scholarly journals Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

2009 ◽  
Vol 9 ◽  
pp. 1449-1462 ◽  
Author(s):  
Baomin Li ◽  
Sonali Jog ◽  
Jose Candelario ◽  
Sita Reddy ◽  
Lucio Comai
Keyword(s):  
Werner Syndrome ◽  
Accelerated Aging ◽  
Natural Aging ◽  
Aging Research ◽  
Cellular Processes ◽  
Functional Connections ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

2021 ◽  
Vol 13 (575) ◽  
pp. eabd2655
Author(s):  
Wei Wang ◽  
Yuxuan Zheng ◽  
Shuhui Sun ◽  
Wei Li ◽  
Moshi Song ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Werner Syndrome ◽  
Embryonic Stem ◽  
Accelerated Aging ◽  
Premature Aging ◽  
Mesenchymal Precursor Cells ◽  
Genome Wide ◽  
A Genome ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

scholarly journals Neurogenesis and brain aging

2019 ◽  
Vol 30 (6) ◽  
pp. 573-580 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elena V. Stelmashook ◽  
Elisaveta E. Genrikhs
Keyword(s):  
Brain Aging ◽  
Werner Syndrome ◽  
Accelerated Aging ◽  
Normal Aging ◽  
Postnatal Period ◽  
Human Aging ◽  
Distinctive Features ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
The Brain

AbstractHuman aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated postmitotic cells, for the majority of which the lifespan in the postnatal period is equal to the lifespan of the entire organism. In this work, we examine the distinctive features of brain aging and neurogenesis during normal aging, pathological aging (Alzheimer’s disease), and accelerated aging (Hutchinson-Gilford progeria syndrome and Werner syndrome).

Abstract 13652: An Innate YAP/TAZ Mechanosensing Deficit in Hutchinson-Gilford Progeria Syndrome

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Brandon K Walther ◽  
Anahita Mojiri ◽  
Navaneeth Krishna Rajeeva Pandian ◽  
Jacques Ohayon ◽  
Huie Wang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Accelerated Aging ◽  
Scaffolding Protein ◽  
Therapeutic Approaches ◽  
Gene Encoding ◽  
New Therapeutic Approaches ◽  
Age Related ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Mechanical Aging

Hutchinson-Gilford Progeria Syndrome (HGPS) is a disease of accelerated aging causing death in the mid-teens from myocardial infarction or stroke. The disease is caused by a point mutation in the gene encoding lamin-A. The mutated scaffolding protein is aberrantly farnesylated inducing a constellation of defects included nuclear abnormalities, genomic damage, and rapid senescence. Therapy targeting the abnormal farnesylation provides a modest extension of life, thus new insights and therapeutic approaches are urgently needed for these children. Consistent with previous morphological observations and new studies implicating YAP/TAZ mechanobiology as an important mechanical pathway for endothelial cell (EC) health under shear stress, we hypothesized that HGPS ECs have an innate mechanical disturbance rendering them unable to respond to external, atheroprotective cues. We used a microfluidic vessel-on-a-chip with channel geometries and fluid flow to precisely model the hemodynamic stimuli present in vasculature as we have previously described. We cultured iPSC-derived HGPS ECs in this system to study mechanoresponse to shear stress and YAP/TAZ signaling. HGPS ECs manifest a rounded, flattened appearance characteristic of senescent ECs, are unable to align in response to flow, and have aberrant YAP/TAZ activity despite unidirectional laminar flow. To explore the physical underpinnings of such biochemical disturbances, we used atomic force microscopy (AFM) to precisely characterize the shape of individual HGPS cells, and their deformation to a controlled force applied by the AFM cantilever. Preliminary measurements confirmed that HGPS cells have a reduced profile and are compositely stiffer (nuclear modulus + cytoskeletal modulus) than cells derived from the unaffected parent of the child. These data provide evidence of altered biophysical properties of senescent cells which we term “mechanical aging,” which is associated with aberrant signaling in response to hemodynamic stimuli. Further characterization of mechanical aging may lead to new therapeutic approaches for HGPS and other age-related diseases.

scholarly journals Modeling transcriptomic age using knowledge-primed artificial neural networks

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Nicholas Holzscheck ◽  
Cassandra Falckenhayn ◽  
Jörn Söhle ◽  
Boris Kristof ◽  
Ralf Siegner ◽  
...  
Keyword(s):  
Accelerated Aging ◽  
Biological Data ◽  
Aging Research ◽  
Invaluable Tool ◽  
Aging Conditions ◽  
New Type ◽  
Artificial Neural ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Insight Into

AbstractThe development of ‘age clocks’, machine learning models predicting age from biological data, has been a major milestone in the search for reliable markers of biological age and has since become an invaluable tool in aging research. However, beyond their unquestionable utility, current clocks offer little insight into the molecular biological processes driving aging, and their inner workings often remain non-transparent. Here we propose a new type of age clock, one that couples predictivity with interpretability of the underlying biology, achieved through the incorporation of prior knowledge into the model design. The clock, an artificial neural network constructed according to well-described biological pathways, allows the prediction of age from gene expression data of skin tissue with high accuracy, while at the same time capturing and revealing aging states of the pathways driving the prediction. The model recapitulates known associations of aging gene knockdowns in simulation experiments and demonstrates its utility in deciphering the main pathways by which accelerated aging conditions such as Hutchinson–Gilford progeria syndrome, as well as pro-longevity interventions like caloric restriction, exert their effects.

scholarly journals Hereditary syndromes with signs of premature aging

2020 ◽  
Vol 22 (3) ◽  
pp. 4-18
Author(s):  
Olga O. Golounina ◽  
Valentin V. Fadeev ◽  
Zhanna E. Belaya
Keyword(s):  
Molecular Mechanisms ◽  
Werner Syndrome ◽  
Accelerated Aging ◽  
Scientific Data ◽  
The Body ◽  
Premature Aging ◽  
Hereditary Diseases ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Age Related Changes

Aging is a multi-factor biological process that inevitably affects everyone. Degenerative processes, starting at the cellular and molecular levels, gradually influence the change in the functional capabilities of all organs and systems. Progeroid syndromes (from Greek. progērōs prematurely old), or premature aging syndromes, represent clinically and genetically heterogeneous group of rare hereditary diseases characterized by accelerated aging of the body. Progeria and segmental progeroid syndromes include more than a dozen diseases, but the most clear signs of premature aging are evident in Hutchinson-Guilford Progeria Syndrome and Werner Syndrome. This review summarizes the latest scientific data reflecting the etiology and clinical picture of progeria and segmental progeroid syndromes in humans. Molecular mechanisms of aging are considered, using the example of progeroid syndromes. Modern possibilities and potential ways of influencing the mechanisms of the development of age-related changes are discussed. Further study of genetic causes, as well as the development of treatment for progeria and segmental progeroid syndromes, may be a promising direction for correcting age-related changes and increasing life expectancy.

scholarly journals Erythrocyte Senescence in a Model of Rat Displaying Hutchinson-Gilford Progeria Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Manoj Kumar Chaudhary ◽  
Syed Ibrahim Rizvi
Keyword(s):  
Oxidative Stress ◽  
Membrane Transport ◽  
Gradient Centrifugation ◽  
Natural Aging ◽  
Premature Aging ◽  
Transport Systems ◽  
Age Related ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Membrane Transport Systems

Background.Increased oxidative stress is a major cause of aging and age-related diseases. Erythrocytes serve as good model for aging studies. Dihydrotachysterol is known to induce premature aging feature in rats mimicking Hutchinson-Gilford progeria syndrome.Aim.In the present study, attempts have been made to explore the differential response of young and senescent erythrocytes separated by density gradient centrifugation from accelerated senescence model of rats mimicking Hutchinson-Gilford progeria syndrome and naturally aged rats.Methods.The erythrocytes of naturally aged and progeroid rats were separated into distinct, young and old cells on the basis of their differential densities. The parameters of oxidative stress and membrane transport systems were studied.Discussion and Conclusion.Our study provides evidence that organismal aging negatively affects oxidative stress markers and membrane transport systems in both young and old erythrocytes. This study further substantiates that the changes in progeria model of rats resemble natural aging in terms of erythrocyte senescence.

Accelerated aging and aging process in the brain

2018 ◽  
Vol 29 (3) ◽  
pp. 233-240 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elisaveta E. Genrikhs ◽  
Maria V. Oborina ◽  
Elena V. Stelmashook
Keyword(s):  
Down Syndrome ◽  
Brain Aging ◽  
Werner Syndrome ◽  
Accelerated Aging ◽  
Whole Body ◽  
Chronic Oxidative Stress ◽  
Neuronal Mechanisms ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
The Brain

AbstractOne of the approaches to the research of the problem of aging is the study of genetic pathologies leading to accelerated aging, such as the Hutchinson-Gilford progeria syndrome, Werner syndrome, and Down syndrome. Probably, this approach can be used in an attempt to understand the neuronal mechanisms underlying normal and pathological brain aging. The analysis of the current state of scientific knowledge about these pathologies shows that in the Hutchinson-Gilford progeria and Werner syndrome, the rate of brain aging is significantly lower than the rate of whole body aging, whereas in Down syndrome, the brain ages faster than other organs due to amyloid-beta accumulation and chronic oxidative stress in the brain tissue. The main point of a previously proposed hypothesis is that the aging of higher animals and humans is associated with an increased level of reactive oxygen species in mitochondria with age, which activates apoptosis, thus reducing the number of functioning cells.

scholarly journals High-Throughput Screen Detects Calcium Signaling Dysfunction in Hutchinson-Gilford Progeria Syndrome

2021 ◽  
Vol 22 (14) ◽  
pp. 7327
Author(s):  
Juan A. Fafián-Labora ◽  
Miriam Morente-López ◽  
Fco. Javier de Toro ◽  
María C. Arufe
Keyword(s):  
Calcium Signaling ◽  
Rare Disease ◽  
Cell Lines ◽  
Healthy Aging ◽  
Accelerated Aging ◽  
Cytosolic Calcium ◽  
Calcium Handling ◽  
Therapeutic Window ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.

scholarly journals Modelling Nuclear Morphology and Shape Transformation: A Review

Membranes ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 540
Author(s):  
Chao Fang ◽  
Jiaxing Yao ◽  
Xingyu Xia ◽  
Yuan Lin
Keyword(s):  
Shape Change ◽  
Boundary Integral ◽  
Shape Transformation ◽  
Cellular Processes ◽  
Physical Mechanisms ◽  
Intracellular Forces ◽  
Cellular Compartments ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Made In

As one of the most important cellular compartments, the nucleus contains genetic materials and separates them from the cytoplasm with the nuclear envelope (NE), a thin membrane that is susceptible to deformations caused by intracellular forces. Interestingly, accumulating evidence has also indicated that the morphology change of NE is tightly related to nuclear mechanotransduction and the pathogenesis of diseases such as cancer and Hutchinson–Gilford Progeria Syndrome. Theoretically, with the help of well-designed experiments, significant progress has been made in understanding the physical mechanisms behind nuclear shape transformation in different cellular processes as well as its biological implications. Here, we review different continuum-level (i.e., energy minimization, boundary integral and finite element-based) approaches that have been developed to predict the morphology and shape change of the cell nucleus. Essential gradients, relative advantages and limitations of each model will be discussed in detail, with the hope of sparking a greater research interest in this important topic in the future.

scholarly journals NAD+Metabolism in Aging and Cancer

2019 ◽  
Vol 3 (1) ◽  
pp. 105-130 ◽  
Author(s):  
Tyler G. Demarest ◽  
Mansi Babbar ◽  
Mustafa N. Okur ◽  
Xiuli Dan ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Accelerated Aging ◽  
Cancer Therapies ◽  
Nad Metabolism ◽  
Cellular Processes ◽  
Cancer Pathogenesis ◽  
Nicotinamide Mononucleotide ◽  
Age Related

Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.

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