Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases

Lautrup, Sofie; Caponio, Domenica; Cheung, Hoi‐Hung; Piccoli, Cláudia; Stevnsner, Tinna; Chan, Wai‐Yee; Fang, Evandro Fei

doi:10.1007/s10522-019-09798-2

Cited by 27 publications

(28 citation statements)

References 121 publications

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“…The pathogenesis of premature aging in WS has been previously investigated largely using nonhuman model organisms (e.g., yeast, fly, worm, and mouse; Lautrup et al, ) or human tissue biopsies (e.g., skin fibroblasts and lymphoblasts; Mazzarello, Ferrari, & Ena, ). Clinical reports on WS provide additional pathological insights into the mechanistic origin of the disease (Goto, Ishikawa, Sugimoto, & Furuichi, ).…”

Section: Discussionmentioning

confidence: 99%

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Wan

Zhang

et al. 2020

Aging Cell

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WRN mutation causes a premature aging disease called Werner syndrome (WS). However, the mechanism by which WRN loss leads to progeroid features evident with impaired tissue repair and regeneration remains unclear. To determine this mechanism, we performed gene editing in reprogrammed induced pluripotent stem cells (iPSCs) derived from WS fibroblasts. Gene correction restored the expression of WRN. WRN+/+ mesenchymal stem cells (MSCs) exhibited improved pro‐angiogenesis. An analysis of paracrine factors revealed that hepatocyte growth factor (HGF) was downregulated in WRN−/− MSCs. HGF insufficiency resulted in poor angiogenesis and cutaneous wound healing. Furthermore, HGF was partially regulated by PI3K/AKT signaling, which was desensitized in WRN−/− MSCs. Consistently, the inhibition of the PI3K/AKT pathway in WRN+/+ MSC resulted in reduced angiogenesis and poor wound healing. Our findings indicate that the impairment in the pro‐angiogenic function of WS‐MSCs is due to HGF insufficiency and PI3K/AKT dysregulation, suggesting trophic disruption between stromal and epithelial cells as a mechanism for WS pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Wan

Zhang

et al. 2020

Aging Cell

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“…Aging is characterized by a progressive loss of physiological integrity, which was driven by a variety of contributing factors, including DNA damage, epigenetic shifts, and altered RNA and protein profiles [1][2][3]. e deterioration inevitably impairs tissue function and increases susceptibility to disease and death and has been demonstrated to be the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases [4].…”

Section: Introductionmentioning

confidence: 99%

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Yuan

Lin

Cui

et al. 2020

BioMed Research International

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The cytosolic isozyme of phosphoenolpyruvate carboxykinase (PCK1) was the first rate-limiting enzyme in the gluconeogenesis pathway, which exerted a critical role in maintaining the blood glucose levels. PCK1 has been established to be involved in various physiological and pathological processes, including glucose metabolism, lipid metabolism, diabetes, and tumorigenesis. Nonetheless, the association of PCK1 with aging process and the detailed underlying mechanisms of PCK1 on aging are still far to be elucidated. Hence, we herein constructed the PCK1-deficient (pck1Δ) and PCK1 overexpression (PCK1 OE) Saccharomyces cerevisiae. The results unveiled that PCK1 deficiency significantly shortened the replicative lifespan (RLS) in the S. cerevisiae, while overexpression of PCK1 prolonged the RLS. Additionally, we noted that the ROS level was significantly enhanced in PCK1-deficient strain and decreased in PCK1 OE strain. Then, a high throughput analysis by deep sequencing was performed in the pck1Δ and wild-type strains, in an attempt to shed light on the effect of PCK1 on the lifespan of aging process. The data showed that the most downregulated mRNAs were enriched in the regulatory pathways of glucose metabolism. Fascinatingly, among the differentially expressed mRNAs, PFK1 was one of the most upregulated genes, which was involved in the glycolysis process and ROS generation. Thus, we further constructed the pfk1Δpck1Δ strain by deletion of PFK1 in the PCK1-deficient strain. The results unraveled that pfk1Δpck1Δ strain significantly suppressed the ROS level and restored the RLS of pck1Δ strain. Taken together, our data suggested that PCK1 deficiency enhanced the ROS level and shortened the RLS of S. cerevisiae via PFK1.

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“…In addition, physicians should monitor any development of arteriosclerosis-related diseases. Treatments for the symptoms of WS include: surgery for refractory ulcers [34] and cataracts [31], anti-aging treatment such as vitamin C [35], or rapamycin [36], either with or without a farnesyltransferase inhibitor [37], and pluripotent stem cell therapy [38,39]. With an increasing awareness of WS, the availability of genetic testing, and the variety of available investigative tools (genomics, epigenomics, transcriptomics, proteomics, and metabonomics), it is hoped that new approaches for the treatment of WS symptoms will also provide for the early recognition and treatment of age-related disorders [39].…”

Section: Discussionmentioning

confidence: 99%

Severe metabolic disorders coexisting with Werner syndrome: a case report

Yang

Shen

et al. 2021

Endocr J

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Werner syndrome, also called adult progeria, is a heritable autosomal recessive human disorder characterized by the premature onset of numerous age-related diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM), osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental progeroid syndrome whose presentation resembles accelerated aging. The most common causes of death for WS patients are atherosclerosis and cancer. A 40-year-old female presented with short stature, bird-like facies, canities with alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The patient reported a history of delayed puberty, abortion, hypertriglyceridemia, and juvenile cataracts. A clinical diagnosis of WS was made and subsequently confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9, which caused a premature termination codon (PTC) at position 369. Variant 2 was a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC at position 383 and has no published reports describing. Patients with WS can show a wide variety of clinical and biological manifestations in endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia). Doctors must be cognizant of early manifestations of WS and treatment options.

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Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases

Cited by 27 publications

References 121 publications

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Severe metabolic disorders coexisting with Werner syndrome: a case report

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