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Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
Open accessAbstract
Cell senescence plays a key role in age-associated organ dysfunction, but the in vivo pathogenesis is largely unclear. Here, we generated a p16-Cre ERT2-tdTomato mouse model to analyze the in vivo characteristics of p16 high cells at a single-cell level. We found tdTomato-positive p16 high cells detectable in all organs, which were enriched with age. We also found that these cells failed to proliferate and had half-lives ranging from 2.6 to 4.2 months, depending on the tissue examined. Single-cell transcriptomics in the liver and kidneys revealed that p16 high cells were present in various cell types, though most dominant in hepatic endothelium and in renal proximal and distal tubule epithelia, and that these cells exhibited heterogeneous senescence-associated phenotypes. Further, elimination of p16 high cells ameliorated nonalcoholic steatohepatitis-related hepatic lipidosis and immune cell infiltration. Our new mouse model and single-cell analysis provide a powerful resource to enable the discovery of previously unidentified senescence functions in vivo.
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“Other mice that have been used to label senescent cells in vivo include a p16-tdTomato mouse 32 and a p16-CreERT2; ROSA26tdTomato double transgenic reporter mouse, 33 among other alternatives reviewed in Ref.”
BackgroundSenolytic Prodrugs: A Promising Approach to Enhancing Senescence‐Targeting Intervention
Chang, M., Dong, Y., Cruickshank‐Taylor, A. B., Gnawali, G. R., Bi, F., & Wang, W. (2024) · ChemBioChem · doi:10.1002/cbic.202400355 · Cited by 20
Qu, Y., Meng, B., Cai, S., Yang, B., He, Y., Fu, C., Li, X., Li, P., Cao, Z., Mao, X., et al. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02820-x · Cited by 22
UBE2E3 regulates cellular senescence and osteogenic differentiation of BMSCs during aging
Liu, Y., Cai, G., Chen, P., Jiang, T., & Xia, Z. (2021) · PeerJ · doi:10.7717/peerj.12253 · Cited by 19
“4C), and the transcription level of p16 ( Omori et al., 2020 ; Xiao et al., 2020 ) and p21 ( Zhang et al., 2019 ), markers of cellular senescence, also increased (Fig.”
Chen, M., Wu, G., Lu, Y., Sun, S., Zhao, Y., Pan, X., Chen, W., Xu, J., Qiu, H., He, W., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.04.002 · Cited by 18
Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise
Hinterleitner, C., Goldberg, H. V., McHugh, D., Barthet, V. J. A., Filliol, A. A., & Lowe, S. W. (2026) · Cell · doi:10.1016/j.cell.2026.03.005 · Cited by 20
Recent Advances in Senolysis for Age-Related Diseases
Aratani, S., & Nakanishi, M. (2023) · Physiology · doi:10.1152/physiol.00003.2023 · Cited by 16
Self-citationIntracellular acidification and glycolysis modulate inflammatory pathway in senescent cells
Kawakami, S., Johmura, Y., & Nakanishi, M. (2024) · The Journal of Biochemistry · doi:10.1093/jb/mvae032 · Cited by 16
“Previously, we generated p16-CreER T2 mouse model that allows the visualization and elimination of p16-high expressing senescent cells in vivo and found that the elimination of senescent cells prevented the progression of non-alcoholic steatohepatitis ( 3 ).”
BackgroundSelf-citationHomologous recombination-mediated irreversible genome damage underlies telomere-induced senescence
Ghadaouia, S., Olivier, M., Martinez, A., Kientega, T., Jian, Q., Lambert-Lanteigne, P., Cardin, G. B., Autexier, C., Malaquin, N., & Rodier, F. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab965 · Cited by 17
“Notwithstanding their rare occurrence, these truly senescent cells may have been diluted by competition with growing cells or by potential clearance, which could explain their low abundance and the difficulties in identifying these cells (81,82).”
BackgroundAging and metabolic dysfunction-associated steatotic liver disease: a bidirectional relationship
Chen, C., & Wang, L. (2025) · Frontiers of Medicine · doi:10.1007/s11684-025-1133-7 · Cited by 15
Ozawa, M., Mori, H., Endo, T., Ishikawa-Yamauchi, Y., Motooka, D., Emori, C., & Ikawa, M. (2023) · iScience · doi:10.1016/j.isci.2023.108456 · Cited by 13
Self-citationMechanisms of cellular senescence-induced vascular aging: evidence of senotherapeutic strategies
Mahoney, S. A., Bloom, S. I., Seals, D. R., Donato, A. J., Rossman, M. J., & Clayton, Z. S. (2025) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2024.31 · Cited by 15
“Indeed, in these settings, senescent vascular cells arise within nearly all tissues, including the eye [207,208] , skeletal muscle [209] , heart [210] , kidney [211,212] , liver [213–215] , pancreas [213] , testes [216] , brain [217–220] , adipose tissue [210,221] , and lung [156,222,223] .”
Stromal senescence contributes to age-related increases in cancer
Ye, J., Melam, A., & Stewart, S. A. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00840-9 · Cited by 16
Shirakami, Y., Kato, J., Maeda, T., Ideta, T., Imai, K., Sakai, H., Shiraki, M., & Shimizu, M. (2023) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.16171 · Cited by 13
Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies
Gazzillo, A., Volponi, C., Soldani, C., Polidoro, M. A., Franceschini, B., Lleò, A., Bonavita, E., & Donadon, M. (2023) · Biomedicines · doi:10.3390/biomedicines12010026 · Cited by 14
Park, S. S., Lee, Y., Kim, Y. H., Park, S. H., Kang, H. Y., Kim, J. C., Kim, D. J., Lim, S. B., Yoon, G., Kim, J., et al. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01354-4 · Cited by 15
Tumor-Associated Senescent Macrophages, Their Markers, and Their Role in Tumor Microenvironment
Pukhalskaia, T. V., Yurakova, T. R., Bogdanova, D. A., & Demidov, O. N. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924050055 · Cited by 12
Yakubo, S., Abe, H., Li, Y., Kudo, M., Kimura, A., Wakabayashi, T., Watanabe, Y., Kimura, N., Setsu, T., Yokoo, T., et al. (2024) · Diseases · doi:10.3390/diseases12120317 · Cited by 12
“In addition, Omori et al. reported that senescent cell removal reduces lipidosis and fibrosis in conditionally KO mice that eliminate p16-positive cells [28].”
Li, D., Wang, T., Aratani, S., Omori, S., Tamatani, M., Johmura, Y., & Nakanishi, M. (2023) · The Journal of Biochemistry · doi:10.1093/jb/mvad021 · Cited by 12
“To infer the role of LONRF1 in cellular senescence, we examined scRNA-seq datasets of LSECs, a rich set of cell types, in normal and NASH livers of the p16-Cre-tdTomato (p16-Tom) mouse model (10) (Figure 3A-3C).”
BackgroundMethodInfluentialSelf-citationSenomorphic effect of diphenyleneiodonium through AMPK/MFF/DRP1 mediated mitochondrial fission
Liao, K.-M., Chen, C., Luo, W., Hsu, C.-W., Yu, S., Yang, P., & Su, K. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114616 · Cited by 11
Sugiyama, Y., Harada, T., Kamei, Y., Yasuda, T., Mashimo, T., Nishikimi, A., & Maruyama, M. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112130 · Cited by 12
Aging microvasculature: Effects on immune cell trafficking and inflammatory diseases
Reglero-Real, N., Rolas, L., & Nourshargh, S. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20242154 · Cited by 11
In vivo dynamics of senescence in rhabdomyolysis-induced acute kidney injury
Harris, A. S., Aratani, S., Johmura, Y., Suzuki, N., Li, D., & Nakanishi, M. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.06.046 · Cited by 11
Self-citationDetecting cellular senescence in vivo: Imagining imaging better
Rabinowitz, Z. M., & Cui, L. (2023) · Aging and Cancer · doi:10.1002/aac2.12067 · Cited by 10
Kientega, T., Marcoux, S., Bourbonnais, J., Montpetit, J., Caru, M., Cardin, G. B., Arbour, N., Marcil, V., Curnier, D. Y., Laverdière, C., et al. (2024) · Blood Cancer Journal · doi:10.1038/s41408-024-01071-1 · Cited by 12
Characterizing primary and secondary senescence in vivo
Sogabe, Y., Shibata, H., Kabata, M., Tanaka, A., Mitsunaga, K., Sunadome, K., Nakajima‐Koyama, M., Hirano, M., Nishida, E., Woltjen, K., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00917-y · Cited by 14
“Since most previous studies have focused on in vitro senescent cells, information about diversity of the individual cell in vivo 77 has been largely unclear.”
Self-citationNanomaterials intervene in cell senescence to reinforce cancer therapy
Sun, S., Yang, N., Nie, J., Yang, Z., Pei, Z., Ding, R., & Cheng, L. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.217012 · Cited by 10
Cellular senescence in kidney diseases
Wang, X., Li, Y., Chu, Q., Lv, H., Li, J., & Yi, F. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003746 · Cited by 12
“[11] The DDR significantly contributes to the development and progression of CKD, especially when combined with additional insults such as infections, exposure to lipopolysaccharides, uremic toxins, or the effects of dialysis treatments.”
Metadata
- Authors
- Omori, S., Wang, T.-W., Johmura, Y., Kanai, T., Nakano, Y., Kido, T., Susaki, E. A., Nakajima, T., Shichino, S., Ueha, S., Ozawa, M., Yokote, K., Kumamoto, S., Nishiyama, A., Sakamoto, T., Yamaguchi, K., Hatakeyama, S., Shimizu, E., Katayama, K., Yamada, Y., Yamazaki, S., Iwasaki, K., Miyoshi, C., Funato, H., Yanagisawa, M., Ueno, H., Imoto, S., Furukawa, Y., Yoshida, N., Matsushima, K., Ueda, H. R., Miyajima, A., & Nakanishi, M.
- Affiliations
- Institute of Medical Science, The University of Tokyo (JP)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- Tokyo University of Science (JP)
- Kanazawa University (JP)
- Japan Agency for Medical Research and Development (JP)
- University of Tsukuba (JP)
- Toho University (JP)
- Kansai Medical University (JP)
- Corresponding author
- Johmura, Yoshikazu
- Nakanishi, Makoto
- ORCID
- Omori, Satotaka
- Wang, Teh-Wei
- Johmura, Yoshikazu
- Kanai, Tomomi
- Nakano, Yasuhiro
- Kido, Taketomo
- Susaki, Etsuo A.
- Shichino, Shigeyuki
- Ueha, Satoshi
- Ozawa, Manabu
- Kumamoto, Soichiro
- Nishiyama, Atsuya
- Sakamoto, Takeharu
- Yamaguchi, Kiyoshi
- Hatakeyama, Seira
- Shimizu, Eigo
- Katayama, Kotoe
- Yamada, Yasuhiro
- Yamazaki, Satoshi
- Miyoshi, Chika
- Funato, Hiromasa
- Yanagisawa, Masashi
- Imoto, Seiya
- Furukawa, Yoichi
- Yoshida, Nobuaki
- Matsushima, Kouji
- Ueda, Hiroki R.
- Miyajima, Atsushi
- Nakanishi, Makoto
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 32
- Issue
- 5
- Pages
- 814-828.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3087571995
- Cited by
- 194
- References
- 98
- Citations by year
- 2026: 30 · 2025: 32 · 2024: 43 · 2023: 37 · 2022: 26 · 2021: 23 · 2020: 3
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Princess Takamatsu Cancer Research Fund (17H06095, 19H03413, JP16H06276, JP18H05026m, JP19H03431, JP20H04940)
- Ministry of Education, Culture, Sports, Science and Technology
- Core Research for Evolutional Science and Technology (A3A28043, AMED JP20am0401411)
- Ono Medical Research Foundation
- Olympus
- Japan Society for the Promotion of Science (JP16K15239, JP17cm0106122, JP17fk0310111, JP17gm5010001, JP20ck0106550, JP22118003, JP26250027)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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, nonalcoholic steatohepatitis, hepatic lipidosis, immune cell infiltration, single-cell analysis
- MeSH terms
- Animals, Cell Line, Humans, Mice, Inbred C57BL, Models, Biological, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Mice, Single-Cell Analysis
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