scholarly journals Illegitimate and Repeated Genomic Integration of Cell-Free Chromatin in the Aetiology of Somatic Mosaicism, Ageing, Chronic Diseases and Cancer

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 407 ◽  
Author(s):  
Gorantla V. Raghuram ◽  
Shahid Chaudhary ◽  
Shweta Johari ◽  
Indraneel Mittra
Keyword(s):  
Dna Damage ◽  
High Throughput Sequencing ◽  
Somatic Mosaicism ◽  
Copy Number Variations ◽  
The Body ◽  
Chromosomal Mosaicism ◽  
Common Mechanism ◽  
Genomic Integration ◽  
Age Related ◽  
Degenerative Disorders

Emerging evidence suggests that an individual is a complex mosaic of genetically divergent cells. Post-zygotic genomes of the same individual can differ from one another in the form of single nucleotide variations, copy number variations, insertions, deletions, inversions, translocations, other structural and chromosomal variations and footprints of transposable elements. High-throughput sequencing has led to increasing detection of mosaicism in healthy individuals which is related to ageing, neuro-degenerative disorders, diabetes mellitus, cardiovascular diseases and cancer. These age-related disorders are also known to be associated with significant increase in DNA damage and inflammation. Herein, we discuss a newly described phenomenon wherein the genome is under constant assault by illegitimate integration of cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body every day. We propose that such repeated genomic integration of cfCh followed by dsDNA breaks and repair by non-homologous-end-joining as well as physical damage to chromosomes occurring throughout life may lead to somatic/chromosomal mosaicism which would increase with age. We also discuss the recent finding that genomic integration of cfCh and the accompanying DNA damage is associated with marked activation of inflammatory cytokines. Thus, the triple pathologies of somatic mosaicism, DNA/chromosomal damage and inflammation brought about by a common mechanism of genomic integration of cfCh may help to provide an unifying model for the understanding of aetiologies of the inter-related conditions of ageing, degenerative disorders and cancer.

scholarly journals Behavior genetics and postgenomics

2012 ◽  
Vol 35 (5) ◽  
pp. 331-358 ◽  
Author(s):  
Evan Charney
Keyword(s):  
Phenotypic Plasticity ◽  
Behavior Genetics ◽  
Association Studies ◽  
Critical Role ◽  
Somatic Mosaicism ◽  
Copy Number Variations ◽  
Human Condition ◽  
The Body ◽  
Chromosomal Mosaicism ◽  
Sole Agent

AbstractThe science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology.

scholarly journals Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Anna Ainslie ◽  
Wouter Huiting ◽  
Lara Barazzuol ◽  
Steven Bergink
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
Genome Stability ◽  
Genome Instability ◽  
Copy Number Variations ◽  
Therapeutic Interventions ◽  
Gene Copy ◽  
Protein Homeostasis ◽  
Age Related

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

scholarly journals Senescence-associated extracellular vesicle release plays a role in senescence-associated secretory phenotype (SASP) in age-associated diseases

2020 ◽  
Author(s):  
Yoko Tanaka ◽  
Akiko Takahashi
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Extracellular Vesicle ◽  
The Body ◽  
Vesicle Release ◽  
Gene Pathway ◽  
Age Related ◽  
Suppression Mechanism ◽  
Inflammatory Proteins ◽  
Secretory Phenotype

Abstract Cellular senescence is an important tumour suppression mechanism that inhibits the proliferation of damaged cells. In senescent cells, irreparable DNA damage causes accumulation of genomic DNA fragments in the cytoplasm, which are recognized by the cyclic GMP-AMP synthase–stimulator of interferon gene pathway, resulting in secretion of numerous inflammatory proteins. This phenomenon is called senescence-associated secretory phenotype, and results in multiple physiological or pathological processes in the body. In addition, DNA damage also increases small extracellular vesicle release from senescent cells. This review presents recent insights into the molecular mechanisms and biological functions of senescence-associated extracellular vesicle release that is associated with age-related diseases, particularly cancer.

scholarly journals Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime

2021 ◽  
Vol 12 ◽  
Author(s):  
Maha Sellami ◽  
Nicola Bragazzi ◽  
Mohammad Shoaib Prince ◽  
Joshua Denham ◽  
Mohamed Elrayess
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Exercise Training ◽  
Epigenetic Modification ◽  
Methylation Status ◽  
The Body ◽  
Training Load ◽  
Activity Level ◽  
Biological Aging ◽  
Age Related

Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5′-TTAGGGn-3′ tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.

scholarly journals A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 163
Author(s):  
Bhabesh Kumar Tripathy ◽  
Kavita Pal ◽  
Snehal Shabrish ◽  
Indraneel Mittra
Keyword(s):  
Recent Observation ◽  
Daily Basis ◽  
The Body ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Genomic Integration ◽  
Degenerative Disorders ◽  
New Perspective

It is estimated that 10–50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day. Repeated genomic integration of cfCh may have catastrophic consequences for the cell, such as DSBs, their faulty repair by nonhomologous end joining (NHEJ) followed by apoptosis with release of more cfCh which would integrate into genomes of surrounding cells. This can creates a vicious cycle of cfCh integration, DSBs, NHEJ, and more apoptosis, thereby providing a potential explanation as to why so many billions of cells die in the body on a daily basis. We also recount the recent observation that cfCh integration and the resulting DSBs activate inflammatory cytokines. This leads us to propose that concurrent DSBs and induction of inflammation occurring throughout life may be the underlying cause of ageing, degenerative disorders, and cancer. Finally, we discuss the prospect that agents that can inactivate/degrade cfCh may hold the key to making healthy ageing a realizable goal.

The influence of osteopathic correction on the rate of various rhythms of the body

2019 ◽  
pp. 64-71 ◽  
Author(s):  
A. E. Chernikova ◽  
Yu. P. Potekhina
Keyword(s):  
Heart Rate ◽  
Respiratory Rate ◽  
Age Groups ◽  
Biomechanical Properties ◽  
Dispersion Analysis ◽  
The Body ◽  
Body Tissues ◽  
Age Related ◽  
Significant Difference ◽  
Before And After

Introduction. An osteopathic examination determines the rate, the amplitude and the strength of the main rhythms (cardiac, respiratory and cranial). However, there are relatively few studies in the available literature dedicated to the influence of osteopathic correction (OC) on the characteristics of these rhythms.Goal of research — to study the influence of OC on the rate characteristics of various rhythms of the human body.Materials and methods. 88 adult osteopathic patients aged from 18 to 81 years were examined, among them 30 men and 58 women. All patients received general osteopathic examination. The rate of the cranial rhythm (RCR), respiratory rate (RR) heart rate (HR), the mobility of the nervous processes (MNP) and the connective tissue mobility (CTM) were assessed before and after the OC session.Results. Since age varied greatly in the examined group, a correlation analysis of age-related changes of the assessed rhythms was carried out. Only the CTM correlated with age (r=–0,28; p<0,05) in a statistically significant way. The rank dispersion analysis of Kruskal–Wallis also showed statistically significant difference in this indicator in different age groups (p=0,043). With the increase of years, the CTM decreases gradually. After the OC, the CTM, increased in a statistically significant way (p<0,0001). The RCR varied from 5 to 12 cycles/min in the examined group, which corresponded to the norm. After the OC, the RCR has increased in a statistically significant way (p<0,0001), the MNP has also increased (p<0,0001). The initial heart rate in the subjects varied from 56 to 94 beats/min, and in 15 % it exceeded the norm. After the OC the heart rate corresponded to the norm in all patients. The heart rate and the respiratory rate significantly decreased after the OC (р<0,0001).Conclusion. The described biorhythm changes after the OC session may be indicative of the improvement of the nervous regulation, of the normalization of the autonomic balance, of the improvement of the biomechanical properties of body tissues and of the increase of their mobility. The assessed parameters can be measured quickly without any additional equipment and can be used in order to study the results of the OC.

PERMEABILITY OF CELLS AND ITS IMPORTANCE IN ASSESSMENT OF FISHES AGE

1970 ◽  
pp. 70-73
Author(s):  
N. I. Maslova
Keyword(s):  
Cholesterol Content ◽  
The Body ◽  
Cellular Structures ◽  
Ratio Estimation ◽  
Carbohydrate Diet ◽  
Spawning Period ◽  
Age Related ◽  
Experimental Base ◽  
Cellular Permeability ◽  
Membrane Strength

The article presents analysis of material and results of their own studies on changes in the permeability of cellular structures, organs and tissues in carp, which is of great importance in determining age-related indicators. The cells permeability in liver and gonads estimation was carried out under the experimental base of VNIIR on two carp genotypes during the pre-spawning period. The carp groups taken for analysis differed significantly in their genotypes. In females of the Khrapunov group the fecundity was 2023.0 thousand units, while the number of oocytes filled with yolk was only 0.7%, in the Ostashevsky ones - 1370.0 thousand units and 8.6%, respectively. During estimation the chemical composition of the generative tissue in females and males it was established that the cholesterol and lecithin content in males is higher than that of females, while feeding dependence is observed, especially on the amount of protein in the diet. For example, in females on protein diet contained less glycogen in gonads than on females on carbohydrate diet. Lecithin and cholesterol are higher in males than in females, which corresponds to increasing the Gyurdy Ratio (estimation of cell membrane strength). In spermatogenesis the content of phospholipids and cholesterol in the liver was decreased less than during ovogenesis. This indicates a lower level of synthetic processes in the milts compared with the ovaries. The cholesterol content in sperm is higher than in caviar in 19.6 times, and phospholipids almost doubled. With increasing age, the Gyordy Ratio for caviar decreases, for sperm it increases, the percentage of caviar fertilization increases. As the body age metabolism deteriorates, cellular permeability decreases (the ratio of lecithin and cholesterol changes significantly). At the same time, the permeability of cells in different organs and tissues varies and depends on living conditions, especially feeding and to some extent on the origin. In fish the gross productivity decreases as growth slows down and more energy is spent on adaptation to environmental conditions.

Oxidative Stress, Ocular Disease and Diabetes Retinopathy

2019 ◽  
Vol 24 (40) ◽  
pp. 4726-4741 ◽  
Author(s):  
Orathai Tangvarasittichai ◽  
Surapon Tangvarasittichai
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Death ◽  
Protein Modification ◽  
Morphological Changes ◽  
Corneal Dystrophy ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Retinal Light Damage ◽  
Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

Effect of Dapagliflozin on Intestinal Flora in MafA-deficient Mice

2018 ◽  
Vol 24 (27) ◽  
pp. 3223-3231 ◽  
Author(s):  
Luyao Li ◽  
Shiyao Xu ◽  
Tingting Guo ◽  
Shouliang Gong ◽  
Chuan Zhang
Keyword(s):  
Blood Glucose ◽  
High Throughput Sequencing ◽  
Fatty Acid Content ◽  
Fasting Blood Glucose ◽  
Intestinal Flora ◽  
Short Chain Fatty Acids ◽  
The Body ◽  
Short Chain ◽  
Control Group ◽  
Deficient Mice

Objective: To investigate the effect of dapagliflozin on intestinal microflora in MafA-deficient mice using an animal model of diabetes. Methods: Male MafA-deficient mice were administered dapagliflozin (1.0 mg/kg/d) intragastrically for 6 weeks. Mouse body weights and fasting blood glucose levels were measured, and intestinal short-chain fatty acids were measured by gas chromatography. A series of methods was used to analyse the number of primary harmful bacteria in the faeces, and high-throughput sequencing was used to sequence the changes in intestinal flora. Results: The weight of the mice decreased after dapagliflozin gavage, and fasting blood glucose was significantly lower than that in the control group (P < 0.001). Acetic acid and butyric acid contents in the intestinal tracts of the mice increased, and the growth of harmful microorganisms, such as Clostridium perfringens, enterococci, Enterobacteriaceae, and intestinal enterococci, was inhibited. Blautia is a species found in the experimental group and was significantly different from the control and blank groups as determined by the LDA score from highthroughput sequencing. Conclusion: Dapagliflozin can reduce fasting blood glucose, decrease body weight, increase short-chain fatty acid content, regulate the intestinal microecological balance of the body and promote blood glucose and energy homeostasis.

scholarly journals Transcriptome Profile Alterations with Carbon Nanotubes, Quantum Dots, and Silver Nanoparticles: A Review

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 794
Author(s):  
Cullen Horstmann ◽  
Victoria Davenport ◽  
Min Zhang ◽  
Alyse Peters ◽  
Kyoungtae Kim
Keyword(s):  
Carbon Nanotubes ◽  
Quantum Dots ◽  
High Throughput Sequencing ◽  
The Body ◽  
Rna Seq ◽  
Mechanisms Of Toxicity ◽  
Promising Tool ◽  
Engineered Nanomaterial ◽  
Next Generation Sequencing Ngs ◽  
Transcriptomic Changes

Next-generation sequencing (NGS) technology has revolutionized sequence-based research. In recent years, high-throughput sequencing has become the method of choice in studying the toxicity of chemical agents through observing and measuring changes in transcript levels. Engineered nanomaterial (ENM)-toxicity has become a major field of research and has adopted microarray and newer RNA-Seq methods. Recently, nanotechnology has become a promising tool in the diagnosis and treatment of several diseases in humans. However, due to their high stability, they are likely capable of remaining in the body and environment for long periods of time. Their mechanisms of toxicity and long-lasting effects on our health is still poorly understood. This review explores the effects of three ENMs including carbon nanotubes (CNTs), quantum dots (QDs), and Ag nanoparticles (AgNPs) by cross examining publications on transcriptomic changes induced by these nanomaterials.

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