J Campisi

..This new discovery is discussed in light of previous findings related to mechanisms of aging...

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..Recent findings have revealed the complexities of the senescence phenotype and unexpected possible consequences for the organism...

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..Both processes are essential for the viability and fitness of young organisms, but may contribute to aging phenotypes, including certain age-related diseases...

..These articles reveal the expected complexities, but also surprising conservation, in mechanisms that link cancer and aging...

..Cross-species comparisons suggest there is a relationship between the senescence of cells in culture and organismal life span, but the relationship is neither quantitative nor direct...

..Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate...

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..Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging...

..Recent evidence indicates that some mammalian tumour-suppressor mechanisms contribute to ageing. How might this have happened, and what are its implications for our ability to control cancer and ageing?..

..In her Perspective, Campisi comments on new work showing that caloric restriction increases longevity in yeast by activating the SIR2 gene, which alters the compactness of chromatin and thus regulates gene expression (Lin et al.)...

..Our findings suggest that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms, suggesting it is an example of evolutionary antagonistic pleiotropy...

..We propose that Ku localizes to internal regions of the telomere via a high-affinity interaction with TRF1. Therefore, Ku acts in a unique way at the telomere to prevent end joining...

..Our findings suggest that BLM is part of a dynamic nuclear matrix-based complex that requires PML and functions during G2 in undamaged cells and recombinational repair after DNA damage...

..In mammals, telomere length and structure can influence cellular, and possibly organismal, aging. Here, we show that clk-2 encodes a regulator of telomere length in C. elegans...

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..Despite the well-documented central role for p53 in the senescence response, many questions remain regarding how p53 senses senescence-inducing stimuli and how it elicits the senescent phenotype...

..The cell death was prevented by the PARP inhibitor 3-aminobenzamide. In vivo, TANK2 may differ from TANK1 in its intrinsic or regulated PARP activity or its substrate specificity...

..These data suggest that DNA-PK and WRN may function together in DNA metabolism and implicate WRN function in non-homologous end joining...

..New molecular tools and model organisms, some already on the horizon, will need to be developed to better understand the roles of apoptosis and cellular senescence in age-associated changes in proliferative homeostasis...

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..They show that the p38-regulated/activated protein kinase (PRAK) induces senescence downstream of oncogenic Ras by directly phosphorylating and activating the tumor-suppressor protein p53...

..Our findings provide a previously unrecognized mechanistic explanation for the observation that ectopically expressed hTERT conveys growth advantages to cells, without having to postulate nontelomeric functions for the enzyme...

..Here, we discuss the role of p53 as a key regulator of the DNA damage responses, and discuss how p53 integrates the outcome of the DNA damage response to optimally balance tumor suppression and longevity...

..Recent evidence lends support to this idea, and suggests that cellular senescence may be an example of evolutionary antagonistic pleiotropy...

..The results suggest that BLM, but not WRN, is an early selected target during the execution of apoptosis...

..BLM recruits 53BP1 to these lesions independent of its helicase activity, and optimal activation of ATM requires both p53 and BLM helicase activities...

..Here, we discuss what is known about the basis for the links between telomeres, aging and cancer, and some of the known and proposed consequences of telomere dysfunction and maintenance for mammalian cells and organisms...

..Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP...

..Our data suggest that Bmi-1 extends the replicative life span of human fibroblasts by suppressing the p16-dependent senescence pathway...

..Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue...

..Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment...

..This Id-1-regulated invasive phenotype could contribute to involution of the mammary gland and possibly to the development of invasive breast cancer...

..Finally, we show that hWRN forms a trimer and interacts with the proliferating cell nuclear antigen in vitro. These findings provide new data on the biochemical activities of WRN that may help elucidate its role(s) in DNA metabolism...

..Our findings suggest that TRF1 is insufficient for control of telomere length in human cells, and that TIN2 is an essential mediator of TRF1 function...

..Here, we review what is known about the structure and function of telomeres in mammalian cells, particularly human cells, and how telomere dysfunction may arise and contribute to cancer and aging phenotypes...

..The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression...

..Our findings identify a mechanism and conditions under which telomerase and telomeres affect the response of human cells to genotoxic agents and may have important implications for anti-cancer interventions...

..New tools and approaches are on the horizon and will need to be developed and implemented before we can fully understand whether and to what extent macromolecular damage drives aging phenotypes...

..Our results identify oxygen sensitivity as a critical difference between mouse and human cells, explaining their proliferative differences in culture, and possibly their different rates of cancer and ageing...

..Recent evidence lends support to this idea, and suggests that senescent stromal fibroblasts may be particularly adept at creating a tissue environment that can promote the development of age-related epithelial cancers...

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..Our findings may in part explain why senescent cells stimulate tumorigenesis in vivo and support the idea that senescent cells may facilitate age-associated cancer development by secreting factors that promote malignant progression...

..Here we show that a novel extra-telomeric organization of TIN2 is associated with the control of cell proliferation and identify TIN2 as an important regulator of mammary epithelial differentiation...

..Our findings suggest that distinct TIN2 complexes exist and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53...

..Our results support a role for telomere structure, rather than length, in replicative senescence...

..Our results indicate that the senescence response to telomere dysfunction is reversible and is maintained primarily by p53. However, p16 provides a dominant second barrier to the unlimited growth of human cells...

..Here, we summarize our knowledge of the SASP and the impact it has on tissue microenvironments and ability to stimulate tumor progression...

..A better understanding of the targets of such interventions, as well as the proximate causes of ageing-related degeneration and disease, is essential before we can evaluate if abrogation of human senescence is a realistic prospect...

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..TIN2 mutants defective in binding of TRF1 or TRF2 induce a DNA damage response and destabilize TRF1 and TRF2 at telomeres in human cells. Our findings suggest that the functions of TRF1 and TRF2 are linked by TIN2...

..Further, apoptosis increased subtly but measurably when human mammary epithelial and skin fibroblast cells entered crisis, indicating that cell death during crisis is largely non-apoptotic...

..Unlike TRF1, TIN2 did not form homodimers. We propose that TIN2 alters the conformation of TRF1, which favours a tertiary telomeric structure that hinders telomerase from gaining access to telomeres...

..Our data indicate that p53 is activated during both quiescence and senescence. They further suggest that p53 activity contributes, albeit not exclusively, to the quiescent growth arrest...

..Our results suggest a dual role for TIN2 in mediating the function of the shelterin complex and tethering telomeres to the nuclear matrix...

..We also summarize the cellular pathways/processes that are known to regulate this phenotype--namely, the DNA damage response, microRNAs, key transcription factors and kinases and chromatin remodeling...

..These findings suggest that BLM is an early responder to damaged replication forks. Moreover, p53 eliminates cells that rapidly assemble BRCA1/NBS1 without BLM, suggesting that BLM is essential for timely BRCA1/NBS1 function...

..CONCLUSIONS: The image analysis-based quantification method we describe here is an easy and reliable way to monitor cells in coculture and should be useful for a variety of cell biological studies...

..Thus, cell surface IL-1alpha is an essential cell-autonomous regulator of the senescence-associated IL-6/IL-8 cytokine network...

..Thus, tobacco may not only initiate mutagenic changes in epithelial cells but also promote the growth and invasion of mutant cells by creating a procarcinogenic stromal environment...

..Here, we discuss the relationship between aging and cancer, the mechanism of metformin action, and the prospects of using this compound for life span extension in humans...

..Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events...

..These data demonstrate the utility of ZFP TFs as precise tools for target validation, and highlight their potential as clinical therapeutics...

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..Maintaining genome integrity has emerged as a major factor in longevity and cell viability. Here we discuss the use of mouse models with defects in genome maintenance for understanding the molecular basis of aging in humans...

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..These findings suggest that WRN and BRCA1 act in a coordinated manner to facilitate repair of DNA ICLs...

..Because it is easy to detect, SA-beta-gal is currently a widely used biomarker of senescence. Here we describe a method to detect SA-beta-gal in detail, including some recent modifications...

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..These findings demonstrate for the first time the impact of oxidative stress on the genomic integrity of murine cells during senescence and immortalization...

..These data suggest that Bmi-1 regulates telomerase expression in MECs and plays a role in the development of human breast cancer...

..This extensive deletion phenotype was complemented by wild-type WRN. These results suggest that WRN can out-compete other exonucleases that participate in double-strand break repair or stabilize the broken DNA end...

..In long-term cultures, the locus is less suitable for studying induced mutations owing to the instability of the cell population...

..These findings provide a rationale for potential gene therapy...

..Given the major demographic consequences if it came about, this possibility merits urgent debate...

..S. population. ..

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..Our studies will provide important insights into how WRN and BLM postpone the development of aging phenotypes and the development of cancer in humans. ..

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..The long range goal is to identify human longevity assurance genes and to know enough about their function to develop rational strategies for therapeutics or interventions. ..