Age-related cellularity loss in silico (original) (raw)
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The two-process model of cellular aging
Experimental Gerontology, 1998
To understand the mechanism of aging at the cellular level, cellular senescence has been extensively studied as an experimental model of aging in vitro. Although several hypotheses have been proposed for the mechanism of cellular senescence, none of them could give a comprehensive framework to the mechanism. In this study, we showed our results of extensive computer simulation designed to identify possible molecular models of cellular senescence. By examining representative cases of various molecular models, we elucidated the requirements for the plausible mechanism of cellular senescence. Based on these simulation results, we proposed a new molecular model of cellular senescence-the two-process model. In this model, we assumed that two independent, but time-aligned regulatory processes functioned in individual cells. We defined these two processes as S-and C-processes. The S-process mainly determines the rate of decline in the proliferative potential of the cell population. The simulation results suggested that the growth-inhibitory cell-to-cell interaction was required to drive the S-process. The C-process determines the latent proliferative potential of individual cells. The effector genes for the C-process are suggested to be regulated by a certain threshold-type mechanism. Both growth kinetics and senescenceassociated gene expression were generated with high accuracy by the combined effect of these two processes. We also succeeded in simulating the effects of simian virus 40 large T antigen and its inducible variant on cellular senescence. From these theoretical considerations, we discuss the validity of the two-process model and the possible involvement of the heterochromatin structure as a determinant of the replicative lifespan of cells. © 1998 Elsevier Science Inc.
Modelling the molecular mechanisms of ageing
Bioscience reports, 2017
The ageing process is driven at the cellular level by random molecular damage which slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the ageing process. The complexity of the ageing process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards, and discusses many specific examples of models which have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field.
Simulation of Drosophila aging in silico
One of the main tasks of modern gerontology is isolation of a group of phenomena essential for aging from epiphenomenona accompanying them. The modern methods of simulation modeling may be the proper tool for correct isolation. The point of their application is reproduction of external aging manifestations in silico, and, in the first place, of standard survival curves with the help of the simplest internal mechanism. It seems that such a mechanism will be prime mover of aging. The aging model of one the most popular objects of experimental biology-a fruit fly (Drosophila melanogaster) created by us (http://winmobile.biz/moton/en/moto.html) , is based on the assumption that the key mechanism of aging is cellularity loss, the speed of which is determined by the parameters of active oxygen forms generation in motoneurons. Aging is an amazing phenomenon and in the course of biology development scientists get more and more interested in studying it. The most intriguing question of this field of knowledge can be formulated as follows: what mechanism provides gradual decrease in viability of a multicellular organism? Development of experimental biology methods aroused a desire to answer it, studying the molecular changes which accompany the aging process. Researchers have revealed many such changes starting from lipofuscin accumulation to telomere shortening [1]. Moreover, the system of mechanisms of the somatic cells programmed death was discovered and its participation in "self-destruction" of the whole organism was proved by the number of observations [5, 14]. The success in the search of processes characteristics of which correlate with age also had a reverse side. A lot of aging theories exaggerating the value of some or another molecular change have sprung up. Redundancy of the existing aging hypotheses pool is evident to the majority of authors trying to analyze the state of things in gerontology [1]. A multicellular organism is a multilevel self-organizing system. Activity of its elements is coordinated by the most complicated network of feedbacks. Any action is accompanied by a loop of gene expression changes, synthesis of hormones, immune and electrophysiological reactions, etc. The majority of them influences fitness. Nevertheless, for understanding of the processes taking place, for example, at digestion of food it is enough to keep in mind not more than ten physiological and biochemical reactions. The dialectics of the cognitive process is such that abstraction from the majority of details allows creating conceptual models which become a basis of the further detailed elaboration, but already without any loss of understanding of the essence of the phenomenon studied. The theorist who is searching for the main laws of biological processes can achieve success only referring the majority of reactions accompanying them to epiphenomena. Distinguishing the group of phenomena essential for aging from epiphenomena accompanying them is one of the main tasks of modern gerontology. We believe that modern methods of mathematical modeling can be the tool for distinguishing them properly. The sense of their application is reproduction of the "external" aging manifestations in silico, first of all of the standard survivor curves , by means of the simplest «internal mechanism». This mechanism will apparently be the most essential aging mover. Naturally "the internal mechanism» modeling should be based on the biological facts without contradicting them. Creating the aging model of one of the most popular experimental biology objects – a fruit fly (Drosophila melanogaster) based on the simplest presuppositions possible was the task of this research. Drosophila melanogaster life expectancy is measured by several weeks. This organism is an insect with complete metamorphosis. All somatic cells of an imago are postmitotic. Nevertheless, drosophila «survivor curves» have the S-shape characteristic for the majority of animals [8, 12]. Aging modeling of the given object is essentially facilitated by the fact that cells responsible for this process are identified reliably enough and that the key role of the free-radical processes in aging [12] is clearly demonstrated. As it is known, the basic source of reactive oxygen species in eukaryotic cells is a respiratory chain of mitochondria. One of the main enzymes-antioxidants is superoxide dismutase (SOD), catalyzing superoxide anion transformation into hydro peroxide and oxygen. It is known that the drosophilae, incapable of SOD synthesis are characterized by short life expectancy [16]. In the early nineties of the last century scientists succeeded in breeding drosophila, having appreciable quantities of human SOD, however, their life expectancy practically didn't differ from that of the wild type. Then the technique appeared that allowed to "switch on" SOD expression only in the necessary tissues by means of additional genetic construction. Specific expression of this gene in motoneurons turned out to make life expectancy longer. Moreover, human SOD introduction into motoneurons only returned life expectancy characteristic for the wild type to the flies defective in this enzyme. Motoneurons are convenient for modeling because of the fact that their quantity in one fly is defined precisely enough and is about 80 [11]. It is possible to assume that the natural death of a drosophila occurs due to the motoneurons number decrease to a critical level. The model of cellularity loss of a homogeneous population of postmitotic cells describedhttp://www.winmobile.biz/shou/en/demoApp.php, in our work [7] has served as the basis for creation of the drosophila aging model. Its logical bases are as follows: • Postmitotic cells are capable to generate a number of substances provoking programmed cellular death (PCD)-for example, hydrogen peroxide. Let us call X the total concentration of such apoptosis signals. • At the increase of X quantity up to a certain limit produced during a time interval which can be named a «cycle»(in this particular case the length of one cycle is 24 hours), the mechanism of self-liquidation works • The average X quantity, produced in cells during a cycle is lower than «a threshold of self-liquidation». • As X quantities for various cells are weakly interdependent, they will be distributed according to the normal law (Gaussian law). The presence of an asymmetry and an excess at the X distribution does not change the analyzed laws essentially. The main thing is that the function of X distribution at convergence of argument to infinity asymptotically approaches zero. As this curve does not cross the X-axis, there can be arbitrary large deviations from average X size. • In a cellular population, at an average level of X production that is lower than the threshold, there will be cells producing the amount of X which will
Current …, 2008
Cell death is as important as cell proliferation for cell turn-over, and susceptibility to cell death is affected by a number of parameters that change with time. A time-dependent derangement of such a crucial process, or even the simple cell loss mediated by cell death impinges upon aging and longevity. In this review we will discuss how cell death phenomena are modulated during aging and what is their possible role in the aging process. We will focus on apoptosis and autophagy, which affect mostly proliferating and post-mitotic cells, respectively, and on mitochondrial degradation in long living cells. Since the "decisional process" that leads the cell to death is very complex, we will also discuss the possibility to address this topic with a systems biology approach.
PloS one, 2012
Increases in cellular Reactive Oxygen Species (ROS) concentration with age have been observed repeatedly in mammalian tissues. Concomitant increases in the proportion of replicatively senescent cells in ageing mammalian tissues have also been observed. Populations of mitotic human fibroblasts cultured in vitro, undergoing transition from proliferation competence to replicative senescence are useful models of ageing human tissues. Similar exponential increases in ROS with age have been observed in this model system. Tracking individual cells in dividing populations is difficult, and so the vast majority of observations have been cross-sectional, at the population level, rather than longitudinal observations of individual cells.One possible explanation for these observations is an exponential increase in ROS in individual fibroblasts with time (e.g. resulting from a vicious cycle between cellular ROS and damage). However, we demonstrate an alternative, simple hypothesis, equally consi...
Encyclopedia of Gerontology and Population Aging, 2019
In 1990, in the yeast (Saccaromyces cerevisiae), the proximity to the telomere of an artificially inserted gene was shown to cause a reversible repression of the gene [Gottschling et al 1990]. This phenomenon, called “telomere position effect” [Gottschling et al 1990], has also been reported for other species, ours included. A work has shown that “chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short.” [Robin et al 2014] and this phenomenon has been suggested as “a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response.” [Robin et al 2014]. However, this mechanism appears too simplistic to explain the several and various regulatory actions that result to be dependent on the subtelomeric DNA and the following explanation is perhaps more convincing.
Cellular aging and the importance of energetic factors
Experimental Gerontology, 1995
The in vitro aging of human fibroblasts has become a classical model for studying cellular aging. This model was lately redefined by showing that these cells represent a stem cell system in which they progressively pass through seven morphotypes. Experimental data showed that external conditions that can be considered as stresses for the cells, can modulate the genome expression by speeding up the passage of the cells from one morphotype to the other.
Modelling telomere shortening and the role of oxidative stress
Mechanisms of Ageing and Development, 2002
Extensive evidence supports the idea that progressive telomere loss contributes to the phenomenon of cell replicative senescence, but the mechanisms responsible for telomere loss are still unclear. In addition to the widely recognized end-replication problem, there is evidence that oxidative stress plays a major role in determining the rate of loss of telomeric DNA, and the action of a C-strand-specific exonuclease is also suggested to be important. We describe a mathematical model which examines the different contributions of these mechanisms to telomere loss and its role in triggering cell senescence. The model allows us to make quantitative predictions about the rates of telomere loss resulting from these alternative mechanisms, and their interactions. By varying the key parameters of the model, it is possible to examine the extent to which the different hypotheses are compatible with quantitative and qualititative features of the experimental data. For example, the model predicts that under low levels of oxidative stress, the main mechanisms of telomere shortening are the end-replication problem plus C-strand processing. However, when levels of oxidative stress are higher, as in cell cultures grown under normoxic or hyperoxic conditions, the model predicts that single strand breaks make an important contribution to telomere loss and their inclusion within the model is necessary to explain the data. We suggest that theoretical models of this kind are valuable tools to bridge the gap between the verbal statements of hypotheses and their rigorous experimental test.