Chemical screen identifies a geroprotective role of quercetin in premature aging

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

Management of cataract in Werner syndrome

Werner syndrome (WS) is a rare progressive disorder. It is characterized by the appearance of unusually accelerated aging (progeria) including bilateral senile cataract. Here, we report a successful management of hypermature cataract in WS.

Recurrent skin ulcer cross-repair and sensory reconstruction in a WRN gene mutational patient

Abstract: A 37-year-old man complained of a refractory posterior malleolar ulceration on his left ankle. He was diagnosed with Werner syndrome according to the progeroid clinical features and genetic testing. To approach the ulceration, a free flow-through right anterolateral thigh perforator flap with anterolateral thigh cutaneous nerve was harvested. One year later, he was readmitted due to a new ulceration on his right ankle. We harvested the left anterolateral thigh perforator flap with anterolateral thigh cutaneous nerve to reconstruct the defect. After one more year of follow-up, there was no recurrence of ulcers, and the sensation of the flap recovered partially after 6 months. We conclude that free flow-through anterolateral thigh perforator flap is a feasible choice for the repair of foot ulcers in Werner syndrome.

Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

Do you know this syndrome? Werner syndrome

Abstract: Werner syndrome is a rare autosomal recessive disorder, caused by mutations in the WRN gene. Clinical findings include: senile appearance, short stature, grey hair, alopecia, bird-like face, scleroderma-like skin changes, skin ulcers, voice abnormalities, cataracts, osteoporosis, type 2 diabetes mellitus, ischemic heart disease and hypogonadism. The syndrome begins to become apparent in adolescence but it is usually diagnosed in the third or fourth decade of life. Since the patients usually die by the age of 40-50 years related to malignant neoplasms or atherosclerotic complications, they should be closely followed and treated for complications

Síndrome de Werner: a propósito de un caso probable / Werner's syndrome, about a probable case

Resumen: el síndrome de Werner es una patología poco frecuente, de herencia autosómica recesiva, caracterizado por signos de envejecimiento prematuro y tendencia a desarrollar tumores malignos. El diagnóstico de esta enfermedad es principalmente clínico, con hallazgos predominantes como talla baja y envejecimiento precoz. En este artículo se presenta el caso de un paciente de 49 años de edad, con signos tempranos de envejecimiento desde los 15 años y ateroesclerosis temprana asociada, que lo lleva a amputación quirúrgica de extremidad inferior derecha. De acuerdo con los criterios diagnósticos del síndrome de Werner este es el primer caso probable en el suroccidente colombiano. (AU)

Abstract: Werner syndrome is a rare, autosomal recessive pathology, characterized by signs of premature aging and tendency to develop malignant tumors. The diagnosis is principally clinical, with predominating findings as short stature and precocious aging. In this article, it's presented the case of a 49-year-old patient with early signs of aging from the age of 15 years and associated early atherosclerosis that leads to the right lower limb surgical amputation. According to the diagnostic criteria of Werner syndrome, this is the first probable case in the Colombian Southwest. (AU)

Vitamin C alleviates aging defects in a stem cell model for Werner syndrome

Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.

Endothelial cell study in a case of Werner's syndrome undergoing phacoemulsification and Yettrium-Aluminum-Garnet laser capsulotomy.

Werner's syndrome (WS) is a rare autosomal recessive disorder with multisystem manifestations of premature aging from the second decade of life. Cataract is one of the features of WS. Cataract surgery is complicated with postoperative wound dehiscence and bullous keratopathy when the surgery is done by intracapsular or conventional extracapsular method. We report the short-term result of phacoemulsification and Neodymimum Yettrium-Aluminum-Garnet laser (Nd YAG) capsulotomy in a case of WS with bilateral cataracts. Postoperatively and post capsulotomy, there was no change in the endothelial cell morphology. There was an 8.6% decrease in endothelial cell count at the end of 15 months postoperatively and 11 months post YAG capsulotomy. This decrease is within the acceptable range of cell loss after phacoemulsification and YAG capsulotomy. To the best of our knowledge, this is the first reported case of YAG laser capsulotomy in WS.

Síndrome de Herlyn Werner Wünderlich. Reporte de tres casos / Herlyn Wunderlich Werner Syndrome. Report of three cases

Caso Clínico 1. J.A, 21 años, nuligesta. Acude por hipermenorragia y síndrome doloroso abdominal. Ecografía informa útero didelfo, hematocolpo en hemivagina ciega, tumoraciones anexiales y agenesia renal derecha conformándose el diagnostico de HWW, es sometida a neosalpingostomia con fimbrioplastia por hematosalpinx derecho por vía laparoscópica. A quince días del postoperatorio presenta cuadro de abdomen agudo. Ecografía informa quiste de ovario con hemorragia intraquística y liquido libre abdominal. Se realiza histerectomía subtotal derecha y drilling del quiste por vía laparotómica. Caso Clínico 2. T.A, 53 años, diagnostico conocido de HWW, cirugías previas histerectomía subtotal y resección del tabique vaginal 38 años antes. Acude por hipermenorrea por miomatosis uterina. Se realiza histerectomía total con resección del 2º cérvix. Caso Clínico 3. S.S, 35 años, diagnostico conocido de HWW, cirugías previas anexectomía izquierda por endometrioma 14 años antes, e histerectomía subtotal, sin resección del tabique en otro hospital 6 años antes. Acude a la consulta donde se diagnostica cervicitis mucopurulenta. Actualmente en planes de resección del tabique vaginal que no se realizo por el cuadro infeccioso presente. Discusión: Hay aproximadamente 200 casos reportados de HWW. La clínica más frecuente es dolor por hematocolpo. Esta patología presenta estrecha relación con infertilidad y endometriosis. Palabras Claves: Síndrome de Herlyn Werner Wünderlich, útero didelfo, hemivagina, agenesia renal.

Objective: To report three cases of diagnosis of Werner Wünderlich Herlyn syndrome (HWWS) in the Central Hospital of Social Security Institute of Paraguay (HC-IPS). Materials and Methods: Data from the records of patients of the Gynecology Service of HC-IPS between January/2010 to enero/2012 diagnosed with HWW. Case 1. J.A., female, 21, nulígesta. Presents abdominal pain and hipermenorragia, ultrasound reports didelphys uterus, hematocolpo, adnexal tumors and right renal agenesia making the diagnosis of HWW, is treated by fimbrioplasty and neosalpingostomy for right hematosalpinx by laparoscopy. Postoperative presents acute abdominal pain, ultrasound reports intracystic hemorrhage and abdominal free fluid. Subtotal hysterectomy is done and drilling of right cyst by laparotomy. Case 2. TA, female, 53, HWW known diagnosis, previous surgery: subtotal hysterectomy and vaginal septum resection 38 years earlier. Presents menorrhagia for uterine fibroids. Total hysterectomy is performed with resection of the second cervix. Case 3. SS, female, 35, known diagnosis of HWW, previous surgeries: left adnexectomy for endometrioma 14 years earlier, and subtotal hysterectomy with out removal of the vaginal septum in another hospital 6 years earlier. Attending the clinic where they diagnosed mucopurulent cervicitis. Currently in plans of vaginal septum resection that was not performed by the infection present. Discussion: There are approximately 200 reported cases of HWW. The most frequent symptom is pain by hematocolopo. Keep in mind the strong association with infertility and endometriosis of this disease. Keywords: Werner Syndrome Wünderlich Herlyn, uterus didelphys, hemivagina, renal agenesis.

Novel LMNA Gene Mutation in a Patient With Atypical Werner's Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner's syndrome are representative types of progeroid syndrome. LMNA (Lamin A/C) gene mutation with atypical Werner's syndrome have recently been reported. Atypical Werner's syndrome with the severe metabolic complications, the extent of the lipodystrophy is associated with A133L mutation in the LMNA gene and these patients present with phenotypically heterogeneous disorders. We experienced a 15-yr-old Korean female with progeroid features, generalized lipodystrophy, hypertriglyceridemia, fatty liver, steatohepatitis, and type 2 diabetes mellitus. Skin fibroblasts from the patient showed marked abnormal nuclear morphology, compared with that from normal persons. Gene analysis revealed that this patient had T506del of exon 2 in the LMNA gene. We report here the first case of atypical Werner's syndrome with frameshift mutation that was caused by T506del.

A case of Werner Syndrome Complicated by Bone Metastasis of Rhabdomyosarcoma

Werner syndrome (WRN), or adult progeria, is a very rare, autosomal recessive disorder characterized by the appearance of accelerated aging, including cataracts, gray hair, skin atrophy, and atherosclerosis. This syndrome is caused by mutations in the WRN gene and had a high risk of a spectrum of rare neoplasms including: i) non-epithelial malignant or pre-malignant tumors/conditions, osteosarcomas and soft tissue sarcomas, malignant melanomas, myeloid leukemia and myelodysplastic syndrome; ii) an epithelial neoplasm, thyroid carcinoma, and iii) meningiomas. Recently, authors experienced a case of Werner syndrome complicated by bone metastasis of rhabdomyosarcoma in a 20-year old Korean man. The patient revealed a painful mass on his right knee and progeroid features, short stature, scalp alopecia, abnormal dentition, craniofacial disproportion, hypothyroidsm, cataracts and osteoporosis. The onset of symptoms of Werner syndrome generally precedes any later symptoms of associated conditions, such as malignant tumor. Therefore, early recognition of Werner syndrome is important to assist identification of malignant tumors at an early stage in this patient group.

A case of atypical Werner syndrome without WRN gene mutations / 대한내과학회지

Werner syndrome is a rare autosomal recessive, hereditary disease that demonstrates progeroid features and has characteristic WRN gene mutations. Atypical Werner syndrome refers to a small subset of individuals who produce the normal WRN protein, but show some signs and symptoms that sufficiently overlap with Werner syndrome. Recently, we experienced a case of atypical Werner syndrome. A 43-year-old woman was admitted to our hospital due to being severely underweight. She had an operative history of cataracts in both eyes and had suffered from multiple skin ulcers, deafness, and vision loss. Physical examination revealed short stature, low body weight, flat feet, and a scleroderma-like skin change. Laboratory and clinical tests showed that the patient had diabetes mellitus, osteoporosis, and premature atherosclerotic features. Her clinical presentation and laboratory findings were consistent with Werner syndrome. We performed a WRN, LMNA gene sequence analysis, but no mutations were detected. The patient was diagnosed with atypical Werner syndrome.

Síndrome de Werner associada a quadro esclerodermiforme: relato de caso e revisão da literatura / Werner's syndrome associated with scleroderma-like syndrome: case report and literature revision

A síndrome de Werner é uma doença autossômica recessiva rara associada a envelhecimento precoce, cujo quadro cutâneo deve ser distinguido daquele encontrado na esclerose sistêmica (ES). Descrevemos aqui o caso de uma paciente de 39 anos de idade, portadora de síndrome de Werner, encaminhada ao nosso serviço com hipótese diagnóstica inicial de ES. A paciente apresentava várias manifestações associadas à síndrome de Werner, incluindo cabelos precocemente grisalhos, voz estridente, baixa estatura, alterações cutâneas esclerodermiformes, diabetes melito, catarata, hipogonadismo, hipotireoidismo e hiperlipidemia. Não apresentava fenômeno de Raynaud, manifestações viscerais típicas da ES, alterações capilaroscópicas periungueais ou auto-anticorpos. O diagnóstico de síndrome de Werner, apesar de raro, deve ser lembrado no diagnóstico diferencial de ES, principalmente na presença de manifestações atípicas e na ausência de alterações típicas da ES.

Werner's syndrome is a rare autosomal recessive disease associated with premature ageing. Skin alteration must be distinguished from cutaneous manifestation of systemic sclerosis (SSc). We describe a case of a 39 years old patient with Werner's syndrome admitted with an initial diagnostic hypothesis of SSc. The patient had many characteristic features associated with Werner's syndrome including gray hair, hoarseness, short stature, scleroderma-like skin changes, diabetes mellitus, cataracts, hypogonadism, hypothyroidism, and hyperlipidemia. There was no Raynaud's phenomenon, other typical visceral manifestation of SSc, nailfold capillary alterations or autoantibodies. Werner's syndrome diagnosis notwithstanding rare, should be remember in the differential diagnosis of SSc, mainly in the presence of atypical manifestations and in the absence of typical features of SSc.

El nucléolo como un regulador del envejecimiento celular / The nucleolus as a regulator of cellular senescence

El nucléolo, considerado únicamente como el sitio de síntesis de los ribosomas, actualmente representa una estructura nuclear dinámica que participa en la regulación de importantes procesos celulares. Numerosas evidencias han demostrado que el envejecimiento celular es una de las diversas funciones que son controladas por el nucléolo. Las mutaciones en las proteínas de localización nucleolar promueven el envejecimiento prematuro en levaduras y humanos. La carencia de represión en la transcripción de genes que codifican para el ARNr que se encuentran dañados, y las mutaciones en las helicasas del ADN encargadas de minimizar la formación de círculos extra-cromosómicos del ADN que codifica para el ARNr, provocan modificaciones en la estructura del nucléolo e inducen envejecimiento prematuro en levaduras. De igual manera, en los humanos la carencia de las helicasas del ADN localizadas en el nucléolo y que participan en el mantenimiento de la integridad genómica, favorecen el desarrollo de aquellas enfermedades asociadas con el envejecimiento acelerado. Además, la presencia de algunos componentes de la telomerasa en el nucléolo, indica que parte de la biosíntesis de esta enzima se realiza en esta estructura nuclear, sugiriendo una conexión entre el nucléolo y la síntesis de los telómeros en la regulación del envejecimiento celular. Por otra parte, el nucléolo secuestra proteínas para regular su actividad biológica durante el inicio o término de la vida replicativa celular.

The nucleolus has been considered originally only as the site for the ribosome synthesis, but now it is well known that it represents a dynamic nuclear structure involved in important cellular processes. Several evidences have demonstrated that the nucleolus regulates the cellular senescence. Specific mutations on the DNAs codifying for nucleolar proteins induced premature senescence from yeast to human. The failure to repress the genes transcription codifying for damaged rRNA, and the mutations in DNA helicases, which minimizes the formation of DNA extra-chromosomal circles codifying for rRNA, modify the nucleolar structure and induce premature senescence in yeast. Similarly, in humans, the reduction of these DNA helicases levels, which are localized in the nucleoli and participate in maintenance of genomic integrity, helps to the development of those diseases associated with premature senescence. Furthermore, the presence in the nucleolus of some telomerase components, indicates that part of the biosynthesis of this enzyme occurred in this nuclear structure; suggesting a communication between the nucleolus and the synthesis of the telomeres in the regulation of cell senescence. On the other hand, the nucleolus sequesters proteins to regulate its own biological activity, from the start to the end of cellular replication. In addition this nuclear structure is involved in the biosynthesis of most cellular ribonucleoprotein particles, as well as in cell cycle regulation, making it central to gene expression. In conclusion, the nucleolus became a multifunctional subnuclear structure involved from cell proliferation to cell senescence.