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Strategies for targeting senescent cells in human disease
Open accessAbstract
Cellular senescence represents a distinct cell fate characterized by replicative arrest in response to a host of extrinsic and intrinsic stresses. Senescence provides programming during development and wound healing, while limiting tumorigenesis. However, pathologic accumulation of senescent cells is implicated in a range of diseases and age-associated morbidities across organ systems. Senescent cells produce distinct paracrine and endocrine signals, causing local tissue dysfunction and exerting deleterious systemic effects. Senescent cell removal by apoptosis-inducing "senolytic" agents or therapies that inhibit the senescence-associated secretory phenotype, SASP inhibitors, have demonstrated benefit in both pre-clinical and clinical models of geriatric decline and chronic diseases, suggesting senescent cells represent a pharmacologic target for alleviating effects of fundamental aging processes. However, senescent cell populations are heterogeneous in form, function, tissue distribution, and even differ among species, possibly explaining issues of bench-to-bedside translation in current clinical trials. Here, we review features of senescent cells and strategies for targeting them, including immunologic approaches, as well as key intracellular signaling pathways. Additionally, we survey current senolytic therapies in human trials. Collectively, there is demand for research to develop targeted senotherapeutics that address the needs of the aging and chronically-ill.
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“Through upregulation of pro-survival and antiapoptotic pathways such as SRC kinases, the PI3K-AKT signaling pathway, heat shock protein (HSP) pathways, serpines, mitochondrial pathways or apoptosis regulator BCL-2-related proteins, those senescent cells with a proapoptotic SASP can survive, despite the cytotoxic microenvironment they create6,7,14,34,35,54–58.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [58]
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“but also enhance SASP autocrine loop, as found in multiple previous studies,124,125,126,127”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [127]
Experimental — accuracy not yet measuredIn the citing paper
“Persistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis33,96,112,177,178.”
From COVID-19 and cellular senescence (2023) · cites this paper as [96]
In the citing paper
“Senescent cells are highly associated with aging and pathological conditions and could be targeted to slow the aging process.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [3]
In the citing paper
“At the transcript level, p16 and p21 are the two most commonly used markers for senescent cells [3,16].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [3]
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Self-citation
Cited by
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Items 201–300 of 500
Lysosomal-Associated Protein Transmembrane 5, Tubular Senescence, and Progression of CKD
Liu, X., Zhan, P., Zhang, Y., Jin, H., Wang, Y., Yang, Y., Wang, Z., Wang, X., Xu, Q., Zhen, J., et al. (2024) · Journal of the American Society of Nephrology · doi:10.1681/asn.0000000000000446 · Cited by 16
“27 30 Transplantation of a small number of senescent renal scattered tubular-like cells are suf fi cient to induce kidney injury.”
CAR T treatment beyond cancer: Hope for immunomodulatory therapy of non-cancerous diseases
Yang, Z., Liu, Y., & Hai, Z. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122556 · Cited by 16
Transcription factor networks in cellular quiescence
Mitra, M., Batista, S., & Coller, H. A. (2025) · Nature Cell Biology · doi:10.1038/s41556-024-01582-w · Cited by 16
“The reversibility of cellular quiescence is in contrast with the irreversible nature of the senescent cell state (an irreversible G0 state) that is encountered during development, ageing and certain diseases, where the cells permanently exit the cell cycle 105 (see figure).”
Balaraman, A. K., Altamimi, A. S. A., Babu, M. A., Goyal, K., Padmapriya, G., Bansal, P., Rajotiya, S., Kumar, M., Rajput, P., Imran, M., et al. (2025) · Biogerontology · doi:10.1007/s10522-025-10190-6 · Cited by 16
“In rodent models, senolytics have demonstrated improved outcomes, such as reduced infarct size and enhanced myocardial repair (Gasek et al. 2021).”
Stem Cell-Derived Extracellular Vesicles in Skin Antiaging Treatments
Park, J. Y., Jung, S. Y., Yoo, D., Lee, S., Go, D., Bui, V. D., Jung, W., You, D. G., Park, J. H., & Um, W. (2025) · ACS Nano · doi:10.1021/acsnano.4c17406 · Cited by 18
Wu, H., Zhang, Q., Zhu, J., Wu, L., Xiao, Y., & Yang, X. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.09.002 · Cited by 18
“Although senolytic agents that selectively induce apoptosis by targeting anti-apoptotic pathways have shown remarkable potential in preclinical studies [32,147 – 151], their clinical translation faces core obstacles rooted in poor pharmacokinetics and a lack of target specificity [152, 153].”
Deryabin, P. I., Shatrova, A. N., & Borodkina, A. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214251 · Cited by 15
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“Cellular senescence is a mostly irreversible state of proliferative arrest enforced by expression of cyclin-dependent kinase inhibitors like p21 and p16 (Gasek et al., 2021).”
BackgroundSelf-citationSun, Y. (2023) · Translational Medicine of Aging · doi:10.1016/j.tma.2023.06.001 · Cited by 15
Diniz, B. S., Seitz‐Holland, J., Sehgal, R., Kasamoto, J., Higgins‐Chen, A., & Lenze, E. J. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.09.014 · Cited by 15
T-cell immunity against senescence: potential role and perspectives
Matveeva, K. S., Vasilieva, M., Minskaia, E., Александрович, Р. С., & Shevyrev, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1360109 · Cited by 17
“Thus, despite the encouraging results of recent years in the fi eld of anti-aging therapies (36), the problem of fi nding and developing an effective and safe method for the elimination of senescent cells with the potential for translation into clinical medicine is still acute.”
BackgroundExpanding the horizon of CAR T cell therapy: from cancer treatment to autoimmune diseases and beyond
Yang, Z., Ha, B., Wu, Q., Ren, F., Yin, Z., & Zhang, H. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1544532 · Cited by 18
“CAR-T cells have been applied to autoimmune diseases (46 – 48), infectious diseases (49 – 51), senescence-associated diseases (52), and other fi elds (Figure 3, Table 2).”
Zhang, X., Zhuang, M., Zhang, H., Zhu, Y., Yang, J., Wu, X., Yu, X., Tao, J., & Liu, X. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108438 · Cited by 15
Aging 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
Transitioning from native to synthetic receptors: broadening T-cell engineering and beyond
Li, Y., Liu, Y., & Lin, X. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01304-8 · Cited by 17
Jiang, S.-L., Wang, D., Zou, C., Zhu, Z., Luo, C., & Wang, Z. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108906 · Cited by 14
Cellular senescence in adult pulmonary hypertension: current state and future challenges
Lemay, S.-E. S., Kuwabara, Y., Bonnet, S., Potus, F., Provencher, S., Adnot, S., & Boucherat, O. (2025) · European Respiratory Review · doi:10.1183/16000617.0030-2025 · Cited by 15
Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes
Bochyńska, A., Stenzel, A. T., Sayadi-Boroujeni, R., Kuo, C., Barsoum, M., Liang, W., Bussmann, P., Costa, I. G., Lüscher‐Firzlaff, J., & Lüscher, B. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac591 · Cited by 14
“These have been described to selectively kill senescent cells (36).”
BackgroundShyu, Y., Liao, P.-C., Huang, T., Yang, C., Lu, M., Huang, S., Lin, X., Liou, C., Kao, Y.-J., Lu, C.-H., et al. (2022) · Advanced Science · doi:10.1002/advs.202201409 · Cited by 12
Kapoor, N., Bhattacharjee, A., Chakraborty, S., & Katti, D. S. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176136 · Cited by 14
The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies
Nunkoo, V. S., Cristian, A., Jurcău, A., Diaconu, R. G., & Jurcău, M. C. (2024) · Biomedicines · doi:10.3390/biomedicines12112540 · Cited by 15
Jiang, B., Zhang, H., Xu, Q., Jiang, Z., He, R., Fu, Q., & Sun, Y. (2025) · Aging Cell · doi:10.1111/acel.70138 · Cited by 14
“As an emerging therapeutic modality, senotherapy represents a feasible and effective therapeutic strategy to prevent, delay, or mitigate diverse age-related dysfunctions and disorders, thus having received intensive attention (Gasek et al. 2021).”
Exploring replication stress and cellular senescence as key targets in novel cancer therapies
Ray, S. K., & Mukherjee, S. (2025) · Cancer Genetics · doi:10.1016/j.cancergen.2025.09.002 · Cited by 14
Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies
Dey, A. K., Banarjee, R., Boroumand, M., Rutherford, D. V., Strassheim, Q., Nyunt, T., Olinger, B., & Basisty, N. (2023) · Biology · doi:10.3390/biology12101301 · Cited by 12
“While we discuss here the emerging use and need for proteomic biomarkers in clinical research, we direct readers elsewhere for more comprehensive reviews of current and planned senolytic trials [3,115].”
BackgroundIdentified senescence endotypes in aged cartilage are reflected in the blood metabolome
Boone, I., Tuerlings, M., de Almeida, R. C., Lehmann, J., Ramos, Y. F., Nelissen, R. G. H. H., Slagboom, P. E., de Keizer, P. L. J., & Meulenbelt, I. (2023) · GeroScience · doi:10.1007/s11357-023-01001-2 · Cited by 13
“The field has in recent years developed multiple drugs to target senescent cells either by selectively killing senescent cells (senolytics) or modifying their behavior (senomorphics) [12].”
BackgroundCellular 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
The enchanting canvas of CAR technology: Unveiling its wonders in non-neoplastic diseases
Shu, J., Xie, W., Chen, Z., Offringa, R., Hu, Y., & Mei, H. (2024) · Med · doi:10.1016/j.medj.2024.03.016 · Cited by 13
scDOT: optimal transport for mapping senescent cells in spatial transcriptomics
Nguyen, N. D., Rosas, L., Khaliullin, T. O., Jiang, P., Hasanaj, E., Ovando-Ricárdez, J. A., Bueno, M., Rahman, I., Pryhuber, G., Li, D., et al. (2024) · Genome biology · doi:10.1186/s13059-024-03426-0 · Cited by 12
From bench to bedside: The critical need for standardized senescence detection
Shah, J., Al-Hashimi, A., Benedetto, M., & Ruchaya, P. J. (2025) · Archives of cardiovascular diseases · doi:10.1016/j.acvd.2024.12.008 · Cited by 13
Wlaschek, M., Maity, P., Koroma, A. K., Geiger, H., Singh, K., & Scharffetter‐Kochanek, K. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.03.024 · Cited by 17
Circadian rhythm, hypoxia, and cellular senescence: From molecular mechanisms to targeted strategies
Nie, T., Nepovimová, E., & Wu, Q. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177290 · Cited by 13
Zhang, Z., He, X., Sun, Y., Li, J., & Sun, J. (2025) · Aging and Disease · doi:10.14336/ad.2025.0233 · Cited by 16
“In recent years, studies on senolytics have pointed to the fact that senescent cells release large amounts of pro-inflammatory factors that exacerbate IR and β -cell hypoplasia and that targeted removal of these cells can help reduce inflammation and improve the overall metabolic environment [216].”
Li, P. L., Tang, J., Li, X. T., Zhao, S. R., Xu, R. X., Zhao, Z. D., Zhong, L., Li, Z. L., Yin, B. F., Yu, F., et al. (2025) · Science Advances · doi:10.1126/sciadv.adu2294 · Cited by 16
“Moreover, accumulating evidence reveals that cellular senescence exhibits considerable heterogeneity across different tissues ( 25 , 26 ), highlighting the importance of characterizing senescent cell heterogeneity to develop targeted senolytic therapies.”
Liu, Y., Feng, Y., Cheng, L. L., Xu, Y., Wu, A., & Cheng, P. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07915-3 · Cited by 12
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“Cellular senescence is one of the hallmarks of aging and is usually accompanied by various senescence-related features [24].”
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“Current practices to detect senescence rely on the combination of multiple markers such as the expression of cyclin-dependent kinase inhibitors p16Ink4a and p21Cip1 (contribute to G1/S cell cycle blockade), serine 139 phosphorylated H2A histone family member X (γ-H2AX), presence of Senescence Associated Secretory Phen…”
BackgroundKuai, Z., Chao, X., He, Y., & Ren, W. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112331 · Cited by 16
Li, S., Wang, F., Xing, X., Yue, X., Sun, S., Lin, H., & Xu, C. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202303476 · Cited by 12
Cellular senescence in acute kidney injury: Target and opportunity
Li, T., Yang, K., Gao, W., Peng, F., & Zou, X. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.149744 · Cited by 13
Zhang, Y., Zhang, J., Lesani, P., Lu, Z., & Zreiqat, H. (2024) · Stem Cell Reviews and Reports · doi:10.1007/s12015-024-10707-5 · Cited by 12
“Ideally, senescent cell rejuvenation strategies should target ameliorating detrimental effects while maintaining beneficial functions [44].”
BackgroundResultIron retardation in lysosome protects senescent cells from ferroptosis
Feng, Y., Wei, H., Lyu, M., Yu, Z., Chen, J., Lyu, X., & Zhuang, F. (2024) · Aging · doi:10.18632/aging.205777 · Cited by 14
Cellular senescence in metastatic prostate cancer: A therapeutic opportunity or challenge (Review)
Jin, C., Liao, S., Lu, G., Geng, B. D., Ye, Z., Xu, J., Ge, G., & Yang, D. (2024) · Molecular Medicine Reports · doi:10.3892/mmr.2024.13286 · Cited by 12
“This dual‑phase strategy aims to avoid the possible tumor‑promoting effects of senescent cells (105).”
BackgroundResultMorelli, N. R., Préfontaine, C., Pipella, J., & Thompson, P. J. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00257.2024 · Cited by 12
Cellular senescence: A new perspective on the suppression of periodontitis (Review)
Lin, X.-J., Yuan, Q., Zhou, J., Dong, Y., Sunchuri, D., & Guo, Z.-L. (2024) · Molecular Medicine Reports · doi:10.3892/mmr.2024.13362 · Cited by 14
“Activation of the SASP initiates a milieu of chronic inflammation in addi‑ tion to the age‑induced stressors, leading to a self‑perpetuating cycle of senescent cell accumulation (43).”
BackgroundTokuhiro, T., Matsumae, G., Endo, T., Ogawa, Y., Ogawa, T., Chen, L., Nishida, Y., Alhasan, H., Kobayashi, H., Ebata, T., et al. (2024) · Journal of Autoimmunity · doi:10.1016/j.jaut.2024.103334 · Cited by 12
DNA damage, inflammation and aging: Insights from mice
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“The use of senolytic drugs that can selectively eliminate senescent cells (and by inference also the release of pro-inflammatory SASP factors) or the targeting of the SASP response itself (rather than the senescent cells) may serve as an alternative way to reduce the inflammatory load driven by irreparable DNA damage…”
BackgroundPark, J., Chen, Y., Kim, J., Hwang, E., Park, G. H., Yang, C. H., Ryter, S. W., Park, J. W., Chung, H., & Joe, Y. (2023) · PubMed Central · doi:10.14336/ad.2023.0120 · Cited by 13
“Several studies have reported that the elimination of senescent cells alleviates the symptoms of aging [15] and various age-related diseases [16].”
BackgroundYoung gut microbiota transplantation improves the metabolic health of old mice
Xie, J., Kim, T., Liu, Z., Panier, H. A., Bokoliya, S. C., Xu, M., & Zhou, Y. (2025) · mSystems · doi:10.1128/msystems.01601-24 · Cited by 13
“Some overlapping pathways such as apoptosis, IL6-JA-STAT3 signaling, and NFkB pathway are highly associated with inflammation and cellular senescence (30–33), suggesting that FMT with young fecal microbiota may alleviate inflammation and cellular senescence in old recipients’ amygdala.”
Self-citationRewinding the Clock: Emerging Pharmacological Strategies for Human Anti-Aging Therapy
Delrue, C., Speeckaert, R., & Speeckaert, M. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199372 · Cited by 12
Current aspects of targeting cellular senescence for the therapy of neurodegenerative diseases
Jaganathan, R., Iyaswamy, A., Krishnamoorthi, S., Thakur, A., Durairajan, S. S. K., Yang, C., & Wankhar, D. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1627921 · Cited by 12
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Senomorphic 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
Nijs, J., Wyns, A., & Hendrix, J. (2024) · Brazilian Journal of Physical Therapy · doi:10.1016/j.bjpt.2024.101061 · Cited by 11
“22,25,26 Such immune aging is characterized by an increased number of senescent T-lymphocytes, which show defects in proliferation and effector functions, and produce high amounts of proin fl ammatory cytokines.”
BackgroundUnraveling the metabolic heterogeneity and commonality in senescent cells using systems modeling
Li, G., Li, Y., Yu, Q., Zhou, Q.-Q., Zhang, R., Weng, C.-J., Ge, M., & Kong, Q.-P. (2025) · Life Medicine · doi:10.1093/lifemedi/lnaf003 · Cited by 11
“Therefore, modulating senescence may offer novel therapeutic strategies for enhancing health span and life span [11].”
Gao, X., Hu, Y., Zhang, Y., Huang, Y., Zhang, G., Zhang, X., Zhou, Y., & Zhang, D. (2025) · Science Advances · doi:10.1126/sciadv.adr2833 · Cited by 11
“Nonetheless, senolytics may elicit off-target effects or negatively affect beneficial cell populations ( 4 , 6 ).”
Thomas, A. L., Godarova, A., Wayman, J. A., Miraldi, E. R., Hildeman, D. A., & Chougnet, C. A. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101836 · Cited by 12
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“However, this specific marker also had limitations, and it was preferable to combine with other markers [38].”
BackgroundTripathi, U., Suda, M., Kulshreshtha, V., Piatkowski, B. T., Palmer, A. K., Giorgadze, N., Inman, C. L., Gasek, N. S., Xu, M., Johnson, K. O., et al. (2025) · Aging Cell · doi:10.1111/acel.70358 · Cited by 10
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Opioids exacerbate inflammation in people with well-controlled HIV
Dang, C. M., Nelson, C. M., Feaster, D. J., Kizhner, A., Forrest, D. W., Nakamura, N., Iyer, A., Ghanta, P. P., Jayaweera, D. T., Rodriguez, A. E., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1277491 · Cited by 13
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“Finally, animal models and exploration of other human cancer survivor cohorts could be bene fi cial in improving our comprehension of the biological mechanism that results in post-treatment changes in TREC levels.”
BackgroundImmunomodulation: A new approach to cancer cachexia, potentially suitable for aging
Penna, F., Rubini, G., & Costelli, P. (2024) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2024.101318 · Cited by 10
“Senolytic compounds have been developed to face the aberrant accumulation of senescent cells and/or the high levels of SASP mediators (Gasek et al., 2021).”
Al‐Naggar, I. M., Antony, M. B., Baker, D. S., Wang, L., Godoy, L. D. C., Kuo, C., Fraser, M. O., Smith, P. P., Xu, M., & Kuchel, G. A. (2024) · Aging Cell · doi:10.1111/acel.14399 · Cited by 11
“Senescent cells (SnCs) are cells that have permanently exited the cell cycle, in response to stress and accumulation of damage (Gasek et al., 2021 ; Suryadevara et al., 2024 ).”
Self-citationChen, Y., Huang, H., Luo, Y., Wu, H., Deng, W., Min, X., Lao, H., & Xiong, H. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156772 · Cited by 12
Targeting vulnerabilities of aneuploid cells for cancer therapy
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Metadata
- Authors
- Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M.
- Affiliations
- University of Connecticut (US)
- Mayo Clinic (US)
- Corresponding author
- Xu, Ming
- Venue
- Nature Aging
- Published
- 2021-10-07
- Volume
- 1
- Issue
- 10
- Pages
- 870-879
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC8612694
- OpenAlex
- W3202997660
- Cited by
- 501
- References
- 152
- Citations by year
- 2026: 78 · 2025: 120 · 2024: 141 · 2023: 95 · 2022: 63 · 2021: 4
- FWCI
- 10.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG063528,R33AG061456, R37AG013925, R01AG072301, P01AG062413, R21AG063528,R03AG072374,R01AG066679, R01AG068860)
- 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, senolytics, senescence-associated secretory phenotype, senolytic therapy, senotherapeutics, aging, age-related diseases, intracellular signaling, bench-to-bedside translation, chronic disease
- MeSH terms
- Senescence-Associated Secretory Phenotype, Aging, Cell Differentiation, Chronic Disease, Humans, Signal Transduction, Cellular Senescence
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