Nuclear envelope budding inhibition slows down progerin-induced aging process.

Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high-throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding-induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin-induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in anti-aging, and provide a distinct avenue for treating HGPS.

Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes.

Lipodystrophic laminopathies are a group of ultra-rare disorders characterised by the presence of pathogenic variants in the same gene (LMNA) and other related genes, along with an impaired adipose tissue pattern and other features that are specific of each of these disorders. The most fascinating traits include their complex genotype-phenotype associations and clinical heterogeneity, ranging from Dunnigan disease, in which the most relevant feature is precisely adipose tissue dysfunction and lipodystrophy, to the other laminopathies affecting adipose tissue, which are also characterised by the presence of signs of premature ageing (Hutchinson Gilford-progeria syndrome, LMNA-atypical progeroid syndrome, mandibuloacral dysplasia types A and B, Nestor-Guillermo progeria syndrome, LMNA-associated cardiocutaneous progeria). This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes and variable degrees of metabolic abnormalities. The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies. In addition, it also summarises the key aspects for their differential diagnosis.

Inflammation and Fibrosis in Progeria: Organ-Specific Responses in an HGPS Mouse Model.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder that causes accelerated aging, due to a pathogenic variant in the LMNA gene. This pathogenic results in the production of progerin, a defective protein that disrupts the nuclear lamina's structure. In our study, we conducted a histopathological analysis of various organs in the LmnaG609G/G609G mouse model, which is commonly used to study HGPS. The objective of this study was to show that progerin accumulation drives systemic but organ-specific tissue damage and accelerated aging phenotypes. Our findings show significant fibrosis, inflammation, and dysfunction in multiple organ systems, including the skin, cardiovascular system, muscles, lungs, liver, kidneys, spleen, thymus, and heart. Specifically, we observed severe vascular fibrosis, reduced muscle regeneration, lung tissue remodeling, depletion of fat in the liver, and disruptions in immune structures. These results underscore the systemic nature of the disease and suggest that chronic inflammation and fibrosis play crucial roles in the accelerated aging seen in HGPS. Additionally, our study highlights that each organ responds differently to the toxic effects of progerin, indicating that there are distinct mechanisms of tissue-specific damage.

Radiological insights into mandibuloacral dysplasia: A case report.

Mandibulo-acral dysplasia was first described by Young et al in 1971. It is a rare, autosomal genetic disorder describing characteristic general, craniofacial, and oral manifestations. However, the detailed characteristics of this multisystemic disease have not yet been clarified due to its rarity and the limited number of cases described. Through a clinical case, we have tried to expose some of the most common clinical and radiological signs especially in their bucco-facial location, some modalities of management and the importance of an early diagnosis which turns out to be a real challenge especially for dentists in their daily practice.

Surgical treatment of lung cancer associated with Werner's syndrome: A case report and review of the literature.

Werner's syndrome is a rare progressive disorder that is characterized by a variety of clinical manifestations which mimic features of advanced ageing. Malignancy is one of the most problematic complications of Werner's syndrome. Lung cancer associated with Werner's syndrome is rare. A 54-year-old woman with Werner's syndrome was referred to our department because an abnormal shadow had been detected on routine chest radiography. Chest computed tomography revealed an abnormal nodule in the left upper lobe. Bronchoscopic examination revealed the presence of squamous cell carcinoma. Other imaging studies showed no metastatic lesions; therefore, the patient was diagnosed with stage IA3 squamous cell carcinoma. She underwent left upper lobectomy and lymph node dissection without major complications, and no recurrence was found for 2 years postoperatively.

Mechanotransduction of the vasculature in Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder that causes severe cardiovascular disease, resulting in the death of patients in their teenage years. The disease pathology is caused by the accumulation of progerin, a mutated form of the nuclear lamina protein, lamin A. Progerin binds to the inner nuclear membrane, disrupting nuclear integrity, and causes severe nuclear abnormalities and changes in gene expression. This results in increased cellular inflammation, senescence, and overall dysfunction. The molecular mechanisms by which progerin induces the disease pathology are not fully understood. Progerin's detrimental impact on nuclear mechanics and the role of the nucleus as a mechanosensor suggests dysfunctional mechanotransduction could play a role in HGPS. This is especially relevant in cells exposed to dynamic, continuous mechanical stimuli, like those of the vasculature. The endothelial (ECs) and smooth muscle cells (SMCs) within arteries rely on physical forces produced by blood flow to maintain function and homeostasis. Certain regions within arteries produce disturbed flow, leading to an impaired transduction of mechanical signals, and a reduction in cellular function, which also occurs in HGPS. In this review, we discuss the mechanics of nuclear mechanotransduction, how this is disrupted in HGPS, and what effect this has on cell health and function. We also address healthy responses of ECs and SMCs to physiological mechanical stimuli and how these responses are impaired by progerin accumulation.

Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.

BACKGROUND: Ageing is a complex multifactorial process, impacting all organs and tissues, with DNA damage accumulation serving as a common underlying cause. To decelerate ageing, various strategies have been applied to model organisms and evaluated for health and lifespan benefits. Dietary restriction (DR, also known as caloric restriction) is a well-established long-term intervention recognized for its universal anti-ageing effects. DR temporarily suppresses growth, and when applied to progeroid DNA repair-deficient mice doubles lifespan with systemic health benefits. Counterintuitively, attenuation of myostatin/activin signalling by soluble activin receptor (sActRIIB), boosts the growth of muscle and, in these animals, prevents muscle wasting, improves kidney functioning, and compresses morbidity. METHODS: Here, we investigated a combined approach, applying an anabolic regime (sActRIIB) at the same time as DR to Ercc1Δ/- progeroid mice. Following both single treatments and combined, we monitored global effects on body weight, lifespan and behaviour, and local effects on muscle and tissue weight, muscle morphology and function, and ultrastructural and transcriptomic changes in muscle and kidney. RESULTS: Lifespan was mostly influenced by DR (extended from approximately 20 to 40 weeks; P < 0.001), with sActRIIB clearly increasing muscle mass (35-65%) and tetanic force (P < 0.001). The combined regime yielded a stable uniform body weight, but increased compared with DR alone, synergistically improved motor coordination and further delayed the onset and development of balance problems. sActRIIB significantly increased muscle fibre size (P < 0.05) in mice subjected to DR and lowered all signs of muscle damage. Ercc1Δ/- mice showed abnormal neuromuscular junctions. Single interventions by sActRIIB treatment or DR only partially rescued this phenotype, while in the double intervention group, the regularly shaped junctional foldings were maintained. In kidney of Ercc1Δ/- mice, we observed a mild but significant foot process effacement, which was restored by either intervention. Transcriptome analysis also pointed towards reduced levels of DNA damage in muscle and kidney by DR, but not sActRIIB, while these levels retained lower in the double intervention. CONCLUSIONS: In muscle, we found synergistic effects of combining sActRIIB with DR, but not in kidney, with an overall better health in the double intervention group. Crucially, the benefits of each single intervention are not lost when administered in combination, but rather strengthened, even when sActRIIB was applied late in life, opening opportunities for translation to human.

Premature aging effects on COVID-19 pathogenesis: new insights from mouse models.

Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using an Hutchinson-Gilford progeria syndrome (HGPS) mouse model, a premature aging disease model, with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SARS-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract hemorrhage, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a useful tool for investigating COVID-19 pathogenesis in individuals with premature aging.

Navigating Lipodystrophy: Insights from Laminopathies and Beyond.

Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.

The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice.

The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24-/- mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a LmnaG609G/G609G mouse model. In both cases dapansutrile reduced progerin accumulation, NLRP3-inflammasome activation and secretory phenotype of senescence, extended the lifespan of progeroid animals, preserved bodyweight, and reduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile further improved the effect of lonafarnib, the only FDA-approved drug for the progeria. The combination of both drugs reduced the inflammation and senescence, extended survival and ameliorated various progeroid defects both in vitro and in vivo, compared with treatment using lonafarnib alone. These findings and the safety of dapansutrile demonstrated in several clinical trials proposes it as a possible co-adjuvant treatment with lonafarnid in HGPS.

Endothelial-to-Mesenchymal Transition Contributes to Accelerated Atherosclerosis in Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Atherosclerosis is the main medical problem in Hutchinson-Gilford progeria syndrome, a rare premature aging disorder caused by the mutant lamin-A protein progerin. Recently, we found that limiting progerin expression to vascular smooth muscle cells (VSMCs) is sufficient to hasten atherosclerosis and death in Apoe-deficient mice. However, the impact of progerin-driven VSMC defects on endothelial cells (ECs) remained unclear. METHODS: Apoe- or Ldlr-deficient C57BL/6J mice with ubiquitous, VSMC-, EC- or myeloid-specific progerin expression fed a normal or high-fat diet were used to study endothelial phenotype during Hutchinson-Gilford progeria syndrome-associated atherosclerosis. Endothelial permeability to low-density lipoproteins was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein and confocal microscopy analysis of the aorta. Leukocyte recruitment to the aortic wall was evaluated by en face immunofluorescence. Endothelial-to-mesenchymal transition (EndMT) was assessed by quantitative polymerase chain reaction and RNA sequencing in the aortic intima and by immunofluorescence in aortic root sections. TGFß (transforming growth factor ß) signaling was analyzed by multiplex immunoassay in serum, by Western blot in the aorta, and by immunofluorescence in aortic root sections. The therapeutic benefit of TGFß1/SMAD3 pathway inhibition was evaluated in mice by intraperitoneal injection of SIS3 (specific inhibitor of SMAD3), and vascular phenotype was assessed by Oil Red O staining, histology, and immunofluorescence in the aorta and the aortic root. RESULTS: Both ubiquitous and VSMC-specific progerin expression in Apoe-null mice provoked alterations in aortic ECs, including increased permeability to low-density lipoprotein and leukocyte recruitment. Atherosclerotic lesions in these progeroid mouse models, but not in EC- and myeloid-specific progeria models, contained abundant cells combining endothelial and mesenchymal features, indicating extensive EndMT triggered by dysfunctional VSMCs. Accordingly, the intima of ubiquitous and VSMC-specific progeroid models at the onset of atherosclerosis presented increased expression of EndMT-linked genes, especially those specific to fibroblasts and extracellular matrix. Aorta in both models showed activation of the TGFß1/SMAD3 pathway, a major trigger of EndMT, and treatment of VSMC-specific progeroid mice with SIS3 alleviated the aortic phenotype. CONCLUSIONS: Progerin-induced VSMC alterations promote EC dysfunction and EndMT through TGFß1/SMAD3, identifying this process as a candidate target for Hutchinson-Gilford progeria syndrome treatment. These findings also provide insight into the complex role of EndMT during atherogenesis.

A Pair of Sibling Patients With Premature Aging Syndrome of Unknown Etiology.

Premature aging syndrome is a rare condition characterized by premature aging and death. The exact pathogenic mechanisms underlying most premature aging syndromes are poorly understood. Here, we describe two sibling cases of premature aging syndrome of unknown etiology, with no identified significant genetic mutation, with the primary symptom of a prematurely aged appearance, and a chief complaint of marked short stature. The first patient was an eight-year-old Cambodian boy born to a third-degree consanguineous marriage. He visited our hospital with the chief complaint of short stature. His development was originally normal until he developed pneumonia when he was three years old. Neither of his parents had any symptoms or family history of similar abnormalities, except for his five-year-old sister, who also has a markedly short stature of 80.4 cm and a low body weight of 8.7 kg. Her face showed distinct macrognathia and relative macrocephaly. The brother's low-density lipoprotein cholesterol level was high (198 mg/dl), and brain magnetic resonance angiography and carotid ultrasound revealed severe atherosclerotic changes. Whole-exome sequencing results were insignificant for both patients. This case report aims to elucidate the pathogenesis and treatment of progeria. This report indicates the possibility of an unidentified type of premature aging syndrome.

Maintenance of germline stem cell homeostasis despite severe nuclear distortion.

Stem cell loss in aging and disease is associated with nuclear deformation. Yet, how nuclear shape influences stem cell homeostasis is poorly understood. We investigated this connection using Drosophila germline stem cells, as survival of these stem cells is compromised by dysfunction of the nuclear lamina, the extensive protein network that lines the inner nuclear membrane and gives shape to the nucleus. To induce nuclear distortion in germline stem cells, we used the GAL4-UAS system to increase expression of the permanently farnesylated nuclear lamina protein, Kugelkern, a rate limiting factor for nuclear growth. We show that elevated Kugelkern levels cause severe nuclear distortion in germline stem cells, including extensive thickening and lobulation of the nuclear envelope and nuclear lamina, as well as alteration of internal nuclear compartments. Despite these changes, germline stem cell number, proliferation, and female fertility are preserved, even as females age. Collectively, these data demonstrate that disruption of nuclear architecture does not cause a failure of germline stem cell survival or homeostasis, revealing that nuclear deformation does not invariably promote stem cell loss.

Cardiac and skeletal muscle manifestations in the G608G mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence-associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS.

A Review of Research on the Mechanism of Tumor Regulation by N-Acetyltransferase 10.

N-acetyltransferase 10 (NAT10) is an important acetyltransferase that regulates telomerase activity and participates in DNA damage reactions, ribosomal RNA (rRNA) transcriptional activation, cell division, microtubule acetylation, and other important cellular processes. Abnormalities in the expression or distribution of NAT10 result in diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and various tumors, with serious consequences. Remodelin, an inhibitor of NAT10, delays HGPS progression; many studies have been conducted on its role in tumor therapy. A major breakthrough in the study of NAT10 was the discovery of mRNA N4-acetylcytidine (ac4C) modification, which can increase mRNA stability and translation efficiency significantly. In addition, NAT10 modifies the mRNA of ac4C, which is associated with tumor development. Here, we present a review of pertinent studies focusing on NAT10, particularly its role in cancer, to provide researchers with a concise and informative summary of the current state of knowledge about this topic. The conclusions drawn from this review could provide a new direction for tumor treatment.

Hutchinson-Gilford progeria syndrome mice display accelerated arterial thrombus formation and increased platelet reactivity.

INTRODUCTION: Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown. METHODS: Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated. RESULTS: LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals. CONCLUSIONS: LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.

Vitexin promotes the anti-senescence effect via inhibiting JAK2/STAT3 in D-Galactose-induced progeria mice and stress-induced premature senescence.

Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H2O2), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway.

The mouse Social Frailty Index (mSFI): a novel behavioral assessment for impaired social functioning in aging mice.

Various approaches exist to quantify the aging process and estimate biological age on an individual level. Frailty indices based on an age-related accumulation of physical deficits have been developed for human use and translated into mouse models. However, declines observed in aging are not limited to physical functioning but also involve social capabilities. The concept of "social frailty" has been recently introduced into human literature, but no index of social frailty exists for laboratory mice yet. To fill this gap, we developed a mouse Social Frailty Index (mSFI) consisting of seven distinct assays designed to quantify social functioning which is relatively simple to execute and is minimally invasive. Application of the mSFI in group-housed male C57BL/6 mice demonstrated a progressively elevated levels of social frailty through the lifespan. Conversely, group-housed females C57BL/6 mice manifested social frailty only at a very old age. Female mice also showed significantly lower mSFI score from 10 months of age onward when compared to males. We also applied the mSFI in male C57BL/6 mice under chronic subordination stress and in chronic isolation, both of which induced larger increases in social frailty compared to age-matched group-housed males. Lastly, we show that the mSFI is enhanced in mouse models that show accelerated biological aging such as progeroid Ercc1-/Δ and Xpg-/- mice of both sexes compared to age matched littermate wild types. In summary, the mSFI represents a novel index to quantify trajectories of biological aging in mice and may help elucidate links between impaired social behavior and the aging process.

Progerin Can Induce DNA Damage in the Absence of Global Changes in Replication or Cell Proliferation.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, and individuals with HGPS seldom live beyond their mid-teens. The syndrome is commonly caused by a point mutation in the LMNA gene which codes for lamin A and its splice variant lamin C, components of the nuclear lamina. The mutation causing HGPS leads to production of a truncated, farnesylated form of lamin A referred to as "progerin." Progerin is also expressed at low levels in healthy individuals and appears to play a role in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs) and alterations in the nature of DSB repair. The source of DSBs in HGPS is often attributed to stalling and subsequent collapse of replication forks in conjunction with faulty recruitment of repair factors to damage sites. In this work, we used a model system involving immortalized human cell lines to investigate progerin-induced genomic damage. Using an immunofluorescence approach to visualize phosphorylated histone H2AX foci which mark sites of genomic damage, we report that cells engineered to express progerin displayed a significant elevation of endogenous damage in the absence of any change in the cell cycle profile or doubling time of cells. Genomic damage was enhanced and persistent in progerin-expressing cells treated with hydroxyurea. Overexpression of wild-type lamin A did not elicit the outcomes associated with progerin expression. Our results show that DNA damage caused by progerin can occur independently from global changes in replication or cell proliferation.

The Use of Peripheral Nerve Block and Intra-articular Steroid Injection for Pain Management in an Adolescent with Hutchinson-Gilford Progeria Syndrome: A Case Report.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder causing accelerated aging and age-related pathologies. Weighing benefits and risks on doing surgical versus conservative pain management require multidisciplinary planning and consideration in HGPS patients. This presents a case of a 15-year-old patient with HGPS with severe pain from bilateral hip dislocation managed with peripheral nerve block and steroid injection. This afforded her immediate pain relief allowing her to undergo physical rehabilitation comfortably.