An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo
Open accessAbstract
The role of senescent cells has been implicated in various tissue dysfunction associated with aging, obesity, and other pathological conditions. Currently, most transgenic mouse models only target p16 Ink4a-highly-expressing (p16 high) cells. Here, we generated a p21-Cre mouse model, containing a p21 promoter driving inducible Cre, enabling us to examine p21 Cip1-highly-expressing (p21 high) cells, a previously unexplored cell population exhibiting several characteristics typical of senescent cells. By crossing p21-Cre mice with different floxed mice, we managed to monitor, sort, image, eliminate, or modulate p21 high cells in vivo. We showed p21 high cells can be induced by various conditions, and percentages of p21 high cells varied from 1.5 to 10% across different tissues in 23-month-old mice. Intermittent clearance of p21 high cells improved physical function in 23-month-old mice. Our study demonstrates that the p21-Cre mouse model is a valuable and powerful tool for studying p21 high cells to further understand the biology of senescent cells.
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Many senescence triggers activate DNA damage response signaling and p53/p21, p16/RB or other pathways, producing cell cycle arrest and a SASP.
“Many such stressors activate DNA damage response signaling and activation of the p53/p21CIP1/WAF1, p16INK4a/retinoblastoma protein or other pathways, resulting in cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP)24,40,48−53”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [49]
The Introduction (page not available) says that stimuli including DNA damage can drive senescence through p16/Rb, p53/p21 and probably other pathways, with growth arrest and a SASP. It does not say that many of those stressors activate DNA damage response signaling, so that part of the attributed claim is not supported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe accumulation of p21+ cells has been identified in aged tissues in vivo, and clearance of this population in rodents has been shown to both extend lifespan and improve healthspan.
“The accumulation of p21 positive (p21+) cells has been identified in aged tissues in vivo, and clearance of this population in rodents has been shown to both extend lifespan and improve healthspan [7,8,9].”
From Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution (2026) · cites this paper as [8]
The Results section reports that p21-high cells accumulate in tissues with aging. It also reports that clearing these cells alleviated physical frailty in old mice, supporting improved healthspan-related function. The paper does not report that clearing p21-high cells extended lifespan; page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredp21-Cre dual-reporter mice on C57BL/6 background were generated as previously described.
“p21-Cre dual-reporter mice on C57BL/6 background were generated as previously described [7,8,13].”
From Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution (2026) · cites this paper as [8]
The Results sections on model generation and p21-high cells describe generating p21-Cre mice with a GFP reporter and crossing them with floxed tdTomato mice to produce reporter mice. The cited paper therefore supports the mouse-model identification, but the passages do not establish that the mice were on a C57BL/6 background. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThese p21+ cells accumulated across multiple tissues in 23-month-old mice, whereas minimal labeling was present in 3-month-old mice, and their depletion improved lifespan and physical function.
“These p21+ cells also accumulated across multiple tissues in 23-month-old mice, whereas minimal labeling was present in 3-month-old mice, and their depletion improved lifespan and physical function [7,8,13].”
From Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution (2026) · cites this paper as [8]
The Results section on tissue accumulation reports more labeled p21-high cells in several tissues of 23-month-old mice and very few in 3-month-old mice. The Results section on clearance reports improved physical function after depletion, but our copy does not report that depletion of these cells increased lifespan; its Introduction discusses lifespan findings for p16-high cells instead. No page numbers are available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCdkn1ahigh and Cdkn2ahigh cells exist as two distinct cell populations in adipose tissue, indicating heterogeneity and complexity of senescent cell populations.
“Importantly, Cdkn1ahigh and Cdkn2ahigh cells exist as two distinct cell populations122,125, indicating the heterogeneity and complexity of senescent cell populations in adipose tissue.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [125]
In prior study, reporter-positive cells showed increased p21 expression together with enlarged cell size, increased SA-β-gal activity, reduced EdU incorporation, and decreased Lamin B1 expression.
“In our prior study, reporter-positive cells showed increased p21 expression together with enlarged cell size, increased SA-β-gal activity, reduced EdU incorporation, and decreased Lamin B1 expression [8].”
From Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution (2026) · cites this paper as [8]
Age-related changes in the immune system are characterized by altered ratios of naïve and memory T cells, lymphoid to myeloid cells, CD4+ to CD8+ cells, and thymic atrophy.
“These age-related changes are characterized by altered ratios of naïve and memory T cells, lymphoid to myeloid cells, CD4+ to CD8+ cells, and thymic atrophy.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [91]
The Results section on p16-high and p21-high cells describes immune cell types in aged mouse tissues, but not age-related changes in their ratios. Searches for naïve and memory T cells, CD4/CD8 ratios, lymphoid-to-myeloid ratios, and thymic atrophy found no passage addressing the claimed pattern; the References mention memory-like T cells only in another paper’s title. (LLM, conf=0.76)
Experimental — accuracy not yet measuredWith aging, the immune system loses its ability to mount an effective immune response against invading pathogens and cancer cells, termed immunosenescence.
“With aging, the immune system loses its ability to mount an effective immune response against invading pathogens and cancer cells, a phenomenon termed immunosenescence91.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [91]
The Introduction (page unavailable) discusses cellular senescence and its increase with aging, not an age-related loss of immune responses to pathogens or cancer cells. Searches for “immunosenescence,” immune responses, pathogens, and cancer found no passage defining or substantiating the claimed phenomenon; a reference to impaired immune surveillance concerns senescent-cell accumulation instead. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSenescence markers beyond p16 include p21, p19, uPAR, and GPNMB.
“Studies have begun to reveal the remarkable heterogeneity of cellular senescence in different tissues, highlighting the importance of cellular senescence markers beyond p16 – including Cdkn1a (p21) [7–10], Cdkn2d (p19) [11], uPAR [12], and glycoprotein non-metastatic melanoma protein B (GPNMB) [13] – and emphasizing the urgent need for a better understanding of senescent cell heterogeneity.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [9]
Clearance of p21high cells reduces senescence markers, improves physical function in aged mice, and alleviates metabolic dysfunction in obese mice.
“Remarkably, clearance of p21high cells reduces senescence markers, improves physical function in aged mice [9], and alleviates metabolic dysfunction in obese mice [10].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [9]
A p21-Cre transgenic mouse model targets p21high cells in vivo, which comprise 1-10% of cells in various tissues in aged mice, are distinct from p16high cells, and both display key characteristics of senescence.
“In 2021, a p21-Cre transgenic mouse model was generated, containing a p21 promoter driving an inducible Cre. This model targets p21 highly expressing (p21high) cells in vivo, which comprise 1–10% of cells in various tissues in aged mice, and are distinct from p16high cells, with both displaying a number of key characteristics of senescence [9].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [9]
Similar discrepancies between p21high and p16high cells were recapitulated in aged mice.
“Similar discrepancies were recapitulated in aged mice [9].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [9]
Imaging flow cytometry allows protein-level detection of several senescence markers or reporters along with assessment of several senescence features at the single-cell level in a relatively high-throughput manner.
“Another useful technology for examining senescent cells is imaging flow cytometry, which has been used to examine senescent cells in vivo [9,10,36]. The major advantage of this method is that it allows for protein-level detection of several senescence markers or reporters along with assessment of several senescence features at the single-cell level in a relatively high-throughput manner.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [9]
Similar approaches are emerging for the elimination of p21-expresing cells.
“Similar approaches are emerging for the elimination of p21-expresing cells (Wang et al., 2021).”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Wang et al., 2021
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Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
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Senescent cell turnover slows with age providing an explanation for the Gompertz law
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Diphtheria toxin. Site and configuration of ADP-ribosylation of diphthamide in elongation factor 2.
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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
Self-citationA Blueprint for Characterizing Senescence
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Transplanting cells from old but not young donors causes physical dysfunction in older recipients
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Cellular 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
Self-citationStrategies 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
Self-citationSenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
“Importantly, Cdkn1a high and Cdkn2a high cells exist as two distinct cell populations 122,125 , indicating the heterogeneity and complexity of senescent cell populations in adipose tissue.”
Self-citationGuidelines 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
Self-citationThe 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
Self-citationNuclear 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
Senescent alveolar macrophages promote early-stage lung tumorigenesis
Prieto, L. I., Sturmlechner, I., Graves, S. I., Zhang, C., Goplen, N. P., Yi, E. S., Sun, J., Li, H., & Baker, D. J. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.006 · Cited by 212 · see citing works
Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
Wang, L., Wang, B., Gasek, N. S., Zhou, Y., Cohn, R. L., Martin, D. E., Zuo, W., Flynn, W. F., Guo, C., Jellison, E. R., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.11.002 · Cited by 163 · see citing works
Self-citationSenNet Consortium, Writing Group, Lee, P. J., Benz, C. C., Blood, P., Börner, K., Campisi, J., Chen, F., Daldrup-Link, H., De Jager, P., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00326-5 · Cited by 122 · see citing works
Self-citationAntignano, I., Liu, Y., Offermann, N., & Capasso, M. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04775-y · Cited by 117 · see citing works
Chandra, A., Lagnado, A. B., Farr, J. N., Doolittle, M., Tchkonia, T., Kirkland, J. L., LeBrasseur, N. K., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13602 · Cited by 120 · see citing works
Self-citationLee, G., Kim, Y. Y., Jang, H., Han, J. S., Nahmgoong, H., Park, Y. J., Han, S. M., Cho, C., Lim, S., Noh, J.-R., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.03.010 · Cited by 111 · see citing works
Englund, D. A., Zhang, X., Aversa, Z., & LeBrasseur, N. K. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111595 · Cited by 94 · see citing works
The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress
Anerillas, C., Mazan-Mamczarz, K., Herman, A. B., Munk, R., Lam, K.-W. G., Calvo-Rubio, M., Garrido, A., Tsitsipatis, D., Martindale, J. L., Altés, G., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00480-4 · Cited by 76 · 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
Wang, B., Wang, L., Gasek, N. S., Kuo, C.-L., Nie, J., Kim, T., Yan, P., Zhu, J., Torrance, B. L., Zhou, Y., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.07.006 · Cited by 59 · see citing works
Self-citationDoolittle, 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
Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing
Gasek, N. S., Yan, P., Zhu, J., Purushothaman, K.-R., Kim, T., Wang, L., Wang, B., Flynn, W. F., Sun, M., Guo, C., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00755-4 · Cited by 43 · see citing works
Self-citationAdvancing biological understanding of cellular senescence with computational multiomics
Li, S., Agudelo Garcia, P. A., Aliferis, C., Becich, M. J., Calyeca, J., Cosgrove, B. D., Elisseeff, J., Farzad, N., Fertig, E. J., Glass, C., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02314-y · Cited by 40 · see citing works
Self-citationA p21-GFP zebrafish model of senescence for rapid testing of senolytics in vivo
Morsli, S., Henriques, C. M., Ellis, P. S., Mortiboys, H., Baxendale, S., Loynes, C. A., Renshaw, S. A., & Bellantuono, I. (2023) · Aging Cell · doi:10.1111/acel.13835 · Cited by 21 · see citing works
Hsu, J.-E., Wang, B., Hwang, Y., Cheng, W., Zhao, Q., Si, Y., Xu, M., Kang, H.-M., & Lee, J. H. (2026) · Biomolecules · doi:10.3390/biom16040579
“In our prior study, reporter-positive cells showed increased p21 expression together with enlarged cell size, increased SA-β -gal activity, reduced EdU incorporation, and decreased Lamin B1 expression [8].”
InfluentialSelf-citation
- Authors
- Wang, B., Wang, L., Gasek, N. S., Zhou, Y., Kim, T., Guo, C., Jellison, E. R., Haynes, L., Yadav, S., Tchkonia, T., Kuchel, G. A., Kirkland, J. L., & Xu, M.
- Affiliations
- University of Connecticut (US)
- Central South University (CN)
- UConn Health (US)
- Mayo Clinic (US)
- Corresponding author
- Xu, Ming
- ORCID
- Venue
- Nature Aging
- Published
- 2021-10-07
- Volume
- 1
- Issue
- 10
- Pages
- 962-973
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC8746571
- OpenAlex
- W3202638310
- Cited by
- 145
- References
- 67
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 42 · 2023: 32 · 2022: 24 · 2021: 3
- FWCI
- 15.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG063528, AG066679, AG068860)
- 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
- senescent cells, p21, cellular senescence, p16INK4a, aging, physical function, senolytics, cell clearance, tissue dysfunction, obesity
- MeSH terms
- Aging, Animals, Mice, Transgenic, Cellular Senescence, Integrases, Cyclin-Dependent Kinase Inhibitor p16, Mice
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