Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan
Open accessAbstract
The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16 Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16 High senescence is a slow process that manifests around 10-12 months of age. The majority of p16 High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16 High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.
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Emerging evidence indicates that targeted senolysis in mice may be severely toxic to the liver and perivascular tissue, due to removal of p16-expressing endothelial cells, adipocytes, and macrophages in aged organs, all of which have structural roles.
“Lastly, emerging evidence suggests that targeted senolysis in mice may be profoundly toxic in the liver and perivascular tissue, because of the eradication of p16-expressing endothelial cells, adipocytes and macrophages in aged organs, which all have structural functions254.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [254]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSenescence in non-mammals impacts many aspects of organismal physiology, from development to regeneration and ageing.
“Senescence in non-mammals impacts on many aspects of organismal physiology, from development116,122 to regeneration (e.g., salamander limbs117, zebrafish fins118, whole hydra polyps120) and ageing119,123,124.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [117]
The paper’s opening summary (page unavailable) reports that age-induced senescence affects health in mice, supporting the ageing aspect of the citation. Mice are mammals, however, so it does not support the sentence’s claim specifically about non-mammals. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSenolytic treatment to eliminate senescent cells has been successfully applied in fish and salamanders, enabling both functional assessment and validation of senescence through targeted reduction.
“This has been successfully applied in fish118 and salamanders117,126, enabling both the functional assessment and validation of senescence through targeted reduction.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [117]
The section on dasatinib and quercetin reports targeted reduction of p16-high macrophages in mice, and the Discussion assesses consequences of removing other senescent cell types. Neither passage reports senolytic treatment in fish or salamanders, so the species-specific claim is unsupported by this source (page numbers unavailable in our copy). (LLM, conf=0.83)
Experimental — accuracy not yet measuredExcessive clearance of senescent cells has been reported to accompany the dilemma faced by cells that cannot be replenished in time, although Quercetin + Dasatinib clears mainly p16 macrophages.
“Excessive clearance of senescent cells (especially for senescent liver sinusoidal endothelial cells or adipocytes) has also been reported to accompany the dilemma faced by cells that cannot be replenished in time, although Quercetin + Dasatinib clears mainly p16 macrophages.348”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [348]
The section on removal of p16High cells reports that senescent liver endothelial cells were not replaced after removal and that fibrosis developed instead (page not available). The D+Q section reports that dasatinib plus quercetin primarily removed p16High macrophages, not LSECs or adipocytes. The cited passages do not establish that senescent adipocytes likewise cannot be replenished, so that part of the citing sentence is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA recent report shows that removing senescent cells expressing high p16 can lead to fibrosis in mice, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues.
“This is in agreement with a recent report showing that the removal of senescent cells expressing high levels of p16INK4a can lead to fibrosis in mice101, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues22,71,73,75,102.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [101]
Clearing liver sinusoid endothelial cells promotes fibrosis.
“the recent finding that clearing certain populations of senescent cells, such as liver sinusoid endothelial cells, promotes fibrosis (Grosse et al. 2020)”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Grosse et al. 2020
p16INK4a expression is considered a common and robust, albeit not necessarily specific, marker of senescence, and its promoter activity and transcriptional activation are extensively exploited as reporters of senescent cells in vivo.
“p16 INK4a expression is considered a common and robust, albeit not necessarily specific, marker of senescence, and its promoter activity and transcriptional activation are extensively exploited as reporters of senescent cells invivo 20,23,27,28 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [23]
Some senescent cell types have indispensable structural functions in organ integrity and their forced clearance in mice leads to tissue damage and organ impairment.
“some senescent cell types have indispensable structural functions in organ integrity and their forced clearance in mice leads to tissue damage and organ impairment 23”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [23]
The presence of senescent LSECs is indispensable in aged mice.
“indicating that the presence of senescent LSECs is indispensable in aged mice [118].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [118]
Senolytic intervention targeting p16-high liver sinusoidal endothelial cells (LSECs) in aged mice resulted in liver fibrosis and health deterioration.
“senolytic intervention targeting p16-high liver sinusoidal endothelial cells (LSECs) in aged mice resulted in liver fibrosis and health deterioration”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [118]
Cellular senescence is not a mammalian-specific phenomenon but is widespread across the animal kingdom, including vertebrate and invertebrate organisms.
“Cellular senescence is not a mammalian-specific phenomenon but is widespread across the animal kingdom, including vertebrate and invertebrate organisms.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [117]
The paper’s introductory passage describes cellular senescence, and its study reports findings in mice, but neither addresses whether senescence occurs in invertebrates or is widespread across the animal kingdom. Searches for vertebrates, invertebrates, and non-mammalian organisms found no passage establishing that distribution. (LLM, conf=0.75)
Experimental — accuracy not yet measuredMarkers of senescence have been detected in birds, amphibians, fish, and invertebrates.
“Markers of senescence have been detected in birds (e.g., quail114), amphibians (e.g., axolotls115, xenopus116, and newts117), fish (e.g., zebrafish118 and killifish119), and invertebrates (e.g., hydra120 and Drosophila121).”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [117]
The citation is attached to the quail example. The paper’s ‘Identification of p16 High senescent cells in vivo’ section reports senescence markers in mouse liver cells, but our copy does not address quail or other birds (searched: quail, birds, avian). (LLM, conf=0.76)
Experimental — accuracy not yet measuredRemoval of some senescent cell types can adversely affect wound healing and fibrosis of liver and perivascular tissue.
“Removal of some senescent cell types can adversely affect wound healing and fibrosis of liver and perivascular tissue (54, 55).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [55]
Elimination of senescent cells using senolytics may have adverse side effects.
“However, the elimination of senescent cells using senolytics may also have adverse side effects.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [189]
p16Ink4a expression is essentially undetectable in young and healthy tissues.
“The expression of p16Ink4a is essentially undetectable in young and healthy tissues, but p16Ink4a+ cells accumulate in many aged or diseased tissues.18,19,21,22,23,28”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [19]
p16Ink4a+ cells accumulate in many aged or diseased tissues.
“The expression of p16Ink4a is essentially undetectable in young and healthy tissues, but p16Ink4a+ cells accumulate in many aged or diseased tissues.18,19,21,22,23,28”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [19]
Genetic removal of liver sinusoidal endothelial cells with high expression of p16 hampered the healthspan of mice because the procedure induced fibrosis in the liver and systemic perivasculature.
“Grosse and colleagues 111 reported that genetic removal of liver sinusoidal endothelial cells with high expression of p16 hampered the healthspan of mice because the procedure induced fibrosis in the liver and systemic perivasculature.”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [111]
Given high expression of p16, dasatinib and quercetin treatment removed senescent macrophages, but was ineffective against senescent liver sinusoidal endothelial cells in mice.
“Interestingly, given the high expression of p16, dasatinib and quercetin treatment removed senescent macrophages, but was ineffective against senescent liver sinusoidal endothelial cells in mice.111”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [111]
Multiple p16-based mouse models might not target the same p16high cells in vivo due to different transgene designs.
“Moreover, multiple p16-based mouse models [15,26–28] might not target the same p16high cells in vivo due to different transgene designs (such as different p16 promoters or transgene locations).”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [26]
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Cites
NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556 · see citing works
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
Aging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · 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
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
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045 · see citing works
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64098 · Cited by 1,774 · see citing works
Cellular senescence mediates fibrotic pulmonary disease
Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., Oberg, A. L., Birch, J., Salmonowicz, H., Zhu, Y., et al. (2017) · Nature Communications · doi:10.1038/ncomms14532 · Cited by 1,613 · see citing works
Jeon, O. H., Kim, C., Laberge, R.-M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., et al. (2017) · Nature Medicine · doi:10.1038/nm.4324 · Cited by 1,515 · 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
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
Senescent intimal foam cells are deleterious at all stages of atherosclerosis
Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016) · Science · doi:10.1126/science.aaf6659 · Cited by 1,195 · 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
Liver sinusoidal endothelial cells: Physiology and role in liver diseases
Poisson, J., Lemoinne, S., Boulanger, C., Durand, F., Moreau, R., Valla, D., & Rautou, P.-E. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2016.07.009 · Cited by 1,047 · see citing works
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
Yosef, R., Pilpel, N., Tokarsky-Amiel, R., Biran, A., Ovadya, Y., Cohen, S., Vadai, E., Dassa, L., Shahar, E., Condiotti, R., et al. (2016) · Nature Communications · doi:10.1038/ncomms11190 · Cited by 1,032 · see citing works
Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.015 · Cited by 1,032 · see citing works
Bracken, A. P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Mönch, K., Minucci, S., Porse, B. T., Marine, J.-C., et al. (2007) · Genes & Development · doi:10.1101/gad.415507 · Cited by 850 · see citing works
Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., Hagler, M., Jurk, D., Smith, L. A., Casaclang‐Verzosa, G., et al. (2016) · Aging Cell · doi:10.1111/acel.12458 · Cited by 738 · see citing works
Identification of HSP90 inhibitors as a novel class of senolytics
Fuhrmann-Stroissnigg, H., Ling, Y. Y., Zhao, J., McGowan, S. J., Zhu, Y., Brooks, R. W., Grassi, D., Gregg, S. Q., Stripay, J. L., Dorronsoro, A., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00314-z · Cited by 701 · see citing works
Thrombocytopenia and prognosis in intensive care
Vanderschueren, S., Weerdt, A. D., Malbrain, M. L. N. G., et al. (2000) · Critical Care Medicine · doi:10.1097/00003246-200006000-00031 · Cited by 600 · see citing works
Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging
Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., Kim, L.-J., Osborne, B., Joshi, S., Lu, Y., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.008 · Cited by 496 · 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
Hall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., Rydkina, E., Vujcic, S., Balan, K., Gitlin, I. I., et al. (2017) · Aging · doi:10.18632/aging.101268 · Cited by 407 · see citing works
Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice
Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., Curran, G. L., Ogrodnik, M., Jurk, D., Johnson, K. O., et al. (2016) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glw154 · Cited by 352 · see citing works
Kotake, Y., Cao, R., Viatour, P., Sage, J., Zhang, Y., & Xiong, Y. (2007) · Genes & Development · doi:10.1101/gad.1499407 · Cited by 314 · see citing works
Liver Sinusoidal Endothelial Cells
Sørensen, K. K., Simón-Santamaría, J., McCuskey, R. S., & Smedsrød, B. H. (2015) · Comprehensive physiology · doi:10.1002/cphy.c140078 · Cited by 290 · see citing works
Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats
Wang, L., Wang, X., Xie, G., Wang, L., Hill, C. K., & DeLeve, L. D. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58789 · Cited by 194 · see citing works
Age‐related pseudocapillarization of the human liver
McLean, A. J., Cogger, V. C., Chong, G. C., Warren, A., Markus, A. M. A., Dahlstrom, J. E., & Couteur, D. G. L. (2003) · The Journal of Pathology · doi:10.1002/path.1328 · Cited by 170 · see citing works
Liver Sinusoidal Endothelial Cell: An Update
Maretti-Mira, A. C., & DeLeve, L. D. (2017) · Seminars in Liver Disease · doi:10.1055/s-0037-1617455 · Cited by 161 · see citing works
Cellular Senescence and the Biology of Aging, Disease, and Frailty
LeBrasseur, N. K., Tchkonia, T., & Kirkland, J. L. (2015) · Nestlé Nutrition Institute Workshop Series · doi:10.1159/000382054 · Cited by 147 · see citing works
Hodes, R. J., Sierra, F., Austad, S. N., Epel, E., Neigh, G. N., Erlandson, K. M., Schafer, M. J., LeBrasseur, N. K., Wiley, C., Campisi, J., et al. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13299 · Cited by 132 · see citing works
Li, R., Oteiza, A., Sørensen, K. K., McCourt, P., Olsen, R. F., Smedsrød, B. H., & Svistounov, D. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00215.2010 · Cited by 127 · see citing works
Golwala, Z. M., Shah, H., Gupta, N., et al. (2016) · African Health Sciences · doi:10.4314/ahs.v16i2.3 · Cited by 59 · see citing works
Manipulating fenestrations in young and old liver sinusoidal endothelial cells
Hunt, N. J., Lockwood, G. P., Warren, A., Mao, H., McCourt, P., Couteur, D. G. L., & Cogger, V. C. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00179.2018 · Cited by 58 · see citing works
Øie, C. I., Wolfson, D. L., Tanji, Y., Dumitriu, G., Sørensen, K. K., McCourt, P., Ahluwalia, B. S., & Smedsrød, B. H. (2020) · Scientific Reports · doi:10.1038/s41598-020-57652-0 · Cited by 58 · see citing works
Coagulation Studies in Liver Disease
Hallén, A., & Nilsson, I. M. (1964) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1654805 · Cited by 54 · see citing works
Duong, L., Radley‐Crabb, H. G., Gardner, J. K., Tomay, F., Dye, D. E., Grounds, M. D., Pixley, F. J., Nelson, D. J., & Jackaman, C. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00526 · Cited by 54 · see citing works
Frescas, D., Hall, B. M., Strom, E., Virtuoso, L. P., Gupta, M., Gleiberman, A. S., Rydkina, E., Balan, V., Vujcic, S., Chernova, O. B., et al. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1339850 · Cited by 34 · see citing works
Serum Thrombopoietin Levels and Its Relationship WithThrombocytopenia in Patients With Cirrhosis
Temel, T., Cansu, D. Ü., & Özakyol, A. (2014) · Hepatitis Monthly · doi:10.5812/hepatmon.18556 · Cited by 22 · see citing works
Long‐Term Treatment of Native LDL Induces Senescence of Cultured Human Endothelial Cells
Oh, S.-T., Park, H., Yoon, H. J., & Yang, S. Y. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/6487825 · Cited by 13 · see citing works
Oh, S.-T., Park, H., Yoon, H. J., et al. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/4576985 · Cited by 2 · see citing works
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Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177 · see citing works
“To design senotherapies targeted to specific diseases, wewill need to better understand what cell types undergo senescence, particularly since eliminating certain senescent cell types can be harmful (Grosse et al. 2020).”
BackgroundCellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,105 · see citing works
Exploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
A guide to assessing cellular senescence <i>in vitro</i> and <i>in vivo</i>
González‐Gualda, E., Baker, A. G., Fruk, L., & Muñoz‐Espín, D. (2021) · The FEBS Journal · doi:10.1111/febs.15570 · Cited by 645 · see citing works
Strategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
Guidelines for minimal information on cellular senescence experimentation in vivo
Ogrodnik, M., Carlos Acosta, J., Adams, P. D., d’Adda di Fagagna, F., Baker, D. J., Bishop, C. L., Chandra, T., Collado, M., Gil, J., Gorgoulis, V., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.059 · Cited by 376 · 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
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
Haston, S., Gonzalez-Gualda, E., Morsli, S., Ge, J., Reen, V., Calderwood, A., Moutsopoulos, I., Panousopoulos, L., Deletic, P., Carreno, G., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.004 · Cited by 251 · see citing works
Han, Y., & Kim, S. Y. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00906-w · Cited by 201 · see citing works
Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
Omori, S., Wang, T.-W., Johmura, Y., Kanai, T., Nakano, Y., Kido, T., Susaki, E. A., Nakajima, T., Shichino, S., Ueha, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.006 · Cited by 194 · see citing works
Connecting aging biology and inflammation in the omics era
Walker, K. A., Basisty, N., Wilson, D. M., & Ferrucci, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158448 · Cited by 189 · see citing works
Senescent immune cells release grancalcin to promote skeletal aging
Li, C.-J., Xiao, Y., Sun, Y.-C., He, W.-Z., Liu, L., Huang, M., He, C., Huang, M., Chen, K.-X., Hou, J., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.009 · Cited by 190 · see citing works
Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., Ravishankar, S., Cassandras, M., Wang, C., Khan, I., et al. (2022) · Science · doi:10.1126/science.abf3326 · Cited by 181 · see citing works
Fracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence
Saul, D., & Khosla, S. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac008 · Cited by 185 · see citing works
Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce
Li, Q., Hagberg, C. E., Silva Cascales, H., Lang, S., Hyvönen, M. T., Salehzadeh, F., Chen, P., Alexandersson, I., Terezaki, E., Harms, M. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01501-8 · Cited by 178 · see citing works
Similarities and interplay between senescent cells and macrophages
Behmoaras, J., & Gil, J. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202010162 · Cited by 158 · see citing works
Wang, B., Wang, L., Gasek, N. S., Zhou, Y., Kim, T., Guo, C., Jellison, E. R., Haynes, L., Yadav, S., Tchkonia, T., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00107-6 · Cited by 145 · see citing works
The role of cellular senescence and SASP in tumour microenvironment
Takasugi, M., Yoshida, Y., Hara, E., & Ohtani, N. (2023) · The FEBS Journal · doi:10.1111/febs.16381 · Cited by 144 · see citing works
Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression
Born, E., Lipskaia, L., Breau, M., Houssaini, A., Beaulieu, D., Marcos, E., Pierre, R., Do Cruzeiro, M., Lefevre, M., Derumeaux, G., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.058794 · Cited by 148 · see citing works
Self-citationThe costs and benefits of senotherapeutics for human health
Raffaele, M., & Vinciguerra, M. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00300-7 · Cited by 140 · see citing works
Paramos-de-Carvalho, D., Jacinto, A., & Saúde, L. (2021) · eLife · doi:10.7554/elife.72449 · Cited by 111 · see citing works
Gaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117 · see citing works
Cell senescence in liver diseases: pathological mechanism and theranostic opportunity
Sanfeliu-Redondo, D., Gibert-Ramos, A., & Gracia-Sancho, J. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00913-4 · Cited by 117 · see citing works
Chromatin basis of the senescence-associated secretory phenotype
Hao, X., Wang, C., & Zhang, R. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.12.003 · Cited by 94 · see citing works
Tsuji, S., Minami, S., Hashimoto, R., Konishi, Y., Suzuki, T., Kondo, T., Sasai, M., Torii, S., Ono, C., Shichinohe, S., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00170-7 · Cited by 84 · see citing works
Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota
Kawamoto, S., Uemura, K., Hori, N., Takayasu, L., Konishi, Y., Katoh, K., Matsumoto, T., Suzuki, M., Sakai, Y., Matsudaira, T., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01145-5 · Cited by 91 · see citing works
Efficacy and limitations of senolysis in atherosclerosis
Garrido, A. M., Kaistha, A., Uryga, A. K., Oc, S., Foote, K., Shah, A., Finigan, A., Figg, N., Dobnikar, L., Jørgensen, H., et al. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvab208 · Cited by 83 · see citing works
“Our data are therefore consistent with studies that show that deleting p16þ cells can have neutral or detrimental effects in development, wound healing and a variety of disease states.(10,11,19,44,45) While cycles of ABT-263 do reduce atherosclerosis, ABT-263 had no effect on tissue markers of cell senescence, and als…”
ResultA Blueprint for Characterizing Senescence
Roy, A. L., Sierra, F., Howcroft, K., Singer, D. S., Sharpless, N., Hodes, R. J., Wilder, E. L., & Anderson, J. M. (2020) · Cell · doi:10.1016/j.cell.2020.10.032 · Cited by 81 · see citing works
Obesity accelerates cardiovascular ageing
Ruperez, C., Madeo, F., de Cabo, R., Kroemer, G., & Abdellatif, M. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf216 · Cited by 73 · see citing works
Targeting aging and age-related diseases with vaccines
Wu, R., Sun, F., Zhang, W., Ren, J., & Liu, G.-H. (2024) · Nature Aging · doi:10.1038/s43587-024-00597-0 · Cited by 66 · see citing works
Raffaele, M., Kovacovicova, K., Frohlich, J., Lo Re, O., Giallongo, S., Oben, J. A., Faldyna, M., Leva, L., Giannone, A. G., Cabibi, D., et al. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00731-0 · Cited by 60 · see citing works
Doolittle, M. L., Saul, D., Kaur, J., Rowsey, J. L., Vos, S. J., Pavelko, K. D., Farr, J. N., Monroe, D. G., & Khosla, S. (2023) · Nature Communications · doi:10.1038/s41467-023-40393-9 · Cited by 57 · see citing works
The challenge of identifying senescent cells
Gil, J. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01267-w · Cited by 58 · see citing works
Cardiovascular disease and the biology of aging
Moturi, S., Ghosh-Choudhary, S. K., & Finkel, T. (2022) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2022.04.005 · Cited by 56 · see citing works
Doolittle, M. L., Saul, D., Kaur, J., Rowsey, J. L., Vos, S. J., Pavelko, K. D., Farr, J. N., Monroe, D. G., & Khosla, S. (2023) · doi:10.1101/2023.01.12.523760 · Cited by 57 · see citing works
Roadmap for alleviating the manifestations of ageing in the cardiovascular system
Liberale, L., Tual-Chalot, S., Sedej, S., Ministrini, S., Georgiopoulos, G., Grunewald, M., Bäck, M., Bochaton-Piallat, M.-L., Boon, R. A., Ramos, G. C., et al. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01130-5 · Cited by 59 · see citing works
Fang, Y., Medina, D., Stockwell, R., McFadden, S., Quinn, K., Peck, M. R., Bartke, A., Hascup, K. N., & Hascup, E. R. (2021) · doi:10.1101/2021.11.08.467509 · Cited by 53 · see citing works
A Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice
Sun, J., Wang, M., Zhong, Y., Ma, X., Sun, S., Xu, C., Peng, L., Li, G., Zhang, L., Liu, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34801-9 · Cited by 52 · see citing works
Context‐dependent roles of cellular senescence in normal, aged, and disease states
Moiseeva, V., Cisneros, A., Cobos, A. C., Tarrega, A. B., Oñate, C. S., Perdiguero, E., Serrano, A. L., & Muñoz‐Cánoves, P. (2023) · The FEBS Journal · doi:10.1111/febs.16573 · Cited by 34 · see citing works
Research progress on interferon and cellular senescence
Wang, D., Chen, K., Wang, Z., Wu, H., & Li, Y. (2024) · The FASEB Journal · doi:10.1096/fj.202400808rr · Cited by 23 · see citing works
Cellular Models of Aging and Senescence
Kim, B., Lee, D. I., Basisty, N., & Dai, D.-F. (2025) · Cells · doi:10.3390/cells14161278 · Cited by 16 · see citing works
Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline
Rojas-Vázquez, S., Blasco-Chamarro, L., López-Fabuel, I., Martínez-Máñez, R., & Fariñas, I. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.666881 · Cited by 15 · see citing works
Wakita, M., Ito, K., Fujii, K., Sakamoto, D., Mikawa, T., Sugawara, S., Zhou, X., Park, J. H., Miyagawa, H., Motooka, D., et al. (2026) · Nature Aging · doi:10.1038/s43587-025-01057-z · Cited by 9 · see citing works
Human dermal fibroblast senescence in response to single and recurring oxidative stress
McCarty, T. Y., & Kearney, C. J. (2025) · Frontiers in Aging · doi:10.3389/fragi.2025.1504977 · Cited by 8 · see citing works
Kawabata, S., Iijima, H., Kanemura, N., & Murata, K. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04666-8
- Authors
- Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K.-D., & Bulavin, D. V.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Bulavin, Dmitry V.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 32
- Issue
- 1
- Pages
- 87-99.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3028992072
- Cited by
- 460
- References
- 44
- Citations by year
- 2026: 73 · 2025: 84 · 2024: 80 · 2023: 80 · 2022: 60 · 2021: 62 · 2020: 21
- FWCI
- 33.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- HAL (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, p16, liver sinusoidal endothelial cells, healthspan, aging, senolytics, liver fibrosis, perivascular fibrosis, blood-tissue barrier, mouse model
- MeSH terms
- Aging, Animals, Cells, Cultured, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Endothelial Cells, Mice
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