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Calcified Tissue International Jul 2023Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype... (Review)
Review
Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype (SASP). The SASP factors, which are heterogeneous and tissue specific, normally include chemokines, cytokines, growth factors, adhesion molecules, and lipid components that can lead to multiple age-associated disorders by eliciting local and systemic consequences. The skeleton is a highly dynamic organ that changes constantly in shape and composition. Senescent cells in bone and bone marrow produce diverse SASP factors that induce alterations of the skeleton through paracrine effects. Herein, we refer to bone cell-associated SASP as "bone-SASP." In this review, we describe current knowledge of cellular senescence and SASP, focusing on the role of senescent cells in mediating bone pathologies during natural aging and premature aging syndromes. We also summarize the role of cellular senescence and the bone-SASP in glucocorticoids-induced bone damage. In addition, we discuss the role of bone-SASP in the development of osteoarthritis, highlighting the mechanisms by which bone-SASP drives subchondral bone changes in metabolic syndrome-associated osteoarthritis.
Topics: Cellular Senescence; Bone and Bones; Osteocytes; Cytokines; Phenotype
PubMed: 37256358
DOI: 10.1007/s00223-023-01100-4 -
Hormones (Athens, Greece) Dec 2022With the exception of HIV-associated lipodystrophy, lipodystrophy syndromes are rare conditions characterized by a lack of adipose tissue, which is not generally... (Review)
Review
With the exception of HIV-associated lipodystrophy, lipodystrophy syndromes are rare conditions characterized by a lack of adipose tissue, which is not generally recovered. As a consequence, an ectopic deposition of lipids frequently occurs, which usually leads to insulin resistance, atherogenic dyslipidemia, and hepatic steatosis. These disorders include certain accelerated aging syndromes or progeroid syndromes. Even though each of them has unique clinical features, most show common clinical characteristics that affect growth, skin and appendages, adipose tissue, muscle, and bone and, in some of them, life expectancy is reduced. Although the molecular bases of these Mendelian disorders are very diverse and not well known, genomic instability is frequent as a consequence of impairment of nuclear organization, chromatin structure, and DNA repair, as well as epigenetic dysregulation and mitochondrial dysfunction. In this review, the main clinical features of the lipodystrophy-associated progeroid syndromes will be described along with their causes and pathogenic mechanisms, and an attempt will be made to identify which of López-Otín's hallmarks of aging are present.
Topics: Humans; Progeria; Lipodystrophy; Syndrome; Insulin Resistance; Aging
PubMed: 35835948
DOI: 10.1007/s42000-022-00386-7 -
Science Translational Medicine Aug 2022Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and...
Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that () RNA accumulation was an early event in both typical and atypical human progeroid syndromes. RNA negatively regulated the enzymatic activity of the histone-lysine -methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as , , (), (), (), (), and (). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.
Topics: Aging, Premature; Animals; Antigens, Differentiation; Cockayne Syndrome; Heterochromatin; Histones; Humans; Immediate-Early Proteins; Long Interspersed Nucleotide Elements; Lysine; Mice; Phenotype; Progeria; RNA; Telomere; Tumor Suppressor Proteins
PubMed: 35947677
DOI: 10.1126/scitranslmed.abl6057 -
Presse Medicale (Paris, France : 1983) Nov 2021Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently... (Review)
Review
Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.
Topics: Acyltransferases; Age of Onset; Caveolin 1; DNA-Binding Proteins; Diabetes Mellitus, Lipoatrophic; Diagnosis, Differential; G Protein-Coupled Inwardly-Rectifying Potassium Channels; GTP-Binding Protein gamma Subunits; Genital Diseases; Humans; Hypertension; Hypertriglyceridemia; Insulin Resistance; Lamin Type A; Lipodystrophy; Lipodystrophy, Congenital Generalized; Mandible; Membrane Proteins; Metalloendopeptidases; Mutation; Progeria; Proteinuria; RNA Polymerase III; RNA-Binding Proteins; Syndrome; Werner Syndrome Helicase
PubMed: 34562560
DOI: 10.1016/j.lpm.2021.104075 -
Science Advances Feb 2020Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence....
Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence. Here, we generated a knock-in mouse model with the causative Hutchinson-Gilford progeria syndrome (HGPS) mutation, called progerin. The ;TC mice with progerin expression induced by exhibit defective microvasculature and neovascularization, accelerated aging, and shortened life span. Single-cell transcriptomic analysis of murine lung endothelial cells revealed a substantial up-regulation of inflammatory response. Molecularly, progerin interacts and destabilizes deacylase Sirt7; ectopic expression of alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium-targeted gene therapy, driven by an promoter, improves neovascularization, ameliorates aging features, and extends life span in ;TC mice. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.
Topics: Animals; Cellular Senescence; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Gene Expression Profiling; Genetic Therapy; Humans; Longevity; Mice; Mice, Knockout; Platelet Endothelial Cell Adhesion Molecule-1; Progeria; Single-Cell Analysis; Sirtuins; Vasodilation
PubMed: 32128409
DOI: 10.1126/sciadv.aay5556 -
The Application of Clinical Genetics 2021Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for... (Review)
Review
Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to (MADaM). The overlapping signs and symptoms among different premature-ageing syndromes, resulting from both a large genetic heterogeneity and shared pathological pathways underlying these conditions, require an expert clinical evaluation in specialized centers paralleled by next-generation sequencing of panels of genes involved in these disorders in order to establish as early as possible an accurate clinical and molecular diagnosis for a proper patient management.
PubMed: 34103969
DOI: 10.2147/TACG.S273525 -
Free Neuropathology Jan 2022In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis...
In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis of vascular malformations, the first on brain arteriovenous malformations, and the second on cerebral cavernous malformations. These disorders can lead to significant brain injuries from intracerebral hemorrhage (if they rupture) or other neurological complications, including seizures. The next set of papers reflects work that has advanced our understanding of how the brain and the immune system "communicate" after brain injury, including stroke (papers 3-6). The first of these shows that T cells are involved in white matter repair after ischemic injury, an effect dependent on microglia, demonstrating the important cross-talk between innate and adaptive immunity. The next two papers focus on B cells, which have been relatively understudied in the context of brain injury. The contribution of antigen-experienced B cells from the meninges and skull bone marrow, rather than blood-derived B cells in neuroinflammation opens up a very novel area of investigation. The possibility that antibody secreting B cells may contribute to vascular dementia will certainly be an active area for future investigations. Similarly, in paper 6, investigators found that CNS-infiltrating myeloid cells can originate from brain borders tissues. These cells have unique transcriptional signatures that are distinct from their blood-derived counterparts, and likely contribute to myeloid cell infiltration from bone-marrow niches in close proximity to the brain. The contribution of microglia, the primary innate immune cell of the brain, to amyloid deposition and propagation is then discussed, followed by work on how perivascular Aβ is potentially cleared along the cerebral vessels in patients with cerebral amyloid angiopathy. The final two papers focus on the contribution of senescent endothelial cells and pericytes. The first used a model of accelerated senescence (Hutchinson-Gilford progeria syndrome; HGPS) and shows the translational potential of an approach to reduce telomere shortening to slow aging. The final paper demonstrates how capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Interestingly, several of the papers identified therapeutic strategies that could be potentially translated into clinical populations.
PubMed: 37284161
DOI: 10.17879/freeneuropathology-2022-3910 -
Annual Review of Pathology Jan 2022The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding... (Review)
Review
The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.
Topics: Humans; Lamin Type A; Laminopathies; Mutation; Signal Transduction
PubMed: 34672689
DOI: 10.1146/annurev-pathol-042220-034240 -
Biomedicines Sep 2022Since ancient times aging has also been regarded as a disease, and humankind has always strived to extend the natural lifespan. Analyzing the genes involved in aging and...
Since ancient times aging has also been regarded as a disease, and humankind has always strived to extend the natural lifespan. Analyzing the genes involved in aging and disease allows for finding important indicators and biological markers for pathologies and possible therapeutic targets. An example of the use of omics technologies is the research regarding aging and the rare and fatal premature aging syndrome progeria (Hutchinson-Gilford progeria syndrome, HGPS). In our study, we focused on the in silico analysis of differentially expressed genes (DEGs) in progeria and aging, using a publicly available RNA-Seq dataset (GEO dataset GSE113957) and a variety of bioinformatics tools. Despite the GSE113957 RNA-Seq dataset being well-known and frequently analyzed, the RNA-Seq data shared by Fleischer et al. is far from exhausted and reusing and repurposing the data still reveals new insights. By analyzing the literature citing the use of the dataset and subsequently conducting a comparative analysis comparing the RNA-Seq data analyses of different subsets of the dataset (healthy children, nonagenarians and progeria patients), we identified several genes involved in both natural aging and progeria (KRT8, KRT18, ACKR4, CCL2, UCP2, ADAMTS15, ACTN4P1, WNT16, IGFBP2). Further analyzing these genes and the pathways involved indicated their possible roles in aging, suggesting the need for further in vitro and in vivo research. In this paper, we (1) compare "normal aging" (nonagenarians vs. healthy children) and progeria (HGPS patients vs. healthy children), (2) enlist genes possibly involved in both the natural aging process and progeria, including the first mention of IGFBP2 in progeria, (3) predict miRNAs and interactomes for WNT16 (hsa-mir-181a-5p), UCP2 (hsa-mir-26a-5p and hsa-mir-124-3p), and IGFBP2 (hsa-mir-124-3p, hsa-mir-126-3p, and hsa-mir-27b-3p), (4) demonstrate the compatibility of well-established R packages for RNA-Seq analysis for researchers interested but not yet familiar with this kind of analysis, and (5) present comparative proteomics analyses to show an association between our RNA-Seq data analyses and corresponding changes in protein expression.
PubMed: 36289702
DOI: 10.3390/biomedicines10102440