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European Journal of Human Genetics :... Aug 2016We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of... (Review)
Review
We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of the FBN1 gene. A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals. We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy for which the name marfanoid-progeroid-lipodystrophy syndrome would be appropriate.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Fibrillin-1; Genetic Pleiotropy; Humans; Lipodystrophy; Male; Marfan Syndrome; Progeria
PubMed: 26860060
DOI: 10.1038/ejhg.2016.6 -
The Biochemical Journal Oct 2021Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced... (Review)
Review
Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.
Topics: Aging; Animals; Extremities; Gasotransmitters; Humans; Hydrogen Sulfide; Ischemia; Longevity; Metalloproteins; Osteoporosis; Progeria; Protein Processing, Post-Translational; Signal Transduction
PubMed: 34613340
DOI: 10.1042/BCJ20210517 -
Nature Reviews. Nephrology Aug 2017An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction.... (Review)
Review
An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects.
Topics: Aging; Animals; DNA Methylation; Epigenesis, Genetic; Humans; Inflammation; Kidney; Progeria
PubMed: 28626222
DOI: 10.1038/nrneph.2017.78 -
Arteriosclerosis, Thrombosis, and... Jul 2019Approximately 20% of the world's population will be around or above 65 years of age by the next decade. Out of these, 40% are suspected to have cardiovascular diseases... (Review)
Review
Approximately 20% of the world's population will be around or above 65 years of age by the next decade. Out of these, 40% are suspected to have cardiovascular diseases as a cause of mortality. Arteriosclerosis, characterized by increased vascular calcification, impairing Windkessel effect and tissue perfusion, and determining end-organ damage, is a hallmark of vascular pathology in the elderly population. Risk factors accumulated during aging affect the normal physiological and vascular aging process, which contributes to the progression of arteriosclerosis. Traditional risk factors, age-associated diseases, and respective regulating mechanisms influencing vascular calcification and vascular stiffness have been extensively studied for many years. Despite the well-known fact that aging alone can induce vascular damage, specific mechanisms that implicate physiological aging in vascular calcification, contributing to vascular stiffness, are poorly understood. This review focuses on mechanisms activated during normal aging, for example, cellular senescence, autophagy, extracellular vesicles secretion, and oxidative stress, along with the convergence of premature aging models' pathophysiology, such as Hutchinson-Gilford Progeria (prelamin accumulation) and Klotho deficiency, to understand vascular calcification in aging. Understanding the mechanisms of vascular damage in aging that intersect with age-associated diseases and risk factors is crucial to foster innovative therapeutic targets to mitigate cardiovascular disease. Visual Overview- An online visual overview is available for this article.
Topics: Aging; Animals; Autophagy; Cellular Senescence; Extracellular Vesicles; Glucuronidase; Humans; Klotho Proteins; Osteoporosis; Oxidative Stress; Progeria; Reactive Oxygen Species; Vascular Calcification
PubMed: 31144990
DOI: 10.1161/ATVBAHA.118.311576 -
Current Opinion in Cell Biology Jun 2016Acute cellular stress caused by oncogene activation or high levels of DNA damage can engage a tumour suppressive response, which can lead to cellular senescence. Chronic... (Review)
Review
Acute cellular stress caused by oncogene activation or high levels of DNA damage can engage a tumour suppressive response, which can lead to cellular senescence. Chronic cellular stress evoked by low levels of DNA damage or telomere erosion is involved in the ageing process. In oncogene induced senescence in fibroblasts, a dramatic rearrangement of heterochromatin into foci and accumulation of constitutive heterochromatin is well documented. In contrast, a loss of heterochromatin has been described in replicative senescence and premature ageing syndromes. The distinct nuclear phenotypes that accompany the stress response highlight the differences between acute and chronic stress models, and this review will address the differences and similarities between these models with a focus on chromosome organisation and heterochromatin.
Topics: Aging; Animals; Cell Nucleus; Cellular Senescence; Chromosomes; DNA Damage; Fibroblasts; Heterochromatin; Humans; Progeria; Stress, Physiological
PubMed: 27101466
DOI: 10.1016/j.ceb.2016.03.020 -
Molecular Cell Sep 2016DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death... (Review)
Review
DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis, or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this Perspective, we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.
Topics: Acid Anhydride Hydrolases; Aging; Animals; BRCA1 Protein; Cell Cycle Proteins; Cellular Senescence; DNA; DNA Breaks, Double-Stranded; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Endonucleases; Gene Expression Regulation; Humans; Ku Autoantigen; MRE11 Homologue Protein; Mice; Models, Genetic; Nuclear Proteins; Progeria; Saccharomyces cerevisiae; Signal Transduction
PubMed: 27588601
DOI: 10.1016/j.molcel.2016.08.004 -
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 -
Cell Reports May 2023One of the major cellular mechanisms to ensure cellular protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is triggered by accumulation...
One of the major cellular mechanisms to ensure cellular protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is triggered by accumulation of misfolded proteins in the ER lumen. The ER stress response is also activated in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here, we explore the mechanism of activation of the ER stress response in HGPS. We find that aggregation of the diseases-causing progerin protein at the nuclear envelope triggers ER stress. Induction of ER stress is dependent on the inner nuclear membrane protein SUN2 and its ability to cluster in the nuclear membrane. Our observations suggest that the presence of nucleoplasmic protein aggregates can be sensed, and signaled to the ER lumen, via clustering of SUN2. These results identify a mechanism of communication between the nucleus and the ER and provide insight into the molecular disease mechanisms of HGPS.
Topics: Humans; Aging, Premature; Nuclear Envelope; Cell Nucleus; Progeria; Membrane Proteins; Endoplasmic Reticulum Stress; Lamin Type A; Intracellular Signaling Peptides and Proteins
PubMed: 37210724
DOI: 10.1016/j.celrep.2023.112534 -
Proceedings of the National Academy of... Nov 2023Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of...
Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.
Topics: Humans; Mice; Animals; Progeria; Aging, Premature; Heart; DNA Damage; Genomic Instability; AMP-Activated Protein Kinases; Lamin Type A
PubMed: 37967221
DOI: 10.1073/pnas.2309200120 -
Methods (San Diego, Calif.) Mar 2019The nuclear lamins A, B, and C are intermediate filament proteins that form a nuclear scaffold adjacent to the inner nuclear membrane in higher eukaryotes, providing... (Review)
Review
The nuclear lamins A, B, and C are intermediate filament proteins that form a nuclear scaffold adjacent to the inner nuclear membrane in higher eukaryotes, providing structural support for the nucleus. In the past two decades it has become evident that the final step in the biogenesis of the mature lamin A from its precursor prelamin A by the zinc metalloprotease ZMPSTE24 plays a critical role in human health. Defects in prelamin A processing by ZMPSTE24 result in premature aging disorders including Hutchinson Gilford Progeria Syndrome (HGPS) and related progeroid diseases. Additional evidence suggests that defects in prelamin A processing, due to diminished ZMPSTE24 expression or activity, may also drive normal physiological aging. Because of the important connection between prelamin A processing and human aging, there is increasing interest in how ZMPSTE24 specifically recognizes and cleaves its substrate prelamin A, encoded by LMNA. Here, we describe two humanized yeast systems we have recently developed to examine ZMPSTE24 processing of prelamin A. These systems differ from one another slightly. Version 1.0 is optimized to analyze ZMPSTE24 mutations, including disease alleles that may affect the function or stability of the protease. Using this system, we previously showed that some ZMPSTE24 disease alleles that affect stability can be rescued by the proteasome inhibitor bortezomib, which may have therapeutic implications. Version 2.0 is designed to analyze LMNA mutations at or near the ZMPSTE24 processing site to assess whether they permit or impede prelamin A processing. Together these systems offer powerful methodology to study ZMPSTE24 disease alleles and to dissect the specific residues and features of the lamin A tail that are required for recognition and cleavage by the ZMPSTE24 protease.
Topics: Aging; Bortezomib; Cell Nucleus; Humans; Intermediate Filament Proteins; Lamin Type A; Membrane Proteins; Metalloendopeptidases; Mutation; Progeria; Proteasome Inhibitors; Saccharomyces cerevisiae
PubMed: 30625386
DOI: 10.1016/j.ymeth.2019.01.001