severely obese patients

Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation

MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/- mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. "MycKO" mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.

Association of DNA methylation signatures with premature ageing and cardiovascular death in patients with end-stage kidney disease: a pilot epigenome-wide association study

ABSTRACT Patients with end-stage kidney disease (ESKD) display features of premature aging. There is strong evidence that changes in DNA methylation (DNAm) contribute to age-related pathologies; however, little is known about their association with premature aging and cardiovascular mortality in patients with ESKD. We assayed genome-wide DNAm in a pilot case-control study of 60 hemodialysis patients with (n=30, cases) and without (n=30, controls) a fatal cardiovascular event. DNAm was profiled on the Illumina EPIC BeadChip. Four established DNAm clocks (i.e., Horvath-, Hannum-, Pheno-, and GrimAge) were used to estimate epigenetic age (DNAmAge). Epigenetic age acceleration (EAA) was derived as the residuals of regressing DNAmAge on chronological age (chroAge), and its association with cardiovascular death was examined using multivariable conditional logistic regression. An epigenome-wide association study (EWAS) was performed to identify differentially methylated CpGs associated with cardiovascular death. All clocks performed well at predicting chroAge (correlation between DNAmAges and chroAge of r=0.76-0.89), with GrimAge showing the largest deviation from chroAge (a mean of +21.3 years). There was no significant association of EAAs with cardiovascular death. In the EWAS, a CpG (cg22305782) in the FBXL19 gene had the strongest association with cardiovascular death with significantly lower DNAm in cases vs. controls (P FDR=2.0x10−6). FBXL19 is involved in cell apoptosis, inflammation, and adipogenesis. Overall, we observed more accelerated aging in patients with ESKD, although there was no significant association of EAAs with cardiovascular death. EWAS suggests a potential novel DNAm biomarker for premature cardiovascular mortality in ESKD.

Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence

PurposeRothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789). MethodsTwo newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts. ResultsAll CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate. ConclusionCRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.

Abstract IA002: Inherited DNA repair defects and premature aging

Abstract Fanconi anemia (FA), a DNA repair disorder, is the most frequently inherited bone marrow failure (BMF) syndrome. Patients with FA suffer from early childhood onset of BMF, developmental abnormalities, and heightened susceptibility to solid tumors. FA patients also have a strong predisposition to myelo- dysplastic syndrome (MDS) and acute myeloid leukemia (AML). FA is caused by biallelic mutations in one of 23 FANC genes, whose protein products cooperate in the FA/BRCA DNA repair pathway and regulate cellular resistance to DNA cross-linking agents. Because of their underlying DNA repair defect, FA cells exhibit chromosomal instability and hypersensitivity to genotoxic DNA cross-linking agents, such as mitomycin C (MMC). FA bone marrow (BM) HSPCs are also hypersensitive to oxidative stress and inflammatory cytokines. FA patients and FA cells exhibit many features of Premature Aging. FA patients develop BMF because of HSPC exhaustion. Progressive age-related attrition is observed in CD34+ cell content in FA patients. Additionally, FA patients and FA mice exhibit HSPC functional defects. BMF in FA results from accumulation of DNA damage in HSPCs caused by endogenous cross-linking agents or physiological stress. In response to genotoxic stress, FA HSPCs hyperactivate growth-suppressive pathways, such as the p53 pathway (Ceccaldi et al, Cell Stem Cell, 2012) and the transforming growth factor (TGF-b) pathway (Zhang et al, Cell Stem Cell, 2016), further contributing to BMF. The molecular pathways in FA HSPCs leading to BMF and MDS/AML remain unknown. Although primary HSPCs from BM of FA patients are a useful model system, studying these cells is challenging because of their heterogeneity and low numbers. Sub-populations of HSPCs with heterogeneous transcriptional profiles may co-exist in the BM of FA patients. These subpopulations may include (1) stressed HSPCs sustaining hematopoiesis, (2) HSPCs committed to apoptosis resulting from accumulation of unrepaired DNA damage, and (3) premalignant/malignant cells that eventually lead to clinically detectable MDS or AML. Recently, in order to identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients (Rodriguez et al, Cell Stem Cell, 2020). In addition to overexpression of p53 and TGF-b pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow. In my seminar, I will describe the cellular and clinical manifestations of senescence and premature aging in FA patients. Specifically, FA patients exhibit the three major causes of cellular senescence including 1) replicative senescence 2) oncogene-induced senescence (OIS) and 3) stress-induced senescence. Citation Format: Alan D. D'Andrea. Inherited DNA repair defects and premature aging [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA002.

Vasoactive intestinal peptide deficiency promotes ovarian dysfunction associated to a proinflammatory microenvironment reminiscent of premature aging

Complex immune regulation during pregnancy is required to ensure a successful pregnancy outcome. Vasoactive intestinal peptide (VIP) has local immunoregulatory effects on the ovary, uterus and maternal-fetal interface that favor a tolerogenic maternal microenvironment. Since the VIP Knockout (KO) mice are subfertile, we investigated the mechanisms underlying the effects of VIP deficiency on ovarian physiology and immune homeostasis. Therefore, we studied VIP KO, deficient (HT) and wild type (WT) female mice in estrus at 3 or 8 months of age. Young KO mice showed abnormal cycle timing and regularity associated with dysfunctional ovaries. Ovaries presented higher number of atretic follicles and reduced number of corpora lutea leading to a lower ovulation rates. Part of the VIP KO mice (25 %) failed to ovulate or ovulated oocytes incompetent to be fertilized (50 %). In particular, ovaries of young KO mice exhibited features of premature aging accompanied by a pro-inflammatory milieu with increased levels of IL-1β. A unique macrophage subpopulation identified as “foamy macrophages” was found. On the other hand, aged VIP KO females did not gain body weight probably due to the sustained production of E2. Finally, the adoptive transfer of FOXP3+ cells to infertile VIP KO females resulted in their selective recruitment to the ovary. It increased FOXP3/RORγt and TGFβ/IL-6 ratio improving ovarian microenvironment and pregnancy rate. The present results suggest that VIP contributes to ovarian homeostatic mechanisms required for a successful pregnancy.

Arterial thrombosis in Hutchinson-Gilford Progeria Syndrome

Abstract Introduction Arterial thrombosis is the most common age-associated event underlying major adverse cardiovascular (CV) events. The interplay between the vascular endothelium, platelets, and the coagulation cascade leads to thrombus formation, which results in the cessation of blood supply to the downstream tissues. Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition with striking features of premature aging. It is caused by defects in the nuclear A-type lamin gene, leading to intracellular accumulation of progerin. This genetic disorder is characterized by shortened lifespan, primarily due to an increased incidence of myocardial infarction and ischemic stroke. Declined vascular function and compliance have been reported in HGPS patients. Nevertheless, the effect of the specific A-type lamin gene mutation on coagulation and thrombus formation has not been investigated previously. Methods 28- to 30-week-old male and female transgenic heterozygous LmnaG609G knock-in (HGPS) mice and corresponding wild-type (WT) littermate controls were exposed to photochemically-induced carotid artery endothelial injury to trigger arterial thrombosis. Vascular and circulating levels of tissue factor (TF), plasminogen activator inhibitor (PAI)-1, and von Willebrand factor (vWF) were measured using enzyme-linked immunosorbent assay (ELISA). TF activity assay was also performed on carotid artery homogenates of WT and HGPS animals. Results HGPS mice displayed accelerated thrombus formation compared to the WT animals as underlined by a shortened time to occlusion. Although this finding suggests an increased activation of the extrinsic coagulation cascade, no significant differences were found in TF expression and activity in carotid artery lysates. Circulating and vascular expression of the fibrinolytic factor PAI-1 was also found to be similar between WT and HGPS animals. Furthermore, no significant difference in plasma vWF between the two groups was observed. Conclusions Our results show an increased arterial thrombotic response in HGPS mice as compared to WT littermates. This novel observation could provide a mechanistic explanation for the increased incidence of acute cardiovascular events observed in HGPS patients. Further studies will be conducted to investigate the molecular mechanism underlying the observed effects, in particular, on the potential involvement of platelets. Funding Acknowledgement Type of funding sources: None.

Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow.

Aging is a progressive loss of physiological function and increased susceptibility to major pathologies. Degenerative diseases in both brain and bone including Alzheimer disease (AD) and osteoporosis are common in aging groups. TERC is RNA component of telomerase, and its deficiency accelerates aging-related phenotypes including impaired life span, organ failure, bone loss, and brain dysfunction. In this study, we investigated the traits of bone marrow-brain cross-tissue communications in young mice, natural aging mice, and premature aging (TERC deficient, TERC-KO) mice by single-cell transcriptome sequencing. Differentially expressed gene analysis of brain as well as bone marrow between premature aging mouse and young mouse demonstrated aging-related inflammatory response and suppression of neuron development. Further analysis of senescence-associated secretory phenotype (SASP) landscape indicated that TERC-KO perturbation was enriched in oligodendrocyte progenitor cells (OPCs) and hematopoietic stem and progenitor cells (HSPC). Series of inflammatory associated myeloid cells was activated in premature aging mice brain and bone marrow. Cross-tissue comparison of TERC-KO mice brain and bone marrow illustrated obvious ligand-receptor communications between brain glia cells, macrophages, and bone marrow myeloid cells in premature aging-induced inflammation. Enrichment of co-regulation modules between brain and bone marrow identified premature aging response genes such as Dusp1 and Ifitm3. Our study provides a rich resource for understanding premature aging-associated perturbation in brain and bone marrow and supporting myeloid cells and endothelial cells as promising therapy targeting for age-related brain-bone diseases.

Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

End-Stage Renal Disease-Related Accelerated Immune Senescence: Is Rejuvenation of the Immune System a Therapeutic Goal?

End-stage renal disease (ESRD) patients exhibit clinical features of premature ageing, including frailty, cardiovascular disease, and muscle wasting. Accelerated ageing also concerns the immune system. Patients with ESRD have both immune senescence and chronic inflammation that are resumed in the so-called inflammaging syndrome. Immune senescence is particularly characterised by premature loss of thymic function that is associated with hyporesponsiveness to vaccines, susceptibility to infections, and death. ESRD-related chronic inflammation has multiple causes and participates to accelerated cardiovascular disease. Although, both characterisation of immune senescence and its consequences are relatively well-known, mechanisms are more uncertain. However, prevention of immune senescence/inflammation or/and rejuvenation of the immune system are major goal to ameliorate clinical outcomes of ESRD patients.

Generalized acquired cutis laxa and urticarial dermatosis associated with k-chain IgA micromolecular myeloma.

Cutis laxa (CL) is a group of rare cutaneous disease, inherited or acquired, characterized by inelastic, redundant, wrinkled, loose skin, with loss of elasticity and features of premature aging [...].

Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools

Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.

Immunofluorescence studies to dissect the impact of Cockayne syndrome A alterations on the protein interaction and cellular localization

BackgroundCockayne syndrome (CS), which was discovered by Alfred Cockayne nearly 75 years ago, is a rare autosomal recessive disorder characterized by growth failure, neurological dysfunction, premature aging, and other clinical features including microcephaly, ophthalmologic abnormalities, dental caries, and cutaneous photosensitivity. These alterations are caused by mutations in the CSA or CSB genes, both of which are involved in transcription-coupled nucleotide excision repair (TC-NER), the sub-pathway of NER that rapidly removes UV-induced DNA lesions which block the progression of the transcription machinery in the transcribed strand of active genes. Several studies assumed that CSA and CSB genes can play additional roles outside TC-NER, due to the wide variations in type and severity of the CS phenotype and the lack of a clear relationship between genotype and phenotype. To address this issue, our lab generated isogenic cell lines expressing wild type as well as different versions of mutated CSA proteins, fused at the C-terminus with the Flag and HA epitope tags (CSAFlag-HA). In unpublished data, the identity of the CSA-interacting proteins was determined by mass spectrometry. Among which three subunits (namely, CCT3, CCT8, and TCP1) of the TRiC/CCT complex appeared as novel interactors. TRiC is a chaperonin involved in the folding of newly synthesized or unfolded proteins. The aim of this study is directed to investigate by immunofluorescence analysis the impact of the selected CSA mutations on the subcellular localization of the CSA protein itself as well as on its novel interactors CCT3, CCT8, and TCP1. ResultsWe showed that specific CSA mutations impair the proper cellular localization of the protein, but have no impact on the cellular distribution of the TRiC subunits or CSA/TRiC co-localization. ConclusionWe suggested that the activity of the TRiC complex does not rely on the functionality of CSA.

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences.

Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.

The HRDC domain oppositely modulates the unwinding activity of E. coli RecQ helicase on duplex DNA and G-quadruplex

RecQ family helicases are highly conserved from bacteria to humans and have essential roles in maintaining genome stability. Mutations in three human RecQ helicases cause severe diseases with the main features of premature aging and cancer predisposition. Most RecQ helicases shared a conserved domain arrangement which comprises a helicase core, an RecQ C-terminal domain, and an auxiliary element helicase and RNaseD C-terminal (HRDC) domain, the functions of which are poorly understood. In this study, we systematically characterized the roles of the HRDC domain in E. coli RecQ in various DNA transactions by single-molecule FRET. We found that RecQ repetitively unwinds the 3'-partial duplex and fork DNA with a moderate processivity and periodically patrols on the ssDNA in the 5'-partial duplex by translocation. The HRDC domain significantly suppresses RecQ activities in the above transactions. In sharp contrast, the HRDC domain is essential for the deep and long-time unfolding of the G4 DNA structure by RecQ. Based on the observations that the HRDC domain dynamically switches between RecA core- and ssDNA-binding modes after RecQ association with DNA, we proposed a model to explain the modulation mechanism of the HRDC domain. Our findings not only provide new insights into the activities of RecQ on different substrates but also highlight the novel functions of the HRDC domain in DNA metabolisms.

Premature Ocular Aging Features in Childhood Acute Lymphoblastic Leukemia Survivors.

Purpose: Childhood cancer survivors (CCS) demonstrate features of premature aging in a multitude of organ systems. The aim of this pilot study is to determine the presence of premature ocular aging features in CCS, specifically childhood acute lymphoblastic leukemia (ALL) survivors. Methods: This prospective case-control study was conducted over a period of 21 months, starting July 2015 till March 2017. A total of 59 childhood ALL survivors who attended the Paediatric Oncology Clinic of University Malaya Medical Centre (UMMC) and 48 age, race, and gender-matched controls went through a series of ocular examinations and tests. Inclusion criteria used to recruit survivors were age above 16 years, history of ALL in childhood, completion of treatment for ALL, and a remission period of at least 5 years. Patients with ocular disease and those who received hematopoietic stem cell transplantation were excluded. The parameters measured were visual acuity, amplitude of accommodation, pupil cycle time (PCT), and tear break-up time (TBUT). Results: Survivors of childhood ALL demonstrated significant differences in amplitude of accommodation, PCT, and TBUT compared to age-matched controls. Survivors had a lower median (interquartile range [IQR]) amplitude of accommodation compared to controls (11.0 D [9.0-13.0] vs. 12.0 D [10.5-15]; p = 0.045). Survivors also showed a longer median (IQR) PCT in comparison to controls (931.00 mseconds (857.00-1063.00) vs. 875.50 mseconds (825.75-966.00); p = 0.024). In addition, median (IQR) TBUT was worse in survivors in comparison to the control group (9 seconds [6-13] vs. 11 seconds [10-15]; p = 0.001). Conclusion: Survivors of childhood ALL demonstrate premature ocular aging features compared to age-matched controls. Thus, survivors may benefit from having ocular examinations as part of their routine late-effects screening to detect age-related ocular morbidities early in its course.

Association between Nrf2 and CDKN2A expression in patients with end-stage renal disease: a pilot study.

Patients with end-stage renal disease (ESRD) display phenotypic features of premature biological aging, characterized by disproportionately high morbidity and mortality at a younger age. Nuclear factor erythroid 2-related factor 2 (Nrf2) activity, a master regulator of antioxidative responses, declines with age and is implicated in the pathogenesis of age-related disorders; however, little is known about the association between Nrf2 and premature biological aging in ESRD patients. In a cross-sectional pilot cohort of 34 ESRD patients receiving maintenance hemodialysis, we measured the expression of Nrf2 and cyclin-dependent kinase inhibitor 2A (CDKN2A, or p16INK4a, a biomarker of biological aging) genes in whole blood and examined the association of Nrf2 with CDKN2A expression, using Spearman’s rank correlation and multivariable linear regression models with adjustment for potential confounders. There was a significant negative correlation between Nrf2 and CDKN2A expression (rho=-0.51, P=0.002); while no significant correlation was found between Nrf2 expression and chronological age (rho=-0.02, P=0.91). After multivariable adjustment, Nrf2 expression remained significantly and negatively associated with CDKN2A expression (β coefficient=-1.51, P=0.01), independent of chronological age, gender, race, and diabetes status. These findings suggest a potential contribution of Nrf2 dysfunction to the development of premature biological aging and its related morbidities in ESRD patients.

Development of a new drug for progeria syndrome; Past, Present and Future

Hutchinson-Gilford progeria syndrome (HGPS) is the best characterized genetic disorder with premature aging features. Classic HGPS is very rare, sporadic orphan disease, inherited in an autosomal dominant manner without gender or ethnic differences. Children with HGPS appear normal at birth, but begin to develop segmental progeroid symptoms within the first years of life. Patients suffer from sarcopenia, lipodystrophy, diabetes, cataracts, atherosclerosis but not cancer and neurodegenerative diseases. Genetic factors that are associated with this syndrome have been identified, mouse models of disease have been developed, and clinical studies have been conducted for many years. Although many medical and treatment approaches were implemented and showed some efficacy, these therapies could not be considered as a complete cure, and more effective therapeutic approaches were needed for HGPS patients. This report introduces a novel drug called progerinin, which is a binding inhibitor of lamin A and progerin, for patients affected with HGPS.

Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders

BackgroundSegmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated.MethodsSince 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes.We analyzed the results obtained in 4 years on 66 patients issued from France and abroad.ResultsGlobally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives.ConclusionsHigh throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms (“Medicine France Genomics 2025” Plan), in families without molecular diagnosis.

Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson\u2013Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.