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Synopsis on Cellular Senescence and Apoptosis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector BASIC SCIENCE REVIEW Synopsis on cellular senescence and apoptosis Joseph D. Raffetto, MD,a Martin Leverkus, MD,b Hee-Young Park, PhD,a and James O. Menzoian, MD,a,c Boston, Mass, and Wuerzburg, Germany In this review of basic vascular science, the two cellu- characterization of diploid human fibroblasts derived from lar events consisting of cellular senescence and apoptosis fetal tissues. Their study results demonstrated unequivo- are defined, and their molecular properties are elucidated. cally that cells in culture had a finite number of subculti- We emphasize that these are two unique cellular functions vations (also referred to as cell passage) of approximately and should not be used interchangeably. Their importance 50 before achieving growth arrest. These findings were in vascular biology is only recently beginning to be real- not caused by medium components or culture conditions, ized, and they may have potential mechanistic implications but instead were an inherent property of the cells them- in providing a better understanding of arterial and venous selves in culture. This phenomenon was interpreted as diseases. Cellular senescence has been shown to be a char- aging at the cell level, therefore refuting the concept of acteristic in venous ulcer fibroblast grown in culture and a cell immortality, and was established as an in vitro model marker of endothelial cells found in diseased arteries. for which exhaustion of the doubling capacity in human Likewise, apoptosis is responsible for cell turnover and cel- diploid fibroblasts is recognized as cellular senescence. In lular environment homeostasis and appears to be altered in the last 35 years, many cell types from various animal diseased arterial and venous tissues, and it is possibly a species have been studied and shown to have a finite contributing factor in the pathophysiology of atheroscle- replicative life span. By definition, postmitotic cells, which rosis. In addition, the difference between apoptosis and do not replicate, do not undergo cellular senescence. cell necrosis will be highlighted. Instead, cellular senescence affects the phenotype of divid- ing cells only. CELLUAR SENESCENCE In the last decade, the model of cellular senescence has The hallmark of cellular or replicative senescence is an been applied in vitro to human cells comprising living tis- irreversible arrest of cell proliferation with maintenance of sues, with the implication of possibly having an important cell functions. At the turn of the 20th century, Alexis role in the function of tissue integrity. The role of cellular Carrel, a distinguished Nobel laureate, surgeon, and cell senescence has been extended to explain the aging culturist, demonstrated that fibroblasts from the chick process, tumor suppression, and impaired tissue function heart were immortal in tissue culture. Because of this find- resulting in poor wound healing. In the aforementioned ing and the duplication of these results by other laborato- normal process of aging and disease states related to neo- ries, the prevailing dogma until the 1960s was the belief plastic transformation and wound impairment, it is worth- that all cultured cells were immortal. Because it was rec- while to review the expected replicative capacity of cells as ognized that on occasion and at exceedingly low frequen- they undergo sequential population doublings. As seen in cies immortal cells can arise spontaneously from normal Fig 1, the proliferative capacity of the cells decreases with cell cultures and that external stimuli such as carcinogens, increasing population doublings. As fibroblasts approach radiation, and oncogenic viruses are required for cell senescence, each cell at a given passage will have under- transformation and immortality, the hypothesis of Carrel gone a finite number of divisions, and the population of was challenged. In 1961, the extensive tissue culture stud- fibroblasts as a whole will be at varying stages toward ies of Hayflick and Moorhead described the isolation and senescence, depending on the number of population dou- blings. The entire population of fibroblasts can be said to From Boston University Medical Center,a University Hospital of have reached cellular senescence when every cell in the Wuerzburg, Germany,b and Boston University School of Medicine.c culture has completed its replicative life span. At this stage, Competition of interest: nil. J Vasc Surg 2001;34:173-7. growth arrest is irreversible, and a senescent cell cannot be Reprint requests: James O. Menzoian, MD, Boston Medical Center, stimulated by any physiologic mitogens to initiate DNA Department of Surgery, Section of Vascular Surgery, D506, One Boston replication. Medical Center Pl, Boston, MA 02118. Copyright © 2001 by The Society for Vascular Surgery and The American MOLECULAR CHARACTERISTICS Association for Vascular Surgery. OF CELLULAR SENESCENCE 0741-5214/2001/$35.00 + 0 24/9/115964 doi:10.1067/mva.2001.115964 The hallmark of cellular senescence is the irreversible 173 JOURNAL OF VASCULAR SURGERY 174 Raffetto et al July 2001 receptor structural moiety and in the postreceptor sec- ondary messenger pathways. The changes in secondary messenger signal transduction involve different molecules consisting of phospholipid metabolite arachidonic acid and the production of prostaglandins, diacylglycerol, pro- tein kinase A and C, cyclic adenosine monophosphate, and intracellular calcium. There are a number of normally expressed genes in the cell cycle that are not expressed in senescent cells. These genes, such as cyclin A, proliferating cell nuclear antigen, thymidine kinase, and DNA polymerase α, are regulated by the transcription factor E2F. The inability of senescent cells to synthesize and replicate DNA during the cell cycle Fig 1. Replicative capacity of normal somatic mammalian cells involves in part the suppression of at least three positive- undergoing sequential population doublings (PD; 1PD = popula- acting genes. In senescent fibroblasts, the expression of tion of cells that has doubled in number). Replicative capacity c-fos proto-oncogene, helix-loop-helix id-1 and id-2 depends on type, age, environmental influences (eg, viruses), and pathologic state of cells. During normal proliferative capacity (eg, genes, and the components of the E2F transcriptional newborn fibroblasts, adult dermal fibroblasts), cells undergo factor is inhibited, triggering the inability of the cell for many population doublings before replicative exhaustion (A). DNA synthesis. The alterations of the growth-regulating Fibroblasts cultured from tissue with concomitant pathology (eg, genes in senescent fibroblasts are intimately coupled to venous ulcers) have reduced growth potential and are at a higher various cell-cycle dependent proteins. The expression of stage toward reaching cellular senescence than normal fibroblast cell-cycle regulator proteins tumor suppressor p53, cyclin- (B). At the end of life span of cell, proliferative capacity has been dependent kinase inhibitor p21 (cip1/sdi1/waf1) and exhausted, and cells are senescent (C). Cells that have completed p16 (cdkn2/ink4a), and the tumor suppressor retinoblas- their PDs can escape cellular senescence and become immortal toma susceptibility protein pRb is involved directly or either spontaneously (rare) or be transformed by viruses to con- indirectly in the regulation of cell proliferation. The over- tinue to replicate and extend their normal PDs (D). expression of p21 is an important regulator of cell prolif- eration in senescent cells. Because p21 (and also p16) inhibits cyclin-dependent protein kinases, which leads to the constitutive underphosphorylation of pRb and E2F growth arrest of the cell, with preservation of metabolic suppression, this protein plays a major role in inhibiting function. Morphologically, senescent cells are larger in size cell proliferation in senescent cells. It is suggested by evi- and can have polygonal shapes. This appearance may be dence that inactivation of p21 by genetic modulation can caused in part by a number of growth regulatory depen- bypass the events of senescence in human diploid fibro- dent genes being repressed. Although these aspects are the blasts and that oncogenic ras (a proliferation cell-regulat- primary characteristics of a senescent cell, the molecular ing protein) can lead to accumulation of p16 and p53, events involving alterations in signal transduction and the leading to premature cellular senescence. regulation of DNA replication are fundamental in distin- Senescent cells display altered differentiated functions, guishing senescent cells from replicating cells and cells which can impart changes on the extracellular environ- undergoing apoptosis. Fig 2 is a schematic representation ment. Senescent cells display resistance to apoptosis prob- of a senescent cell, demonstrating the effect of physiologic ably through the overexpression of Bcl-2 protein. Because mitogens or environmental stimuli on the molecular path- senescent cells would resist programmed cell death, invari- ways involving the interaction of cell receptors, secondary ably this would lead to the accumulation of these cells messenger moieties, and regulatory proteins leading to the within tissues. The accumulation of senescent cells in vivo inhibition of DNA replication. The loss of proliferative that have achieved growth arrest has been postulated to capacity in senescent
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