The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age
Open accessAbstract
Significance: A hallmark of aging is chronic sterile inflammation, which is closely associated with frailty and age-related diseases. We found that senescent fat progenitor cells accumulate in adipose tissue with aging and acquire a senescence-associated secretory phenotype (SASP), with increased production of proinflammatory cytokines compared with nonsenescent cells. These cells provoked inflammation in adipose tissue and induced macrophage migration. The JAK pathway is activated in adipose tissue with aging, and the SASP can be suppressed by inhibiting the JAK pathway in senescent cells. JAK1/2 inhibitors reduced inflammation and alleviated frailty in aged mice. One possible mechanism contributing to reduced frailty is SASP inhibition. Our study points to the JAK pathway as a potential target for countering age-related dysfunction.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Sncs can directly cause insulin resistance through release of SASP factors such as IL-6 and TNF-α (39, 40).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [39]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We showed that aged 3xTg-AD male mice in particular, exhibit elevated plasma levels of known SASP factors [65, 66], including IL-12, IL-10, IL-6, CXCL2, CXCL1, and G-CSF”
From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [66]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This concept is supported by a study of aged mice demonstrating that pharmacologic inhibition of the JAK pathway, which regulates the SASP in senescent preadipocytes and endothelial cells in vitro, suppresses markers of both adipose tissue and systemic inflammation and improved parameters of muscle strength, endurance, and coordination (39).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [39]
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, JAK inhibitors alleviated frailty in aged mice99.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [99]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Similarly, other inhibitors of proinflammatory signalling (e.g. JAK/STAT [124] and p38 [60]) and antibodies targeting IL-6 [125], IL-1 [126] and TNFa [127], might be potentially effective senomorphic drugs.”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [124]
In the citing paper
“Alternatively, it is possible to modulate individual components of the SASP by inhibiting Janus kinase (JAK) 1/2148 and JAK2/signal transducer and activator of transcription 3 (STAT3).149”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [148]
In the citing paper
“Similarly, the inhibition of pro-inflammatory JAK signalling in the same model was shown to attenuate pathogenesis by reducing the infiltration of monocytes to the lung130–132.”
From COVID-19 and cellular senescence (2023) · cites this paper as [131]
In the citing paper
“However, senomorphic treatment may require continuous administration and could potentially disrupt tissue homeostasis due to SASP blockade.”
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 [192]
In the citing paper
“In terms of alleviating age-related phenotypes, minimizing the SASP using Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibition is very similar to eliminating or reducing the burden of senescent cells genetically (e.g., using INK-ATTAC mice) or pharmacologically with senolytic agents [4, 11, 13, 60].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [13]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Frailty in Older Adults: Evidence for a Phenotype
Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., Gottdiener, J., Seeman, T., Tracy, R., Kop, W. J., Burke, G., et al. (2001) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/56.3.m146 · Cited by 24,907
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
The metabolic phenotype in obesity: Fat mass, body fat distribution, and adipose tissue function
Goossens, G. H. (2017) · Obesity Facts · doi:10.1159/000471488 · Cited by 8,481
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383
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 · cited 4×
“(iii) p16positive senescent cells were the main cause of increased IL-6 expression in the stromal vascular fraction of adipose tissue digests from older progeroid mice (21).”
BackgroundMethodInfluentialSelf-citationPrinciples of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · cited 1×
“IL-6, a major SASP component, signals through the JAK/ STAT pathway (61) and has been shown to be critical in stabilizing cellular senescence (62).”
Background
Cited by
Sorted by citations
Items 101–200 of 921
van Vliet, T., Varela-Eirin, M., Wang, B., Borghesan, M., Brandenburg, S. M., Franzin, R., Evangelou, K., Seelen, M., Gorgoulis, V., & Demaria, M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.018 · Cited by 172
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
Self-citationCellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
Lucas, V., Cavadas, C., & Aveleira, C. A. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000622 · Cited by 172
Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis
Waters, D. W., Blokland, K. E. C., Pathinayake, P. S., Burgess, J. K., Mutsaers, S. E., Prêle, C. M., Schuliga, M. J., Grainge, C., & Knight, D. A. (2018) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00037.2018 · Cited by 171
Kandhaya-Pillai, R., Miro-Mur, F., Alijotas-Reig, J., Tchkonia, T., Kirkland, J. L., & Schwartz, S. (2017) · Aging · doi:10.18632/aging.101328 · Cited by 165
“In addition, cytokine signaling pathways, such as NF-κB, Ras-MEF-ERK, and Janus Kinase (JAK)/ signal transducers and activators of transcription (STAT), are among pathways that contribute to senescence and the SASP [30-34].”
BackgroundInfluentialSelf-citationSenescence 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
Turning back time with emerging rejuvenation strategies
Mahmoudi, S., Xu, L., & Brunet, A. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0206-0 · Cited by 171
Shen-Orr, S. S., Furman, D., Kidd, B. A., Hadad, F., Lovelace, P., Huang, Y.-W., Rosenberg-Hasson, Y., Mackey, S., Grisar, F. A. G., Pickman, Y., et al. (2016) · Cell Systems · doi:10.1016/j.cels.2016.09.009 · Cited by 154
“This senescence-associated secretory phenotype (Tchkonia et al., 2013; Xu et al., 2015) may explain in part the age-related elevation in circulating cytokines and in baseline pSTAT levels and the lack of responses to in vitro cell stimulations we observe.”
Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases
Ji, S., Xiong, M., Chen, H., Liu, Y., Zhou, L., Hong, Y., Wang, M., Wang, C., Fu, X., & Sun, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01343-5 · Cited by 172
“JAK inhibitors repress SASP function, alleviate systemic inflammation, and eventually enhance physical function.(297) Glucocorticoids act as potent inhibitors of selected pro-inflammatory cytokines (IL-6, IL1α, and MCP-1).”
BackgroundZhang, B., Fu, D., Xu, Q., Cong, X., Wu, C., Zhong, X., Ma, Y., Lv, Z., Chen, F., Han, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04010-4 · Cited by 157
Oxidative stress, cellular senescence and ageing
Pole, A., Dimri, M., & Dimri, G. P. (2016) · AIMS molecular science · doi:10.3934/molsci.2016.3.300 · Cited by 168
“Other recent studies demonstrated that the senolytic drugs that eliminate senescent cells via inhibition of pro-survival molecules such as p21, BCL-2, BCL-XL, PI3K and PAI2, can improve cardiac function and healthy lifespan, and delay age-related pathologies in general [173,174].”
BackgroundRejuvenating Strategies for Stem Cell-Based Therapies in Aging
Neves, J., Sousa‐Victor, P., & Jasper, H. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.01.008 · Cited by 160
COVID-19 and cellular senescence
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00785-2 · Cited by 153
Self-citationThe heterogeneity of mesenchymal stem cells: an important issue to be addressed in cell therapy
Li, J., Wu, Z., Zhao, L., Liu, Y., Su, Y., Gong, X., Liu, F., & Zhang, L. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03587-y · Cited by 157
“In particular, through senescence-associated secretory phenotype (SASP), aging cells themselves produce many pro-inflammatory cytokines and chemokines [49, 50].”
BackgroundWang, 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
Self-citationThe 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
Immunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 168
“203 Conventional tumor therapies, typically chemotherapy, radiotherapy, and surgery, can induce both spontaneous and therapy-induced senescence (TIS), accompanied by the accumulation of SnCs.”
InfluentialTargeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss
Chandra, A., Lagnado, A. B., Farr, J. N., Monroe, D. G., Park, S., Hachfeld, C., Tchkonia, T., Kirkland, J. L., Khosla, S., Passos, J. F., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3978 · Cited by 138
“Accumulation of senescent cells is accompanied by the proinflammatory SASP, and its reduction is associated with improved tissue function with aging.((42)) We showed that the SASP is prominent at both early (day 14, Fig.”
BackgroundSelf-citationCurrent advances in regulation of bone homeostasis
Al‐Bari, M. A. A., & Mamun, A. A. (2020) · FASEB BioAdvances · doi:10.1096/fba.2020-00058 · Cited by 150
Chini, C., Hogan, K. A., Warner, G. M., Tarragó, M. G., Peclat, T. R., Tchkonia, T., Kirkland, J. L., & Chini, E. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.03.199 · Cited by 138
“Abdominal subcutaneous adipose tissue for primary preadipocyte isolation [16] was obtained during intra-abdominal surgery from 2 consented clinically obese subjects (BMI Chini et al.”
BackgroundSelf-citationNess, K. K., Kirkland, J. L., Gramatges, M. M., Wang, Z., Kundu, M., McCastlain, K., Li-Harms, X., Zhang, J., Tchkonia, T., Pluijm, S. M. F., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.7467 · Cited by 143
Self-citationInflammaging: The ground for sarcopenia?
Liang, Z., Zhang, T., Liu, H., Li, Z., Peng, L., Wang, C., & Wang, T. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111931 · Cited by 156
Li, M., You, L., Xue, J., & Lü, Y. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00522 · Cited by 153
“…(II) Ruxolitinib (INCB18424) JAK pathway (I) Senescent human primary. preadipocytes (in vitro) (II) 24-month-old C57BL/6 male mice (in vivo) Xu et al., 2015 ABT-737 BCL-2, BCL-W, and BCL-XL (I) Irradiated male mice (in vivo) (II) Double-transgenic K5-rtTA/tet-p14 mice Yosef et al.,…”
The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders
Liu, Z., Wu, K. K.-L., Jiang, X. X., Xu, A., & Cheng, K. K. Y. (2020) · Clinical Science · doi:10.1042/cs20190966 · Cited by 148
Lozano-Torres, B., Estepa-Fernández, A., Rovira, M., Orzáez, M., Serrano, M., Martínez-Máñez, R., & Sancenón, F. (2019) · Nature Reviews Chemistry · doi:10.1038/s41570-019-0108-0 · Cited by 140
Strategies and Challenges in Clinical Trials Targeting Human Aging
Newman, J. C., Milman, S., Hashmi, S. K., Austad, S. N., Kirkland, J. L., Halter, J. B., & Barzilai, N. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw149 · Cited by 141
“Growth and differentiation factor-11–related agents (23,24), drugs that selectively clear senescent cells—senolytic agents (25–27), drugs that protect against the proinflammatory senescence-associated secretory phenotype (28,29), drugs that are related to mitochondrial function (30), agents that impact protein synthes…”
BackgroundSelf-citationSenescence and the tumor-immune landscape: Implications for cancer immunotherapy
Chibaya, L., Snyder, J. T., & Ruscetti, M. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.005 · Cited by 146
Mitochondrial peptides modulate mitochondrial function during cellular senescence
Kim, S., Mehta, H. H., Wan, J., Kuehnemann, C., Chen, J., Hu, J., Hoffman, A. R., & Cohen, P. (2018) · Aging · doi:10.18632/aging.101463 · Cited by 140
“As JAK activation correlates with certain SASP factors, and gp130/JAK/STAT pathway regulates IL-6 signaling [56,57], humanin treatment may increase SASP production in senescent cells through JAK activation.”
Curcumin and o-Vanillin Exhibit Evidence of Senolytic Activity in Human IVD Cells In Vitro
Cherif, H., Bisson, D. G., Jarzem, P. F., Weber, M. H., Ouellet, J. A., & Haglund, L. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8040433 · Cited by 140
“Examples of senomorphic compounds, include free radical scavengers and inhibitors of IkB kinase (IKK), nuclear factor (NFkB) [8] and the Janus kinase (JAK) pathways [9].”
BackgroundLee, J., & Lee, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094843 · Cited by 151
Mi, B., Xiong, Y., Knoedler, S. A., Alfertshofer, M. G., Panayi, A. C., Wang, H., Lin, S., Li, G., & Liu, G. (2024) · Bone Research · doi:10.1038/s41413-024-00346-4 · Cited by 147
A toolbox for the longitudinal assessment of healthspan in aging mice
Bellantuono, I., de Cabo, R., Ehninger, D., Di Germanio, C., Lawrie, A., Miller, J., Mitchell, S. J., Navas-Enamorado, I., Potter, P. K., Tchkonia, T., et al. (2020) · Nature Protocols · doi:10.1038/s41596-019-0256-1 · Cited by 145
Self-citationSARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress
Chang, R. P., Mamun, A., Dominic, A., & Le, N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.605908 · Cited by 136
Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis
Khosla, S., Farr, J. N., & Kirkland, J. L. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-02694 · Cited by 130
Self-citationPrattichizzo, F., De Nigris, V., La Sala, L., Procopio, A. D., Olivieri, F., & Ceriello, A. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1810327 · Cited by 129
“Upstream, p38 [44], JAK [45], and other MAP kinases [46], are all involved in SASP induction and control.”
BackgroundTargeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
Cianflone, E., Torella, M., Biamonte, F., Angelis, A. D., Urbanek, K., Costanzo, F. S., Rota, M., Ellison, G. M., & Torella, D. (2020) · Cells · doi:10.3390/cells9061558 · Cited by 137
Hou, J., Chen, K.-X., He, C., Li, X., Huang, M., Jiang, Y., Jiao, Y., Xiao, Q.-N., He, W., Liu, L., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00694-0 · Cited by 143
Justice, J. N., Gregory, H., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., Kritchevsky, S. B., & Nicklas, B. J. (2018) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glx134 · Cited by 129
“In rodents, elevated adipose senescent cell burden induced by aging or “fast-food” westernized-diet accompanies systemic inflammation and physical dysfunction (4,11), but even modest reductions in the number of senescent cells can positively impact health and function.”
BackgroundSelf-citationTargeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
Song, S., Tchkonia, T., Jiang, J., Kirkland, J. L., & Sun, Y. (2020) · Advanced Science · doi:10.1002/advs.202002611 · Cited by 129
Self-citationEmerging use of senolytics and senomorphics against aging and chronic diseases
Martel, J., Ojcius, D. M., Wu, C., Peng, H., Voisin, L., Perfettini, J., Ko, Y., & Young, J. D. (2020) · Medicinal Research Reviews · doi:10.1002/med.21702 · Cited by 127
Chronic inflammation and sarcopenia: A regenerative cell therapy perspective
Chhetri, J. K., Barreto, P. D. S., Fougère, B., Rolland, Y., Vellas, B. J., & Cesari, M. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2017.12.023 · Cited by 129
The Immune Landscape of Visceral Adipose Tissue During Obesity and Aging
Khan, S. M., Chan, Y. T., Revelo, X. S., & Winer, D. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00267 · Cited by 140
“During aging, the accumulation of senescent preadipocytes in the adipose tissue leads to increased production of pro-inflammatory cytokines in a process dependent on the JAK pathway (31).”
BackgroundMurakami, T., Inagaki, N., & Kondoh, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.869414 · Cited by 137
Farr, J. N., Rowsey, J. L., Eckhardt, B. A., Thicke, B. S., Fraser, D. G., Tchkonia, T., Kirkland, J. L., Monroe, D. G., & Khosla, S. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3729 · Cited by 127
“In addition, we treated old wild‐type mice with a “senomorphic” drug (ie, the JAK inhibitor, ruxolitinib((20))) to inhibit the SASP.”
Self-citationMyeloid-Derived Suppressor Cells: Not Only in Tumor Immunity
Pawelec, G., Verschoor, C. P., & Ostrand‐Rosenberg, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01099 · Cited by 126
“Cellular senescence contributes to agerelated functional outcomes and systemic inflammation (i.e., the senescence-associated secretory phenotype, SASP) (61).”
Ionizing radiation-induced cellular senescence promotes tissue fibrosis after radiotherapy. A review
Nguyen, H. Q., To, N. H., Zadigue, P., Kerbrat, S., TAILLE, A. D. L., Gouvello, S. L., & Belkacémi, Y. (2018) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2018.06.012 · Cited by 129
Kandhaya‐Pillai, R., Yang, X., Tchkonia, T., Martin, G. M., Kirkland, J. L., & Oshima, J. (2022) · Aging Cell · doi:10.1111/acel.13646 · Cited by 119
“Multiple cytokines signal via the JAK/STAT pathway and its activation are linked to both cellular senescence and COVID- 19 infection (Kandhaya- Pillai et al., 2017; Matsuyama et al., 2020; Xu et al., 2015; Yan et al., 2021).”
BackgroundSelf-citationErratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease
Mora, A. L., Rojas, M., Pardo, A., & Selman, M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.225 · Cited by 122
Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases
(2020) · International Review of Neurobiology · doi:10.1016/bs.irn.2020.03.019 · Cited by 114
Self-citationSenotherapeutic drugs for human intervertebral disc degeneration and low back pain
Cherif, H., Bisson, D. G., Mannarino, M., Rabau, O., Ouellet, J. A., & Haglund, L. (2020) · eLife · doi:10.7554/elife.54693 · Cited by 119
“Senescent cells secrete a range of cytokines, chemokines, growth factors, and proteases termed as the senescence-associated secretory phenotype (SASP) (Herbig et al., 2006; Kuilman et al., 2008; Coppé et al., 2008; Xu et al., 2015).”
BackgroundGaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117
Han, D., Gong, H., Wei, Y., Xu, Y., Zhou, X., Wang, Z., & Feng, F. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154680 · Cited by 118
Senescent Cells: A Therapeutic Target in Cardiovascular Diseases
Suda, M., Paul, K. H., Minamino, T., Miller, J. D., Lerman, A., Ellison, G. M., Tchkonia, T., & Kirkland, J. L. (2023) · Cells · doi:10.3390/cells12091296 · Cited by 119
“Senescent endothelial cells exhibit increased production of ROS and certain SASP markers, such as intercellular adhesion molecule-1 (ICAM-1) [102,103], IL-1 [104], IL-6 [105], IL-8 [106], and MCP-1 [106], facilitating immune cell infiltration of tissues.”
BackgroundInfluentialSelf-citationDiabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging
Wang, Q., Nie, L., Zhao, P., Zhou, X., Ding, Y., Chen, Q., & Wang, Q. (2021) · International Journal of Oral Science · doi:10.1038/s41368-021-00116-6 · Cited by 113
Expansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence
Ogrodnik, M., Salmonowicz, H., Jurk, D., & Passos, J. F. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.06.011 · Cited by 104
Self-citationEvidence and perspectives of cell senescence in neurodegenerative diseases
Si, Z., Sun, L., & Wang, X. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111327 · Cited by 105
Fibroblast Senescence in Idiopathic Pulmonary Fibrosis
Lin, Y., & Xu, Z. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.593283 · Cited by 109
How good is the evidence that cellular senescence causes skin ageing?
Low, E., Alimohammadiha, G., Smith, L. A., Costello, L., Przyborski, S. A., von Zglinicki, T., & Miwa, S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101456 · Cited by 116
“Frequencies of senescent preadipocytes in subcutaneous fat (assessed as γH2AX-positive, Ki67-negative cells) increased from about 3% to 10% with age in both humans and rats (Xu et al., 2015).”
BackgroundTargeting senescence as an anticancer therapy
Bousset, L., & Gil, J. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13312 · Cited by 113
Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging
Sun, Y., Li, Q., & Kirkland, J. L. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac030 · Cited by 105
Self-citationGuipaud, O., Jaillet, C., Clément-Colmou, K., François, A., Supiot, S., & Milliat, F. (2018) · British Journal of Radiology · doi:10.1259/bjr.20170762 · Cited by 110
Strategies to Prevent or Remediate Cancer and Treatment-Related Aging
Guida, J., Agurs‐Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark‐Wahnefried, W., Dietrich, J., Fuldner, R., Gallicchio, L. M., Green, P. A., et al. (2020) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djaa060 · Cited by 113
Self-citationAdipose tissue as a linchpin of organismal ageing
Nguyen, T., & Corvera, S. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01046-3 · Cited by 118
“Cells displaying senescence markers have been detected in adipose tissue of progeroid mice 135 , of mice defective in DNA repair 136 , and in normally aged rats and mice 91,137 .”
Tripathi, U., Misra, A., Tchkonia, T., & Kirkland, J. L. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111548 · Cited by 104
“JAK-STAT3 inhibition leads to reprogramming of the SASP, which decreases frailty and bone loss in old animals [50].”
Self-citationReproductive Ageing: Inflammation, immune cells, and cellular senescence in the aging ovary
Isola, J. V. V., Hense, J. D., Osorio, C. A. P., Biswas, S., Alberola‐Ila, J., Ocañas, S. R., Schneider, A., & Stout, M. B. (2024) · Reproduction · doi:10.1530/rep-23-0499 · Cited by 115
“The SASP can adversely affect the local microenvironment by increasing pro-inflammatory responses in neighboring cells and recruiting circulating immune cells (Xu et al. 2015, Palmer et al. 2019).”
Self-citationTargeting Senescent Cells in Fibrosis: Pathology, Paradox, and Practical Considerations
Schafer, M. J., Haak, A. J., Tschumperlin, D. J., & LeBrasseur, N. K. (2018) · Current Rheumatology Reports · doi:10.1007/s11926-018-0712-x · Cited by 106
Self-citationCellular senescence and its role in white adipose tissue
Smith, U., Li, Q., Rydén, M., & Spalding, K. L. (2021) · International Journal of Obesity · doi:10.1038/s41366-021-00757-x · Cited by 109
Cellular senescence and the skeleton: pathophysiology and therapeutic implications
Khosla, S., Farr, J. N., & Monroe, D. G. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154888 · Cited by 106
“, JAK/STAT pathway inhibitors, mTOR inhibitors) as well as potential future compounds that may inhibit the SASP through novel mechanisms (13).”
BackgroundMethodThe clinical impact and biological mechanisms of skeletal muscle aging
Aversa, Z., Zhang, X., Fielding, R. A., Lanza, I. R., & LeBrasseur, N. K. (2019) · Bone · doi:10.1016/j.bone.2019.05.021 · Cited by 113
“This potential mechanism is in line with a prior report showing pharmacological inhibition of the Jak pathway, which was shown to regulate the SASP in senescent preadipocytes and endothelial cells in vitro, suppressed markers of both adipose tissue and systemic inflammation and improved parameters of physical function…”
ResultSelf-citationJustice, J., Miller, J. D., Newman, J. C., Hashmi, S. K., Halter, J., Austad, S. N., Barzilai, N., & Kirkland, J. L. (2016) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glw126 · Cited by 96
“Senolytic agents delay multiple frailty-associated phenotypes in progeroid mice (8) and Janus kinase (JAK1/2) inhibitors, which attenuate the senescence-associated secretory phenotype, alleviate frailty in older mice (6).”
Self-citationMolecular pathways of senescence regulate placental structure and function
Gal, H., Lysenko, M., Stroganov, S., Vadai, E., Youssef, S. A., Geffen, K. T., Rotkopf, R., Biron‐Shental, T., de Bruin, A., Neeman, M., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2018100849 · Cited by 103
“Regulation of the SASP is complex, and the expression of its components is governed in a coordinated manner by the DNA damage response and the NF-j B and JAK-STAT signaling systems (Acosta et al , 2008; Kuilman et al , 2008; Rodier et al , 2009; Chien et al , 2011; Xu et al , 2015).”
Aging adipose: Depot location dictates age-associated expansion and dysfunction
Bank, H. C. V., Kirsh, C., & Simcox, J. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101259 · Cited by 109
“Senescence causes preadipocytes to secrete inflammatory molecules such as IL-6 that can promote inflammation in other cells in vitro [61].”
BackgroundMolecular basis of ageing in chronic metabolic diseases
Spinelli, R., Parrillo, L., Longo, M., Florese, P., Desiderio, A., Zatterale, F., Miele, C., Raciti, G. A., & Bèguinot, F. (2020) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01255-z · Cited by 105
“They undergo a wide range of functional changes during ageing [13], including a reduction in replicative capacity [34, 58], an impairment of adipogenesis [31, 34, 39, 58, 59], a decrease in the handling of fatty acids [60], and an increase in secretion of pro-inflammatory cytokines and chemokines, metalloproteases, an…”
BackgroundInfluentialAging and IBD: A New Challenge for Clinicians and Researchers
Faye, A. S., & Colombel, J. (2021) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izab039 · Cited by 97
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
“These SASP components can alter the microenvironment within tissues and affect the function of neighboring cells, which can eventually lead to local and systemic dysfunction.”
InfluentialSelf-citationEndothelial cell senescence and thrombosis: Ageing clots
Bochenek, M. L., Schütz, E., & Schäfer, K. (2016) · Thrombosis Research · doi:10.1016/j.thromres.2016.09.019 · Cited by 96
Liu, H., Zhao, H., & Sun, Y. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.11.004 · Cited by 100
Midlife Systemic Inflammation Is Associated With Frailty in Later Life: The ARIC Study
Walker, K. A., Walston, J., Gottesman, R. F., Kucharska-Newton, A., Palta, P., & Windham, B. G. (2019) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gly045 · Cited by 91
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
Self-citationEarly Vascular Ageing and Cellular Senescence in Chronic Kidney Disease
Dai, L., Qureshi, A. R., Witasp, A., Lindholm, B., & Stenvinkel, P. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.06.015 · Cited by 98
Obesity-related kidney disease: Beyond hypertension and insulin-resistance
Arabi, T. Z., Shafqat, A., Sabbah, B. N., Ashraf, N., Shah, H., Abdulkader, H. S., Razak, A., Sabbah, A. N., & Arabi, Z. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1095211 · Cited by 102
Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice
Zhou, Y., Xin, X., Wang, L., Wang, B., Chen, L., Liu, O., Rowe, D. W., & Xu, M. (2021) · npj Regenerative Medicine · doi:10.1038/s41536-021-00145-z · Cited by 95
Self-citationInflammation and aging-related disease: A transdisciplinary inflammaging framework
Andonian, B. J., Hippensteel, J. A., Abuabara, K., Boyle, E. M., Colbert, J. F., Devinney, M. J., Faye, A. S., Kochar, B. D., Lee, J., Litke, R. R., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01364-0 · Cited by 109
The Senescence–Stemness Alliance – A Cancer-Hijacked Regeneration Principle
Milanovic, M., Yu, Y., & Schmitt, C. A. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.09.001 · Cited by 92
The role of senescence in cancer development
Mavrogonatou, E., Pratsinis, H., & Kletsas, D. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.06.018 · Cited by 95
Targeting cellular senescence in cancer and aging: roles of p53 and its isoforms
Beck, J. A., Turnquist, C., Horikawa, I., & Harris, C. C. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa071 · Cited by 97
Inflammatory Trajectory of Type 2 Diabetes: Novel Opportunities for Early and Late Treatment
Pellegrini, V., Grotta, R. L., Carreras, F., Giuliani, A., Sabbatinelli, J., Olivieri, F., Berra, C., Ceriello, A., & Prattichizzo, F. (2024) · Cells · doi:10.3390/cells13191662 · Cited by 105
“Moreover, senescent preadipocytes show diminished capacity for both proliferation and differentiation, and their SASP further impairs the adipogenic potential of nearby progenitor cells, inducing senescence in them as well [39].”
BackgroundDissecting primary and secondary senescence to enable new senotherapeutic strategies
Admasu, T. D., Rae, M. J., & Stolzing, A. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101412 · Cited by 98
Age and Sex: Impact on adipose tissue metabolism and inflammation
Varghese, M., Song, J., & Singer, K. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111563 · Cited by 100
Potential Regulators of the Senescence-Associated Secretory Phenotype During Senescence and Aging
Han, X., Lei, Q., Xie, J., Liu, H., Li, J., Zhang, X., Zhang, T., & Gou, X. (2022) · The Journals of Gerontology Series A · doi:10.1093/gerona/glac097 · Cited by 100
Interventions for age-related diseases: Shifting the paradigm
Figueira, I., Fernandes, A. M. A., Mladenović, A., Lopez-Contreras, A. J., Henriques, C. M., Selman, C., Ferreiro, E. B., Gonos, E. S., Trejo, J. L., Misra, J., et al. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.09.009 · Cited by 92
The redox-senescence axis and its therapeutic targeting
Ngoi, N. Y. L., Liew, A. Q. X., Chong, S. J. F., Davids, M. S., Clement, M., & Pervaiz, S. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102032 · Cited by 94
The Molecular Mechanism of Polyphenols with Anti-Aging Activity in Aged Human Dermal Fibroblasts
Lee, J. H., Park, J., & Shin, D. W. (2022) · Molecules · doi:10.3390/molecules27144351 · Cited by 92
Targeting immunosenescence and inflammaging: advancing longevity research
Nguyen, T. Q. T., & Cho, K. A. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01527-9 · Cited by 100
“Emerging evidence also highlights the role of autophagy induction in suppressing SASP-mediated in fl ammation and restoring cellular homeostasis in aging models 47,127,128 .”
de Carvalho, F. G., Justice, J. N., de Freitas, E. C., Kershaw, E. E., & Sparks, L. M. (2019) · Nutrients · doi:10.3390/nu11112553 · Cited by 93
“Therefore, senescent cells accumulate in adipose tissue with aging across a number of mammalian species including humans [55,59,62] and, given that adipose is frequently the largest organ in humans, this may have profound systemic consequences.”
BackgroundEpigenetic regulations of cellular senescence in osteoporosis
Huo, S., Tang, X., Chen, W., Gan, D., Guo, H., Yao, Q., Liao, R., Huang, T., Wu, J., Yang, J., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102235 · Cited by 94
JAK2/STAT3 regulates estrogen-related senescence of bone marrow stem cells
Wu, W., Fu, J., Gu, Y., Yu, W., Ma, P., & Wu, J. (2020) · Journal of Endocrinology · doi:10.1530/joe-19-0518 · Cited by 88
Blocking negative effects of senescence in human skin fibroblasts with a plant extract
Lämmermann, I., Terlecki-Zaniewicz, L., Weinmüllner, R., Schosserer, M., Dellago, H., de Matos Branco, A. D., Autheried, D., Sevcnikar, B., Kleissl, L., Berlin, I., et al. (2018) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-018-0023-5 · Cited by 84
Wang, Y., Che, L., Chen, X., He, Z., Song, D., Yuan, Y., & Liu, C. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.01.009 · Cited by 86
Musculoskeletal senescence: a moving target ready to be eliminated
Baar, M. P., Perdiguero, E., Muñoz-Cánoves, P., & de Keizer, P. L. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.05.007 · Cited by 83
“In contrast, frailty is reduced by the JAK/STAT inhibitor Ruxolitinib, which reduces inflammation in naturally aged mice [9].”
Background
Metadata
- Authors
- Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K., & Kirkland, J. L.
- Affiliations
- Mayo Clinic (US)
- Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-11-02
- Volume
- 112
- Issue
- 46
- Pages
- E6301-10
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4655580
- OpenAlex
- W1932046626
- Cited by
- 915
- References
- 68
- Citations by year
- 2026: 104 · 2025: 110 · 2024: 112 · 2023: 98 · 2022: 110 · 2021: 115 · 2020: 72 · 2019: 70 · 2018: 59 · 2017: 30 · 2016: 33 · 2015: 1
- FWCI
- 30.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- HHS | NIH | National Institute on Aging (AG041122, AG013925)
- 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
- JAK inhibition, cellular senescence, senescence-associated secretory phenotype, frailty, aging, age-related inflammation, adipose tissue, preadipocytes, macrophage migration, conditioned medium, endothelial cells, physical function, JAK inhibitors
- MeSH terms
- Adipose Tissue, Animals, Cell Movement, Extracellular Matrix, Humans, Macrophages, Signal Transduction, Cellular Senescence, Adipocytes, RNA, Small Interfering, Mice, Janus Kinases, Human Umbilical Vein Endothelial Cells
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
