Cellular senescence

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tetracycline transactivator (tta) protein to control p53 expression using doxycycline, a tetracycline analog and tetracycline responsive short hairpin RNA (shRNA). In the absence of Dox, p53 was actively suppressed as the microRNA levels increased, so as Dox was administered, p53 microRNA was turned off to facilitate the expression of p53. The liver cancers that expressed Ras showed signs of senescence following p53 reactivation including an increase in senescence associated B-galactosidase protein. Even if the expression of p53 was transiently activated or deactivated, senescence via SA B-gal was observed. Xue et al. show that by briefly reactivating p53 in tumors without functional p53 activity, tumor regression is observed. The induction of cellular senescence was associated with an increase in inflammatory cytokines as is expected based on the SASP. The presence of both senescence and an increase in immune activity is able to regress and limit liver carcinoma growth in this mouse model.

444:. More specifically p16INK4a-pRb tumor suppressor and p53 are known effectors of senescence. Most cancer cells have a mutated p53 and p16INK4a-pRb, which allows the cancer cells to escape a senescent fate. The p16 protein is a cyclin dependent kinase (CDK) inhibitor and it activates Rb tumor suppressor. p16 binds to CDK 4/6 to inhibit the kinase activity and inhibit Rb tumor suppressor via phosphorylation. The Rb tumor suppressor has been shown to associate with E2F1 (a protein necessary for transcription) in its monophosphorylated form, which inhibits transcription of downstream target genes involved in the G1/S transition. As part of a feedback loop, increased phosphorylation of Rb increases p16 expression that inhibits Cdk4/6. Reduced Cdk4/6 kinase activity results in higher levels of the hypo-phosphorylated (monophosphorylated) form of Rb, which subsequently leads to reduced levels of p16 expression. 310:

increase in Ras. This finding has been highly reproducible in benign prostate lesions, in melanocytic lesions of UV-irradiated HGF/SF-transgenic mice, in lymphocytes and in the mammary gland from N-Ras transgenic mice, and in hyperplasias of the pituitary gland of mice with deregulated E2F activity. The key to these findings is that genetic manipulations that abrogated the senescence response led to full-blown malignancy in those carcinomas. As such, the evidence suggests senescent cells can be associated with pre-malignant stages of the tumor. Further, it has been speculated that a senescent phenotype might serve as a promising marker for staging. There are two types of senescence

455:, resulting in apoptosis. A BubR1 H/H mouse model known to experience the clinicopathological characteristics of aging-infertility, abnormal curvature to the spine, sarcopenia, cataracts, fat loss, dermal thinning, arrhythmias, etc. was used to test the consequences of p16INK4a removal. In these mice p16 INK4a aggregates in aging tissues including the skeletal and eye muscle, and adipose tissues. Baker et al. found that if the senescent cells are removed, it is possible to delay age-associated disorders. Not only does p16 play an important role in aging, but also in auto-immune diseases like rheumatoid arthritis that progressively lead to mobility impairment in advanced disease. 31: 5370: 40: 616:. SASPs have distinct effects depending on the cellular context, including inflammatory or anti-inflammatory and tumor or anti-tumor effects. While considered a pro-tumorogenic effect, they likely support already tumor-primed cells instead of shifting healthy cells into transformation. Likewise, they operate as anti-tumor protectors by facilitating the elimination of damaged cells by 285:

replicative senescence. Theoretically, it is possible upon the discovery of the exact mechanism of biological immortality to genetically engineer cells with the same capability. The length of the telomere strand has senescent effects; telomere shortening activates extensive alterations in alternative RNA splicing that produce senescent toxins such as

78:. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, 858:

is another example of a disease that may be related to cell senescence. The disease is thought to be caused by mutations in the DNA damage response, telomere shortening, or a combination of the two. Progeroid syndromes are all examples of aging diseases where cell senescence appears to be implicated.

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In the nervous system, senescence has been described in astrocytes and microglia, but is less understood in neurons. Because senescence arrests cell division, studies of senescence in the brain were focused mainly on glial cells and less studies were focused on nondividing neurons. Analyzing single

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The Hayflick limit deliberates that the average cell will divide around 50 times before reaching a stage known as senescence. As the cell divides, the telomeres on the end of a linear chromosome get shorter. The telomeres will eventually no longer be present on the chromosome. This end stage is the

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activities. The prolonged DDR activates both ATM and ATR DNA damage kinases. The phosphorylation cascade initiated by these two kinases causes the eventual arrest of the cell cycle. Depending on the severity of the DNA damage, the cells may no longer be able to undergo repair and either go through

314:. The irreversible senescence which is mediated by INK4a/Rb and p53 pathways and the reversible senescent phenotype which is mediated by p53. This suggests that p53 pathway could be effectively harnessed as a therapeutic intervention to trigger senescence and ultimately mitigate tumorigenesis. 309:

Interestingly, even after oncogenic activation of a tissue, several researchers have identified a senescent phenotype. Researchers have identified a senescent phenotype in benign lesions of the skin carrying oncogenic mutations in neurofibroma patients with a defect that specifically causes an

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The negative implications of cellular senescence present themselves in the transition from acute to chronic senescence. When the immune system cannot clear senescent cells at the rate at which senescent cells are being produced, possibly as a result of the decline in immune function with age,

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is also believed to limit the number of divisions of the cell, contributing to aging. After sufficient shortening, proteins responsible for maintaining telomere structure, such as TRF2, are displaced, resulting in the telomere being recognized as a site of a double-strand break. This induces

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paper by Xue et al., RNAi was used to regulate endogenous p53 in a liver carcinoma model. Xue et al. utilized a chimaeric liver cancer mouse model and transduced this model with the ras oncogene. They took embryonic progenitor cells, transduced those cells with oncogenic ras, along with the

362:(Cdk 6). p16 is responsible for the induction of premature, stress-induced senescence. This is not irreversible; silencing of p16 through promotor methylation or deletion of the p16 locus allows the cell to resume the cell cycle if senescence was initiated by p16 activation. 723:) results in a diminished capacity of the immune system to remove senescent cells, thereby leading to an increase in senescent cells. Chronic inflammation due to SASP from senescent cells can also reduce the capacity of the immune system to remove senescent cells. 412:

Senescent cells are highly heterogenous, which has caused most authorities in the field to believe that a universal marker of senescent cells will not be found, and that a multi-marker approach is required for the detection of senescent cells. For this reason, the

1001:(i.e., cells experience replicative senescence). How and why cells become post-mitotic in some species has been the subject of much research and speculation, but it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of 624:

drugs to kill and eliminate senescent cells to improve health in the elderly. The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).

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There are several reported signaling pathways that lead to cellular senescence including the p53 and p16 pathways. Both of these pathways are activated in response to cellular stressors and lead to cell cycle inhibition. p53 activates p21 which deactivates

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are DNA tandem repeats at the end of chromosomes that shorten during each cycle of cell division. Recently, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of

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Senescent cells affect tumor suppression, wound healing and possibly embryonic/placental development, and play a pathological role in age-related diseases. There are two primary tumor suppressor pathways known to mediate senescence:

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in structure and function, resembling NK cells. Immune system cells can be recruited by SASP to senescent cells, after which the SASP from the senescent cells can induce the immune system cells to become senescent.

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drugs take advantage of the senescent-cell anti-apoptotic pathways (SCAPs); knocking out expression of the proteins involved in these pathways can lead to the death of senescent cells, leaving healthy cells.

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which results in increased p53 activation and p16 upregulation. The transition to a state of senescence due to oncogene mutations are irreversible and have been termed oncogene-induced senescence (OIS).

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Radosavljevic M, Cuillerier B, Wilson MJ, Clément O, Wicker S, Gilfillan S, et al. (January 2002). "A cluster of ten novel MHC class I related genes on human chromosome 6q24.2-q25.3".

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Shafqat, Areez; Khan, Saifullah; Omer, Mohamed H.; Niaz, Mahnoor; Albalkhi, Ibrahem; AlKattan, Khaled; Yaqinuddin, Ahmed; Tchkonia, Tamara; Kirkland, James L.; Hashmi, Shahrukh K. (2023).

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if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunologic phenotype that enables them to be eliminated by the immune system.

428:. Senescent cells are usually larger than non-senescent cells. Transformation of a dividing cell into a non-dividing senescent cell is a slow process that can take up to six weeks. 4799:

Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (October 2012). "Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans".

3264:"Expression of p16 and p21 in the frontal association cortex of ALS/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease" 2544:

Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. (August 2005). "Oncogene-induced senescence as an initial barrier in lymphoma development".

964:. Removing the senescent cells by inducing apoptosis is the most straightforward option, and there are several agents that have been shown to accomplish this. Some of these 451:

paper by Baker et al. a novel transgene, INK-ATTAC, was used to inducibly eliminate p16 INK4A-positive senescent cells by action of a small molecule-induced activation of

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or cell senescence. Such senescent cells in mammalian culture and tissues retain DSBs and DDR markers. It has been proposed that retained DSBs are major drivers of the

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Malaquin N, Martinez A, Rodier F (September 2016). "Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype".

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nucleus RNA-Seq data from human brains suggested p19 as a marker for senescent neurons, which are strongly associated with neurons containing neurofibrillary tangle.

260:(DNA-SCARS). Senescent cells affect tumour suppression, wound healing and possibly embryonic/placental development and a pathological role in age-related diseases. 74:

in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the

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have been termed as major senescence signalling factors, allowing them to serve as markers. Other markers register morphology changes, reorganization of

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Transplantation of only a few (1 per 10,000) senescent cells into lean middle-aged mice was shown to be sufficient to induce frailty, early onset of

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could prevent progression of liver fibrosis, although this has not been implemented as a therapy, and would carry the risk of hepatic dysfunction.

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Due to the heterogeneous nature of senescent cells, different immune system cells eliminate different senescent cells. Specific components of the

620:. The SASP is associated with many age-related diseases, including type 2 diabetes and atherosclerosis. This has motivated researchers to develop 154:. Normally, cell senescence is reached through a combination of a variety of factors (i.e., both telomere shortening and oxidative stress). The 690: 4985:"Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model" 634: 494: 468: 202: 731:, and NK cells have all been reported to become senescent themselves. Senescent-like aging CD8+ cytotoxic T-lymphocytes become more 3749:

Lawrence Berkeley National Laboratory. United States. Department of Energy. Office of Scientific and Technical Information (2008).

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The removal of aggregated p16 INK 4A positive senescent cells can delay tissue dysfunction and ultimately extend life. In the 2011

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Kuehnemann, Chisaka; Hughes, Jun-Wei B.; Desprez, Pierre-Yves; Melov, Simon; Wiley, Christopher D.; Campisi, Judith (2022-12-20).

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Sagiv A, Krizhanovsky V (December 2013). "Immunosurveillance of senescent cells: the bright side of the senescence program".

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BRAF and Ras are two oncogenes implicated in cellular senescence. BRAF induces senescence through synthesis and secretion of

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Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

1765:"A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues" 5374: 205:, the up-regulation of immune ligands, a pro-survival response, promiscuous gene expression (pGE), and stain positive for 4287:

Antonangeli F, Zingoni A, Soriani A, Santoni A (June 2019). "Senescent cells: Living or dying is a matter of NK cells".

3774:"Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity" 2948: 2897: 1104:

Gao, Haoyu; Nepovimova, Eugenie; Heger, Zbynek; Valko, Marian; Wu, Qinghua; Kuca, Kamil; Adam, Vojtech (2023-08-01).

942: 221:. However, this results in a false positive for cells that naturally have these two proteins such as maturing tissue 197:

Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt an immunogenic

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Targeting senescent cells is a promising strategy to overcome age-related disease, simultaneous alleviate multiple

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play a major role in clearance of senescent cells. Natural killer cells directly kill senescent cells, and produce

580:β increase the level of SASP expression. Regulation of the SASP is managed through a transcription level autocrine 390: 155: 4699:

Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, et al. (November 2013).

1230:"Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal" 701: 534: 17: 4934:"Emergence of Microglia Bearing Senescence Markers During Paralysis Progression in a Rat Model of Inherited ALS" 2944:"NIH SenNet Consortium to map senescent cells throughout the human lifespan to understand physiological health" 750:

to eliminate senescent cells in mice. Chimeric antigen receptor natural killer cells have been proposed as an

873: 837: 51:: MEFs became senescent after passages. Cells grow larger, flatten shape and expressed senescence-associated 1595:"Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential" 5390: 509:

is another characteristic feature of senescent cells. There are many SASP effector mechanisms that utilize

2338:"Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7" 2289:"Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts" 5410: 5261:"Secrets from immortal worms: What can we learn about biological ageing from the planarian model system?" 5260: 4423:"Senescent B cells in aging and age-related diseases: Their role in the regulation of antibody responses" 3102:

Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. (November 2011).

2597:"Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland" 162:(DSBs), are repaired. Senescent cells display persistent DDR that appears to be resistant to endogenous 1059: 686: 180: 762:

It is important to recognize that cellular senescence is not inherently a negative phenomenon. During

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have been proposed as an alternative means to senolytic drugs for the elimination of senescent cells.

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regulator. This represses the transcriptional targets of E2F1, leading to cell cycle arrest after the

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Lyamina S, Baranovskii D, Kozhevnikova E, Ivanova T, Kalish S, Sadekov T, et al. (March 2023).

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also serve as SASP molecules. From the cellular perspective, cooperation of transcriptional factors

93:, and more recently, aging, development, and tissue repair. Senescent cells contribute to the aging 4983:

Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, et al. (May 2019).

3921:"Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a" 3647:

Baker JR, Vuppusetty C, Colley T, Hassibi S, Fenwick PS, Donnelly LE, et al. (February 2019).

917: 4752:"Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives" 3364:"Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology" 3050:

Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. (June 2008).

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Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. (February 2007).

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p53 has been shown to have promising therapeutic relevance in an oncological context. In the 2007

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Ben-Porath I, Weinberg RA (May 2005). "The signals and pathways activating cellular senescence".

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Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, et al. (August 2013).

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Tumor dormancy, quiescence, and senescence, Volume 2: Aging, cancer, and noncancer pathologies

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Vazquez-Villaseñor I, Garwood CJ, Heath PR, Simpson JE, Ince PG, Wharton SB (February 2020).

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once they have fulfilled their function. When these cells have accomplished these tasks, the

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also use NKG2D receptors to detect senescent cells, and promote killing similar to NK cells.

697: 522: 3700:"A complex secretory program orchestrated by the inflammasome controls paracrine senescence" 2654:"Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas" 1355: 159: 4601: 4534: 4085: 3984: 3411:

Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. (June 2008).

3115: 2741:"The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging" 2553: 2498: 2192: 1495: 732: 638: 490: 370: 339:(pRB) remains in its active, hypophosphorylated form and binds to the transcription factor 218: 5034:"Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes" 1933: 1544:"Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies" 1172: 993:. In other organisms, where cellular senescence is observed, cells eventually become post- 8: 5415: 4932:

Trias E, Beilby PR, Kovacs M, Ibarburu S, Varela V, Barreto-Núñez R, et al. (2019).

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Milanovic M, Fan DN, Belenki D, Däbritz JH, Zhao Z, Yu Y, et al. (January 2018).

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Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, et al. (October 2011).

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have been found to be highly expressed on senescent cells, leading researchers to use

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The physiological importance for cell senescence has been attributed to prevention of

5349: 5345: 5320: 5316: 5280: 5241: 5192: 5143: 5102: 5082: 5063: 5014: 4965: 4914: 4865: 4816: 4785: 4773: 4732: 4678: 4627: 4574: 4562: 4503: 4452: 4403: 4368: 4304: 4264: 4198: 4160: 4103: 4054: 4000: 3942: 3901: 3852: 3803: 3754: 3731: 3680: 3629: 3578: 3529: 3489: 3477: 3434: 3393: 3344: 3295: 3244: 3193: 3141: 3073: 3027: 2975: 2924: 2870: 2819: 2770: 2721: 2683: 2634: 2616: 2569: 2526: 2487:"ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence" 2485:

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was created to identify and characterize senescent cells in different body tissues.

248:, a pro-survival response, promiscuous gene expression (pGE) and stain positive for 46:: Primary mouse embryonic fibroblast cells (MEFs) before senescence. Spindle-shaped. 5341: 5312: 5272: 5231: 5223: 5182: 5174: 5133: 5094: 5053: 5045: 5004: 4996: 4955: 4945: 4904: 4896: 4855: 4847: 4808: 4763: 4750:

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activity. The nucleus of senescent cells is characterized by senescence-associated

98: 79: 67: 4900: 1716:"Cellular senescence in aging and age-related disease: from mechanisms to therapy" 5276: 3821:

Casella G, Munk R, Kim KM, Piao Y, De S, Abdelmohsen K, Gorospe M (August 2019).

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Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF (June 2014).

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They serve to direct tissue repair and regeneration. Cellular senescence limits

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which activate macrophages which remove senescent cells. Senescent cells can be

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process. Mutations in genes relating to genome maintenance has been linked with

5405: 5098: 5049: 4812: 4717: 4700: 4663: 4547: 4522: 4354: 3429: 3412: 3379: 3068: 3051: 2961: 2910: 2893:"Spatial mapping of cellular senescence: emerging challenges and opportunities" 2805: 2491:

Proceedings of the National Academy of Sciences of the United States of America

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Shay JW, Wright WE (October 2000). "Hayflick, his limit, and cellular ageing".

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Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD (October 2017).

5163:"Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells" 4300: 2856: 2511: 2453: 1560: 797:

clears them away. This phenomenon is termed acute senescence. Senescence of

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resistance, altered metabolism, enlarged cytoplasm or abnormal shape of the

400:) suppresses cellular senescence, hence cellular senescence is inhibited by 5353: 5324: 5284: 5245: 5196: 5147: 5067: 5018: 4969: 4918: 4869: 4820: 4777: 4736: 4682: 4631: 4566: 4557: 4507: 4456: 4407: 4399: 4372: 4308: 4268: 4233:"Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases" 4202: 4164: 4107: 4058: 4040: 4004: 3905: 3856: 3807: 3735: 3684: 3649:"MicroRNA-570 is a novel regulator of cellular senescence and inflammaging" 3633: 3582: 3533: 3481: 3438: 3397: 3348: 3299: 3248: 3197: 3145: 3077: 3031: 2979: 2928: 2874: 2823: 2774: 2725: 2687: 2638: 2573: 2530: 2471: 2417: 2371: 2322: 2273: 2214: 2157: 2104: 2052: 2003: 1951: 1899: 1866:"Targeting senescent cells to attenuate cardiovascular disease progression" 1847: 1798: 1749: 1689: 1630: 1579: 1525: 1468: 1408: 1317: 1271: 1214: 1188: 1149: 1006: 676: 660: 613: 538: 482: 302: 3946: 3665: 2408: 2391: 2034: 1173:"Reversal of human cellular senescence: roles of the p53 and p16 pathways" 5267:. Science communication in the field of fundamental biomedical research. 4249: 3838: 3789: 3614: 3564: 957: 805:

accumulation of these cells leads to a disruption in tissue homeostasis.

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infiltration and subsequent clearance of senescent cells. A study on the

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are likely to cause senescence without affecting healthy neighbor cells.

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of older individuals. The accumulation of senescent cells in tissues of

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phenotype that enables them to be eliminated by the immune system. This

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response (DDR) arrests cell cycle progression until DNA damage, such as

5178: 4982: 3013: 2392:"Cellular senescence in tissue repair: every cloud has a silver lining" 1780: 1762: 1245: 1132: 1069: 1064: 1054: 982: 825: 778:

in mice highlighted the importance of cellular senescence for eventual

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Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR (February 2008).

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activity. Two proteins, senescence-associated beta-galactosidase and

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Biomarkers of cellular senescence have been shown to accumulate in

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Cellular senescence is not observed in some organisms, including

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1433:

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525:

because of an accumulation of unfolded proteins, resulting in

258:

DNA segments with chromatin alterations reinforcing senescence

134:

Mechanistically, replicative senescence can be triggered by a

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concept that links the deterioration of telomeres to aging.

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Phenomenon characterized by the cessation of cell division

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of the embryonic kidney and the inner ear, respectively.

704:

on senescent cells. The senescent cells are killed using

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is very complex. The products are mainly associated with

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with age is thought to contribute to the development of

4834:

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during wound closure by inducing cell cycle arrest in

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p16 also activates pRB, but through inactivation of

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Inhibition of the mechanistic target of rapamycin (

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1421: 1420: 1401:10.1038/35036093 1384: 1378: 1377: 1361: 1351: 1345: 1344: 1339:Hayat M (2014). 1336: 1330: 1329: 1311: 1287: 1276: 1275: 1265: 1225: 1219: 1218: 1208: 1177:The EMBO Journal 1168: 1162: 1161: 1135: 1125: 1101: 999:cellular mitosis 721:immunosenescence 387:oxidative stress 256:foci (SAHF) and 201:consisting of a 99:frailty syndrome 80:oxidative stress 68:Leonard Hayflick 21: 5431: 5430: 5426: 5425: 5424: 5422: 5421: 5420: 5381: 5380: 5365: 5360: 5298: 5296:Further reading 5293: 5292: 5257: 5253: 5208: 5204: 5159: 5155: 5118: 5114: 5079: 5075: 5038:Cell Metabolism 5030: 5026: 4981: 4977: 4930: 4926: 4881: 4877: 4832: 4828: 4797: 4793: 4748: 4744: 4697: 4690: 4643: 4639: 4586: 4582: 4533:(7814): 37–38. 4519: 4515: 4468: 4464: 4419: 4415: 4384: 4380: 4335: 4324: 4285: 4276: 4229: 4218: 4179: 4172: 4127: 4123: 4099:10.1038/479481a 4070: 4066: 4021: 4012: 3972: 3966: 3962: 3917: 3913: 3868: 3864: 3819: 3815: 3770: 3766: 3747: 3743: 3717:10.1038/ncb2784 3696: 3692: 3645: 3641: 3594: 3590: 3545: 3541: 3504: 3497: 3458: 3454: 3409: 3405: 3360: 3356: 3311: 3307: 3260: 3256: 3209: 3205: 3160: 3153: 3100: 3093: 3048: 3039: 2994: 2987: 2940: 2936: 2889: 2882: 2835: 2831: 2786: 2782: 2737: 2733: 2702: 2695: 2650: 2646: 2593: 2589: 2542: 2538: 2483: 2479: 2434: 2425: 2388: 2379: 2334: 2330: 2285: 2281: 2234: 2230: 2185:Current Biology 2169: 2165: 2116: 2112: 2067: 2060: 2015: 2011: 1966: 1959: 1914: 1907: 1862: 1855: 1810: 1806: 1761: 1757: 1732:10.1038/nm.4000 1720:Nature Medicine 1712: 1697: 1642: 1638: 1591: 1587: 1540: 1533: 1480: 1476: 1431: 1424: 1385: 1381: 1374: 1352: 1348: 1337: 1333: 1288: 1279: 1226: 1222: 1169: 1165: 1102: 1098: 1093: 1026: 975: 954: 952:Senolytic drugs 928:Seckel syndrome 923:Fanconi anaemia 879:Werner syndrome 865: 846:type 2 diabetes 811: 760: 669:Senolytic drugs 651:(NK cells) and 631: 471: 465: 410: 367:gene expression 343:, an important 328: 295: 266: 254:heterochromatin 132: 127: 53:β-galactosidase 47: 28: 23: 22: 18:Senescent cells 15: 12: 11: 5: 5429: 5419: 5418: 5413: 5408: 5403: 5398: 5393: 5379: 5378: 5364: 5363:External links 5361: 5359: 5358: 5340:(3): 614–636. 5329: 5311:(3): 585–621. 5299: 5297: 5294: 5291: 5290: 5251: 5202: 5173:(7): 719–735. 5153: 5132:(5): 667–674. 5112: 5093:(7): 382–382. 5073: 5024: 4995:(5): 719–728. 4975: 4924: 4875: 4846:(5): 263–275. 4826: 4807:(5): 331–341. 4791: 4742: 4688: 4637: 4580: 4513: 4462: 4413: 4394:(1): 114–123. 4378: 4322: 4274: 4216: 4189:(6): 617–628. 4183:Biogerontology 4170: 4121: 4064: 4010: 3960: 3931:(5): 593–602. 3911: 3862: 3813: 3764: 3741: 3710:(8): 978–990. 3690: 3639: 3588: 3539: 3495: 3452: 3403: 3354: 3305: 3274:(2): 171–185. 3254: 3203: 3151: 3091: 3037: 3008:(5): 518–536. 2985: 2934: 2905:(7): 776–790. 2880: 2851:(4): 739–757. 2829: 2800:(2): 397–408. 2780: 2731: 2712:(5): 961–976. 2693: 2644: 2587: 2536: 2477: 2423: 2377: 2348:(3): 363–374. 2328: 2279: 2228: 2173:Smogorzewska A 2163: 2110: 2058: 2029:(4): 547–556. 2009: 1957: 1905: 1853: 1824:(5): 729–738. 1818:Molecular Cell 1804: 1775:(2): 422–427. 1755: 1695: 1636: 1585: 1531: 1474: 1422: 1379: 1372: 1346: 1331: 1302:(2): 223–233. 1277: 1220: 1163: 1095: 1094: 1092: 1089: 1088: 1087: 1085:Carcinogenesis 1082: 1077: 1072: 1067: 1062: 1057: 1052: 1047: 1042: 1037: 1032: 1025: 1022: 974: 971: 953: 950: 949: 948: 945: 940: 935: 930: 925: 920: 915: 910: 901: 896: 891: 886: 884:Bloom syndrome 881: 876: 871: 864: 861: 848:, and various 810: 807: 791:myofibroblasts 759: 756: 689:to detect the 630: 627: 503:growth factors 467:Main article: 464: 461: 426:adipose tissue 409: 406: 327: 324: 294: 291: 265: 262: 131: 128: 126: 123: 117:contribute to 91:carcinogenesis 76:Hayflick limit 26: 9: 6: 4: 3: 2: 5428: 5417: 5414: 5412: 5409: 5407: 5404: 5402: 5399: 5397: 5394: 5392: 5389: 5388: 5386: 5376: 5371: 5367: 5366: 5355: 5351: 5347: 5343: 5339: 5335: 5330: 5326: 5322: 5318: 5314: 5310: 5306: 5301: 5300: 5286: 5282: 5278: 5274: 5270: 5266: 5262: 5255: 5247: 5243: 5238: 5233: 5229: 5225: 5221: 5217: 5213: 5206: 5198: 5194: 5189: 5184: 5180: 5176: 5172: 5168: 5164: 5157: 5149: 5145: 5140: 5135: 5131: 5127: 5123: 5116: 5108: 5104: 5100: 5096: 5092: 5088: 5084: 5077: 5069: 5065: 5060: 5055: 5051: 5047: 5043: 5039: 5035: 5028: 5020: 5016: 5011: 5006: 5002: 4998: 4994: 4990: 4986: 4979: 4971: 4967: 4962: 4957: 4952: 4947: 4943: 4939: 4935: 4928: 4920: 4916: 4911: 4906: 4902: 4898: 4895:(1): 97–109. 4894: 4890: 4886: 4879: 4871: 4867: 4862: 4857: 4853: 4849: 4845: 4841: 4837: 4830: 4822: 4818: 4814: 4810: 4806: 4802: 4795: 4787: 4783: 4779: 4775: 4770: 4765: 4761: 4757: 4753: 4746: 4738: 4734: 4729: 4724: 4719: 4714: 4710: 4706: 4702: 4695: 4693: 4684: 4680: 4675: 4670: 4665: 4660: 4656: 4652: 4648: 4641: 4633: 4629: 4624: 4619: 4615: 4611: 4607: 4603: 4599: 4595: 4591: 4584: 4576: 4572: 4568: 4564: 4559: 4558:10044/1/80980 4554: 4549: 4544: 4540: 4536: 4532: 4528: 4524: 4517: 4509: 4505: 4500: 4495: 4490: 4485: 4481: 4477: 4473: 4466: 4458: 4454: 4449: 4444: 4440: 4436: 4432: 4428: 4424: 4417: 4409: 4405: 4401: 4397: 4393: 4389: 4382: 4374: 4370: 4365: 4360: 4356: 4352: 4348: 4344: 4340: 4333: 4331: 4329: 4327: 4318: 4314: 4310: 4306: 4302: 4298: 4294: 4290: 4283: 4281: 4279: 4270: 4266: 4261: 4256: 4251: 4246: 4242: 4238: 4234: 4227: 4225: 4223: 4221: 4212: 4208: 4204: 4200: 4196: 4192: 4188: 4184: 4177: 4175: 4166: 4162: 4157: 4152: 4148: 4144: 4140: 4136: 4135:Endocrinology 4132: 4125: 4117: 4113: 4109: 4105: 4100: 4095: 4091: 4087: 4083: 4079: 4075: 4068: 4060: 4056: 4051: 4046: 4042: 4038: 4035:(2): 99–114. 4034: 4030: 4026: 4019: 4017: 4015: 4006: 4002: 3998: 3994: 3990: 3986: 3982: 3978: 3971: 3964: 3956: 3952: 3948: 3944: 3939: 3934: 3930: 3926: 3922: 3915: 3907: 3903: 3898: 3893: 3889: 3885: 3882:(1): 99–118. 3881: 3877: 3873: 3866: 3858: 3854: 3849: 3844: 3840: 3836: 3832: 3828: 3824: 3817: 3809: 3805: 3800: 3795: 3791: 3787: 3783: 3779: 3775: 3768: 3760: 3756: 3752: 3745: 3737: 3733: 3728: 3723: 3718: 3713: 3709: 3705: 3701: 3694: 3686: 3682: 3677: 3672: 3667: 3662: 3658: 3654: 3653:FASEB Journal 3650: 3643: 3635: 3631: 3626: 3621: 3616: 3611: 3607: 3603: 3599: 3592: 3584: 3580: 3575: 3570: 3566: 3562: 3558: 3554: 3550: 3543: 3535: 3531: 3526: 3521: 3517: 3513: 3509: 3502: 3500: 3491: 3487: 3483: 3479: 3475: 3471: 3467: 3463: 3456: 3448: 3444: 3440: 3436: 3431: 3426: 3422: 3418: 3414: 3407: 3399: 3395: 3390: 3385: 3381: 3377: 3373: 3369: 3365: 3358: 3350: 3346: 3341: 3336: 3332: 3328: 3324: 3320: 3316: 3309: 3301: 3297: 3292: 3287: 3282: 3277: 3273: 3269: 3265: 3258: 3250: 3246: 3241: 3236: 3231: 3226: 3222: 3218: 3214: 3207: 3199: 3195: 3190: 3185: 3181: 3177: 3173: 3169: 3165: 3158: 3156: 3147: 3143: 3138: 3133: 3129: 3125: 3121: 3117: 3113: 3109: 3105: 3098: 3096: 3087: 3083: 3079: 3075: 3070: 3065: 3061: 3057: 3053: 3046: 3044: 3042: 3033: 3029: 3024: 3019: 3015: 3011: 3007: 3003: 2999: 2992: 2990: 2981: 2977: 2972: 2967: 2963: 2959: 2955: 2951: 2950: 2945: 2938: 2930: 2926: 2921: 2916: 2912: 2908: 2904: 2900: 2899: 2894: 2887: 2885: 2876: 2872: 2867: 2862: 2858: 2854: 2850: 2846: 2845: 2844:FEBS Open Bio 2840: 2833: 2825: 2821: 2816: 2811: 2807: 2803: 2799: 2795: 2791: 2784: 2776: 2772: 2767: 2762: 2758: 2754: 2750: 2746: 2742: 2735: 2727: 2723: 2719: 2715: 2711: 2707: 2700: 2698: 2689: 2685: 2680: 2675: 2671: 2667: 2663: 2659: 2655: 2648: 2640: 2636: 2631: 2626: 2622: 2618: 2614: 2610: 2606: 2602: 2598: 2591: 2583: 2579: 2575: 2571: 2567: 2563: 2559: 2555: 2551: 2547: 2540: 2532: 2528: 2523: 2518: 2513: 2508: 2504: 2500: 2496: 2492: 2488: 2481: 2473: 2469: 2464: 2459: 2455: 2451: 2447: 2443: 2439: 2432: 2430: 2428: 2419: 2415: 2410: 2405: 2401: 2397: 2393: 2386: 2384: 2382: 2373: 2369: 2364: 2359: 2355: 2351: 2347: 2343: 2339: 2332: 2324: 2320: 2315: 2310: 2306: 2302: 2298: 2294: 2290: 2283: 2275: 2271: 2266: 2261: 2256: 2251: 2247: 2243: 2239: 2232: 2224: 2220: 2216: 2212: 2207: 2202: 2198: 2194: 2190: 2186: 2182: 2178: 2174: 2167: 2159: 2155: 2150: 2145: 2141: 2137: 2133: 2129: 2125: 2121: 2114: 2106: 2102: 2097: 2092: 2088: 2084: 2080: 2076: 2072: 2065: 2063: 2054: 2050: 2045: 2040: 2036: 2032: 2028: 2024: 2020: 2013: 2005: 2001: 1996: 1991: 1987: 1983: 1979: 1975: 1971: 1964: 1962: 1953: 1949: 1944: 1939: 1935: 1931: 1927: 1923: 1919: 1912: 1910: 1901: 1897: 1892: 1887: 1883: 1879: 1875: 1871: 1867: 1860: 1858: 1849: 1845: 1840: 1835: 1831: 1827: 1823: 1819: 1815: 1808: 1800: 1796: 1791: 1786: 1782: 1778: 1774: 1770: 1766: 1759: 1751: 1747: 1742: 1737: 1733: 1729: 1725: 1721: 1717: 1710: 1708: 1706: 1704: 1702: 1700: 1691: 1687: 1682: 1677: 1673: 1669: 1664: 1659: 1655: 1651: 1647: 1640: 1632: 1628: 1623: 1618: 1613: 1608: 1604: 1600: 1596: 1589: 1581: 1577: 1572: 1567: 1562: 1557: 1553: 1549: 1545: 1538: 1536: 1527: 1523: 1518: 1513: 1509: 1505: 1501: 1497: 1493: 1489: 1485: 1478: 1470: 1466: 1461: 1456: 1452: 1448: 1444: 1440: 1436: 1429: 1427: 1418: 1414: 1410: 1406: 1402: 1398: 1394: 1390: 1383: 1375: 1369: 1365: 1360: 1359: 1350: 1342: 1335: 1327: 1323: 1319: 1315: 1310: 1305: 1301: 1297: 1293: 1286: 1284: 1282: 1273: 1269: 1264: 1259: 1255: 1251: 1247: 1243: 1240:(1): e13750. 1239: 1235: 1231: 1224: 1216: 1212: 1207: 1202: 1198: 1194: 1190: 1186: 1182: 1178: 1174: 1167: 1159: 1155: 1151: 1147: 1143: 1139: 1134: 1129: 1124: 1119: 1115: 1111: 1107: 1100: 1096: 1086: 1083: 1081: 1078: 1076: 1073: 1071: 1068: 1066: 1063: 1061: 1058: 1056: 1053: 1051: 1048: 1046: 1043: 1041: 1038: 1036: 1033: 1031: 1028: 1027: 1021: 1019: 1015: 1012: 1008: 1007:Somatic cells 1004: 1000: 996: 992: 988: 984: 980: 970: 967: 963: 959: 958:comorbidities 946: 944: 941: 939: 936: 934: 931: 929: 926: 924: 921: 919: 916: 914: 911: 909: 905: 902: 900: 897: 895: 892: 890: 887: 885: 882: 880: 877: 875: 872: 870: 867: 866: 860: 857: 853: 851: 847: 843: 839: 835: 831: 827: 823: 818: 816: 806: 802: 800: 796: 795:immune system 792: 788: 783: 781: 780:morphogenesis 777: 773: 769: 765: 755: 753: 749: 745: 741: 737: 734: 730: 726: 722: 717: 715: 711: 708:pore-forming 707: 703: 700:which become 699: 696: 692: 688: 685: 680: 678: 674: 671:which induce 670: 666: 662: 658: 654: 650: 646: 644: 640: 636: 626: 623: 619: 615: 611: 607: 603: 599: 595: 591: 587: 583: 582:feedback loop 579: 575: 571: 567: 563: 559: 555: 551: 547: 542: 540: 536: 532: 528: 524: 520: 516: 512: 508: 504: 500: 496: 492: 488: 487:proliferation 484: 480: 477:of senescent 476: 470: 460: 456: 454: 450: 445: 443: 439: 435: 429: 427: 423: 418: 416: 405: 403: 399: 394: 392: 388: 384: 380: 376: 372: 368: 363: 361: 357: 352: 350: 346: 342: 338: 334: 323: 320: 315: 313: 307: 304: 300: 290: 288: 283: 279: 275: 270: 261: 259: 255: 251: 247: 243: 239: 235: 230: 228: 224: 220: 216: 212: 208: 204: 200: 195: 193: 189: 186:Depletion of 184: 182: 178: 174: 170: 165: 161: 157: 153: 149: 145: 141: 137: 122: 120: 116: 112: 108: 104: 100: 96: 92: 87: 85: 81: 77: 73: 69: 65: 64:cell division 61: 54: 50: 45: 41: 32: 19: 5401:Cell biology 5337: 5333: 5308: 5304: 5268: 5264: 5254: 5219: 5215: 5205: 5170: 5166: 5156: 5129: 5125: 5115: 5090: 5086: 5076: 5041: 5037: 5027: 4992: 4988: 4978: 4941: 4937: 4927: 4892: 4888: 4878: 4843: 4839: 4829: 4804: 4800: 4794: 4759: 4755: 4745: 4708: 4704: 4654: 4650: 4640: 4597: 4593: 4583: 4530: 4526: 4516: 4479: 4475: 4465: 4430: 4426: 4416: 4391: 4387: 4381: 4346: 4342: 4292: 4288: 4240: 4236: 4186: 4182: 4138: 4134: 4124: 4081: 4077: 4067: 4032: 4028: 3980: 3976: 3963: 3928: 3924: 3914: 3879: 3875: 3865: 3830: 3826: 3816: 3781: 3777: 3767: 3750: 3744: 3707: 3703: 3693: 3656: 3652: 3642: 3605: 3601: 3591: 3556: 3552: 3542: 3515: 3511: 3465: 3461: 3455: 3420: 3416: 3406: 3371: 3368:Nature Aging 3367: 3357: 3322: 3318: 3308: 3271: 3267: 3257: 3220: 3216: 3206: 3171: 3167: 3111: 3107: 3059: 3055: 3005: 3001: 2953: 2949:Nature Aging 2947: 2937: 2902: 2898:Nature Aging 2896: 2848: 2842: 2832: 2797: 2793: 2783: 2748: 2744: 2734: 2709: 2705: 2661: 2657: 2647: 2604: 2600: 2590: 2549: 2545: 2539: 2494: 2490: 2480: 2445: 2442:EMBO Reports 2441: 2399: 2395: 2345: 2341: 2331: 2296: 2292: 2282: 2245: 2242:eBioMedicine 2241: 2231: 2188: 2184: 2166: 2134:(1): 30–39. 2131: 2127: 2113: 2078: 2074: 2026: 2022: 2012: 1977: 1973: 1925: 1921: 1873: 1869: 1821: 1817: 1807: 1772: 1768: 1758: 1723: 1719: 1653: 1649: 1639: 1602: 1598: 1588: 1554:(8): e2134. 1551: 1547: 1491: 1487: 1477: 1442: 1438: 1395:(1): 72–76. 1392: 1388: 1382: 1357: 1349: 1340: 1334: 1299: 1295: 1237: 1233: 1223: 1180: 1176: 1166: 1113: 1109: 1099: 976: 955: 854: 832:, including 819: 812: 803: 784: 761: 738: 718: 681: 661:phagocytized 647: 632: 543: 539:inflammaging 483:inflammation 472: 457: 448: 446: 430: 419: 411: 395: 373:, including 364: 358:(Cdk 4) and 353: 329: 318: 316: 311: 308: 303:MAPK cascade 296: 267: 231: 196: 185: 133: 109:. Senescent 97:, including 88: 59: 58: 48: 43: 5271:: 108–121. 4243:(3): E671. 3608:(7): 6372. 2794:GeroScience 2120:Karlseder J 1928:: 685–705. 1133:10481/84477 826:vertebrates 772:mesonephros 702:upregulated 665:neutrophils 653:macrophages 588:. Proteins 535:upregulated 527:proteotoxic 381:. Aberrant 278:chromosomal 234:immunogenic 223:macrophages 152:cell fusion 150:, and cell- 72:fibroblasts 5416:Senescence 5385:Categories 4762:: 111572. 4349:: 101275. 2177:de Lange T 1876:: 101072. 1769:Aging Cell 1234:Aging Cell 1116:: 106841. 1091:References 1070:Cell cycle 1065:DNA repair 1060:DNA damage 1055:Senescence 844:including 768:macrophage 752:allogeneic 677:phagocytic 618:phagocytes 345:cell cycle 282:cell cycle 229:with p16. 215:biomarkers 164:DNA repair 156:DNA damage 136:DNA damage 111:astrocytes 103:sarcopenia 5107:1759-5037 4786:237524296 4575:220260026 4433:: 55–58. 3759:893411490 3490:207584394 3468:: 39–49. 2621:842574443 2248:: 14–20. 2171:Takai H, 1980:(2): 27. 1672:1663-4365 1254:1474-9718 1197:1460-2075 1158:259295481 1142:1043-6618 1075:Telomeres 1040:Apoptosis 1035:Senolytic 1018:cancerous 1014:mutations 979:perennial 966:senolytic 712:protein. 710:cytolytic 673:apoptosis 657:cytokines 622:senolytic 610:apoptosis 606:chromatin 562:caspase-1 531:Autophagy 515:paracrine 511:autocrine 507:proteases 499:cytokines 475:secretome 453:caspase 8 402:rapamycin 383:oncogenes 269:Telomeres 242:secretome 238:phenotype 199:phenotype 169:apoptosis 148:oncogenes 140:telomeres 115:microglia 95:phenotype 84:autophagy 5354:14315085 5325:13905658 5285:28818620 5246:28869295 5197:27482812 5148:25027075 5068:31155496 5019:30936558 4970:30873018 4919:22723221 4870:32161396 4821:22560929 4778:34536446 4737:24238962 4683:32518575 4632:32555459 4567:32601490 4508:27867379 4457:28687479 4408:11827464 4388:Genomics 4373:31088710 4317:73469394 4309:30811627 4269:32164335 4203:24114507 4165:34363464 4116:36154048 4108:22113687 4059:24449267 4005:29258294 3955:17518294 3906:20078217 3857:31251810 3808:21979375 3736:23770676 3685:30156909 3634:37047346 3625:10094085 3583:29620049 3534:31153901 3482:27235851 3439:18555777 3398:35531351 3349:25281806 3300:31077599 3249:24876129 3198:22025288 3146:22048312 3086:15295092 3078:18555778 3032:32686219 2980:36936385 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