Cellular Aging And Cell Death Pdf

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Programmed cell death PCD ; sometimes referred to as cellular suicide [1] is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose ; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development. Apoptosis and autophagy are both forms of programmed cell death. Necrosis was long seen as a non-physiological process that occurs as a result of infection or injury, [4] but in the s, a form of programmed necrosis, called necroptosis , [5] was recognized as an alternative form of programmed cell death.

Cell death

Review Series Free access Phone: Find articles by Herranz, N. Find articles by Gil, J. Published April 2, - More info.

Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation.

In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non—cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored.

In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.

Cellular senescence was originally identified as a stable exit from the cell cycle caused by the finite proliferative capacity of cultured human fibroblasts 1 , 2. Currently, senescence is considered a stress response that can be induced by a wide range of intrinsic and extrinsic insults, including oncogenic activation, oxidative and genotoxic stress, mitochondrial dysfunction, irradiation, or chemotherapeutic agents 3. While the defining characteristic of senescence is the establishment of a stable growth arrest that limits the replication of damaged and old cells, many other phenotypic alterations associated with the senescent program are relevant to understanding the pathophysiological functions of senescent cells 4.

For example, senescent cells undergo morphology changes, chromatin remodeling, and metabolic reprogramming, and secrete a complex mix of mostly proinflammatory factors termed the senescence-associated secretory phenotype SASP Figure 1.

Here, we review the molecular mechanisms controlling cellular senescence with a special focus on their translational relevance and suitability for identifying and characterizing senescent cells in vivo. Phenotypic characteristics of senescent cells.

Diagram depicting some of the phenotypic alterations associated with senescence initiation, early senescence, and late phases of senescence. Cellular senescence was initially dismissed as a tissue culture artifact. However, a wealth of data has demonstrated that senescent cells can influence disease and aging, as well as normal tissue homeostasis 5. Indeed, senescence can be engaged during development 6 , 7 and is also necessary for tissue remodeling.

For instance, transient induction of senescent cells is observed during wound healing and contributes to wound resolution 8 , 9.

Senescence can also be a protective stress response. In fact, senescence is best known as a potent anticancer mechanism that prevents malignancies by limiting the replication of preneoplastic cells However, the accumulation of senescent cells also drives aging and age-related diseases 11 , The connection between senescence and aging was initially grounded on observations of the accumulation of senescent cells in aged tissues It was suggested that, during aging, senescence of stem and progenitor cells could hinder tissue homeostasis by interfering with the capacity of tissues to repair and regenerate.

Two lines of research have facilitated this awareness. First, the use of transgenic models that allow for the detection of senescent cells has enabled a systematic identification of these cells in many age-related pathologies 5. Second, the development of genetic and drug strategies to selectively eliminate senescent cells, spearheaded by the van Deursen laboratory, has demonstrated that senescent cells can indeed play a causal role in aging and related pathologies The confirmation that selectively killing senescent cells significantly improves the health span of mice in the context of normal aging and ameliorates the consequences of age-related disease or cancer therapy 14 — 19 has ignited interest in the identification of compounds that can clear senescent cells.

These so-called senolytic therapies, however, still face important caveats. In addition to their potential side effects, the evaluation of senolytic compounds is compromised by limitations such as the lack of universal senescence biomarkers and the heterogeneity of senescent phenotypes in vivo Ongoing research into the pathways that initiate and maintain senescence will provide insights to identify biomarkers and potential therapies to target senescent cells.

Senescence has been traditionally considered as a defined, static cell fate. However, it is now recognized that senescence is a dynamic multistep process A simplified model Figure 1 suggests that although the initial senescence-inducing signals are sufficient to initiate cell cycle exit, this merely constitutes an early step in the senescence process.

It is tempting to suggest that the concept of senescence progression may help account for the heterogeneity of senescent cells and their associated phenotypes in vivo. Indeed, the senescent responses occurring in vivo can be categorized into two types. Acute senescence seems to be a programmed process that is triggered in response to discrete stressors, is established with fast kinetics, and normally contributes to tissue homeostasis.

In contrast, chronic senescence may result from long-term unscheduled damage, and it is often associated with detrimental processes such as aging. Only chronic senescence is associated with the presence of cells in a state of late, deep senescence. Nevertheless, there is no conclusive evidence proving an irrefutable relationship between the different stages of senescence identified in cultured cells and the physiopathological functions associated with senescent cells. However, the effects of the SASP may be difficult to predict.

On one hand, the senescent secretome is a heterogeneous mix of proteins whose composition depends not only on the stage of senescence progression but also on the affected cell type and the nature of the inducing stressor s. The efficiency and kinetics of the clearance of senescent cells may vary depending on the organ in which they accumulate or the general ability to mount an effective immune response.

For example, while cells undergoing oncogene-induced senescence OIS in the liver are efficiently cleared by the immune system 21 , senescent cells in melanocytic nevi often manage to evade immune clearance and persist Overall, therapeutic approaches aiming to modulate senescent phenotypes will benefit from a better understanding of the steps driving and defining the evolution of senescent cells in vitro.

One of the defining features of senescent cells is their stable cell cycle arrest. Unlike quiescent cells, senescent cells are nonresponsive to mitogenic or growth factor stimuli; thus, they are unable to reenter the cell cycle even in advantageous growth conditions. Senescent cells are also distinct from terminally differentiated cells, which are also irreversibly withdrawn from cell cycle.

While terminal differentiation is the result of a defined developmental program, which turns undifferentiated precursors into specialized effector cells, senescence is mainly implemented as a cellular stress response. However, terminally differentiated cells such as neurons, adipocytes, and hepatocytes can also undergo senescence, or at least show senescence-like features, during aging or in response to oncogenic activation or DNA damage 21 , 23 — This indicates that the onset of senescence can occur independently of an active cell cycle arrest.

Molecular pathways controlling growth arrest during senescence. A variety of stressors induce senescence-associated growth arrest. Figure reproduced with permission from McHugh and Gil For instance, during replicative senescence of human fibroblasts, progressive telomere shortening ultimately exposes an uncapped, double-stranded chromosome free end, which is sensed as a double-strand break by the DDR machinery In response to mitotic signals, an increase in usage of DNA replication origins leads to accumulation of genomic damage and activation of a DDR because of stalled replication forks 9 , 28 , The DDR associated with replicative senescence is telomere-dependent: it correlates with telomere uncapping and an overall loss of telomeric length Moreover, the majority of cells expressing markers of DNA damage in vivo, especially in a nonpathological setting, are not in fact senescent; rather, they are responding to a transient reparable damage.

Once activated, p53 regulates a complex antiproliferative transcriptional program The most relevant function of p53 in senescence is to induce the transcription of the cyclin-dependent kinase inhibitor CDKi p21 CIP1 , which in turn blocks CDK2 activity, resulting in hypophosphorylated Rb and cell cycle exit In agreement with this, inactivation of p53 signaling by different means interferes with the onset of cellular senescence 36 — Importantly, if the stress that triggers senescence is transient, p53 induction can enact a quiescent state and activate DNA repair processes.

Upon resolution of the stress, cells can resume cycling It has been suggested that the role of p21 CIP1 may be limited to the onset of senescence, whereas p16 INK4a maintains a durable growth arrest, possibly signifying the existence of differently regulated phases of senescence. Indeed, although the induction of p21 CIP1 is important for senescence initiation, its expression does not necessarily persist in senescent cells Although p21 CIP1 can be a valuable marker of senescence in some settings, it is also induced during transient cell cycle arrest or in response to DNA damage, and it should be used as a senescence marker only in combination with others.

Indeed, loss-of-function mutations in p16 INK4a are among the most frequent in human malignant cancers 43 , suggesting that loss of p16 INK4a enables senescence bypass and tumor progression.

The suggested model is that interaction with transcription factors e. On the other hand, senescence-dependent transcriptional regulation of some of these chromatin modifiers, such as JMJD3 or EZH2, may drive the activation of the locus. Further highlighting its functional relevance, p16 INK4a stands out as one of most specific markers of senescence in vivo While p16 INK4a expression is almost undetectable in young healthy organisms, it markedly increases during tumorigenesis and aging.

This evidence is the combined result of expression studies and the use of mouse models reporting for p16 INK4 56 , For instance, the Sharpless group 57 demonstrated an exponential increase in p16 INK4a expression during aging. In these studies, while p16 INK4a activity did not correlate with mortality, it did predict cancer initiation with higher sensitivity than glucose uptake measured by fluorodeoxyglucose-PET. More recently, mouse models have been generated in which p16 INK4a -positive cells can be selectively eliminated based on the expression of inducible suicide genes under the control of p16 INK4a regulatory elements 9 , These models have served to unequivocally show the causal roles of senescent cells in aging, age-related diseases, wound healing, and cancer therapy.

The findings reported in these studies will be described in more detail in the other Reviews of this series. Despite the clear benefits of exploiting p16 INK4a activation as a tool to understand the role of senescence in pathophysiology, its use as an in vivo biomarker of senescence has limitations. First, forms of p16 INK4a -independent senescence can occur in vitro.

More importantly, p16 INK4a can be expressed in nonsenescent cells e. Finally, the currently available antibodies are rather poor at detecting p16 INK4a in murine tissues.

Cellular senescence was initially considered to be a cell-intrinsic program. Increasing evidence, however, has shown that senescent cells have the ability to signal and influence their surrounding environment. Senescent cells produce a complex mixture of soluble and insoluble factors that are collectively termed senescence-associated secretory phenotype SASP or senescence-messaging secretome 58 , SASP is the general term given to the combination of cytokines, chemokines, extracellular matrix proteases, growth factors, and other signaling molecules secreted by senescent cells.

Importantly, its specific composition varies depending on the cell type and the senescence inducer. Likewise, the functions attributed to the SASP, or at least some of its members, are also very diverse and depend not only on the nature of the SASP, but on the surrounding environment and the genetic context of the cells being exposed to the senescent secretome. The SASP is the best-studied mechanism by which senescent cells influence their neighbors, but is not the only one.

Functions of the SASP. The SASP reinforces the senescence growth arrest in vitro by implementing an autocrine positive-feedback loop. This autocrine loop contributes to the tumor-suppressive function of senescence. Interestingly, the SASP can also induce nonmalignant proliferating neighbor cells to undergo senescence termed paracrine senescence 61 , 67 , This suggests that senescent cells could also amplify the antitumoral response by limiting the proliferation of nearby cells exposed to similar stressors.

The SASP is an important mediator of the pathophysiological functions of senescent cells. Scheme summarizing some of the functions associated with the SASP.

The Pivotal Role of Senescence in Cell Death and Aging: Where Do We Stand?

Cellular theories of aging propose that human aging is the result of cellular aging, whereby an increasing proportion of cells reach senescence, a terminal stage at which cells will cease to divide. This will limit the body's ability to regenerate and to respond to injury or stress. This process will occur over time in dividing cells; cell division gradually slows with each successive division, until a point of replicative senescence, at which point no further divisions will occur. The mechanism of replicative senescence is thought to involve some type of biological clock within the cell, which measures the number of cellular divisions and signals the cell to discontinue division at some genetically predetermined time. The process of cell growth and division into two identical daughter cells occurs in a series of regulated steps called the cell cycle. Skip to main content Skip to table of contents. This service is more advanced with JavaScript available.

During aging, accumulated cellular damage and non-optimal systemic signaling can cause too little cell death (hyperproliferation and cancer), or too much cell.

The Pivotal Role of Senescence in Cell Death and Aging: Where Do We Stand?

Cells go through a natural life cycle which includes growth, maturity, and death. This natural life cycle is regulated by a number of factors, and the disruption of the cycle is involved in many disease states. For example, cancer cells do not die the way normal cells do at the end of their life cycle. Here we look at the various processes by which cells age and die, both programmed and unprogrammed. Cellular senescence is part of the normal aging of a diploid cell where it loses its ability to divide.

Review Series Free access Phone: Find articles by Herranz, N. Find articles by Gil, J. Published April 2, - More info.

Aging is a progressive disease affecting around million people worldwide, and in recent years, the mechanism of aging and aging-related diseases has been well studied. Treatments for aging-related diseases have also made progress. For the long-term treatment of aging-related diseases, herbal medicine is particularly suitable for drug discovery.

Формула Цифровой крепости зашифрована с помощью Цифровой крепости. Танкадо предложил бесценный математический метод, но зашифровал. Зашифровал, используя этот самый метод. - Сейф Бигглмана, - протянула Сьюзан. Стратмор кивнул.

Кроме того, он был фанатом всевозможных прибамбасов, и его автомобиль стал своего рода витриной: он установил в нем компьютерную систему глобального позиционирования, замки, приводящиеся в действие голосом, пятиконечный подавитель радаров и сотовый телефонфакс, благодаря которому всегда мог принимать сообщения на автоответчик. На номерном знаке авто была надпись МЕГАБАЙТ в обрамлении сиреневой неоновой трубки.


  1. Gavina P. 10.05.2021 at 20:55

    for multicellular organisms that the attainment of a permanent non-dividing state (​replicative senescence) and patterned cell death (apoptosis).

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    Cellular senescence acts as a brake pedal of the car in our system to avert accidents like cancer.

  3. Aaron S. 14.05.2021 at 15:39

    Cell death is the event of a biological cell ceasing to carry out its functions.

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