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Nature Aging Jun 2023
PubMed: 37130978
DOI: 10.1038/s43587-023-00427-9 -
Aging May 2023Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease....
Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.
Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.
Topics: Humans; Kidney; Follow-Up Studies; Werner Syndrome; Cross-Sectional Studies; Sarcopenia; Cardiovascular Diseases; Kidney Diseases; Neoplasms; Creatinine
PubMed: 37130431
DOI: 10.18632/aging.204681 -
Nature Aging Feb 2023An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson-Gilford progeria syndrome (HGPS), which is a...
An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson-Gilford progeria syndrome (HGPS), which is a premature aging disease caused by progerin accumulation. Here, we found that BUBR1, a core component of the spindle assembly checkpoint, was downregulated during HGPS cellular senescence. The remaining BUBR1 was anchored to the nuclear membrane by binding with the C terminus of progerin, thus further limiting the function of BUBR1. Based on this, we established a unique progerin C-terminal peptide (UPCP) that effectively blocked the binding of progerin and BUBR1 and enhanced the expression of BUBR1 by interfering with the interaction between PTBP1 and progerin. Finally, UPCP significantly inhibited HGPS cellular senescence and ameliorated progeroid phenotypes, extending the lifespan of Lmna mice. Our findings reveal an essential role for the progerin-PTBP1-BUBR1 axis in HGPS. Therapeutics designed around UPCP may be a beneficial strategy for HGPS treatment.
Topics: Mice; Animals; Progeria; Aging, Premature; Phenotype
PubMed: 37118121
DOI: 10.1038/s43587-023-00361-w -
Nature Communications Apr 2023Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause...
Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.
Topics: Mice; Animals; Progeria; Electron Transport Complex III; Mitochondrial Diseases; Cellular Senescence; Cell Cycle
PubMed: 37095097
DOI: 10.1038/s41467-023-38027-1 -
Archives of Cardiovascular Diseases May 2023Myocardial infarction is rare in children, teenagers and young adults (aged<20 years). The most common aetiologies identified include Kawasaki disease, familial... (Review)
Review
Myocardial infarction is rare in children, teenagers and young adults (aged<20 years). The most common aetiologies identified include Kawasaki disease, familial hypercholesterolaemia, collagen vascular disease-induced coronary arteritis, substance abuse (cocaine, glue sniffing), trauma, complications of congenital heart disease surgery, genetic disorders (such as progeria), coronary artery embolism, occult malignancy and several other rare conditions. Nephrotic syndrome is a very rare cause of myocardial infarction, but it is probably underestimated. The purpose of this review was to determine the current state of knowledge on acute coronary syndrome related to nephrotic syndrome. We thus performed a comprehensive structured literature search of the Medline database for articles published between January 1st, 1969 and December 31st, 2021. Myocardial infarction in young adults can be broadly divided into two groups: cases of angiographically normal coronary arteries; and cases of coronary artery disease of varying aetiology. There are several possible mechanisms underlying the association between acute coronary syndrome and nephrotic syndrome: (1) coronary thrombosis related to hypercoagulability and/or platelet hyperactivity; (2) atherosclerosis related to hyperlipidaemia; and (3) drug treatment. All of these mechanisms must be evaluated systematically in the acute phase of disease because they evolve rapidly with the treatment of nephrotic syndrome. In this review, we propose a decision algorithm for the management of acute coronary syndrome in the context of nephrotic syndrome. The final part of the review presents the short- and medium-term therapeutic strategies available. Thromboembolism related to nephrotic syndrome is a rare non-atherosclerotic cause of acute coronary syndrome, and prospective studies are needed to evaluate a systematic approach with personalized therapeutic strategies.
Topics: Humans; Adolescent; Young Adult; Child; Acute Coronary Syndrome; Nephrotic Syndrome; Myocardial Infarction; Coronary Artery Disease; Atherosclerosis
PubMed: 37088677
DOI: 10.1016/j.acvd.2023.03.002 -
Circulation Research Apr 2023The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors.... (Review)
Review
The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors. Within the scenario of uncontrolled artery wall aging processes, CKD (chronic kidney disease) stands out as a valid model for detailed structural, functional, and molecular studies of this process. The cardiorenal syndrome relates to the detrimental bidirectional interplay between the kidney and the cardiovascular system. In addition to established risk factors, this group of patients is subjected to a plethora of other emerging vascular risk factors, such as inflammation, oxidative stress, mitochondrial dysfunction, vitamin K deficiency, cellular senescence, somatic mutations, epigenetic modifications, and increased apoptosis. A better understanding of the molecular mechanisms through which the uremic milieu triggers and maintains early vascular aging processes, has provided important new clues on inflammatory pathways and emerging risk factors alike, and to the altered behavior of cells in the arterial wall. Advances in the understanding of the biology of uremic early vascular aging opens avenues to novel pharmacological and nutritional therapeutic interventions. Such strategies hold promise to improve future prevention and treatment of early vascular aging not only in CKD but also in the elderly general population.
Topics: Humans; Aged; Renal Insufficiency, Chronic; Aging; Vascular Diseases; Kidney; Cellular Senescence
PubMed: 37053277
DOI: 10.1161/CIRCRESAHA.122.321751 -
DNA Repair Jun 2023Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging and a life expectancy of about 14 years. HGPS is...
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging and a life expectancy of about 14 years. HGPS is commonly caused by a point mutation in the LMNA gene which codes for lamin A, an essential component of the nuclear lamina. The HGPS mutation alters splicing of the LMNA transcript, leading to a truncated, farnesylated form of lamin A termed "progerin." Progerin is also produced in small amounts in healthy individuals by alternative splicing of RNA and has been implicated in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs), suggesting alteration of DNA repair. DSB repair normally occurs by either homologous recombination (HR), an accurate, templated form of repair, or by nonhomologous end-joining (NHEJ), a non-templated rejoining of DNA ends that can be error-prone; however a good portion of NHEJ events occurs precisely with no alteration to joined sequences. Previously, we reported that over-expression of progerin correlated with increased NHEJ relative to HR. We now report on progerin's impact on the nature of DNA end-joining. We used a model system involving a DNA end-joining reporter substrate integrated into the genome of cultured thymidine kinase-deficient mouse fibroblasts. Some cells were engineered to express progerin. Two closely spaced DSBs were induced in the integrated substrate through expression of endonuclease I-SceI, and DSB repair events were recovered through selection for thymidine kinase function. DNA sequencing revealed that progerin expression correlated with a significant shift away from precise end-joining between the two I-SceI sites and toward imprecise end-joining. Additional experiments revealed that progerin did not reduce HR fidelity. Our work suggests that progerin suppresses interactions between complementary sequences at DNA termini, thereby shifting DSB repair toward low-fidelity DNA end-joining and perhaps contributing to accelerated and normal aging through compromised genome stability.
Topics: Mice; Animals; Lamin Type A; Thymidine Kinase; Progeria; DNA; Chromosomes, Mammalian; Mammals
PubMed: 37018982
DOI: 10.1016/j.dnarep.2023.103491 -
Aging Cell May 2023Ageing is the greatest risk factor of late-onset neurodegenerative diseases. In the realm of sporadic tauopathies, modelling the process of biological ageing in... (Review)
Review
Ageing is the greatest risk factor of late-onset neurodegenerative diseases. In the realm of sporadic tauopathies, modelling the process of biological ageing in experimental animals forms the foundation of searching for the molecular origin of pathogenic tau and developing potential therapeutic interventions. Although prior research into transgenic tau models offers valuable lessons for studying how tau mutations and overexpression can drive tau pathologies, the underlying mechanisms by which ageing leads to abnormal tau accumulation remains poorly understood. Mutations associated with human progeroid syndromes have been proposed to be able to mimic an aged environment in animal models. Here, we summarise recent attempts in modelling ageing in relation to tauopathies using animal models that carry mutations associated with human progeroid syndromes, or genetic elements unrelated to human progeroid syndromes, or have exceptional natural lifespans, or a remarkable resistance to ageing-related disorders.
Topics: Animals; Humans; Aged; tau Proteins; Tauopathies; Aging; Disease Models, Animal; Longevity; Cockayne Syndrome
PubMed: 37013265
DOI: 10.1111/acel.13830 -
Frontiers in Bioscience (Landmark... Mar 2023Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the () gene. Patients with PXE show molecular and clinical characteristics...
BACKGROUND
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the () gene. Patients with PXE show molecular and clinical characteristics of known premature aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS). Nevertheless, PXE has only barely been discussed against the background of premature aging, although a detailed characterization of aging processes in PXE could contribute to a better understanding of its pathogenesis. Thus, this study was performed to evaluate whether relevant factors which are known to play a role in accelerated aging processes in HGPS pathogenesis are also dysregulated in PXE.
METHODS
Primary human dermal fibroblasts from healthy donors (n = 3) and PXE patients (n = 3) and were cultivated under different culture conditions as our previous studies point towards effects of nutrient depletion on PXE phenotype. Gene expression of , , , and were determined by quantitative real-time polymerase chain reaction. Additionally, protein levels of lamin A, C and nucleolin were evaluated by immunofluorescence and the telomere length was analyzed.
RESULTS
We could show a significant decrease of and gene expression in PXE fibroblasts under nutrient depletion compared to controls. The gene expression of and showed a significant increase in PXE fibroblasts when cultivated in 10% fetal calf serum (FCS) compared to controls. Immunofluorescence microscopy of and and mRNA expression of and showed no significant changes in any case. The determination of the relative telomere length showed significantly longer telomeres for PXE fibroblasts compared to controls when cultivated in 10% FCS.
CONCLUSIONS
These data indicate that PXE fibroblasts possibly undergo a kind of senescence which is independent of telomere damage and not triggered by defects of the nuclear envelope or nucleoli deformation.
Topics: Humans; Progeria; Aging, Premature; Lamin Type A; Pseudoxanthoma Elasticum; Farnesyltranstransferase; Metalloproteases; Zinc; Fibroblasts
PubMed: 37005749
DOI: 10.31083/j.fbl2803055 -
BioRxiv : the Preprint Server For... Mar 2023Somatic cell fate is an outcome set by the activities of specific transcription factors and the chromatin landscape and is maintained by gene silencing of alternate cell...
Somatic cell fate is an outcome set by the activities of specific transcription factors and the chromatin landscape and is maintained by gene silencing of alternate cell fates through physical interactions with the nuclear scaffold. Here, we evaluate the role of the nuclear scaffold as a guardian of cell fate in human fibroblasts by comparing the effects of transient loss (knockdown) and mutation (progeria) of functional Lamin A/C, a core component of the nuclear scaffold. We observed that Lamin A/C deficiency or mutation disrupts nuclear morphology, heterochromatin levels, and increases access to DNA in lamina-associated domains. Changes in Lamin A/C were also found to impact the mechanical properties of the nucleus when measured by a microfluidic cellular squeezing device. We also show that transient loss of Lamin A/C accelerates the kinetics of cellular reprogramming to pluripotency through opening of previously silenced heterochromatin domains while genetic mutation of Lamin A/C into progerin induces a senescent phenotype that inhibits the induction of reprogramming genes. Our results highlight the physical role of the nuclear scaffold in safeguarding cellular fate.
PubMed: 36993714
DOI: 10.1101/2023.03.12.532246