p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
Open accessAbstract
Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.
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p16Ink4a-induced senescent beta cells show increased insulin secretion rather than reduced insulin secretion.
“a surprising finding was that, rather than being reduced, insulin secretion was actually increased in p16Ink4a-induced senescent cells [38].”
From Cellular senescence: at the nexus between ageing and diabetes (2019) · cites this paper as [38]
In humans, accumulation of senescent markers has been demonstrated in skin, T lymphocytes, atherosclerotic lesions, insulin-producing β cells, kidney, endothelium, visceral fat, joint cartilage, cardiac muscle, liver, and many other tissues.
“In humans, the accumulation of senescent markers has been demonstrated in the skin, T lymphocytes, atherosclerotic lesions, insulin-producing β cells, kidney, endothelium, visceral fat, joint cartilage, cardiac muscle, liver, and many others tissues98,101–107.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [101]
p16-induced senescence of mouse and human pancreatic beta cells promotes insulin secretion.
“p16Ink4a (encoded by the INK4a/ARF locus, also known as CDKN2a, hereafter referred to as p16)-induced senescence of mouse and human pancreatic beta cells also promotes insulin secretion [10].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [10]
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Cites
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · see citing works
Differential analysis of gene regulation at transcript resolution with RNA-seq
Trapnell, C., Hendrickson, D. G., Sauvageau, M., Goff, L., Rinn, J. L., & Pachter, L. (2013) · Nature Biotechnology · doi:10.1038/nbt.2450 · Cited by 3,492 · see citing works
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,891 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623 · see citing works
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · see citing works
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · see citing works
Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation
Dor, Y., Brown, J., Martinez, O. I., & Melton, D. A. (2004) · Nature · doi:10.1038/nature02520 · Cited by 2,219 · see citing works
Self-citationPPARγ signaling and metabolism: the good, the bad and the future
Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., & Evans, R. M. (2013) · Nature Medicine · doi:10.1038/nm.3159 · Cited by 2,016 · see citing works
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819 · see citing works
Debacq-Chainiaux, F., Erusalimsky, J. D., Campisi, J., & Toussaint, O. (2009) · Nature Protocols · doi:10.1038/nprot.2009.191 · Cited by 1,668 · see citing works
Palbociclib in hormone-receptor-positive advanced breast cancer
Turner, N. C., Ro, J., André, F., Loi, S., Verma, S., Iwata, H., Harbeck, N., Loibl, S., Huang Bartlett, C., Zhang, K., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1505270 · Cited by 1,590 · see citing works
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486 · see citing works
Programmed cell senescence during mammalian embryonic development
Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.019 · Cited by 1,428 · see citing works
Senescence is a developmental mechanism that contributes to embryonic growth and patterning
Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.041 · Cited by 1,186 · see citing works
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106 · see citing works
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
Fingar, D. C., Salama, S., Tsou, C., Harlow, E., & Blenis, J. (2002) · Genes & Development · doi:10.1101/gad.995802 · Cited by 1,093 · see citing works
The Regulation of INK4/ARF in Cancer and Aging
Kim, W. Y., & Sharpless, N. E. (2006) · Cell · doi:10.1016/j.cell.2006.10.003 · Cited by 1,009 · see citing works
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003 · see citing works
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972 · see citing works
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
Sharpless, N. E., Bardeesy, N., Lee, K.-H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., & DePinho, R. A. (2001) · Nature · doi:10.1038/35092592 · Cited by 848 · see citing works
Morita, M., Gravel, S.-P., Chénard, V., Sikström, K., Zheng, L., Alain, T., Gandin, V., Avizonis, D., Arguello, M., Zakaria, C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.001 · Cited by 842 · see citing works
Non-Cell-Autonomous Tumor Suppression by p53
Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., Bolden, J. E., Zhao, Z., Thapar, V., Joyce, J. A., Krizhanovsky, V., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.020 · Cited by 766 · see citing works
Rane, S. G., Dubus, P., Mettus, R. V., Galbreath, E. J., Boden, G., Reddy, E. P., & Barbacid, M. (1999) · Nature Genetics · doi:10.1038/8751 · Cited by 700 · see citing works
Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasisPreprint
Ruvinsky, I., Sharon, N., Lerer, T., Cohen, H., Stolovich-Rain, M., Nir, T., Dor, Y., Zisman, P., & Meyuhas, O. (2005) · Genes & Development · doi:10.1101/gad.351605 · Cited by 640 · see citing works
Self-citationA key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence
Kaplon, J., Zheng, L., Meissl, K., Chaneton, B., Selivanov, V. A., Mackay, G., van der Burg, S. H., Verdegaal, E. M. E., Cascante, M., Shlomi, T., et al. (2013) · Nature · doi:10.1038/nature12154 · Cited by 633 · see citing works
Recovery from diabetes in mice by β cell regeneration
Nir, T., Melton, D. A., & Dor, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32959 · Cited by 595 · see citing works
Self-citationSynthetic lethal metabolic targeting of cellular senescence in cancer therapy
Dörr, J. R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Däbritz, J. H. M., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., et al. (2013) · Nature · doi:10.1038/nature12437 · Cited by 541 · see citing works
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533 · see citing works
Mechanisms of the Age-Associated Deterioration in Glucose Tolerance
Basu, R., Breda, E., Oberg, A. L., Powell, C. C., Dalla Man, C., Basu, A., Vittone, J. L., Klee, G. G., Arora, P., Jensen, M. D., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.7.1738 · Cited by 440 · see citing works
Pro-senescence therapy for cancer treatment
Nardella, C., Clohessy, J. G., Alimonti, A., & Pandolfi, P. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3057 · Cited by 437 · see citing works
Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model
Burd, C. E., Sorrentino, J. A., Clark, K. S., Darr, D. B., Krishnamurthy, J., Deal, A. M., Bardeesy, N., Castrillon, D. H., Beach, D. H., & Sharpless, N. E. (2013) · Cell · doi:10.1016/j.cell.2012.12.010 · Cited by 419 · see citing works
Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence
Chicas, A., Wang, X., Zhang, C., McCurrach, M., Zhao, Z., Mert, O., Dickins, R. A., Narita, M., Zhang, M., & Lowe, S. W. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.023 · Cited by 388 · see citing works
Chen, H., Gu, X., Su, I.-H., Bottino, R., Contreras, J. L., Tarakhovsky, A., & Kim, S. K. (2009) · Genes & Development · doi:10.1101/gad.1742509 · Cited by 366 · see citing works
Global reorganization of the nuclear landscape in senescent cells
Chandra, T., Ewels, P. A., Schoenfelder, S., Furlan-Magaril, M., Wingett, S. W., Kirschner, K., Thuret, J.-Y., Andrews, S., Fraser, P., & Reik, W. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.055 · Cited by 348 · see citing works
Conditional Gene Targeting in Mouse Pancreatic β-Cells
Wicksteed, B. L., Briššová, M., Yan, W., Opland, D. M., Plank, J. L., Reinert, R. B., Dickson, L. M., Tamarina, N. A., Philipson, L. H., Shostak, A., et al. (2010) · Diabetes · doi:10.2337/db10-0624 · Cited by 321 · see citing works
Self-citationCyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression
Lee, Y., Dominy, J. E., Choi, Y. J., Jurczak, M., Tolliday, N., Camporez, J. P., Chim, H., Lim, J.-H., Ruan, H.-B., Yang, X., et al. (2014) · Nature · doi:10.1038/nature13267 · Cited by 234 · see citing works
Experimental control of pancreatic development and maintenance
Holland, A. M., Hale, M. A., Kagami, H., Hammer, R. E., & MacDonald, R. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192255099 · Cited by 230 · see citing works
Independent Influence of Age on Basal Insulin Secretion in Nondiabetic Humans
Iozzo, P., Beck‐Nielsen, H., Laakso, M., Smith, U., Yki‐Järvinen, H., & Ferrannini, E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.3.5542 · Cited by 213 · see citing works
Ohn, J. H., Kwak, S. H., Cho, Y. M., Lim, S. K., Jang, H. C., Park, K. S., & Cho, N. H. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00336-8 · Cited by 209 · see citing works
Avrahami, D., Li, C., Zhang, J., Schug, J., Avrahami, R., Rao, S., Stadler, M. B., Burger, L., Schübeler, D., Glaser, B., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.025 · Cited by 207 · see citing works
Development of a conditionally immortalized human pancreatic β cell line
Scharfmann, R., Pechberty, S., Hazhouz, Y., von Bülow, M., Bricout-Neveu, E., Grenier-Godard, M., Guez, F., Rachdi, L., Lohmann, M., Czernichow, P., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72674 · Cited by 180 · see citing works
van Arensbergen, J., García-Hurtado, J., Morán, I., Maestro, M., Xu, X.-B., de Casteele, M. V., Skoudy, A., Palassini, M., Heimberg, H., & Ferrer, J. (2010) · Genome Research · doi:10.1101/gr.101709.109 · Cited by 174 · see citing works
Cdk4 promotes adipogenesis through PPARγ activation
Abella, A., Dubus, P. R., Malumbres, M., Rane, S. G., Kiyokawa, H., Sicard, A., Vignon, F., Langin, D., Barbacid, M., & Lluis Fajas, A. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.003 · Cited by 170 · see citing works
Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues.
Nielsen, G. P., Stemmer-Rachamimov, A. O., Shaw, J., Roy, J. E., Koh, J., & Louis, D. N. (1999) · PubMed · Cited by 169 · see citing works
Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets
Dai, C., Brissova, M., Hang, Y., Thompson, C., Poffenberger, G., Shostak, A., Chen, Z., Stein, R., & Powers, A. (2011) · Diabetologia · doi:10.1007/s00125-011-2369-0 · Cited by 166 · see citing works
Self-citationMitochondria: Are they causal players in cellular senescence?
Correia-Melo, C., & Passos, J. F. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.017 · Cited by 160 · see citing works
The role of aging upon β cell turnover
Kushner, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64095 · Cited by 156 · see citing works
Weaning Triggers a Maturation Step of Pancreatic β Cells
Stolovich-Rain, M., Enk, J., Vikeså, J., Nielsen, F. C., Saada, A., Gläser, B., & Dor, Y. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.002 · Cited by 151 · see citing works
Self-citationMitochondrial signals drive insulin secretion in the pancreatic β-cell
Wiederkehr, A., & Wollheim, C. B. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.07.016 · Cited by 133 · see citing works
Effects of Aging on Insulin Secretion
Gumbiner, B., Polonsky, K. S., Beltz, W. F., Wallace, P., Brechtel, G., & Fink, R. I. (1989) · Diabetes · doi:10.2337/diab.38.12.1549 · Cited by 132 · see citing works
The CDK4–pRB–E2F1 pathway controls insulin secretion
Annicotte, J., Blanchet, É., Carine Chavey, A., Iankova, I., Costes, S., Assou, S., Teyssier, J., Dalle, S., Sardet, C., & Lluis Fajas, A. (2009) · Nature Cell Biology · doi:10.1038/ncb1915 · Cited by 127 · see citing works
Gauthier, B. R., Wiederkehr, A., Baquié, M., Dai, C., Powers, A. C., Kerr-Conte, J., Pattou, F., MacDonald, R. J., Ferrer, J., & Wollheim, C. B. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.07.002 · Cited by 115 · see citing works
Self-citationWalsh, R. M., Saavedra, J. R. A., Lentz, G., Guerron, A. D., Scheman, J., Stevens, T., Trucco, M., Bottino, R., & Hatipoğlu, B. (2012) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-012-1914-6 · Cited by 103 · see citing works
Takebayashi, S., Tanaka, H., Hino, S., Nakatsu, Y., Igata, T., Sakamoto, A., Narita, M., & Nakao, M. (2015) · Aging Cell · doi:10.1111/acel.12351 · Cited by 84 · see citing works
Nicolay, B., Danielian, P. S., Kottakis, F., Lapek, J. D., Sanidas, I., Miles, W. O., Dehnad, M., Tschöp, K., Gierut, J. J., Manning, A. L., et al. (2015) · Genes & Development · doi:10.1101/gad.264127.115 · Cited by 84 · see citing works
Bandyopadhyay, D., Curry, J. L., Lin, Q., Richards, H. W., Chen, D., Hornsby, P. J., Timchenko, N. A., & Medrano, E. E. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00308.x · Cited by 81 · see citing works
Koyanagi, M., Asahara, S., Matsuda, T., Hashimoto, N., Shigeyama, Y., Shibutani, Y., Kanno, A., Fuchita, M., Mikami, T., Hosooka, T., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023238 · Cited by 69 · see citing works
B-cell size influences glucose-stimulated insulin secretion
Giordano, E., Cirulli, V., Bosco, D., Rouiller, D. G., Halban, P. A., & Meda, P. (1993) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1993.265.2.c358 · Cited by 65 · see citing works
O’Gorman, D., Kin, T., Imes, S., Pawlick, R. L., Senior, P. A., & Shapiro, A. M. J. (2010) · Transplantation · doi:10.1097/tp.0b013e3181e117ce · Cited by 55 · see citing works
Self-citationMilo-Landesman, D., Surana, M., Berkovich, I., Compagni, A., Christofori, G., Fleischer, N., & Efrat, S. (2001) · Cell Transplantation · doi:10.3727/000000001783986422 · Cited by 50 · see citing works
Navarro, H. G., Vinué, Á., Sanz, M., Delgado, M., Pozo, M. A., Serrano, M., Burks, D. J., & Andrés, V. (2012) · Aging Cell · doi:10.1111/acel.12023 · Cited by 33 · see citing works
Association between Type 2 Diabetes and CDKN2A/B: a meta-analysis study
Bao, X. Y., Xie, C., & Yang, M. S. (2011) · Molecular Biology Reports · doi:10.1007/s11033-011-0900-5 · Cited by 33 · see citing works
Moreno‐Asso, A., Castaño, C., Grilli, A., Novials, A., & Servitja, J. (2013) · Diabetologia · doi:10.1007/s00125-013-2930-0 · Cited by 23 · see citing works
Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis
Tokarsky-Amiel, R., Azazmeh, N., Helman, A., Stein, Y., Hassan, A., Maly, A., & Ben‐Porath, I. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3730 · Cited by 21 · see citing works
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Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Ferrucci, L., & Fabbri, E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0064-2 · Cited by 3,690 · see citing works
Senolytics improve physical function and increase lifespan in old age
Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0092-9 · Cited by 2,287 · see citing works
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
Senescent cells: an emerging target for diseases of ageing
Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R.-M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.116 · Cited by 1,284 · see citing works
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
The metabolic roots of senescence: mechanisms and opportunities for intervention
Wiley, C. D., & Campisi, J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00483-8 · Cited by 691 · see citing works
The role of cellular senescence in ageing and endocrine disease
Khosla, S., Farr, J. N., Tchkonia, T., & Kirkland, J. L. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0335-y · Cited by 523 · see citing works
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Aguayo-Mazzucato, C., Andle, J., Lee, T. B., Midha, A., Talemal, L., Chipashvili, V., Hollister-Lock, J., van Deursen, J., Weir, G., & Bonner-Weir, S. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.006 · Cited by 469 · see citing works
Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk
Chia, C. W., Egan, J. M., & Ferrucci, L. (2018) · Circulation Research · doi:10.1161/circresaha.118.312806 · Cited by 454 · see citing works
DNA damage-how and why we age?
Yousefzadeh, M., Henpita, C., Vyas, R., Soto-Palma, C., Robbins, P., & Niedernhofer, L. (2021) · eLife · doi:10.7554/elife.62852 · Cited by 399 · see citing works
Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes
Thompson, P. J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., & Bhushan, A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.021 · Cited by 353 · see citing works
Cellular senescence: all roads lead to mitochondria
Martini, H., & Passos, J. F. (2023) · The FEBS Journal · doi:10.1111/febs.16361 · Cited by 334 · see citing works
Cellular senescence: at the nexus between ageing and diabetes
Palmer, A. K., Gustafson, B., Kirkland, J. L., & Smith, U. (2019) · Diabetologia · doi:10.1007/s00125-019-4934-x · Cited by 337 · see citing works
Stress, cell senescence and organismal ageing
de Magalhães, J. P., & Passos, J. F. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.07.001 · Cited by 316 · see citing works
Borghesan, M., Fafián-Labora, J., Eleftheriadou, O., Carpintero-Fernández, P., Paez-Ribes, M., Vizcay-Barrena, G., Swisa, A., Kolodkin-Gal, D., Ximénez-Embún, P., Lowe, R., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.095 · Cited by 315 · see citing works
“We also observed an increase in the number of lysosomes, secretory vesicles, and mitochondria per cell in PanINs when compared to WT epithelial ducts (Figure S4B) (Helman et al., 2016).”
ResultSelf-citationLiu, J.-Y., Souroullas, G. P., Diekman, B. O., Krishnamurthy, J., Hall, B. M., Sorrentino, J. A., Parker, J. S., Sessions, G. A., Gudkov, A. V., & Sharpless, N. E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818313116 · Cited by 306 · see citing works
Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle
Chiche, A., Le Roux, I., von Joest, M., Sakai, H., Aguín, S. B., Cazin, C., Salam, R., Fiette, L., Alegria, O., Flamant, P., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2016.11.020 · Cited by 295 · see citing works
Aging of the cells: Insight into cellular senescence and detection Methods.
Mohamad Kamal, N. S., Safuan, S., Shamsuddin, S., & Foroozandeh, P. (2020) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2020.151108 · Cited by 287 · see citing works
The heterogeneity of cellular senescence: insights at the single-cell level
Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.04.011 · Cited by 294 · see citing works
Cellular senescence and Alzheimer disease: the egg and the chicken scenario
Saez-Atienzar, S., & Masliah, E. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0325-z · Cited by 257 · see citing works
β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance
Aguayo-Mazzucato, C., van Haaren, M., Mruk, M., Lee, T. B., Crawford, C., Hollister-Lock, J., Sullivan, B. A., Johnson, J. W., Ebrahimi, A., Dreyfuss, J. M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.015 · Cited by 198 · see citing works
Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases
Song, P., An, J., & Zou, M.-H. (2020) · Cells · doi:10.3390/cells9030671 · Cited by 198 · see citing works
Reducing Senescent Cell Burden in Aging and Disease
Pignolo, R. J., Passos, J. F., Khosla, S., Tchkonia, T., & Kirkland, J. L. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.03.005 · Cited by 177 · see citing works
Ogrodnik, M., Salmonowicz, H., & Gladyshev, V. N. (2019) · Aging Cell · doi:10.1111/acel.12841 · Cited by 184 · see citing works
Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds
Wilkinson, H. N., & Hardman, M. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00773 · Cited by 173 · see citing works
Muñoz, D. P., Yannone, S. M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A. M., Rodier, F., Wu, J. D., Desprez, P.-Y., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.124716 · Cited by 162 · see citing works
Cell Senescence, DNA Damage, and Metabolism
Shmulevich, R., & Krizhanovsky, V. (2021) · Antioxidants & Redox Signaling · doi:10.1089/ars.2020.8043 · Cited by 157 · see citing works
Lozano-Torres, B., Estepa-Fernández, A., Rovira, M., Orzáez, M., Serrano, M., Martínez-Máñez, R., & Sancenón, F. (2019) · Nature Reviews Chemistry · doi:10.1038/s41570-019-0108-0 · Cited by 140 · see citing works
Cellular senescence links aging and diabetes in cardiovascular disease
Shakeri, H., Lemmens, K., Gevaert, A. B., De Meyer, G. R. Y., & Segers, V. F. M. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00287.2018 · Cited by 134 · see citing works
Tchkonia, T., Palmer, A. K., & Kirkland, J. L. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa728 · Cited by 129 · see citing works
Sharma, A. K., Roberts, R. L., Benson, R. D., Pierce, J. L., Yu, K., Hamrick, M. W., & McGee-Lawrence, M. E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00354 · Cited by 131 · see citing works
“…+ quercetin senolytic drug combination mentioned above (Xu et al., 2018), have been tested to see the target effect on senescent cells and amelioration of aging or disease phenotypes (Grezella et al., 2018), with some even entering clinical trials (Hickson et al., 2019; Justice et al., 2019).”
BackgroundExpansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence
Ogrodnik, M., Salmonowicz, H., Jurk, D., & Passos, J. F. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.06.011 · Cited by 104 · see citing works
Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction
Xu, M., Tchkonia, T., & Kirkland, J. L. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.05.015 · Cited by 99 · see citing works
“However, senescent cells appear to be important for several biological processes, including prevention of fibrosis (3), promotion of wound healing (50), and insulin secretion (51).”
Mitochondria and cellular senescence: Implications for musculoskeletal ageing
Habiballa, L., Salmonowicz, H., & Passos, J. F. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.417 · Cited by 82 · see citing works
Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence
Collin, G., Huna, A., Warnier, M., Flaman, J.-M., & Bernard, D. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0300-z · Cited by 71 · see citing works
Azazmeh, N., Assouline, B., Winter, E., Ruppo, S., Nevo, Y., Maly, A., Meir, K., Witkiewicz, A. K., Cohen, J., Rizou, S. V., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16475-3 · Cited by 57 · see citing works
Self-citationWalker, E. M., Cha, J., Tong, X., Guo, M., Liu, J.-H., Yu, S., Iacovazzo, D., Mauvais-Jarvis, F., Flanagan, S. E., Korbonits, M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109813 · Cited by 48 · see citing works
Paladino, F. V., Sardinha, L. R., Piccinato, C. A., & Goldberg, A. C. (2017) · Stem Cells International · doi:10.1155/2017/8492797 · Cited by 23 · see citing works
Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks
Mallikarjun, V., & Swift, J. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.11.020 · Cited by 14 · see citing works
- Authors
- Helman, A., Klochendler, A., Azazmeh, N., Gabai, Y., Horwitz, E., Anzi, S., Swisa, A., Condiotti, R., Granit, R. Z., Nevo, Y., Fixler, Y., Shreibman, D., Zamir, A., Tornovsky-Babeay, S., Dai, C., Glaser, B., Powers, A. C., Shapiro, A. M. J., Magnuson, M. A., Dor, Y., & Ben-Porath, I.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- University of Alberta (CA)
- Corresponding author
- Dor, Yuval
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-03-07
- Volume
- 22
- Issue
- 4
- Pages
- 412-420
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5546206
- OpenAlex
- W2295694318
- Cited by
- 351
- References
- 66
- Citations by year
- 2026: 22 · 2025: 39 · 2024: 38 · 2023: 39 · 2022: 33 · 2021: 46 · 2020: 36 · 2019: 29 · 2018: 25 · 2017: 30 · 2016: 13
- FWCI
- 35.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p60dk020593-31)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK089572, P60-DK020593, U01DK089572, DK-72473, DK104211, DK 20593, UC4DK104211, R24DK106755, U01DK072473, P30DK020593)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- p16INK4a, cellular senescence, pancreatic beta cells, insulin secretion, glucose-stimulated insulin secretion, glucose homeostasis, mTOR, PPARγ, beta-cell proliferation, diabetes mellitus, islets
- MeSH terms
- Insulin Secretion, Aging, Animals, Fibroblasts, Gene Expression Regulation, Glucose, Humans, Insulin, Mice, Transgenic, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, PPAR gamma, Cell Proliferation, Insulin-Secreting Cells, Mice, TOR Serine-Threonine Kinases
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