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Hardened skin can be an early indicator of premature ageing: A case report of the progeria syndrome.Acta Paediatrica (Oslo, Norway : 1992) May 2024
Topics: Humans; Progeria; Skin; Aging
PubMed: 38318733
DOI: 10.1111/apa.17151 -
Journal of the American Heart... Feb 2024
Topics: Humans; Progeria; Stroke Volume
PubMed: 38293952
DOI: 10.1161/JAHA.123.031470 -
Frontiers in Aging 2024The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific... (Review)
Review
The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific advances in the field, the complexity of the process has hampered its comprehension. In this context, The Hallmarks of Aging were defined in 2013 with the aim of establishing an organized, systematic and integrative view of this topic, which would serve as a conceptual framework for aging research. Ten years later and promoted by the progress in the area, an updated version included three new hallmarks while maintaining the original scope. The aim of this review is to determine to what extent The Hallmarks of Aging achieved the purpose that gave rise to them. For this aim, we have reviewed the literature citing any of the two versions of The Hallmarks of Aging and conclude that they have served as a conceptual framework not only for aging research but also for related areas of knowledge. Finally, this review discusses the new candidates to become part of the Hallmarks list, analyzing the evidence that supports whether they should or should not be incorporated.
PubMed: 38292053
DOI: 10.3389/fragi.2024.1334261 -
Journal of Neuroscience Research Jan 2024Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain...
Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna mice, primary microglia, Lmna knockout (Lmna-KO) and Lmna-knockdown (Lmna-KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL-1β, IL-6, and TNF-α), were significantly suppressed in all Lamin A/C-deficient models when stimulated with LPS. TMT-based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C-regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune- and proliferation-related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C-mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C.
Topics: Animals; Mice; Cell Proliferation; Lamin Type A; Macrophage Activation; Mechanotransduction, Cellular; Microglia; Phagocytosis; Progeria; Proteomics
PubMed: 38284866
DOI: 10.1002/jnr.25263 -
Nature Cell Biology Feb 2024The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to...
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus-cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm-nucleus shuttling is altered in cells from patients with Hutchinson-Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson-Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.
Topics: Humans; Mice; Animals; Mechanistic Target of Rapamycin Complex 1; Progeria; Active Transport, Cell Nucleus; Regulatory-Associated Protein of mTOR; Amino Acids; Lamin Type A
PubMed: 38267537
DOI: 10.1038/s41556-023-01338-y -
Zhonghua Er Ke Za Zhi = Chinese Journal... Feb 2024To analyze the nutritional status of progeria, and to provide reference for scientific nutritional management of progeria. This cross-sectional study included 15...
To analyze the nutritional status of progeria, and to provide reference for scientific nutritional management of progeria. This cross-sectional study included 15 children with progeria who were treated at Children's Hospital, Zhejiang University School of Medicine, between April 2022 and May 2023. Data of medical history, physical examination, laboratory tests, dietary survey and body composition were collected and analyzed. Among 15 patients there were 7 males and 8 females, aged 7.8 (2.3, 10.8) years. Twelve of the 15 patients exhibited signs of malnutrition. A 24-hour dietary survey was carried out in 14 of them. The daily energy intake of 11 cases was below recommended levels. Carbohydrate intake was insufficient in 10 cases, protein intake was insufficient in 7 cases, and fat intake was insufficient in 12 cases. Deficiencies in calcium, magnesium, iron and zinc were noted in 13, 13, 9 and 10 cases, respectively. Body composition was determined by dual-energy X-ray absorptiometry in 8 cases, and the bone mineral density was below average in 5 of them. Malnutrition, characterized by reduced energy intake, micronutrient deficiencies, and alteration in body composition, is prevalent in children with progeria. Regular routine nutritional assessment and proper interventions may benefit their long-term health status.
Topics: Male; Child; Female; Humans; Nutritional Status; Progeria; Cross-Sectional Studies; Malnutrition; Energy Intake
PubMed: 38264818
DOI: 10.3760/cma.j.cn112140-20230928-00230 -
Diabetology International Jan 2024It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various... (Review)
Review
It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various tissues mainly by means of model mice, and it was revealed that insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis, one of the major diabetic comorbidities. Insulin regulates gluconeogenesis not only in the liver but also in the proximal tubules of the kidney, which is also suppressed by reabsorbed glucose in the latter. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease, but also to bone loss and shorter longevity. Aging is regulated by adipokines as well, and it is deemed to be accelerated by 'imbalanced adipokines' in combination with genetic background of progeria. Moreover, we reported effects of intensive multifactorial intervention on diabetic complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, followed by reports of subsequent sub-analyses of renal events and fracture events. Various approaches to elucidate the mechanisms underlying the development of diabetes and how it should be treated are expected to help us improve diabetes management.
PubMed: 38264227
DOI: 10.1007/s13340-023-00677-3 -
Genes Jan 2024The gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in cause laminopathies, a group of disorders with diverse...
The gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson-Gilford progeria (HGP). Among these, the phenotypic terms for -associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly ( < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.
Topics: Female; Humans; Adult; Progeria; Lamin Type A; Cardiomyopathies; Cardiomyopathy, Dilated; Cell Line; Intermediate Filament Proteins
PubMed: 38255001
DOI: 10.3390/genes15010112 -
Pediatric Research Apr 2024Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. This study aims to...
BACKGROUND
Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. This study aims to investigate the epidemiological and genotypic characteristics of patients with HGPS/PL in China.
METHODS
Using a cross-sectional study design, general characteristics and genotypic data of 46 patients with HGPS/PL from 17 provinces in China were analyzed.
RESULTS
Among the 46 patients with HGPS/PL, 20 patients are HGPS, and the rest are PL; the identified total prevalence of HGPS/PL is 1/23 million. Among 42 patients with gene reports, 3 carried compound heterozygous mutations in the ZMPSTE24 while the other 39 carried LMNA mutations. Among PL, LMNA c.1579 C > T homozygous mutation was the most common. The onset of classic genotype HGPS is skin sclerosis in the first month after birth. The primary clinical manifestations of PL patients include skin abnormalities, growth retardation, and joint stiffness. The median age of onset for PL was 12 (6,12) months.
CONCLUSIONS
In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL were located in LMNA, and the rest in ZMPSTE24. Most patients of HGPS/PL have skin abnormalities as the earliest manifestation. Compared to PL, the classic genotype HGPS starts earlier.
IMPACT STATEMENT
Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. To date, there is a paucity of epidemiological data related to HGPS/PL in China. This study first examined the genotypic, phenotypic, and prevalence characteristics of 40-50% of the cases of HGPS/PL in mainland China through a collaborative international registry effort. In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL are located in LMNA. LMNA c.1579 C > T homozygous mutations are the most common form of gene mutations among the Chinese PL population.
Topics: Humans; Progeria; China; Male; Female; Lamin Type A; Cross-Sectional Studies; Mutation; Child, Preschool; Infant; Prevalence; Child; Membrane Proteins; Metalloendopeptidases; Genotype; Adolescent; Laminopathies; Phenotype
PubMed: 38191824
DOI: 10.1038/s41390-023-02981-9 -
Science China. Life Sciences Mar 2024Cullin-RING E3 ubiquitin ligases (CRLs), the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells, represent core cellular machinery for executing...
Cullin-RING E3 ubiquitin ligases (CRLs), the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells, represent core cellular machinery for executing protein degradation and maintaining proteostasis. Here, we asked what roles Cullin proteins play in human mesenchymal stem cell (hMSC) homeostasis and senescence. To this end, we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models: replicative senescent hMSCs, Hutchinson-Gilford Progeria Syndrome hMSCs, and Werner syndrome hMSCs. Among all family members, we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence. To investigate CUL2-specific underlying mechanisms, we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells (hESCs). When we differentiated these into hMSCs, we found that CUL2 deletion markedly accelerates hMSC senescence. Importantly, we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2 (a known negative regulator of proliferation) through the substrate receptor protein APPBP2, which in turn down-regulates one of the canonical aging marker-P21, and thereby delays senescence. Our work provides important insights into how CRL2-mediated TSPYL2 degradation counteracts hMSC senescence, providing a molecular basis for directing intervention strategies against aging and aging-related diseases.
Topics: Humans; Carrier Proteins; Cellular Senescence; Cullin Proteins; Mesenchymal Stem Cells; Ubiquitin-Protein Ligases; Ubiquitins
PubMed: 38170390
DOI: 10.1007/s11427-023-2451-3