Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors

Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. 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.     

Endothelial senescence after high-cholesterol, high-fat diet challenge in baboons

Increasing evidence indicates that replicative senescence and premature endothelial senescence could contribute to endothelial dysfunction. This study aims at testing the hypothesis that a high-fat diet may lead to premature vascular endothelial senescence in a nonhuman primate model. We isolated endothelial cells from left and right femoral arteries in 10 baboons before and after a 7-wk high-fat dietary treatment. We compared the morphological alterations, replicative capacities, and senescence-associated beta-galactosidase activities (SA-beta-gal) at these two time points. We found that high-fat diet increased the prevalence of endothelial senescence. Endothelial replicative capacities declined dramatically, and SA-beta-gal activities increased significantly in postdietary challenge. There was no change in telomeric length using quantitative flow fluorescence in situ hybridization analysis, suggesting that some stressors lead to cell senescence independent of telomere dysfunction. Our findings that high-fat diet causes endothelial damage through the premature senescence suggest a novel mechanism for the diet-induced endothelial dysfunction.     

Oncogenic RAS regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence

Here, we report a cell-intrinsic mechanism by which oncogenic RAS promotes senescence while predisposing cells to senescence bypass by allowing for secondary hits. We show that oncogenic RAS inactivates the BRCA1 DNA repair complex by dissociating BRCA1 from chromatin. This event precedes senescence-associated cell cycle exit and coincides with the accumulation of DNA damage. Downregulation of BRIP1, a physiological partner of BRCA1 in the DNA repair pathway, triggers BRCA1 chromatin dissociation. Conversely, ectopic BRIP1 rescues BRCA1 chromatin dissociation and suppresses RAS-induced senescence and the DNA damage response. Significantly, cells undergoing senescence do not exhibit a BRCA1-dependent DNA repair response when exposed to DNA damage. Overall, our study provides a molecular basis by which oncogenic RAS promotes senescence. Because DNA damage has the potential to produce additional "hits" that promote senescence bypass, our findings may also suggest one way a small minority of cells might bypass senescence and contribute to cancer development.     

植物衰老中的编程性细胞死亡

本文通过对植物衰老和动植物中编程性细胞死亡(PCD)的研究,阐述了植物衰老中PCD存在的依据,澄清了植物衰老和PCD的关系,提出了植物衰老中可能的PCD发生途径,为调控植物衰老的遗传操作提供依据.     

植物衰老中的编程性细胞死亡

本文通过对植物衰老和动植物中编程性细胞死亡(PCD)的研究,阐述了植物衰老中PCD存在的依据,澄清了植物衰老和PCD的关系,提出了植物衰老中可能的PCD发生途径,为调控植物衰老的遗传操作提供依据。     

Cellular Senescence,Epigenetic Switches and c-Myc

In response to hyperproliferative signaling elicited by transforming oncogenes some normal human cells can enter replicative senescence as a tumor defense mechanism. We recently found that human fibroblasts or endothelial cells with genetically-engineered reduction of proto-oncogene c-Myc expression switched with an increased frequency to a senescent state by a telomere-independent mechanism involving the polycomb group repressor Bmi-1 and the cyclin-dependent kinase inhibitor p16^INK4a. The same regulatory circuit was triggered upon exposure to mild oxidative stress. These findings point to the existence of a mechanism for monitoring hypoproliferative signaling, whose function may be to limit the proliferation and accretion of physiologically compromised cells. This mechanism may be another example of antagonistic pleiotropy leading to organismal aging.     

Ammonium, calcium, and leaf senescence in rice

The possible involvement of calcium in the regulation of ammonium-promoted senescence of detached rice leaves was investigated. Calcium effectively reduced ammonium-promoted senescence of detached rice leaves. The effect of ammonium on the senescence was also significantly reduced by the calcium ionophore A23187. Ammonium-promoted senescence of detached rice leaves may be mediated through blocking the entrance of calcium ions into the cytosol.     

Stem cells, senescence, neosis and self-renewal in cancer

We describe the basic tenets of the current concepts of cancer biology, and review the recent advances on the suppressor role of senescence in tumor growth and the breakdown of this barrier during the origin of tumor growth. Senescence phenotype can be induced by (1) telomere attrition-induced senescence at the end of the cellular mitotic life span (MLS*) and (2) also by replication history-independent, accelerated senescence due to inadvertent activation of oncogenes or by exposure of cells to genotoxins. Tumor suppressor genes p53/pRB/p16INK4A and related senescence checkpoints are involved in effecting the onset of senescence. However, senescence as a tumor suppressor mechanism is a leaky process and senescent cells with mutations or epimutations in these genes escape mitotic catastrophe-induced cell death by becoming polyploid cells. These polyploid giant cells, before they die, give rise to several cells with viable genomes via nuclear budding and asymmetric cytokinesis. This mode of cell division has been termed neosis and the immediate neotic offspring the Raju cells. The latter inherit genomic instability and transiently display stem cell properties in that they differentiate into tumor cells and display extended, but, limited MLS, at the end of which they enter senescent phase and can undergo secondary/tertiary neosis to produce the next generation of Raju cells. Neosis is repeated several times during tumor growth in a non-synchronized fashion, is the mode of origin of resistant tumor growth and contributes to tumor cell heterogeneity and continuity. The main event during neosis appears to be the production of mitotically viable daughter genome after epigenetic modulation from the non-viable polyploid genome of neosis mother cell (NMC). This leads to the growth of resistant tumor cells. Since during neosis, spindle checkpoint is not activated, this may give rise to aneuploidy. Thus, tumor cells also are destined to die due to senescence, but may escape senescence due to mutations or epimutations in the senescent checkpoint pathway. A historical review of neosis-like events is presented and implications of neosis in relation to the current dogmas of cancer biology are discussed. Genesis and repetitive re-genesis of Raju cells with transient "stemness" via neosis are of vital importance to the origin and continuous growth of tumors, a process that appears to be common to all types of tumors. We suggest that unlike current anti-mitotic therapy of cancers, anti-neotic therapy would not cause undesirable side effects. We propose a rational hypothesis for the origin and progression of tumors in which neosis plays a major role in the multistep carcinogenesis in different types of cancers. We define cancers as a single disease of uncontrolled neosis due to failure of senescent checkpoint controls.     

The PPARγ‐SETD8 axis constitutes an epigenetic,p53‐independent checkpoint on p21‐mediated cellular senescence

Cellular senescence is a permanent proliferative arrest triggered by genome instability or aberrant growth stresses, acting as a protective or even tumor‐suppressive mechanism. While several key aspects of gene regulation have been known to program this cessation of cell growth, the involvement of the epigenetic regulation has just emerged but remains largely unresolved. Using a systems approach that is based on targeted gene profiling, we uncovered known and novel chromatin modifiers with putative link to the senescent state of the cells. Among these, we identified SETD8 as a new target as well as a key regulator of the cellular senescence signaling. Knockdown of SETD8 triggered senescence induction in proliferative culture, irrespectively of the p53 status of the cells; ectopic expression of this epigenetic writer alleviated the extent doxorubicin‐induced cellular senescence. This repressive effect of SETD8 in senescence was mediated by directly maintaining the silencing mark H4K20me1 at the locus of the senescence switch gene p21. Further in support of this regulatory link, depletion of p21 reversed this SETD8‐mediated cellular senescence. Additionally, we found that PPARγ acts upstream and regulates SETD8 expression in proliferating cells. Downregulation of PPARγ coincided with the senescence induction, while its activation inhibited the progression of this process. Viewed together, our findings delineated a new epigenetic pathway through which the PPARγ‐SETD8 axis directly silences p21 expression and consequently impinges on its senescence‐inducing function. This implies that SETD8 may be part of a cell proliferation checkpoint mechanism and has important implications in antitumor therapeutics.     

Age-dependent action of an ABA-inducible receptor kinase, RPK1, as a positive regulator of senescence in Arabidopsis leaves

Leaf senescence, which constitutes the final stage of leaf development, involves programmed cell death and is intricately regulated by various internal and environmental signals that are incorporated with age-related information. ABA plays diverse and important physiological roles in plants, and is involved in various developmental events and stress responses. ABA has long been regarded as a positive regulator of leaf senescence. However, the cellular mediators of ABA-induced senescence have not been identified. We sought to understand the ABA-induced senescence signaling process in Arabidopsis by examining the function of an ABA- and age-induced gene, RPK1, which encodes a membrane-bound, leucine-rich repeat-containing receptor kinase (receptor protein kinase 1). Loss-of-function mutants in RPK1 were significantly delayed in age-dependent senescence. Furthermore, rpk1 mutants exhibited reduced sensitivity to ABA-induced senescence but little change to jasmonic acid- or ethylene-induced senescence. RPK1 thus mediates ABA-induced leaf senescence as well as age-induced leaf senescence. Conditional overexpression of RPK1 at the mature stage clearly accelerated senescence and cell death, whereas induction of RPK1 at an early developmental stage retarded growth without triggering senescence symptoms. Therefore, RPK1 plays different roles at different stages of development. Consistently, exogenously applied ABA affected leaf senescence in old leaves but not in young leaves. The results, together, showed that membrane-bound RPK1 functions in ABA-dependent leaf senescence. Furthermore, the effect of ABA and ABA-inducible RPK1 on leaf senescence is dependent on the age of the plant, which in part explains the mechanism of functional diversification of ABA action.     

Cellular senescence and cancer treatment

Cellular senescence, an irreversible cell-cycle arrest, reflects a safeguard program that limits the proliferative capacity of the cell exposed to endogenous or exogenous stress signals. A number of recent studies have clarified that an acutely inducible form of cellular senescence may act in response to oncogenic activation as a natural barrier to interrupt tumorigenesis at a premalignant level. Paralleling the increasing insights into premature senescence as a tumor suppressor mechanism, a growing line of evidence identifies cellular senescence as a critical effector program in response to DNA damaging chemotherapeutic agents. This review discusses molecular pathways to stress-induced senescence, the interference of a terminal arrest condition with clinical outcome, and the critical overlap between premature senescence and apoptosis as both tumor suppressive and drug-responsive cellular programs.     

Replicative senescence as a barrier to human cancer

There is evidence that one critically short telomere may be recognized as DNA damage and, as a consequence, induce a p53/p21WAF- and p16INK4A-dependent G1 cell cycle checkpoint to cause senescence. Additionally, senescence via a p53- and p16(INK4A)-dependent mechanism can be induced by the over- or under-stimulation of certain signalling pathways that are involved in cancer. Central to this alternative senescence mechanism is the p14ARF protein, which connects oncogene activation, but not DNA damage, to p53 activation and senescence. We find that immortal keratinocytes almost invariably have dysfunctional p53 and p16 and have high levels of telomerase, but very often express a wild-type p14(ARF). Furthermore, when normal keratinocytes senesce they show a striking elevation of p16 protein, but not of p14(ARF) or its downstream targets p53 and p21(WAF). These results suggest that p16, rather than p14(ARF), is the more important gene in human keratinocyte senescence, but do not exclude a co-operative role for p14(ARF), perhaps in the induction of senescence by activated oncogenes in neoplasia. Regardless of mechanism, these results suggest that replicative senescence acts as a barrier to human cancer development.     

Methyl jasmonate, calcium, and leaf senescence in rice

The possible involvement of calcium in the regulation of methyl jasmonate-promoted senescence of detached rice (Oryza sativa) leaves was investigated. Calcium effectively reduced methyl jasmonate-promoted senescence of detached rice leaves. The effect of methyl jasmonate on the senescence was also significantly reduced by calcium ionophore A23187. Methyl jasmonate-promoted senescence of detached rice leaves may be mediated through blocking the entrance of calcium ions into the cytosol.     

Senescence as an adaptation to limit the spread of disease

Aging has the hallmarks of an evolved adaptation. It is controlled by genes that have been conserved over vast evolutionary distances, and most organisms are able to forestall aging in the most challenging of environments. But fundamental theoretical considerations imply that there can be no direct selection for aging. Senescence reduces individual fitness, and any group benefits are weak and widely dispersed over non-relatives. We offer a resolution to this paradox, suggesting a general mechanism by which senescence might have evolved as an adaptation. The proposed benefit is that senescence protects against infectious epidemics by controlling population density and increasing diversity of the host population. This mechanism is, in fact, already well-accepted in another context: it is the Red Queen Hypothesis for the evolution of sex. We illustrate the hypothesis using a spatially explicit agent-based model in which disease transmission is sensitive to population density as well as homogeneity. We find that individual senescence provides crucial population-level advantages, helping to control both these risk factors. Strong population-level advantages to individual senescence can overcome the within-population disadvantage of senescence. We conclude that frequent local extinctions provide a mechanism by which senescence may be selected as a population-level adaptation in its own right, without assuming pleiotropic benefits to the individual.     

Senescence and apoptosis: dueling or complementary cell fates?

In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence‐inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence‐associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor‐promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non‐neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.     

Convergence and divergence in gene expression profiles induced by leaf senescence and 27 senescence-promoting hormonal, pathological and environmental stress treatments

In addition to age and developmental progress, leaf senescence and senescence-associated genes (SAGs) can be induced by other factors such as plant hormones, pathogen infection and environmental stresses. The relationship is not clear, however, between these induced senescence processes and developmental leaf senescence, and to what extent these senescence-promoting signals mimic age and developmental senescence in terms of gene expression profiles. By analysing microarray expression data from 27 different treatments (that are known to promote senescence) and comparing them with that from developmental leaf senescence, we were able to show that at early stages of treatments, different hormones and stresses showed limited similarity in the induction of gene expression to that of developmental leaf senescence. Once the senescence process is initiated, as evidenced by visible yellowing, generally after a prolonged period of treatments, a great proportion of SAGs of developmental leaf senescence are shared by gene expression profiles in response to different treatments. This indicates that although different signals that lead to initiation of senescence may do so through distinct signal transduction pathways, senescence processes induced either developmentally or by different senescence-promoting treatments may share common execution events.