- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Recently Accepted Articles ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Journal of Aging Research
Volume 2011 (2011), Article ID 963172, 15 pages
Regulation of Senescence in Cancer and Aging
Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, S7-125, Worcester, MA 01655, USA
Received 15 December 2010; Accepted 12 January 2011
Academic Editor: Amancio Carnero
Copyright © 2011 Yahui Kong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Senescence is regarded as a physiological response of cells to stress, including telomere dysfunction, aberrant oncogenic activation, DNA damage, and oxidative stress. This stress response has an antagonistically pleiotropic effect to organisms: beneficial as a tumor suppressor, but detrimental by contributing to aging. The emergence of senescence as an effective tumor suppression mechanism is highlighted by recent demonstration that senescence prevents proliferation of cells at risk of neoplastic transformation. Consequently, induction of senescence is recognized as a potential treatment of cancer. Substantial evidence also suggests that senescence plays an important role in aging, particularly in aging of stem cells. In this paper, we will discuss the molecular regulation of senescence its role in cancer and aging. The potential utility of senescence in cancer therapeutics will also be discussed.
Senescence was first described as a state of irreversible growth arrest that normal human fibroblasts enter at the end of their replicative lifespan . This phenomenon has been observed in a variety of somatic cells derived from many species, which is in contrast to the infinite replicative capacity displayed by germline, cancer, and certain stem cells . Senescent cells are irreversibly arrested in G1/G0 phase of the cell cycle and lose the ability to respond to growth factors [3, 4]. They show sustained metabolic activity for long periods of time  and become resistant to apoptosis [6, 7]. In addition, senescent cells undergo distinctive changes in morphology to a flat and enlarged cell shape  and are often accompanied by the induction of acidic senescence-associated β-galactosidase (SA-β-gal) activity . At the molecular level, alterations in gene expression specific to senescent cells have been identified [10–14], including those constituting senescence-associated secretome, which can trigger profound changes in the surrounding cells and microenvironment [15–17]. The changes of gene expression in senescent cells can be partially explained by alterations in chromatin structure , including the formation of senescence-associated heterochromatic foci (SAHF), which is associated with trimethylated lysine 9 of histone H3, heterochromatin protein 1, and high-mobility group A protein [18–20]. The formation of SAHF requires the recruitment of pRb to E2F-responsive promoters and is responsible for the stable repression of E2F target genes, possibly contributing to the irreversibility of senescence .
2. Telomere-Dependent Replicative Senescence and Telomere-Independent Premature Senescence
The onset of replicative senescence is determined by the number of times that a population of cells can divide, suggesting that a mitotic clock recording cell divisions governs this cellular process [21, 22]. The discovery that telomeres get progressively shortened with each cell division provides a plausible explanation for the nature of this mitotic clock [23–26]. Because of the inability of DNA polymerases to replicate DNA at the very ends of linear chromosomes, telomeres become progressively shortened during successive cell divisions [23, 27, 28]. Telomerase, which is responsible for de novo synthesis of telomeric repeats and maintenance of telomere length , is expressed in germline, stem and cancer cells, but undetectable in majority of normal somatic cells [30, 31]. In the absence of telomerase, progressive telomere shortening is thought to be the major cause of replicative senescence. Supporting this notion, enforced expression of the telomerase catalytic subunit (TERT) has been shown to prevent telomere shortening and extend the lifespan of human somatic cells [32–34]. Conversely, inhibition of telomerase in immortal cells has been found to limit their replicative lifespan [35, 36]. Critically shortened telomeres lose the protection of telomere-binding proteins, leading to telomere “uncapping” . Recent studies have revealed that DNA damage foci containing multiple DNA damage-response proteins, such as 53BP1, γH2AX, MDC1 and MRE11, are found at telomeres in senescent cells, suggesting that uncapped telomeres are recognized as DNA breaks and thus trigger a DNA damage response [37–39].
In addition to telomere attrition, senescence can be activated by many types of stress, including aberrant activation of certain oncogenes [40–42], damage to chromatin structure [43–45], oxidative stress [46–48], DNA damage [49, 50], and inadequate culture conditions [48, 51, 52]. Collectively, they are referred to as stress-induced premature senescence. Among these senescence-inducing stimuli, oxidative stress has been shown to accelerate telomere shortening [47, 53], possibly by inducing telomeric single-strand breaks . However, stress-induced premature senescence, unlike replicative senescence, is largely independent of the telomere length or the number of cell divisions [55–57].
The final outcome of both replicative senescence and stress-induced premature senescence is remarkably similar in that they share common changes in cell cycle regulation and morphological properties [40, 41, 46, 49, 50, 58, 59]. Although gene expression pattern can vary depending on the specific types of tissues and cells or the specific stimuli to trigger the senescence response, senescent cells display a unique pattern of gene expression that differs from proliferating cells or quiescent cells. In addition to the cell cycle regulatory genes, the expression of DNA damage checkpoint genes, inflammation and stress-associated genes, genes encoding extracellular matrix proteins and extracellular matrix-degrading enzymes, and cytoskeletal genes and metabolic genes is generally altered during replicative and premature senescence. Recent studies suggest that DNA damage could be a common cause for different forms of senescence induced by various stimuli [11, 12, 14, 60–63]. Senescence is now considered as a general stress response in normal cells to various types of cellular damage .
3. Molecular Regulation of Senescence
Despite the commonality shared by senescence induced by various stimuli, regulation of senescence varies significantly among cells derived from different species, or even different types of cells from the same species . For example, telomere shortening is the major cause of senescence in human fibroblasts , whereas mouse fibroblasts undergo senescence that is independent of telomere shortening and probably mediated by oxidative stress [48, 52]. Diverse senescence-inducing stimuli can trigger the senescence response through multiple genetic pathways. However, these pathways seem to converge on p53 and pRb, and inactivation of both the p53 and pRb pathways is often required to prevent the activation of senescence [66–70].
In senescent cells, p53 is phosphorylated and its transactivation activity is elevated, although its mRNA and protein levels are largely unchanged [38, 71–74]. DNA damage response elicited by telomere dysfunction leads to activation of ATM/ATR and Chk1/Chk2, which in turn phosphorylate and stabilize p53 [37–39, 75, 76]. In addition, p53 is activated and plays an important role in stress-induced premature senescence [40, 50, 77–79]. This p53 activation is mediated by p14ARF (or p19ARF in mouse) encoded by the INK4a/Arf locus. ARF stabilizes p53 by sequestering Mdm2, an E3 ubiquitin ligase targeting p53 for degradation . The ARF-p53 axis plays an important role during senescence in mouse cells. Inactivation of p53 or ARF in mouse embryo fibroblasts (MEFs) is sufficient to prevent senescence [81–83].
One of the p53 targets is p21(CIP1/WAF1) (p21), whose increased expression transactivated by p53 is responsible for cell cycle arrest . The expression of p21 is up-regulated during replicative senescence [85–89]. This p21 up-regulation is dependent on signal(s) initiated by telomere shortening, as expression of TERT blocks this up-regulation [89–91]. Overexpression of p21 is able to induce a senescence-like growth arrest in some cells [92, 93], while deletion of p21 can postpone senescent arrest [94, 95]. Collectively, these studies suggest that p53 regulates senescence at least in part by inducing p21. As a cyclin-dependent kinase inhibitor, up-regulation of p21 in senescent cells leads to inhibition of pRb phosphorylation, which controls cell cycle progression [18, 84]. There are instances that inactivation of either p53 or pRb can significantly delay the onset of senescence, supporting a linear p53-pRb pathway [68, 96]. In many other instances, both p53 and pRb need to be inhibited to prevent replicative senescence, suggesting two independent pathways [66–69].
In parallel to p21, p16INK4a (p16) is another cyclin-dependent kinase inhibitor that leads to pRb hypophosphorylation . The expression of p16 is increased during replicative senescence [88, 97–99], but whether increased p16 expression is regulated by telomere shortening is controversial. As telomere shortening is the major cause of replicative senescence in human fibroblasts , and inactivation of both the p53 and pRb pathways is required to prevent replicative senescence , it is reasonable to expect that dysfunctional telomeres may signal into p16-pRb axis. There is indeed an example showing that telomere dysfunction induces p16 expression . However, the dynamics of p16 and p21 elevation in senescent cells are different. The increased expression of p16 occurs after senescence has already been established in culture [88, 97, 98, 100], in contrast to the rapid increase of p21 expression in cells approaching replicative senescence . Within a senescent population of human cells, some cells express p16, while others express p21 [38, 96, 100]. DNA damage foci at telomeres are found only in cells expressing p21, but not in p16 positive cells , suggesting that p16 elevation is independent of telomere shortening. Consistent with this notion, p16 induction during senescence, unlike p21, is not prevented by ectopic expression of TERT .
The expression of p16 is readily increased during premature senescence induced by a variety of stress [40–42, 49, 51, 101]. It is not entirely clear how p16 expression is regulated by various senescence signals [102–104]. Under certain circumstances, p16 is coordinately regulated with Arf, which is also encoded by the INK4a/Arf locus. For example, polycomb complex proteins have been shown to repress the INK4a/Arf locus [100, 105–108]. Decreased expression of polycomb complex proteins relieves the repression of the INK4a/Arf locus and is responsible, at least in part, for the elevation of p16 and Arf in senescent cells [100, 106, 107]. The expression of p16 and Arf can also be regulated independently. Id1, whose expression is decreased in senescent cells , has been shown to specifically suppress p16 expression by forming heterodimers with transcriptional factors Ets1/2 or E47 and inhibiting their ability to transactivate p16 [110–112]. Down-regulation of Id1 in human and mouse fibroblasts has been shown to induce p16 expression and senescence [110, 112], while ectopic expression of Id1 delays senescence in human fibroblasts, mammary epithelial cells, keratinocytes, and endothelial cells [98, 113–115], suggesting an important role for Id1 in regulating p16 and senescence.
The expression of p16 varies significantly among different human cell lines , and this variable expression seems to hold the key to as whether p53 and pRb function in a linear manner or in parallel. In cells with low or no p16 expression, p53 and pRb may function in a linear pathway, whereas p53 and pRb work in parallel in cells with significant p16 expression. In mouse embryo fibroblasts (MEFs), inactivation of p53 or ARF, but not p16, is sufficient to prevent senescence [81–83, 116], indicating that p53-Arf axis is the major regulator of senescence pathway in mouse cells. Human mammary epithelial cells quickly encounter a growth arrest state that is not associated with telomere shortening but mediated by p16 up-regulation [33, 101]. A subset of cells with p16 inactivation emerge from the arrest population and continue to divide until reaching a second growth arrest state that is associated with telomere shortening [33, 51, 101]. Depending on cell types, culture conditions, and the extent of stress, inactivation of either p53-p21-pRb or p16-pRb pathway individually, or both pathways together, is required to prevent senescence.
4. Senescence As a Barrier to Tumorigenesis
Tumorigenesis is a multistep process, in which a normal cell acquires mutations in a number of cancer-causing genes . By restricting cell proliferation and thereby impeding the accumulation of mutations, senescence acts as an important tumor suppression mechanism. Furthermore, senescence induced by aberrant activation of oncogenes, oxidative stress, or DNA damage prevents cells at risk of malignant transformation from proliferating [55, 59, 118, 119]. Senescence represents a physiologic response that cells must overcome in order to divide indefinitely and develop into tumors. Consistent with the notion that senescence is a tumor suppression mechanism, well-established tumor suppressors, including p53, pRb, p16, Arf, and p21, are regulators of senescence [102, 118, 120].
In contrast to normal somatic cells, cells derived from tumors divide indefinitely in culture. The ability to escape senescence (i.e., immortality) is a necessary step for cells to become transformed and one of the hallmarks of cancer cells . 80%–90% of human cancer cells acquire unlimited proliferative potential through reactivation of telomerase [30, 31], while the rest maintain telomere length by a recombination-mediated process termed alternative lengthening of telomeres [121, 122]. These observations in human cancer strongly suggest a connection between telomere checkpoint and tumor suppression. Supporting this connection, inhibition of telomerase activity in cancer cells limits their growth by triggering telomere shortening and cell death [35, 36]. Conversely, ectopic expression of telomerase in normal human cells leads to immortalization and enhances the ability of these cells to be neoplastically transformed [33, 34, 123]. Furthermore, transgenic mice overexpressing TERT show increased propensity to tumorigenesis [124–128].
Genetic studies in mice deficient in telomerase provide further support for telomere shortening as a tumor suppression mechanism. Mice deficient in the telomerase RNA component (mTERC−/−) gradually lose telomeres over several generations , and tumorigenesis is significantly reduced in late generations of mTERC−/− mice with telomere attrition [130–140]. Decreased tumorigenesis is also observed in late generation of mice with a null mutation in telomere catalytic subunit (mTERT−/−), and p53 mutation enables tumor progression in these mice . More importantly, two recent studies provide evidence that senescence induced by telomere shortening is responsible for tumor suppression [142, 143]. When apoptosis is blocked by the expression of Bcl-2 or a specific p53 mutant (R172P), shortened telomeres reduce tumorigenesis in mTERC−/− mice. Suppression of tumor development requires p53-dependent activation of senescence [142, 143], demonstrating that senescence induced by telomere shortening is an effective tumor suppression mechanism in vivo.
The discovery that oncogenic Ras protein can induce a senescent arrest after causing an initial hyperproliferation in normal cells suggests that induction of senescence is an intrinsic cellular response that prevents cells at risk from proliferating . In mouse tumor models with oncogenic Ras, senescent cells are found in premalignant lesions in lung , spleen , breast , and pancreas . The observation of senescent cells has been extended to many premalignant lesions or benign tissues induced by different oncogene activation or tumor suppressor inactivation in mouse [147–155] and human [148, 156–159]. Importantly, senescent cells are absent in malignant tumors [61, 144, 145, 147–150, 152, 156, 158, 160], suggesting that oncogene-induced senescence is a powerful tumor suppression mechanism by restricting proliferation of cells with oncogenic mutations and this senescence block must be evaded for malignancy to progress. Consistently, deletion of senescence regulators such as p53, Arf, p16, p27, SUV39H1 or PRAK abrogates senescence and causes progression of tumors to the malignant stage [144–146, 148–150, 152, 153, 160]. These observations point to a causal link between loss of senescence and malignant transformation.
5. Senescence in Anticancer Therapy
In theory, senescence offers an attractive therapeutic option if it can be induced in tumor cells. Because of the uncertainty in reactivating in cells, a response that otherwise has been overcome, senescence remains as an underappreciated therapeutic approach [161, 162]. Surprisingly, many cancer cells retain the ability to senesce either spontaneously or in response to external stress stimuli, even though most cancer cells have overcome the senescent arrest during tumorigenesis. As tumors often develop resistance to apoptosis induced by anticancer treatment, induction of senescence in tumor cells serves as an alternative approach in cancer therapy, and could be especially effective in treatment of cancer cells in which apoptotic pathways are disabled .
Telomerase is an attractive target for inducing senescence in cancer cells. As telomerase is critical for the maintenance of telomere length , inhibition of telomerase in cancer cells leads to shortening of telomeres, which is a major cause of senescence activation [24, 33, 34]. Since 80–90% of human cancers acquire unlimited proliferative potential through activation of telomerase [30, 31], the strategy of inhibiting telomerase in cancer therapeutics targets a broad range of malignancies. In addition, this approach offers desired specificity in targeting cancer cells, as telomerase is expressed in most cancer cells, but undetectable in the majority of normal cells including adult stem cells [164, 165]. The emerging cancer therapeutics targeting telomerase include small molecule or oligonucleotide inhibitors of telomerase enzymatic activity, antitelomerase immunotherapy, inhibitors of telomerase expression and telomere-disrupting agents [166–168]. The strengths and weaknesses of these different approaches are discussed in an excellent review . Although apoptosis is induced by inhibition of telomerase in some studies, induction of senescence as a result of telomerase inhibition is clearly demonstrated to be responsible for tumor suppression [169–173]. The effectiveness of these approaches has been demonstrated in many studies [174–177], and several clinical trials targeting telomerase for cancer therapeutics are now ongoing .
Senescence induced by oncogene activation or inactivation of tumor suppressor genes must be evaded for tumors to progress to full malignancy, which is often associated with inhibition of crucial senescence regulators. Reactivation of senescence response offers a great opportunity in cancer therapeutics. Considering the critical role of p53 in senescence regulation and common occurrence of p53 mutations in cancer cells, p53 is an attractive target for reactivation of senescence in cancer cells. Various approaches have been developed to target p53 in order to restore normal p53 function in cancer cells, including pharmacological depletion of mutant p53 protein [178, 179], restoring normal function in mutant p53 [180, 181], and reactivation of p53 [182–189]. In most of these reports, apoptosis is the overwhelming response that is responsible for tumor suppression. Senescence as a tumor suppression mechanism after restoring p53 expression has been demonstrated in two recent elegant studies [190, 191]. In a mouse model of hepatocellular carcinoma, reactivation of p53 in these tumors results in rapid activation of senescence and subsequent immune cell infiltration which leads to clearance of tumor cells . In a separate study, restoration of p53 in p53-deficient mouse models of lymphoma, and osteosarcoma leads to tumor regression. Apoptosis is selectively induced by p53 in lymphomas, while senescence induced by p53 in osteosarcomas is responsible for tumor regression , suggesting that tissue type and/or genetic context play a critical role in determining the cellular response in p53-mediated tumor regression. Taken together, restoration of p53 function in tumors offers an effective way to restrict tumor growth by inducing senescence or apoptosis. As p16 and p21 have been shown to induce senescence efficiently , these senescence regulators together with Arf and pRb may provide additional targets for the effective activation of senescence in cancer therapeutics.
In addition to restoration of tumor suppressor genes, oncogene inactivation offers another possible intervention to induce senescence in cancer cells. Suppression of c-Myc oncogene induces senescence and leads to tumor regression in diverse tumor types including hepatocellular carcinoma, lymphoma and osteosarcoma . Senescence induced by Myc inhibition depends on critical senescence regulators such as p53, p16 or pRb.Inactivation of these senescence regulators impairs senescence induction and tumor regression . Inhibition of Myc as therapeutic intervention is further illustrated in lung carcinoma mouse model initiated by oncogenic Ras. Inhibition of Myc triggers rapid tumor regression associated with apoptosis and senescence induction . These studies indicate that senescence response not only is functional in cancer cells, but also can be reactivated to cause tumor regression. Furthermore, these studies suggest that therapeutic intervention aimed at molecules required to support tumor growth may also lead to senescence induction and ultimately tumor regression.
The finding that senescence can be induced by DNA damage [49, 50] suggests that chemotherapeutic drugs, which cause DNA damage, may activate senescence in tumor cells and therefore determine the drug response in cancer treatment . Chemotherapeutic drugs induce senescence in various types of tumor cells in culture [195–199]. In a Myc-driven mouse lymphoma model, chemotherapeutic drug cyclophosphamide induces p53- and p16-dependent senescence in lymphomas, leading to better prognosis following chemotherapy . In human breast cancer, a high percentage of tumors after chemotherapy show positive staining for senescence markers, and induction of senescence in these tumors is associated with p53 and p16. Induction of senescence is not observed in tumors before chemotherapy , suggesting that senescence observed in tumors is induced by chemotherapy. Taken together, these studies show that senescence induction can positively influence the outcome of cancer treatment. Senescence-inducing drugs may be effective alone or in combination with classic therapeutic approaches to reduce tumor growth and toxicity to normal cells.
6. Senescence and Aging
Aging is characterized by progressive deterioration of physiological function in all tissues and organs after a period of development. This biological process is associated with increased susceptibility to major chronic diseases and ultimately mortality. Since the discovery of senescence in cultured cells, it is recognized that cellular senescence and organismal aging may be closely related because of their shared ability to limit lifespan . It is hypothesized that constant tissue regeneration results in accumulation of senescent cells in somatic tissues, which limits tissue renewal, perturbs normal tissue homeostasis and ultimately leads to aging [59, 118, 200]. Cells with characteristics of senescence have been reported to increase with advancing age in mice, primates and humans [9, 201–206]. In addition, accumulation of senescent cells is linked with age-associated pathological conditions, such as osteoarthritis , atherosclerosis [208–211], dementia , liver cirrhosis , and respiratory disease [213, 214]. The initial support for the senescence theory of aging comes from the observation of an inverse correlation between the in vitro lifespan of cells and the age of donors from which they are derived [215–219], although this correlation has been disputed . Subsequent support comes from studies of cells derived from progeroid patients, such as Werner syndrome, which achieve fewer cell divisions before entering senescence than cells derived from normal individuals of same age . Direct evidence supporting senescence as one of the aging mechanisms, however, is still missing. It remains to be determined whether accumulation of senescent cells is responsible for aging or age-related diseases.
Recent studies suggest that telomere checkpoint plays an important role in the aging process. It is evident that telomere shortening occurs in aged human tissues [222–235], at sites of age-related pathological conditions [203, 236–243], or associated with stress and obesity [244, 245]. Although it remains to be demonstrated whether telomere shortening leads to the accumulation of senescent cells in vivo, and more importantly makes a substantial contribution to aging, studies of human premature aging syndromes support a link between telomere attrition and aging. Patients of dyskeratosis congenita and aplastic anemia have mutations in telomerase RNA or catalytic subunit [246–248], and are characterized by accelerated telomere shortening [239, 246]. Further evidence for a role of telomere attrition in aging comes from genetic studies of mice deficient in telomerase. While mice with a null mutation in telomerase RNA (mTERC−/−) are apparently normal in early generations, these mice in later generations gradually lose telomeres  and show accelerated aging phenotypes [140, 249]. Similarly, premature aging phenotypes are observed in mTERC−/− mice on a CAST/EiJ background, which have shorter and more homogenous telomere length than C576BL/6 strain. Even with the presence of telomerase, shortened telomeres in mTERC+/− mice on CAST/EiJ background are associated with premature aging . A recent study shows that telomerase reactivation can reverse much of the premature aging phenotypes in telomerase-deficient mice , indicating that telomere attrition plays a critical role in aging. Furthermore, mutations in WRN or BLM in the telomere dysfunctional background in mouse cause premature aging phenotypes that are characteristics of Werner or Bloom syndrome in human. Such premature aging phenotypes are absent in mice with WRN or BLM mutation but with long telomeres [252, 253]. These studies clearly establish a link between telomere attrition and aging. Whether this link is mediated through senescence triggered by telomere shortening is currently unknown.
Premature aging phenotypes in late generation mTERC−/− mice are associated with reduced renewal capacity in highly regenerative tissues such as skin, intestine, bone marrow and reproductive organs [140, 249–251], suggesting that stem cells may be affected by telomere shortening. Tissue-specific or adult stem cells, which are capable of self-renewal and differentiation, are essential for the normal homeostatic maintenance and regenerative repair of tissues throughout the lifetime of an organism. The self-renewal ability of stem cells is known to decline with advancing age, eventually leading to the accumulation of unrepaired, damaged tissues in old organisms [59, 254–256]. By limiting cell proliferation, senescence in stem cells is hypothesized to contribute to aging by reducing the renewal capacity of these cells [21, 59, 118]. Not all stem cells express high level of telomerase. For example, human mesenchymal stem cells have no detectable telomerase activity , and hematopoietic stem cells from human and mouse have low level of telomerase activity [258–260]. Telomere attrition has been observed in these stem cells [257, 260–263]. It is possible that senescence induced by telomere attrition may occur in stem cells over the lifespan of an organism and would result in the reduction of the renewal capacity of stem cells. However, it remains to be determined whether stem cells undergo senescence during aging.
Several senescence regulators have been found to play a critical role in aging. The expression of p16 increases with advancing age in humans and rodents [264–270]. Increase of p16 in aged rodents is attenuated in several tissues (adrenal, heart, kidney, ovary, and testis) by caloric restriction , which potently slows aging. Moreover, age-related increase of p16 is found to be associated with a decline in the renewal capacity of stem cells in brain, pancreas, and hematopoietic system, and these stem cells derived from aged mice lacking p16 have increased regenerative potential [271–273]. In addition, p53 and p21 have also been implicated to impact aging. It has been shown that p21 is required to maintain quiescence of hematopoietic stem cells (HSCs). In the absence of p21, increased cell cycling leads to stem cell exhaustion, which is responsible for impaired self-renewal of HSCs . Interestingly, deletion of p21 in late generation mTERC−/− mice improves stem cells function and rescues much of the premature aging phenotypes associated with telomere attrition . HSCs from p53-deficient mice have increased stem cell population and enhanced renewal capacity [276, 277]. Suppression of stem cells function by p53 is also observed in neural stem cells . Furthermore, mice with excessive p53 activity maintain cancer protection, but age prematurely including impairment of HSCs [279–282], which is at least in part due to increased sensitivity to senescence-inducing stimuli . Interestingly, concomitant increase of normal p53 and p19Arf leads to increased longevity in mice , although elevation of p53 alone is not sufficient to increase longevity [284, 285]. Collectively, these recent studies support an emerging link between senescence regulation and aging, and show the potential importance of senescence regulation in stem cells aging.
Senescence is regarded as an antagonistic pleiotropy: beneficial as a tumor suppressor, but detrimental to organisms by contributing to aging. Great progress has been made in our understanding of senescence regulation in cancer and aging. Challenges remain as how to effectively utilize senescence as a potent treatment for cancer. The exact function of senescence-associated secretome in cancer and aging is of great interest and needs to be investigated. Investigation of telomere shortening and senescence in stem cells during physiological aging is much needed for our understanding of the role of senescence in aging, which leads to the intriguing question as whether inhibition of senescence may slow aging.
The authors apologize that many important references cannot be included due to space restriction. Their research is supported by Grants from the National Cancer Institute (R01CA131210) and The Ellison Medical Foundation New Scholar in Aging to H. Zhang.
- L. Hayflick and P. S. Moorhead, “The serial cultivation of human diploid cell strains,” Experimental Cell Research, vol. 25, no. 3, pp. 585–621, 1961.
- P. J. Vojta and J. C. Barrett, “Genetic analysis of cellular senescence,” Biochimica et Biophysica Acta, vol. 1242, no. 1, pp. 29–41, 1995.
- S. W. Sherwood, D. Rush, J. L. Ellsworth, and R. T. Schimke, “Defining cellular senescence in IMR-90 cells: a flow cytometric analysis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 23, pp. 9086–9090, 1988.
- V. J. Cristofalo, P. D. Phillips, T. Sorger, and G. Gerhard, “Alterations in the responsiveness of senescent cells to growth factors,” Journals of Gerontology, vol. 44, no. 6, pp. 55–62, 1989.
- T. Matsumura, Z. Zerrudo, and L. Hayflick, “Senescent human diploid cells in culture: survival, DNA synthesis and morphology,” Journals of Gerontology, vol. 34, no. 3, pp. 328–334, 1979.
- E. Wang, “Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved,” Cancer Research, vol. 55, no. 11, pp. 2284–2292, 1995.
- B. Hampel, M. Wagner, D. Teis, W. Zwerschke, L. A. Huber, and P. Jansen-Dürr, “Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP-3,” Aging Cell, vol. 4, no. 6, pp. 325–330, 2005.
- S. Goldstein, “Replicative senescence: the human fibroblast comes of age,” Science, vol. 249, no. 4973, pp. 1129–1133, 1990.
- G. P. Dimri, X. Lee, G. Basile et al., “A biomarker that identifies senescent human cells in culture and in aging skin in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 20, pp. 9363–9367, 1995.
- V. J. Cristofalo, C. Volker, M. K. Francis, and M. Tresini, “Age-dependent modifications of gene expression in human fibroblasts,” Critical Reviews in Eukaryotic Gene Expression, vol. 8, no. 1, pp. 43–80, 1998.
- D. N. Shelton, E. Chang, P. S. Whittier, D. Choi, and W. D. Funk, “Microarray analysis of replicative senescence,” Current Biology, vol. 9, no. 17, pp. 939–945, 1999.
- S. R. Schwarze, S. E. DePrimo, L. M. Grabert, V. X. Fu, J. D. Brooks, and D. F. Jarrard, “Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells,” Journal of Biological Chemistry, vol. 277, no. 17, pp. 14877–14883, 2002.
- H. Zhang, K. H. Pan, and S. N. Cohen, “Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 6, pp. 3251–3256, 2003.
- H. Zhang, B. S. Herbert, K. H. Pan, J. W. Shay, and S. N. Cohen, “Disparate effects of telomere attrition on gene expression during replicative senescence of human mammary epithelial cells cultured under different conditions,” Oncogene, vol. 23, no. 37, pp. 6193–6198, 2004.
- J. P. Coppe, K. Kauser, J. Campisi, and C. M. Beauséjour, “Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence,” Journal of Biological Chemistry, vol. 281, no. 40, pp. 29568–29574, 2006.
- J. P. Coppé, C. K. Patil, F. Rodier et al., “Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor,” PLoS Biology, vol. 6, no. 12, article e301, pp. 2853–2868, 2008.
- T. Kuilman and D. S. Peeper, “Senescence-messaging secretome: SMS-ing cellular stress,” Nature Reviews Cancer, vol. 9, no. 2, pp. 81–94, 2009.
- M. Narita, S. Nũnez, E. Heard et al., “Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence,” Cell, vol. 113, no. 6, pp. 703–716, 2003.
- R. Zhang, M. V. Poustovoitov, X. Ye et al., “Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA,” Developmental Cell, vol. 8, no. 1, pp. 19–30, 2005.
- M. Narita, M. Narita, V. Krizhanovsky et al., “A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation,” Cell, vol. 126, no. 3, pp. 503–514, 2006.
- L. Hayflick, “The cell biology of human aging,” The New England Journal of Medicine, vol. 295, no. 23, pp. 1302–1308, 1976.
- S. Goldstein and D. P. Singal, “Senescence of cultured human fibroblasts: mitotic versus metabolic time,” Experimental Cell Research, vol. 88, no. 2, pp. 359–364, 1974.
- C. B. Harley, A. B. Futcher, and C. W. Greider, “Telomeres shorten during ageing of human fibroblasts,” Nature, vol. 345, no. 6274, pp. 458–460, 1990.
- C. B. Harley, “Telomere loss: mitotic clock or genetic time bomb?” Mutation Research, vol. 256, no. 2–6, pp. 271–282, 1991.
- S. E. Holt, J. W. Shay, and W. E. Wright, “Refining the telomere-telomerase hypothesis of aging and cancer,” Nature Biotechnology, vol. 14, no. 7, pp. 836–839, 1996.
- E. H. Blackburn, “Switching and signaling at the telomere,” Cell, vol. 106, no. 6, pp. 661–673, 2001.
- T. de Lange, L. Shiue, R. M. Myers et al., “Structure and variability of human chromosome ends,” Molecular and Cellular Biology, vol. 10, no. 2, pp. 518–527, 1990.
- U. M. Martens, E. A. Chavez, S. S. S. Poon, C. Schmoor, and P. M. Lansdorp, “Accumulation of short telomeres in human fibroblasts prior to replicative senescence,” Experimental Cell Research, vol. 256, no. 1, pp. 291–299, 2000.
- C. W. Greider and E. H. Blackburn, “Identification of a specific telomere terminal transferase activity in tetrahymena extracts,” Cell, vol. 43, no. 2 I, pp. 405–413, 1985.
- N. W. Kim, M. A. Piatyszek, K. R. Prowse et al., “Specific association of human telomerase activity with immortal cells and cancer,” Science, vol. 266, no. 5193, pp. 2011–2015, 1994.
- J. W. Shay and S. Bacchetti, “A survey of telomerase activity in human cancer,” European Journal of Cancer Part A, vol. 33, no. 5, pp. 787–791, 1997.
- H. Vaziri and S. Benchimol, “Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span,” Current Biology, vol. 8, no. 5, pp. 279–282, 1998.
- T. Kiyono, S. A. Foster, J. I. Koop, J. K. McDougall, D. A. Galloway, and A. J. Klingelhutz, “Both Rb/ inactivation and telomerase activity are required to immortalize human epithelial cells,” Nature, vol. 396, no. 6706, pp. 84–88, 1998.
- A. G. Bodnar, M. Ouellette, M. Frolkis et al., “Extension of life-span by introduction of telomerase into normal human cells,” Science, vol. 279, no. 5349, pp. 349–352, 1998.
- W. C. Hahn, S. A. Stewart, M. W. Brooks et al., “Inhibition of telomerase limits the growth of human cancer cells,” Nature Medicine, vol. 5, no. 10, pp. 1164–1170, 1999.
- X. Zhang, V. Mar, W. Zhou, L. Harrington, and M. O. Robinson, “Telomere shortening and apoptosis in telomerase-inhibited human tumor cells,” Genes & Development, vol. 13, no. 18, pp. 2388–2399, 1999.
- F. d'Adda di Fagagna, P. M. Reaper, L. Clay-Farrace et al., “A DNA damage checkpoint response in telomere-initiated senescence,” Nature, vol. 426, no. 6963, pp. 194–198, 2003.
- U. Herbig, W. A. Jobling, B. P. C. Chen, D. J. Chen, and J. M. Sedivy, “Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21, but not p16,” Molecular Cell, vol. 14, no. 4, pp. 501–513, 2004.
- H. Takai, A. Smogorzewska, and T. de Lange, “DNA damage foci at dysfunctional telomeres,” Current Biology, vol. 13, no. 17, pp. 1549–1556, 2003.
- M. Serrano, A. W. Lin, M. E. McCurrach, D. Beach, and S. W. Lowe, “Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and ,” Cell, vol. 88, no. 5, pp. 593–602, 1997.
- J. Zhu, D. Woods, M. McMahon, and J. M. Bishop, “Senescence of human fibroblasts induced by oncogenic Raf,” Genes & Development, vol. 12, no. 19, pp. 2997–3007, 1998.
- A. W. Lin, M. Barradas, J. C. Stone, L. van Aelst, M. Serrano, and S. W. Lowe, “Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling,” Genes & Development, vol. 12, no. 19, pp. 3008–3019, 1998.
- V. V. Ogryzko, T. H. Hirai, V. R. Russanova, D. A. Barbie, and B. H. Howard, “Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent,” Molecular and Cellular Biology, vol. 16, no. 9, pp. 5210–5218, 1996.
- B. Villeponteau, “The heterochromatin loss model of aging,” Experimental Gerontology, vol. 32, no. 4-5, pp. 383–394, 1997.
- B. H. Howard, “Replicative senescence: considerations relating to the stability of heterochromatin domains,” Experimental Gerontology, vol. 31, no. 1-2, pp. 281–293, 1996.
- Q. Chen, A. Fischer, J. D. Reagan, L. J. Yan, and B. N. Ames, “Oxidative DNA damage and senescence of human diploid fibroblast cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 10, pp. 4337–4341, 1995.
- T. von Zglinicki, G. Saretzki, W. Docke, and C. Lotze, “Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?” Experimental Cell Research, vol. 220, no. 1, pp. 186–193, 1995.
- S. Parrinello, E. Samper, A. Krtolica, J. Goldstein, S. Melov, and J. Campisi, “Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts,” Nature Cell Biology, vol. 5, no. 8, pp. 741–747, 2003.
- S. J. Robles and G. R. Adami, “Agents that cause DNA double strand breaks lead to enrichment and the premature senescence of normal fibroblasts,” Oncogene, vol. 16, no. 9, pp. 1113–1123, 1998.
- A. Di Leonardo, S. P. Linke, K. Clarkin, and G. M. Wahl, “DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts,” Genes & Development, vol. 8, no. 21, pp. 2540–2551, 1994.
- R. D. Ramirez, C. P. Morales, B. S. Herbert et al., “Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions,” Genes & Development, vol. 15, no. 4, pp. 398–403, 2001.
- C. J. Sherr and R. A. DePinho, “Cellular senescence: mitotic clock or culture shock?” Cell, vol. 102, no. 4, pp. 407–410, 2000.
- N. R. Forsyth, A. P. Evans, J. W. Shay, and W. E. Wright, “Developmental differences in the immortalization of lung fibroblasts by telomerase,” Aging Cell, vol. 2, no. 5, pp. 235–243, 2003.
- T. von Zglinicki, R. Pilger, and N. Sitte, “Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts,” Free Radical Biology and Medicine, vol. 28, no. 1, pp. 64–74, 2000.
- W. E. Wright and J. W. Shay, “Cellular senescence as a tumor-protection mechanism: the essential role of counting,” Current Opinion in Genetics and Development, vol. 11, no. 1, pp. 98–103, 2001.
- W. E. Wright and J. W. Shay, “Historical claims and current interpretations of replicative aging,” Nature Biotechnology, vol. 20, no. 7, pp. 682–688, 2002.
- S. Wei, W. Wei, and J. M. Sedivy, “Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts,” Cancer Research, vol. 59, no. 7, pp. 1539–1543, 1999.
- M. Serrano and M. A. Blasco, “Putting the stress on senescence,” Current Opinion in Cell Biology, vol. 13, no. 6, pp. 748–753, 2001.
- N. E. Sharpless and R. A. DePinho, “Telomeres, stem cells, senescence, and cancer,” Journal of Clinical Investigation, vol. 113, no. 2, pp. 160–168, 2004.
- J. Pedro de Magalhães, F. Chainiaux, F. de Longueville et al., “Gene expression and regulation in H2O2-induced premature senescence of human foreskin fibroblasts expressing or not telomerase,” Experimental Gerontology, vol. 39, no. 9, pp. 1379–1389, 2004.
- M. Collado, J. Gil, A. Efeyan et al., “Tumour biology: senescence in premalignant tumours,” Nature, vol. 436, no. 7051, p. 642, 2005.
- S. Franco, A. Canela, P. Klatt, and M. A. Blasco, “Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models,” Carcinogenesis, vol. 26, no. 9, pp. 1613–1626, 2005.
- B. W. Darbro, G. B. Schneider, and A. J. Klingelhutz, “Co-regulation of p16 and migratory genes in culture conditions that lead to premature senescence in human keratinocytes,” Journal of Investigative Dermatology, vol. 125, no. 3, pp. 499–509, 2005.
- I. Ben-Porath and R. A. Weinberg, “The signals and pathways activating cellular senescence,” International Journal of Biochemistry and Cell Biology, vol. 37, no. 5, pp. 961–976, 2005.
- N. E. Sharpless and R. A. DePinho, “Cancer: crime and punishment,” Nature, vol. 436, no. 7051, pp. 636–637, 2005.
- E. Hara, H. Tsurui, A. Shinozaki, S. Nakada, and K. Oda, “Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1,” Biochemical and Biophysical Research Communications, vol. 179, no. 1, pp. 528–534, 1991.
- J. W. Shay, O. M. Pereira-Smith, and W. E. Wright, “A role for both RB and p53 in the regulation of human cellular senescence,” Experimental Cell Research, vol. 196, no. 1, pp. 33–39, 1991.
- W. Wei, U. Herbig, S. Wei, A. Dutriaux, and J. M. Sedivy, “Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts,” EMBO Reports, vol. 4, no. 11, pp. 1061–1066, 2003.
- A. Smogorzewska and T. de Lange, “Different telomere damage signaling pathways in human and mouse cells,” The EMBO Journal, vol. 21, no. 16, pp. 4338–4348, 2002.
- J. Campisi and F. d'Adda Di Fagagna, “Cellular senescence: when bad things happen to good cells,” Nature Reviews Molecular Cell Biology, vol. 8, no. 9, pp. 729–740, 2007.
- C. A. Afshari, P. J. Vojta, L. A. Annab, P. A. Futreal, T. B. Willard, and J. C. Barrett, “Investigation of the role of G1/S cell cycle mediators in cellular senescence,” Experimental Cell Research, vol. 209, no. 2, pp. 231–237, 1993.
- P. Atadja, H. Wong, I. Garkavtsev, C. Veillette, and K. Riabowol, “Increased activity of p53 in senescing fibroblasts,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 18, pp. 8348–8352, 1995.
- K. Webley, J. A. Bond, C. J. Jones et al., “Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage,” Molecular and Cellular Biology, vol. 20, no. 8, pp. 2803–2808, 2000.
- J. Bond, M. Haughton, J. Blaydes, V. Gire, D. Wynford-Thomas, and F. Wyllie, “Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence,” Oncogene, vol. 13, no. 10, pp. 2097–2104, 1996.
- V. Gire, P. Roux, D. Wynford-Thomas, J. M. Brondello, and V. Dulic, “DNA damage checkpoint kinase Chk2 triggers replicative senescence,” The EMBO Journal, vol. 23, no. 13, pp. 2554–2563, 2004.
- V. Gire, “Dysfunctional telomeres at senescence signal cell cycle arrest via Chk2,” Cell Cycle, vol. 3, no. 10, pp. 1217–1220, 2004.
- Q. M. Chen, J. C. Bartholomew, J. Campisi, M. Acosta, J. D. Reagan, and B. N. Ames, “Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication,” The Biochemical Journal, vol. 332, pp. 1–50, 1998.
- G. Ferbeyre, E. de Stanchina, E. Querido, N. Baptiste, C. Prives, and S. W. Lowe, “PML is induced by oncogenic ras and promotes premature senescence,” Genes & Development, vol. 14, no. 16, pp. 2015–2027, 2000.
- M. Pearson, R. Carbone, C. Sebastiani et al., “PML regulates p53 acetylation and premature senescence induced by oncogenic Ras,” Nature, vol. 406, no. 6792, pp. 207–210, 2000.
- F. J. Stott, S. Bates, M. C. James et al., “The alternative product from the human CDKN2A locus, , participates in a regulatory feedback loop with p53 and MDM2,” The EMBO Journal, vol. 17, no. 17, pp. 5001–5014, 1998.
- A. M. G. Dirac and R. Bernards, “Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53,” Journal of Biological Chemistry, vol. 278, no. 14, pp. 11731–11734, 2003.
- M. Harvey, A. T. Sands, R. S. Weiss et al., “In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice,” Oncogene, vol. 8, no. 9, pp. 2457–2467, 1993.
- T. Kamijo, F. Zindy, M. F. Roussel et al., “Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product ,” Cell, vol. 91, no. 5, pp. 649–659, 1997.
- C. J. Sherr and J. M. Roberts, “CDK inhibitors: positive and negative regulators of G-phase progression,” Genes & Development, vol. 13, no. 12, pp. 1501–1512, 1999.
- V. Dulic, L. F. Drullinger, E. Lees, S. I. Reed, and G. H. Stein, “Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 23, pp. 11034–11038, 1993.
- A. Noda, Y. Ning, S. F. Venable, O. M. Pereira-Smith, and J. R. Smith, “Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen,” Experimental Cell Research, vol. 211, no. 1, pp. 90–98, 1994.
- H. Tahara, K. Kamada, E. Sato et al., “Increase in expression levels of interferon-inducible genes in senescent human diploid fibroblasts and in SV40-transformed human fibroblasts with extended lifespan,” Oncogene, vol. 11, no. 6, pp. 1125–1132, 1995.
- G. H. Stein, L. F. Drullinger, A. Soulard, and V. Dulić, “Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts,” Molecular and Cellular Biology, vol. 19, no. 3, pp. 2109–2117, 1999.
- U. Herbig, W. Wei, A. Dutriaux, W. A. Jobling, and J. M. Sedivy, “Real-time imaging of transcriptional activation in live cells reveals rapid up-regulation of the cyclin-dependent kinase inhibitor gene CDKN1A in replicative cellular senescence,” Aging cell, vol. 2, no. 6, pp. 295–304, 2003.
- M. Modestou, V. Puig-Antich, C. Korgaonkar, A. Eapen, and D. E. Quelle, “The alternative reading frame tumor suppressor inhibits growth through p21-dependent and p21-independent pathways,” Cancer Research, vol. 61, no. 7, pp. 3145–3150, 2001.
- W. Wei, R. M. Hemmer, and J. M. Sedivy, “Role of p14 in replicative and induced senescence of human fibroblasts,” Molecular and Cellular Biology, vol. 21, no. 20, pp. 6748–6757, 2001.
- B. B. McConnell, M. Starborg, S. Brookes, and G. Peters, “Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts,” Current Biology, vol. 8, no. 6, pp. 351–354, 1998.
- B. D. Chang, K. Watanabe, E. V. Broude et al., “Effects of p21 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 8, pp. 4291–4296, 2000.
- J. P. Brown, W. Wei, and J. M. Sedivy, “Bypass of senescenoe after disruption of gene in normal diploid human fibroblasts,” Science, vol. 277, no. 5327, pp. 831–834, 1997.
- A. S. C. Medcalf, A. J. P. Klein-Szanto, and V. J. Cristofalo, “Expression of p21 is not required for senescence of human fibroblasts,” Cancer Research, vol. 56, no. 20, pp. 4582–4585, 1996.
- C. M. Beauséjour, A. Krtolica, F. Galimi et al., “Reversal of human cellular senescence: roles of the p53 and p16 pathways,” The EMBO Journal, vol. 22, no. 16, pp. 4212–4222, 2003.
- D. A. Alcorta, Y. Xiong, D. Phelps, G. Hannon, D. Beach, and J. C. Barrett, “Involvement of the cyclin-dependent kinase inhibitor in replicative senescence of normal human fibroblasts,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 13742–13747, 1996.
- E. Hara, R. Smith, D. Parry, H. Tahara, S. Stone, and G. Peters, “Regulation of p16 expression and its implications for cell immortalization and senescence,” Molecular and Cellular Biology, vol. 16, no. 3, pp. 859–867, 1996.
- H. Wong and K. Riabowol, “Differential CDK-inhibitor gene expression in aging human diploid fibroblasts,” Experimental Gerontology, vol. 31, no. 1-2, pp. 311–325, 1996.
- K. Itahana, Y. Zou, Y. Itahana et al., “Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1,” Molecular and Cellular Biology, vol. 23, no. 1, pp. 389–401, 2003.
- S. R. Romanov, B. K. Kozakiewicz, C. R. Holst, M. R. Stampfer, L. M. Haupt, and T. D. Tlsty, “Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes,” Nature, vol. 409, no. 6820, pp. 633–637, 2001.
- W. Y. Kim and N. E. Sharpless, “The regulation of INK4/ARF in cancer and aging,” Cell, vol. 127, no. 2, pp. 265–275, 2006.
- J. Gil and G. Peters, “Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all,” Nature Reviews Molecular Cell Biology, vol. 7, no. 9, pp. 667–677, 2006.
- C. J. Collins and J. M. Sedivy, “Involvement of the INK4a/Arf gene locus in senescence,” Aging Cell, vol. 2, no. 3, pp. 145–150, 2003.
- J. L. Jacobs, K. Kieboom, S. Marino, R. A. DePinho, and M. van Lohuizen, “The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus,” Nature, vol. 397, no. 6715, pp. 164–168, 1999.
- A. P. Bracken, D. Kleine-Kohlbrecher, N. Dietrich et al., “The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells,” Genes & Development, vol. 21, no. 5, pp. 525–530, 2007.
- J. Gil, D. Bernard, D. Martínez, and D. Beach, “Polycomb CBX7 has a unifying role in cellular lifespan,” Nature Cell Biology, vol. 6, no. 1, pp. 67–72, 2004.
- N. Dietrich, A. P. Bracken, E. Trinh et al., “Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus,” The EMBO Journal, vol. 26, no. 6, pp. 1637–1648, 2007.
- E. Hara, T. Yamaguchi, H. Nojima et al., “Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts,” Journal of Biological Chemistry, vol. 269, no. 3, pp. 2139–2145, 1994.
- W. Zheng, H. Wang, L. Xue, Z. Zhang, and T. Tong, “Regulation of cellular senescence and p16 expression by Id1 and E47 proteins in human diploid fibroblast,” Journal of Biological Chemistry, vol. 279, no. 30, pp. 31524–31532, 2004.
- N. Ohtani, Z. Zebedee, T. J. G. Huot et al., “Opposing effects of Ets and Id proteins on p16 expression during cellular senescence,” Nature, vol. 409, no. 6823, pp. 1067–1070, 2001.
- R. M. Alani, A. Z. Young, and C. B. Shifflett, “Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 14, pp. 7812–7816, 2001.
- R. M. Alani, J. Hasskarl, M. Grace, M. C. Hernandez, M. A. Israel, and K. Münger, “Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 17, pp. 9637–9641, 1999.
- B. J. Nickoloff, V. Chaturvedi, P. Bacon, J. Z. Qin, M. F. Denning, and M. O. Diaz, “Id-1 delays senescence but does not immortalize keratinocytes,” Journal of Biological Chemistry, vol. 275, no. 36, pp. 27501–27504, 2000.
- J. Tang, G. M. Gordon, B. J. Nickoloff, and K. E. Foreman, “The helix-loop-helix protein Id-1 delays onset of replicative senescence in human endothelial cells,” Laboratory Investigation, vol. 82, no. 8, pp. 1073–1079, 2002.
- N. E. Sharpless, N. Bardeesy, K. H. Lee et al., “Loss of p16 with retention of p19 predisposes mice to tumorigenesis,” Nature, vol. 413, no. 6851, pp. 86–91, 2001.
- B. Vogelstein and K. W. Kinzler, “The multistep nature of cancer,” Trends in Genetics, vol. 9, no. 4, pp. 138–141, 1993.
- J. Campisi, “Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors,” Cell, vol. 120, no. 4, pp. 513–522, 2005.
- R. Sager, “Senescence as a mode of tumor suppression,” Environmental Health Perspectives, vol. 93, pp. 59–62, 1991.
- D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000.
- T. M. Bryan, A. Englezou, J. Gupta, S. Bacchetti, and R. R. Reddel, “Telomere elongation in immortal human cells without detectable telomerase activity,” The EMBO Journal, vol. 14, no. 17, pp. 4240–4248, 1995.
- A. Muntoni and R. R. Reddel, “The first molecular details of ALT in human tumor cells,” Human Molecular Genetics, vol. 14, no. 2, pp. R191–R196, 2005.
- W. C. Hahn, C. M. Counter, A. S. Lundberg, R. L. Beijersbergen, M. W. Brooks, and R. A. Weinberg, “Creation of human tumour cells with defined genetic elements,” Nature, vol. 400, no. 6743, pp. 464–468, 1999.
- E. González-Suárez, E. Samper, A. Ramírez et al., “Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes,” The EMBO Journal, vol. 20, no. 11, pp. 2619–2630, 2001.
- S. E. Artandi, S. Alson, M. K. Tietze et al., “Constitutive telomerase expression promotes mammary carcinomas in aging mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 12, pp. 8191–8196, 2002.
- A. Canela, J. Martín-Caballero, J. M. Flores, and M. A. Blasco, “Constitutive expression of tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-tert mice,” Molecular and Cellular Biology, vol. 24, no. 10, pp. 4275–4293, 2004.
- A. K. Bednarek, Y. Chu, T. J. Slaga, and C. M. Aldaz, “Telomerase and cell proliferation in mouse skin papillomas,” Molecular Carcinogenesis, vol. 20, no. 4, pp. 329–331, 1997.
- E. González-Suárez, J. M. Flores, and M. A. Blasco, “Cooperation between p53 mutation and high telomerase transgenic expression in spontaneous cancer development,” Molecular and Cellular Biology, vol. 22, no. 20, pp. 7291–7301, 2002.
- M. A. Blasco, H. W. Lee, M. P. Hande et al., “Telomere shortening and tumor formation by mouse cells lacking telomerase RNA,” Cell, vol. 91, no. 1, pp. 25–34, 1997.
- C. M. Khoo, D. R. Carrasco, M. W. Bosenberg, J. H. Paik, and R. A. DePinho, “Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 10, pp. 3931–3936, 2007.
- R. A. Greenberg, L. Chin, A. Femino et al., “Short dysfunctional telomeres impair tumorigenesis in the cancer-prone mouse,” Cell, vol. 97, no. 4, pp. 515–525, 1999.
- E. González-Suárez, E. Samper, J. M. Flores, and M. A. Blasco, “Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis,” Nature Genetics, vol. 26, no. 1, pp. 114–117, 2000.
- K. L. Rudolph, M. Millard, M. W. Bosenberg, and R. A. DePinho, “Telomere dysfunction and evolution of intestinal carcinoma in mice and humans,” Nature Genetics, vol. 28, no. 2, pp. 155–159, 2001.
- K. K. Wong, R. S. Maser, R. M. Bachoo et al., “Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing,” Nature, vol. 421, no. 6923, pp. 643–648, 2003.
- L. Qi, M. A. Strong, B. O. Karim, D. L. Huso, and C. W. Greider, “Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation,” Nature Cell Biology, vol. 7, no. 7, pp. 706–711, 2005.
- L. Qi, M. A. Strong, B. O. Karim, M. Armanios, D. L. Huso, and C. W. Greider, “Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis,” Cancer Research, vol. 63, no. 23, pp. 8188–8196, 2003.
- X. Guo, Y. Deng, Y. Lin et al., “Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis,” The EMBO Journal, vol. 26, no. 22, pp. 4709–4719, 2007.
- A. Lechel, H. Holstege, Y. Begus et al., “Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease,” Gastroenterology, vol. 132, no. 4, pp. 1465–1475, 2007.
- E. González-Suárez, F. A. Goytisolo, J. M. Flores, and M. A. Blasco, “Telomere dysfunction results in enhanced organismal sensitivity to the alkylating agent N-methyl-N-nitrosourea,” Cancer Research, vol. 63, no. 21, pp. 7047–7050, 2003.
- K. L. Rudolph, S. Chang, H. W. Lee et al., “Longevity, stress response, and cancer in aging telomerase-deficient mice,” Cell, vol. 96, no. 5, pp. 701–712, 1999.
- P. A. Farazi, J. Glickman, J. Horner, and R. A. DePinho, “Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression,” Cancer Research, vol. 66, no. 9, pp. 4766–4773, 2006.
- D. M. Feldser and C. W. Greider, “Short telomeres limit tumor progression in vivo by inducing senescence,” Cancer Cell, vol. 11, no. 5, pp. 461–469, 2007.
- W. Cosme-Blanco, M. F. Shen, A. J. F. Lazar et al., “Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence,” EMBO Reports, vol. 8, no. 5, pp. 497–503, 2007.
- M. Braig, S. Lee, C. Loddenkemper et al., “Oncogene-induced senescence as an initial barrier in lymphoma development,” Nature, vol. 436, no. 7051, pp. 660–665, 2005.
- C. J. Sarkisian, B. A. Keister, D. B. Stairs, R. B. Boxer, S. E. Moody, and L. A. Chodosh, “Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis,” Nature Cell Biology, vol. 9, no. 5, pp. 493–505, 2007.
- J. P. Morton, P. Timpson, S. A. Karim et al., “Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 1, pp. 246–251, 2010.
- E. L. Denchi, C. Attwooll, D. Pasini, and K. Helin, “Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland,” Molecular and Cellular Biology, vol. 25, no. 7, pp. 2660–2672, 2005.
- Z. Chen, L. C. Trotman, D. Shaffer et al., “Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis,” Nature, vol. 436, no. 7051, pp. 725–730, 2005.
- D. Dankort, E. Filenova, M. Collado, M. Serrano, K. Jones, and M. McMahon, “A new mouse model to explore the initiation, progression, and therapy of BRAF-induced lung tumors,” Genes & Development, vol. 21, no. 4, pp. 379–384, 2007.
- L. Ha, T. Lchikawa, M. Anver et al., “ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 26, pp. 10968–10973, 2007.
- N. Dhomen, J. S. Reis-Filho, S. da Rocha Dias et al., “Oncogenic Braf induces melanocyte senescence and melanoma in mice,” Cancer Cell, vol. 15, no. 4, pp. 294–303, 2009.
- V. K. Goel, N. Ibrahim, G. Jiang et al., “Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice,” Oncogene, vol. 28, no. 23, pp. 2289–2298, 2009.
- P. K. Majumder, C. Grisanzio, F. O'Connell et al., “A prostatic intraepithelial neoplasia-dependent p27 checkpoint induces senescence and inhibits cell proliferation and cancer progression,” Cancer Cell, vol. 14, no. 2, pp. 146–155, 2008.
- M. Xu, Q. Yu, R. Subrahmanyam, M. J. Difilippantonio, T. Ried, and J. M. Sen, “β-catenin expression results in p53-independent DNA damage and oncogene-induced senescence in prelymphomagenic thymocytes in vivo,” Molecular and Cellular Biology, vol. 28, no. 5, pp. 1713–1723, 2008.
- A. P. Young, S. Schisio, Y. A. Minamishima et al., “VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400,” Nature Cell Biology, vol. 10, no. 3, pp. 361–369, 2008.
- C. Michaloglou, L. C. W. Vredeveld, M. S. Soengas et al., “BRAF-associated senescence-like cell cycle arrest of human naevi,” Nature, vol. 436, no. 7051, pp. 720–724, 2005.
- S. Courtois-Cox, S. M. Genther Williams, E. E. Reczek et al., “A negative feedback signaling network underlies oncogene-induced senescence,” Cancer Cell, vol. 10, no. 6, pp. 459–472, 2006.
- V. C. Gray-Schopfer, S. C. Cheong, H. Chong et al., “Cellular senescence in naevi and immortalisation in melanoma: a role for p16?” British Journal of Cancer, vol. 95, no. 4, pp. 496–505, 2006.
- J. Bartkova, N. Rezaei, M. Liontos et al., “Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints,” Nature, vol. 444, no. 7119, pp. 633–637, 2006.
- P. Sun, N. Yoshizuka, L. New et al., “PRAK is essential for ras-induced senescence and tumor suppression,” Cell, vol. 128, no. 2, pp. 295–308, 2007.
- C. A. Schmitt, “Senescence, apoptosis and therapy—cutting the lifelines of cancer,” Nature Reviews Cancer, vol. 3, no. 4, pp. 286–295, 2003.
- J. W. Shay and I. B. Roninson, “Hallmarks of senescence in carcinogenesis and cancer therapy,” Oncogene, vol. 23, no. 16, pp. 2919–2933, 2004.
- C. A. Schmitt, J. S. Fridman, M. Yang et al., “A senescence program controlled by p53 and p16 contributes to the outcome of cancer therapy,” Cell, vol. 109, no. 3, pp. 335–346, 2002.
- W. E. Wright, M. A. Piatyszek, W. E. Rainey, W. Byrd, and J. W. Shay, “Telomerase activity in human germline and embryonic tissues and cells,” Developmental Genetics, vol. 18, no. 2, pp. 173–179, 1996.
- G. A. Ulaner, J. F. Hu, T. H. Vu, L. C. Giudice, and A. R. Hoffman, “Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts,” Cancer Research, vol. 58, no. 18, pp. 4168–4172, 1998.
- C. B. Harley, “Telomerase and cancer therapeutics,” Nature Reviews Cancer, vol. 8, no. 3, pp. 167–179, 2008.
- L. R. Kelland, “Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics—current status and future prospects,” European Journal of Cancer, vol. 41, no. 7, pp. 971–979, 2005.
- J. W. Shay and W. E. Wright, “Telomerase therapeutics for cancer: challenges and new directions,” Nature Reviews Drug Discovery, vol. 5, no. 7, pp. 577–584, 2006.
- K. Damm, U. Hemmann, P. Garin-Chesa et al., “A highly selective telomerase inhibitor limiting human cancer cell proliferation,” The EMBO Journal, vol. 20, no. 24, pp. 6958–6968, 2002.
- J. H. Kim, J. H. Kim, G. E. Lee, S. W. Kim, and I. K. Chung, “Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells,” The Biochemical Journal, vol. 373, no. 2, pp. 523–529, 2003.
- A. Preto, S. K. Singhrao, M. F. Haughton, D. Kipling, D. Wynford-Thomas, and C. J. Jones, “Telomere erosion triggers growth arrest but not cell death in human cancer cells retaining wild-type p53: implications for antitelomerase therapy,” Oncogene, vol. 23, no. 23, pp. 4136–4145, 2004.
- J. F. Riou, L. Guittat, P. Mailliet et al., “Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 5, pp. 2672–2677, 2002.
- M. A. Shammas, H. Koley, D. G. Beer, C. Li, R. K. Goyal, and N. C. Munshi, “Growth arrest, apoptosis, and telomere shortening of Barrett's-associated adenocarcinoma cells by a telomerase inhibitor,” Gastroenterology, vol. 126, no. 5, pp. 1337–1346, 2004.
- M. W. Djojosubroto, A. C. Chin, N. Go et al., “Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma,” Hepatology, vol. 42, no. 5, pp. 1127–1136, 2005.
- P. F. Brunsvig, S. Aamdal, M. K. Gjertsen et al., “Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer,” Cancer Immunology, Immunotherapy, vol. 55, no. 12, pp. 1553–1564, 2006.
- W. G. Deng, G. Jayachandran, G. Wu, K. Xu, J. A. Roth, and L. Ji, “Tumor-specific activation of human telomerase reverses transcriptase promoter activity by activating enhancer-binding protein-2β in human lung cancer cells,” Journal of Biological Chemistry, vol. 282, no. 36, pp. 26460–26470, 2007.
- A. E. Hochreiter, H. Xiao, E. M. Goldblatt et al., “Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer,” Clinical Cancer Research, vol. 12, no. 10, pp. 3184–3192, 2006.
- W. G. An, R. C. Schnur, L. Neckers, and M. V. Blagosklonny, “Depletion of , Raf-1 and mutant p53 proteins by geldanamycin derivatives correlates with antiproliferative activity,” Cancer Chemotherapy and Pharmacology, vol. 40, no. 1, pp. 60–64, 1997.
- G. Dasgupta and J. Momand, “Geldanamycin prevents nuclear translocation of mutant p53,” Experimental Cell Research, vol. 237, no. 1, pp. 29–37, 1997.
- G. Selivanova, L. Ryabchenko, E. Jansson, V. Iotsova, and K. G. Wiman, “Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain,” Molecular and Cellular Biology, vol. 19, no. 5, pp. 3395–3402, 1999.
- B. A. Foster, H. A. Coffey, M. J. Morin, and F. Rastinejad, “Pharmacological rescue of mutant p53 conformation and function,” Science, vol. 286, no. 5449, pp. 2507–2510, 1999.
- R. E. Buller, I. B. Runnebaum, B. Y. Karlan et al., “A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer,” Cancer Gene Therapy, vol. 9, no. 7, pp. 553–566, 2002.
- K. Butz, C. Denk, A. Ullmann, M. Scheffner, and F. Hoppe-Seyler, “Induction of apoptosis in human papillomavirus-positive cancer cells by peptide aptamers targeting the viral E6 oncoprotein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 12, pp. 6693–6697, 2000.
- P. Seth, U. Brinkmann, G. N. Schwartz et al., “Adenovirus-mediated gene transfer to human breast tumor cells: an approach for cancer gene therapy and bone marrow purging,” Cancer Research, vol. 56, no. 6, pp. 1346–1351, 1996.
- S. R. Quist, S. Wang-Gohrke, T. Köhler, R. Kreienberg, and I. B. Runnebaum, “Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status,” Cancer Gene Therapy, vol. 11, no. 8, pp. 547–554, 2004.
- S. Hietanen, S. Lain, E. Krausz, C. Blattner, and D. P. Lane, “Activation of p53 in cervical carcinoma cells by small molecules,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 15, pp. 8501–8506, 2000.
- T. Maehama, A. Patzelt, M. Lengert et al., “Selective down-regulation of human papillomavirus transcription by 2-deoxyglucose,” International Journal of Cancer, vol. 76, no. 5, pp. 639–646, 1998.
- J. Nemunaitis, S. G. Swisher, T. Timmons et al., “Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 18, no. 3, pp. 609–622, 2000.
- C. P. Martins, L. Brown-Swigart, and G. I. Evan, “Modeling the therapeutic efficacy of p53 restoration in tumors,” Cell, vol. 127, no. 7, pp. 1323–1334, 2006.
- A. Ventura, D. G. Kirsch, M. E. McLaughlin et al., “Restoration of p53 function leads to tumour regression in vivo,” Nature, vol. 445, no. 7128, pp. 661–665, 2007.
- W. Xue, L. Zender, C. Miething et al., “Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas,” Nature, vol. 445, no. 7128, pp. 656–660, 2007.
- C. H. Wu, J. van Riggelen, A. Yetil, et al., “Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 32, pp. 13028–13033, 2007.
- L. Soucek, J. Whitfield, C. P. Martins et al., “Modelling Myc inhibition as a cancer therapy,” Nature, vol. 455, no. 7213, pp. 679–683, 2008.
- I. B. Roninson, “Tumor senescence as a determinant of drug response in vivo,” Drug Resistance Updates, vol. 5, no. 5, pp. 204–208, 2002.
- B.-D. Chang, E. V. Broude, M. Dokmanovic et al., “A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents,” Cancer Research, vol. 59, no. 15, pp. 3761–3767, 1999.
- B. D. Chang, Y. Xuan, E. V. Broude et al., “Role of p53 and in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs,” Oncogene, vol. 18, no. 34, pp. 4808–4818, 1999.
- L. W. Elmore, C. W. Rehder, X. Di et al., “Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction,” Journal of Biological Chemistry, vol. 277, no. 38, pp. 35509–35515, 2002.
- X. Wang, S. C. H. Wong, J. Pan et al., “Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells,” Cancer Research, vol. 58, no. 22, pp. 5019–5022, 1998.
- R. H. te Poele, A. L. Okorokov, L. Jardine, J. Cummings, and S. P. Joel, “DNA damage is able to induce senescence in tumor cells in vitro and in vivo,” Cancer Research, vol. 62, no. 6, pp. 1876–1883, 2002.
- M. Collado, M. A. Blasco, and M. Serrano, “Cellular senescence in cancer and aging,” Cell, vol. 130, no. 2, pp. 223–233, 2007.
- V. Paradis, N. Youssef, D. Dargère et al., “Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas,” Human Pathology, vol. 32, no. 3, pp. 327–332, 2001.
- J. J. Going, R. C. Stuart, M. Downie, A. J. Fletcher-Monaghan, and W. N. Keith, “‘Senescence-associated’ β-galactosidase activity in the upper gastrointestinal tract,” Journal of Pathology, vol. 196, no. 4, pp. 394–400, 2002.
- S. U. Wiemann, A. Satyanarayana, M. Tsahuridu et al., “Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis,” FASEB Journal, vol. 16, no. 9, pp. 935–942, 2002.
- U. Herbig, M. Ferreira, L. Condel, D. Carey, and J. M. Sedivy, “Cellular senescence in aging primates,” Science, vol. 311, no. 5765, p. 1257, 2006.
- K. Mishima, J. T. Handa, A. Aotaki-Keen, G. A. Lutty, L. S. Morse, and L. M. Hjelmeland, “Senescence-associated β-galactosidase histochemistry for the primate eye,” Investigative Ophthalmology and Visual Science, vol. 40, no. 7, pp. 1590–1593, 1999.
- J. C. Jeyapalan, M. Ferreira, J. M. Sedivy, and U. Herbig, “Accumulation of senescent cells in mitotic tissue of aging primates,” Mechanisms of Ageing and Development, vol. 128, no. 1, pp. 36–44, 2007.
- J. S. Price, J. G. Waters, C. Darrah et al., “The role of chondrocyte senescence in osteoarthritis,” Aging Cell, vol. 1, no. 1, pp. 57–65, 2002.
- M. Fenton, S. Barker, D. J. Kurz, and J. D. Erusalimsky, “Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 2, pp. 220–226, 2001.
- C. Matthews, I. Gorenne, S. Scott et al., “Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress,” Circulation Research, vol. 99, no. 2, pp. 156–164, 2006.
- E. Vasile, Y. Tomita, L. F. Brown, O. Kocher, and H. F. Dvorak, “Differential expression of thymosin β-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis,” FASEB Journal, vol. 15, no. 2, pp. 458–466, 2001.
- T. Minamino and I. Komuro, “Vascular cell senescence: contribution to atherosclerosis,” Circulation Research, vol. 100, no. 1, pp. 15–26, 2007.
- B. E. Flanary, N. W. Sammons, C. Nguyen, D. Walker, and W. J. Streit, “Evidence that aging and amyloid promote microglial cell senescence,” Rejuvenation Research, vol. 10, no. 1, pp. 61–74, 2007.
- T. Tsuji, K. Aoshiba, and A. Nagai, “Alveolar cell senescence in patients with pulmonary emphysema,” American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 8, pp. 886–893, 2006.
- K.-C. Müller, L. Welker, K. Paasch et al., “Lung fibroblasts from patients with emphysema showmarkers of senescence in vitro,” Respiratory Research, vol. 7, article 32, 2006.
- E. L. Schneider and Y. Mitsui, “The relationship between in vitro cellular aging and in vivo human age,” Proceedings of the National Academy of Sciences of the United States of America, vol. 73, no. 10, pp. 3584–3588, 1976.
- J. G. Rheinwald and H. Green, “Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells,” Cell, vol. 6, no. 3, pp. 331–334, 1975.
- G. M. Martin, C. A. Sprague, and C. J. Epstein, “Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype,” Laboratory Investigation, vol. 23, no. 1, pp. 86–92, 1970.
- S. A. Bruce, S. F. Deamond, and P. O. P. Ts'o, “In vitro senescence of syrian hamster mesenchymal cells of fetal to aged adult origin. Inverse relationship between in vivo donor age and in vitro proliferative capacity,” Mechanisms of Ageing and Development, vol. 34, no. 2, pp. 151–173, 1986.
- E. L. Bierman, “The effect of donor age on the in vitro life span of cultured human arterial smooth-muscle cells,” In Vitro, vol. 14, no. 11, pp. 951–955, 1978.
- V. J. Cristofalo, R. G. Allen, R. J. Pignolo, B. G. Martin, and J. C. Beck, “Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 18, pp. 10614–10619, 1998.
- S. Goldstein, S. Murano, H. Benes et al., “Studies on the molecular-genetic basis of replicative senescence in Werner syndrome and normal fibroblasts,” Experimental Gerontology, vol. 24, no. 5-6, pp. 461–468, 1989.
- K. I. Nakamura, N. Izumiyama-Shimomura, M. Sawabe et al., “Comparative analysis of telomere lengths and erosion with age in human epidermis and lingual epithelium,” Journal of Investigative Dermatology, vol. 119, no. 5, pp. 1014–1019, 2002.
- R. C. Allsopp, H. Vaziri, C. Patterson et al., “Telomere length predicts replicative capacity of human fibroblasts,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 21, pp. 10114–10118, 1992.
- R. M. Cawthon, K. R. Smith, E. O'Brien, A. Sivatchenko, and R. A. Kerber, “Association between telomere length in blood and mortality in people aged 60 years or older,” The Lancet, vol. 361, no. 9355, pp. 393–395, 2003.
- N. D. Hastie, M. Dempster, M. G. Dunlop, A. M. Thompson, D. K. Green, and R. C. Allshire, “Telomere reduction in human colorectal carcinoma and with ageing,” Nature, vol. 346, no. 6287, pp. 866–868, 1990.
- M. Sugimoto, R. Yamashita, and M. Ueda, “Telomere length of the skin in association with chronological aging and photoaging,” Journal of Dermatological Science, vol. 43, no. 1, pp. 43–47, 2006.
- A. Melk, V. Ramassar, L. M. H. Helms et al., “Telomere shortening in kidneys with age,” Journal of the American Society of Nephrology, vol. 11, no. 3, pp. 444–453, 2000.
- K. Takubo, K. I. Nakamura, N. Izumiyama et al., “Telomere shortening with aging in human liver,” The Journals of Gerontology Series A, vol. 55, no. 11, pp. B533–B536, 2000.
- H. Aikata, H. Takaishi, Y. Kawakami et al., “Telomere reduction in human liver tissues with age and chronic inflammation,” Experimental Cell Research, vol. 256, no. 2, pp. 578–582, 2000.
- G. M. Baerlocher, I. Vulto, G. de Jong, and P. M. Lansdorp, “Flow cytometry and FISH to measure the average length of telomeres (flow FISH),” Nature Protocols, vol. 1, no. 5, pp. 2365–2376, 2006.
- A. Canela, E. Vera, P. Klatt, and M. A. Blasco, “High-throughput telomere length quantification by FISH and its application to human population studies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 13, pp. 5300–5305, 2007.
- E. Chang and C. B. Harley, “Telomere length and replicative aging in human vascular tissues,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 24, pp. 11190–11194, 1995.
- M. Kimura, M. Barbieri, J. P. Gardner et al., “Leukocytes of exceptionally old persons display ultra-short telomeres,” American Journal of Physiology, vol. 293, no. 6, pp. R2210–R2217, 2007.
- M. Kveiborg, M. Kassem, B. Langdahl, E. F. Eriksen, B. F. C. Clark, and S. I. S. Rattan, “Telomere shortening during aging of human osteoblasts in vitro and leukocytes in vivo: lack of excessive telomere loss in osteoporotic patients,” Mechanisms of Ageing and Development, vol. 106, no. 3, pp. 261–271, 1999.
- C. Mondello, C. Petropoulou, D. Monti, E. S. Gonos, C. Franceschi, and F. Nuzzo, “Telomere length in fibroblasts and blood cells from healthy centenarians,” Experimental Cell Research, vol. 248, no. 1, pp. 234–242, 1999.
- T. Kitada, S. Seki, N. Kawakita, T. Kuroki, and T. Monna, “Telomere shortening in chronic liver diseases,” Biochemical and Biophysical Research Communications, vol. 211, no. 1, pp. 33–39, 1995.
- N. Miura, I. Horikawa, A. Nishimoto et al., “Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis,” Cancer Genetics and Cytogenetics, vol. 93, no. 1, pp. 56–62, 1997.
- Y. Urabe, K. Nouso, T. Higashi et al., “Telomere length in human liver diseases,” Liver, vol. 16, no. 5, pp. 293–297, 1996.
- S. E. Ball, F. M. Gibson, S. Rizzo, J. A. Tooze, J. C. W. Marsh, and E. C. Gordon-Smith, “Progressive telomere shortening in aplastic anemia,” Blood, vol. 91, no. 10, pp. 3582–3592, 1998.
- N. J. Samani, R. Boultby, R. Butler, J. R. Thompson, and A. H. Goodall, “Telomere shortening in atherosclerosis,” The Lancet, vol. 358, no. 9280, pp. 472–473, 2001.
- N. Obana, S. Takagi, Y. Kinouchi et al., “Telomere shortening of peripheral blood mononuclear cells in coronary disease patients with metabolic disorders,” Internal Medicine, vol. 42, no. 2, pp. 150–153, 2003.
- L. A. Panossian, V. R. Porter, H. F. Valenzuela et al., “Telomere shortening in T cells correlates with Alzheimer's disease status,” Neurobiology of Aging, vol. 24, no. 1, pp. 77–84, 2003.
- M. Ogami, Y. Ikura, M. Ohsawa et al., “Telomere shortening in human coronary artery diseases,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 3, pp. 546–550, 2004.
- E. S. Epel, E. H. Blackburn, J. Lin et al., “Accelerated telomere shortening in response to life stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 49, pp. 17312–17315, 2004.
- A. M. Valdes, T. Andrew, J. P. Gardner et al., “Obesity, cigarette smoking, and telomere length in women,” The Lancet, vol. 366, no. 9486, pp. 662–664, 2005.
- T. Vulliamy, A. Marrone, R. Szydlo, A. Walne, P. J. Mason, and I. Dokal, “Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC,” Nature Genetics, vol. 36, no. 5, pp. 447–449, 2004.
- T. Vulliamy, A. Marrone, F. Goldman et al., “The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita,” Nature, vol. 413, no. 6854, pp. 432–435, 2001.
- H. Yamaguchi, R. T. Calado, H. Ly et al., “Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia,” The New England Journal of Medicine, vol. 352, no. 14, pp. 1413–1424, 2005.
- H. W. Lee, M. A. Blasco, G. J. Gottlieb, J. W. Horner, C. W. Greider, and R. A. DePinho, “Essential role of mouse telomerase in highly proliferative organs,” Nature, vol. 392, no. 6676, pp. 569–574, 1998.
- L. Y. Hao, M. Armanios, M. A. Strong et al., “Short telomeres, even in the presence of telomerase, limit tissue renewal capacity,” Cell, vol. 123, no. 6, pp. 1121–1131, 2005.
- M. Jaskelioff, F. L. Muller, J.-H. Paik et al., “Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice,” Nature, vol. 469, no. 7328, pp. 102–107, 2011.
- S. Chang, A. S. Multani, N. G. Cabrera et al., “Essential role of limiting telomeres in the pathogenesis of Werner syndrome,” Nature Genetics, vol. 36, no. 8, pp. 877–882, 2004.
- X. Du, J. Shen, N. Kugan et al., “Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes,” Molecular and Cellular Biology, vol. 24, no. 19, pp. 8437–8446, 2004.
- D. J. Rossi, C. H. M. Jamieson, and I. L. Weissman, “Stems cells and the pathways to aging and cancer,” Cell, vol. 132, no. 4, pp. 681–696, 2008.
- T. A. Rando, “Stem cells, ageing and the quest for immortality,” Nature, vol. 441, no. 7097, pp. 1080–1086, 2006.
- I. Beerman, W. J. Maloney, I. L. Weissmann, and D. J. Rossi, “Stem cells and the aging hematopoietic system,” Current Opinion in Immunology, vol. 22, no. 4, pp. 500–506, 2010.
- S. Zimmermann, M. Voss, S. Kaiser, U. Kapp, C. F. Waller, and U. M. Martens, “Lack of telomerase activity in human mesenchymal stem cells,” Leukemia, vol. 17, no. 6, pp. 1146–1149, 2003.
- S. J. Morrison, K. R. Prowse, P. Ho, and I. L. Weissman, “Telomerase activity in hematopoietic cells is associated with self-renewal potential,” Immunity, vol. 5, no. 3, pp. 207–216, 1996.
- R. C. Allsopp, G. B. Morin, R. DePinho, C. B. Harley, and I. L. Weissman, “Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation,” Blood, vol. 102, no. 2, pp. 517–520, 2003.
- J. Yui, C. P. Chiu, and P. M. Lansdorp, “Telomerase activity in candidate stem cells from fetal liver and adult bone marrow,” Blood, vol. 91, no. 9, pp. 3255–3262, 1998.
- R. C. Allsopp, S. Cheshier, and I. L. Weissman, “Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells,” Journal of Experimental Medicine, vol. 193, no. 8, pp. 917–924, 2001.
- R. C. Allsopp and I. L. Weissman, “Replicative senescence of hematopoietic stem cells during serial transplantation: does telomere shortening play a role?” Oncogene, vol. 21, no. 21, pp. 3270–3273, 2002.
- H. Vaziri, W. Dragowska, R. C. Allsopp, T. E. Thomas, C. B. Harley, and P. M. Lansdorp, “Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 21, pp. 9857–9860, 1994.
- J. Krishnamurthy, C. Torrice, M. R. Ramsey et al., “Ink4a/Arf expression is a biomarker of aging,” Journal of Clinical Investigation, vol. 114, no. 9, pp. 1299–1307, 2004.
- A. B. Chkhotua, E. Gabusi, A. Altimari et al., “Increased expression of p16 and p27 cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy,” American Journal of Kidney Diseases, vol. 41, no. 6, pp. 1303–1313, 2003.
- S. Ressler, J. Bartkova, H. Niederegger et al., “ is a robust in vivo biomarker of cellular aging in human skin,” Aging Cell, vol. 5, no. 5, pp. 379–389, 2006.
- G. P. Nielsen, A. O. Stemmer-Rachamimov, J. Shaw, J. E. Roy, J. Koh, and D. N. Louis, “Immunohistochemical survey of expression in normal human adult and infant tissues,” Laboratory Investigation, vol. 79, no. 9, pp. 1137–1143, 1999.
- A. Melk, B. M. W. Schmidt, O. Takeuchi, B. Sawitzki, D. C. Rayner, and P. F. Halloran, “Expression of and other cell cycle regulator and senescence associated genes in aging human kidney,” Kidney International, vol. 65, no. 2, pp. 510–520, 2004.
- H. Chen, X. Gu, I. H. Su et al., “Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus,” Genes & Development, vol. 23, no. 8, pp. 975–985, 2009.
- F. Zindy, D. E. Quelle, M. F. Roussel, and C. J. Sherr, “Expression of the tumor suppressor versus other INK4 family members during mouse development and aging,” Oncogene, vol. 15, no. 2, pp. 203–211, 1997.
- J. Krishnamurthy, M. R. Ramsey, K. L. Ligon et al., “ induces an age-dependent decline in islet regenerative potential,” Nature, vol. 443, no. 7110, pp. 453–457, 2006.
- V. Janzen, R. Forkert, H. E. Fleming et al., “Stem-cell ageing modified by the cyclin-dependent kinase inhibitor ,” Nature, vol. 443, no. 7110, pp. 421–426, 2006.
- A. V. Molofsky, S. G. Slutsky, N. M. Joseph et al., “Increasing expression decreases forebrain progenitors and neurogenesis during ageing,” Nature, vol. 443, no. 7110, pp. 448–452, 2006.
- T. Cheng, N. Rodrigues, H. Shen et al., “Hematopoietic stem cell quiescence maintained by ,” Science, vol. 287, no. 5459, pp. 1804–1809, 2000.
- A. R. Choudhury, Z. Ju, M. W. Djojosubroto et al., “Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation,” Nature Genetics, vol. 39, no. 1, pp. 99–105, 2007.
- Y. Liu, S. E. Elf, Y. Miyata et al., “p53 regulates hematopoietic stem cell quiescence,” Cell Stem Cell, vol. 4, no. 1, pp. 37–48, 2009.
- M. TeKippe, D. E. Harrison, and J. Chen, “Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice,” Experimental Hematology, vol. 31, no. 6, pp. 521–527, 2003.
- K. Meletis, V. Wirta, S. M. Hede, M. Nistér, J. Lundeberg, and J. Frisén, “p53 suppresses the self-renewal of adult neural stem cells,” Development, vol. 133, no. 2, pp. 363–369, 2006.
- S. D. Tyner, S. Venkatachalam, J. Choi et al., “p53 mutant mice that display early ageing-associated phenotypes,” Nature, vol. 415, no. 6867, pp. 45–53, 2002.
- B. Maier, W. Gluba, B. Bernier et al., “Modulation of mammalian life span by the short isoform of p53,” Genes & Development, vol. 18, no. 3, pp. 306–319, 2004.
- S. M. Chambers, C. A. Shaw, C. Gatza, C. J. Fisk, L. A. Donehower, and M. A. Goodell, “Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation,” PLoS Biology, vol. 5, no. 8, article e201, 2007.
- M. Dumble, L. Moore, S. M. Chambers et al., “The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging,” Blood, vol. 109, no. 4, pp. 1736–1742, 2007.
- A. Matheu, A. Maraver, P. Klatt et al., “Delayed ageing through damage protection by the Arf/p53 pathway,” Nature, vol. 448, no. 7151, pp. 375–379, 2007.
- I. García-Cao, M. García-Cao, J. Martín-Caballero et al., “‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally,” The EMBO Journal, vol. 21, no. 22, pp. 6225–6235, 2002.
- I. García-Cao, M. García-Cao, A. Tomás-Loba et al., “Increased p53 activity does not accelerate telomere-driven ageing,” EMBO Reports, vol. 7, no. 5, pp. 546–552, 2006.