Survey of senescent cell markers with age in human tissues
Open accessAbstract
Cellular senescence, triggered by sublethal damage, is characterized by indefinite growth arrest, altered gene expression patterns, and a senescence-associated secretory phenotype. While the accumulation of senescent cells during aging decreases tissue function and promotes many age-related diseases, at present there is no universal marker to detect senescent cells in tissues. Cyclin-dependent kinase inhibitors 2A (p16/CDKN2A) and 1A (p21/CDKN1A) can identify senescent cells, but few studies have examined the numbers of cells expressing these markers in different organs as a function of age. Here, we investigated systematically p16- and p21-positive cells in tissue arrays designed to include normal organs from persons across a broad spectrum of ages. Increased numbers of p21-positive and p16-positive cells with donor age were found in skin (epidermis), pancreas, and kidney, while p16-expressing cells increased in brain cortex, liver, spleen and intestine (colon), and p21-expressing cells increased in skin (dermis). The numbers of cells expressing p16 or p21 in lung did not change with age, and muscle did not appear to have p21- or p16-positive cells. In summary, different organs display different levels of the senescent proteins p16 and p21 as a function of age across the human life span.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Senescent cells accumulate in aged tissues, including the brain.
“senescent cells accumulate in aged tissues,31,32,33 including the brain.34,35,36”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · cited 3× · see citing works
“, p16 and p21), markers of lysosomal activity (such as SA-β-Gal), and markers of secretion (SASP factors) [1].”
BackgroundNaturally 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
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
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
Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline
Bussian, T. J., Aziz, A., Meyer, C. F., Swenson, B. L., van Deursen, J. M., & Baker, D. J. (2018) · Nature · doi:10.1038/s41586-018-0543-y · Cited by 1,289 · 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-messaging secretome: SMS-ing cellular stress
Kuilman, T., & Peeper, D. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2560 · Cited by 909 · see citing works
Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.09.003 · Cited by 609 · 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
Senescence and senotherapeutics: a new field in cancer therapy
Myrianthopoulos, V., Evangelou, K., Vasileiou, P. V. S., Cooks, T., Vassilakopoulos, T. P., Pangalis, G. A., Kouloukoussa, M., Kittas, C., Georgakilas, A. G., & Gorgoulis, V. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.006 · Cited by 160 · see citing works
Age- and tissue-specific expression of senescence biomarkers in mice.
Hudgins, A. D., Tazearslan, C., Tare, A., Zhu, Y., Huffman, D., & Suh, Y. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00059 · Cited by 124 · see citing works
Flagged first, then by citations
Research works printed but not linked: 29
- [2]Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010; 24: 2463– 79. 10.1101/gad.1971610 21078816 PMC2975923 · DOI · Paper page
- [3]Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5: 99– 118. 10.1146/annurev-pathol-121808-102144 20078217 PMC4166495 · DOI · Paper page
- [5]Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995; 92: 9363– 67. 10.1073/pnas.92.20.9363 7568133 PMC40985 · DOI · Paper page
- [6]Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018; 28: 436– 53. 10.1016/j.tcb.2018.02.001 29477613 · DOI · Paper page
- [7]Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell. 2009; 8: 311– 23. 10.1111/j.1474-9726.2009.00481.x 19627270 · DOI · Paper page
- [8]Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014; 17: 324– 28. 10.1097/MCO.0000000000000065 24848532 · DOI · Paper page
- [9]Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014; 15: 482– 96. 10.1038/nrm3823 24954210 · DOI · Paper page
- [10]Krizhanovsky V, Xue W, Zender L, Yon M, Hernando E, Lowe SW. Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. Cold Spring Harb Symp Quant Biol. 2008; 73: 513– 22. 10.1101/sqb.2008.73.048 19150958 PMC3285266 · DOI · Paper page
- [12]Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J, Keyes WM. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell. 2013; 155: 1119– 30. 10.1016/j.cell.2013.10.041 24238961 · DOI · Paper page
- [14]Mosteiro L, Pantoja C, Alcazar N, Marión RM, Chondronasiou D, Rovira M, Fernandez-Marcos PJ, Muñoz-Martin M, Blanco-Aparicio C, Pastor J, Gómez-López G, De Martino A, Blasco MA, et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science. 2016; 354: aaf4445. 10.1126/science.aaf4445 27884981 · DOI · Paper page
- [15]Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014 (Suppl 1); 69: S4– 9. 10.1093/gerona/glu057 24833586 · DOI · Paper page
- [18]Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D. Targeting senescent cells in translational medicine. EMBO Mol Med. 2019; 11: e10234. 10.15252/emmm.201810234 31746100 PMC6895604 · DOI
- [19]van Deursen JM. Senolytic therapies for healthy longevity. Science. 2019; 364: 636– 37. 10.1126/science.aaw1299 31097655 PMC6816502 · DOI · Paper page
- [22]Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016; 354: 472– 77. 10.1126/science.aaf6659 27789842 PMC5112585 · DOI · Paper page
- [24]Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017; 7: 165– 76. 10.1158/2159-8290.CD-16-0241 27979832 PMC5296251 · DOI · Paper page
- [27]Soto-Gamez A, Demaria M. Therapeutic interventions for aging: the case of cellular senescence. Drug Discov Today. 2017; 22: 786– 95. 10.1016/j.drudis.2017.01.004 28111332 · DOI · Paper page
- [28]Ovadya Y, Krizhanovsky V. Strategies targeting cellular senescence. J Clin Invest. 2018; 128: 1247– 54. 10.1172/JCI95149 29608140 PMC5873866 · DOI · Paper page
- [29]Nielsen GP, Stemmer-Rachamimov AO, Shaw J, Roy JE, Koh J, Louis DN. Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab Invest. 1999; 79: 1137– 43. 10496532
- [30]Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114: 1299– 307. 10.1172/JCI22475 15520862 PMC524230 · DOI · Paper page
- [31]Burd CE, Sorrentino JA, Clark KS, Darr DB, Krishnamurthy J, Deal AM, Bardeesy N, Castrillon DH, Beach DH, Sharpless NE. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell. 2013; 152: 340– 51. 10.1016/j.cell.2012.12.010 23332765 PMC3718011 · DOI · Paper page
- [33]Shimizu I, Minamino T. Cellular senescence in cardiac diseases. J Cardiol. 2019; 74: 313– 19. 10.1016/j.jjcc.2019.05.002 31202488 · DOI
- [34]Katsuumi G, Shimizu I, Yoshida Y, Minamino T. Vascular Senescence in Cardiovascular and Metabolic Diseases. Front Cardiovasc Med. 2018; 5: 18. 10.3389/fcvm.2018.00018 29556500 PMC5845435 · DOI · Paper page
- [35]Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes. Cell Metab. 2019; 29: 1045– 1060.e10. 10.1016/j.cmet.2019.01.021 30799288 · DOI · Paper page
- [37]Wang AS, Dreesen O. Biomarkers of cellular senescence and skin aging. Front Genet. 2018; 9: 247. 10.3389/fgene.2018.00247 30190724 PMC6115505 · DOI · Paper page
- [38]Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Dürr P, Wlaschek M. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell. 2006; 5: 379– 89. 10.1111/j.1474-9726.2006.00231.x 16911562 · DOI · Paper page
- [39]Waaijer ME, Parish WE, Strongitharm BH, van Heemst D, Slagboom PE, de Craen AJ, Sedivy JM, Westendorp RG, Gunn DA, Maier AB. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012; 11: 722– 25. 10.1111/j.1474-9726.2012.00837.x 22612594 PMC3539756 · DOI · Paper page
- [40]Knoppert SN, Valentijn FA, Nguyen TQ, Goldschmeding R, Falke LL. Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools. Front Pharmacol. 2019; 10: 770. 10.3389/fphar.2019.00770 31354486 PMC6639430 · DOI
- [41]Ovadya Y, Landsberger T, Leins H, Vadai E, Gal H, Biran A, Yosef R, Sagiv A, Agrawal A, Shapira A, Windheim J, Tsoory M, Schirmbeck R, et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun. 2018; 9: 5435. 10.1038/s41467-018-07825-3 30575733 PMC6303397 · DOI · Paper page
- [42]Calimport SR, Bentley BL, Stewart CE, Pawelec G, Scuteri A, Vinciguerra M, Slack C, Chen D, Harries LW, Marchant G, Fleming GA, Conboy M, Antebi A, et al. To help aging populations, classify organismal senescence. Science. 2019; 366: 576– 78. 10.1126/science.aay7319 31672885 PMC7193988 · DOI
Cited by
Sorted by citations
Diversity and biology of cancer-associated fibroblasts
Biffi, G., & Tuveson, D. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00048.2019 · Cited by 1,265 · 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
Nuclear morphology is a deep learning biomarker of cellular senescence
Heckenbach, I., Mkrtchyan, G. V., Ezra, M. B., Bakula, D., Madsen, J. S., Nielsen, M. H., Oró, D., Osborne, B., Covarrubias, A. J., Idda, M. L., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00263-3 · Cited by 232 · see citing works
Self-citationNovel insights from a multiomics dissection of the Hayflick limit
Chan, M., Yuan, H., Soifer, I., Maile, T. M., Wang, R. Y., Ireland, A., O'Brien, J. J., Goudeau, J., Chan, L. J., Vijay, T., et al. (2022) · eLife · doi:10.7554/elife.70283 · Cited by 99 · see citing works
“Given the observation that fibrosis and senescence markers correlate with increasing age in multiple tissues, it is possible that FMT might be a widespread phenomenon underlying many age-related pathologies ( Yousefzadeh et al., 2020 ; Idda et al., 2020 ).”
Is exercise a senolytic medicine? A systematic review
Chen, X., Yi, Z., Wong, G. T., Hasan, K. M. M., Kwan, J. S., Ma, A. C., & Chang, R. C. (2021) · Aging Cell · doi:10.1111/acel.13294 · Cited by 88 · see citing works
Sanborn, M. A., Wang, X., Gao, S., Dai, Y., & Rehman, J. (2025) · Nature Communications · doi:10.1038/s41467-025-57047-7 · Cited by 82 · 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
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
A BDNF-TrkB autocrine loop enhances senescent cell viability
Anerillas, C., Herman, A. B., Munk, R., Garrido, A., Lam, K.-W. G., Payea, M. J., Rossi, M., Tsitsipatis, D., Martindale, J. L., Piao, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33709-8 · Cited by 35 · see citing works
Self-citationSenescence-like phenotype in post-mitotic cells of mice entering middle age
Raffaele, M., Kovacovicova, K., Bonomini, F., Rezzani, R., Frohlich, J., & Vinciguerra, M. (2020) · Aging · doi:10.18632/aging.103637 · Cited by 28 · 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
Neri, F., Takajjart, S. N., Lerner, C. A., Desprez, P.-Y., Schilling, B., Campisi, J., & Gerencser, A. A. (2024) · GeroScience · doi:10.1007/s11357-024-01167-3 · Cited by 17 · see citing works
Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex
Sloan, N. X., Mares, J., Daly, A. C., Grier, S., Haq, I., Jackson, C. A., Barretto, N., Casel, O., Kang, K., Khiste, S., et al. (2026) · Cell Genomics · doi:10.1016/j.xgen.2025.101127 · Cited by 2 · see citing works
“24 34–36 Further, whole-body clearance of senescent cells in mice, either pharmacologically using dasatinib and quercetin (D + Q) or genetically in INK-ATTAC (p16INK4a apoptosis through targeted activation of caspase 8) 37 mice treated with AP20187, resulted in improved cognitive function and…”
- Authors
- Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Idda, M. Laura
- Gorospe, Myriam
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2020-03-11
- Volume
- 12
- Issue
- 5
- Pages
- 4052-4066
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC7093180
- OpenAlex
- W3010870651
- Cited by
- 188
- References
- 13
- Citations by year
- 2026: 34 · 2025: 37 · 2024: 35 · 2023: 28 · 2022: 24 · 2021: 18 · 2020: 12
- FWCI
- 12.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by
- Locations
- Aging (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Aging
- 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, CDKN2A/p16, CDKN1A/p21, age-related diseases, senescence-associated secretory phenotype, skin, pancreas, kidney, cerebral cortex, liver, spleen, colon, lung, muscle
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Aging, Female, Humans, Intestinal Mucosa, Kidney, Liver, Male, Middle Aged, Organ Specificity, Pancreas, Skin, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
