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
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277
Senolytics improve physical function and increase lifespan in old age
Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0092-9 · Cited by 2,287
Self-citationSarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797
Self-citationAging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,976
“Senomorphic drugs, such as JAK inhibitors and mTOR inhibitors, do not kill senescent cells but inhibit the secretion of SASP components.(615) The JAK inhibitor ruxolitinib reduces the size of the secretome derived from senescent cells.”
BackgroundMechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622
Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.031 · Cited by 1,454
“Interference with JAK-STAT signaling is known not to affect the viability of senescent cells (Xu et al., 2015), and we have previously observed similar effects for NFkB and p53 inhibition (Freund et al.”
ResultAdipogenesis and metabolic health
Ghaben, A. L., & Scherer, P. E. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0093-z · Cited by 1,395
Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.069 · Cited by 1,383
Self-citationCellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
“Ruxolitinib is a Janus kinase inhibitor previously discovered to inhibit production of multiple SASP factors (350).”
BackgroundSenolytic drugs: from discovery to translation
Kirkland, J. L., & Tchkonia, T. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13141 · Cited by 1,227
Self-citationTargeting cellular senescence prevents age-related bone loss in mice
Farr, J. N., Xu, M., Weivoda, M. M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4385 · Cited by 1,182
Self-citationSenescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177
“For instance, the JAK1/2 inhibitor ruxolitinib reduces the proinflammatory SASP, in vitro and in vivo and enhances insulin sensitivity, limits osteoporosis and reduces frailty in ageing mice (Xu et al. 2015a,b; Farr et al. 2017).”
BackgroundCellular senescence: the good, the bad and the unknown
Huang, W., Hickson, L. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00601-z · Cited by 1,150
Self-citationCellular 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 1,134
Self-citationFisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.015 · Cited by 1,032
“Reducing senescent cell burden can lead to reduced inflammation, decreased macromolecular dysfunction, and enhanced function of stem/progenitor cells [1,3,19].”
BackgroundSelf-citationCellular senescence: a translational perspective
Kirkland, J. L., & Tchkonia, T. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.04.013 · Cited by 1,013
Self-citationKalinkovich, A., & Livshits, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.008 · Cited by 882
The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948
Mechanisms and therapeutic implications of cellular senescence in osteoarthritis
Coryell, P. R., Diekman, B. O., & Loeser, R. F. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-00533-7 · Cited by 761
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794
Targeting senescent cells alleviates obesity-induced metabolic dysfunction
Palmer, A. K., Xu, M., Zhu, Y., Pirtskhalava, T., Weivoda, M. M., Hachfeld, C. M., Prata, L. G., van Dijk, T. H., Verkade, E., Casaclang‐Verzosa, G., et al. (2019) · Aging Cell · doi:10.1111/acel.12950 · Cited by 658
Self-citationTargeting cellular senescence with senotherapeutics: senolytics and senomorphics
Zhang, L. J., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022) · FEBS Journal · doi:10.1111/febs.16350 · Cited by 674
Cellular senescence: a key therapeutic target in aging and diseases
Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158450 · Cited by 631
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588
Targeting senescent cells enhances adipogenesis and metabolic function in old age
Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., Sepe, A., Johnson, K. O., Stout, M. B., Giorgadze, N., et al. (2015) · eLife · doi:10.7554/elife.12997 · Cited by 604
“Administering JAK inhibitor did not change metabolic rate or food intake in aged mice (Figure 6—figure supplement 1), and was previously found by us to actually increase activity of old mice (Xu et al., 2015).”
BackgroundMethodInfluentialSelf-citationThe senescence-associated secretory phenotype and its regulation
Lopes-Paciencia, S., Saint-Germain, E., Rowell, M.-C., Ruiz, A. F., Kalegari, P., & Ferbeyre, G. (2019) · Cytokine · doi:10.1016/j.cyto.2019.01.013 · Cited by 601
Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases
Barnes, P. J., Baker, J. R., & Donnelly, L. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201810-1975tr · Cited by 571
The Clinical potential of Senolytic Drugs
Kirkland, J. L., Tchkonia, T., Zhu, Y., Niedernhofer, L. J., & Robbins, P. D. (2017) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14969 · Cited by 539
“Targeting senescent cells, even in late life in rodents, appears to reduce immobility, weakness, fat tissue loss, and other parameters associated with frailty.(17,22,37) Senolytics may be tested in short-term clinical trials that include older adults with a moderate degree of frailty to determine whether strength, gai…”
BackgroundSelf-citationThe role of cellular senescence in ageing and endocrine disease
Khosla, S., Farr, J. N., Tchkonia, T., & Kirkland, J. L. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0335-y · Cited by 523
Self-citationMechanisms underlying T cell ageing
Goronzy, J. J., & Weyand, C. M. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0180-1 · Cited by 506
Linking cellular stress responses to systemic homeostasis
Galluzzi, L., Yamazaki, T., & Kroemer, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0068-0 · Cited by 556
Strategies 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
Self-citationSenescent cell clearance by the immune system: Emerging therapeutic opportunities
Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2019.04.003 · Cited by 497
“attenuates the SASP [23,54] was found to closely parallel that by the senolytic combination, dasatinib plus quercetin, as well as that by induced genetic clearance of highly p16Ink4aexpressing cells from INK-ATTAC mice [15].”
BackgroundResultInfluentialSelf-citationTransient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
Bitto, A., Ito, T. K., Pineda, V. V., LeTexier, N. J., Huang, H. Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K., et al. (2016) · eLife · doi:10.7554/elife.16351 · Cited by 474
“Of particular note are two studies reporting improved healthspan from short-term treatments in older mice with a JAK pathway inhibitor (Xu et al., 2015) and increased lifespan after transient treatment with the NAD precursor nicotinamide riboside (Zhang et al.”
Ageing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448
“Ruxolitinib (Jakafi) JAK inhibitor decreased systemic inflammation in aged animals and improved age-related dysfunctions and alleviating frailty Polycytemia vera, Myelofibrosis senomorphic [357]”
BackgroundLin, H., Sohn, J., Shen, H., Langhans, M. T., & Tuan, R. S. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.06.026 · Cited by 455
“14 generate many pro-inflammatory cytokines and chemokines [96, 97].”
BackgroundMechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395
“In old mice, SASP inhibition reduces adipose tissue and systemic inflammation and enhances physical function [329].”
BackgroundEmerging 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.2017.170 · Cited by 406
The senescence-associated secretome as an indicator of age and medical risk
Schafer, M. J., Zhang, X., Kumar, A., Atkinson, E. J., Zhu, Y., Jachim, S., Mazula, D. L., Brown, A. K., Berning, M., Aversa, Z., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.133668 · Cited by 401
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
“119–122).”
Self-citationRapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., Caples, K., Bradley, L., Beaver, L. M., Ho, E., et al. (2017) · Aging Cell · doi:10.1111/acel.12587 · Cited by 360
“For example, inhibition of the JAK pathway by JAK inhibitors (Xu et al., 2015) rescues in part the SASP in senescent pre-adipocytes in vivo.”
BackgroundTargeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes
Thompson, P. J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., & Bhushan, A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.021 · Cited by 353
Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice
Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., Curran, G. L., Ogrodnik, M., Jurk, D., Johnson, K. O., et al. (2016) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glw154 · Cited by 352
“We previously reported that senescent cells increase immune cell chemoattraction (19).”
BackgroundSelf-citationCD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels
Chini, C. C. S., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., Gomez, L. S., Hogan, K. A., Tarragó, M. G., Puranik, A. S., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00298-z · Cited by 349
Self-citationSenolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
Robbins, P. D., Jurk, D., Khosla, S., Kirkland, J. L., LeBrasseur, N. K., Miller, J. D., Passos, J. F., Pignolo, R. J., Tchkonia, T., & Niedernhofer, L. J. (2021) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-050120-105018 · Cited by 360
“Adipose tissue becomes a major contributor to insulin resistance in old age due to changes in immune cell populations, including a shift of macrophages toward a proinflammatory phenotype and a loss of regulatory T cells, and increased release of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and ost…”
BackgroundSelf-citationMitochondrial dysfunction and cell senescence: deciphering a complex relationship
Chapman, J., Fielder, E., & Passos, J. F. (2019) · FEBS Letters · doi:10.1002/1873-3468.13498 · Cited by 325
Aging and adipose tissue: potential interventions for diabetes and regenerative medicine
Palmer, A. K., & Kirkland, J. L. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.02.013 · Cited by 324
“In co-culture experiments, senescent cells have been shown to affect the function of adipose-derived progenitors as well as impair insulin sensitivity of adipose tissue (Xu et al., 2015a, 2015b).”
InfluentialSelf-citationAged-senescent cells contribute to impaired heart regeneration
Lewis‐McDougall, F. C., Ruchaya, P. J., Domenjo‐Vila, E., Shin Teoh, T., Prata, L., Cottle, B. J., Clark, J. E., Punjabi, P. P., Awad, W., Torella, D., et al. (2019) · Aging Cell · doi:10.1111/acel.12931 · Cited by 317
“senescent cells possess a senescence-associated secretory phenotype (SASP), consisting of pro-inflammatory cytokines, chemokines and ECM-degrading proteins, which have deleterious paracrine and systemic effects [10-13].”
Self-citationIslam, M. T., Tuday, E., Allen, S., Kim, J., Trott, D. W., Holland, W. L., Donato, A. J., & Lesniewski, L. A. (2023) · Aging Cell · doi:10.1111/acel.13767 · Cited by 313
Adipose tissue aging: mechanisms and therapeutic implications
Ou, M., Zhang, H., Tan, P., Zhou, S., & Li, Q. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04752-6 · Cited by 352
“Inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which plays a significant role in adipose tissue development and function and regulates the SASP, can partially inhibit SASP secretion [75].”
BackgroundCellular Senescence in the Kidney
Docherty, M.-H., O’Sullivan, E. D., Bonventre, J. V., & Ferenbach, D. A. (2019) · Journal of the American Society of Nephrology · doi:10.1681/asn.2018121251 · Cited by 291
Cytoplasmic DNA: sources, sensing, and role in aging and disease
Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D. (2021) · Cell · doi:10.1016/j.cell.2021.09.034 · Cited by 288
Targeting senescent cells in translational medicine
Paez‐Ribes, M., González‐Gualda, E., Doherty, G. J., & Muñoz‐Espín, D. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201810234 · Cited by 293
“Treatment of irradiation-induced senescent adipocytes with the JAK1/2 inhibitor ruxolitinib significantly reduced SASP factor secretion (Xu et al, 2015).”
BackgroundCuollo, L., Antonangeli, F., Santoni, A., & Soriani, A. (2020) · Biology · doi:10.3390/biology9120485 · Cited by 291
Mesenchymal Stem/Stromal Cell Senescence: Hallmarks, Mechanisms, and Combating Strategies
Weng, Z., Wang, Y., Ouchi, T., Liu, H., Qiao, X., Wu, C., Zhao, Z., Li, L., & Li, B. (2022) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szac004 · Cited by 303
A Senescence-Centric View of Aging: Implications for Longevity and Disease
Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.07.002 · Cited by 267
“For example, the FDA-approved Janus kinase (JAK 1/2) and signal transducer and activator of transcription protein 3 (STAT3) inhibitor, ruxolitinib, shown to be a SASP inhibitor [53], reduce bone resorption while promoting new bone formation [47].”
BackgroundLagoumtzi, S. M., & Chondrogianni, N. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.05.003 · Cited by 279
Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D., & Zheng, G. (2016) · Aging · doi:10.18632/aging.101100 · Cited by 274
Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty
Stout, M. B., Justice, J. N., Nicklas, B. J., & Kirkland, J. L. (2017) · Physiology · doi:10.1152/physiol.00012.2016 · Cited by 272
Self-citationCellular senescence and SASP in tumor progression and therapeutic opportunities
Dong, Z., Luo, Y., Yuan, Z., Tian, Y., Jin, T., & Feng, X. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02096-7 · Cited by 315
Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue
Schafer, M. J., White, T. A., Evans, G., Tonne, J. M., Verzosa, G. C., Stout, M. B., Mazula, D. L., Palmer, A. K., Baker, D. J., Jensen, M. D., et al. (2016) · Diabetes · doi:10.2337/db15-0291 · Cited by 267
“More recently, senolytics, the term given to pharmacological agents selected for their ability to kill senescent cells or inhibit the SASP, have shown therapeutic benefit on parameters of physical health and function when administered to chronologically aged, progeroid, and/or irradiated mice (15,16).”
BackgroundSelf-citationHuman T cell immunosenescence and inflammation in aging
Bektas, A., Schurman, S. H., Sen, R., & Ferrucci, L. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ri0716-335r · Cited by 274
Senescence in COPD and Its Comorbidities
Barnes, P. J. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034314 · Cited by 278
Farr, J. N., & Khosla, S. (2019) · Bone · doi:10.1016/j.bone.2019.01.015 · Cited by 263
“Furthermore, given that administration of the senomorphic, ruxolitinib, to old mice improves physical function [91] and that similarly elimination of senescent cells with senolytics, D+Q, does the same and increases lifespan in old mice [88], targeting senescent cells in humans may not only prevent bone loss but also…”
BackgroundMethodHuman CD 8 + EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK
Callender, L. A., Carroll, E. C., Beal, R. W. J., Chambers, E. S., Nourshargh, S., Akbar, A. N., & Henson, S. M. (2017) · Aging Cell · doi:10.1111/acel.12675 · Cited by 278
“The components of the SASP have been shown to vary depending on the cell type, with differing levels of cytokines and other inflammatory mediators being found in epithelial cells and mesenchymal cells (Xu et al., 2015).”
BackgroundMacrophages in age-related chronic inflammatory diseases
Oishi, Y., & Manabe, I. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.18 · Cited by 262
“Within adipose tissue, senescent preadipocytes accumulate with aging in both humans and rats.(59) Radiationinduced senescence in preadipocytes activates production of a number of proinflammatory cytokines in vitro, while JAK inhibition suppresses in vitro expression of SASP factors and alleviates adipose tissue and sy…”
BackgroundThe bystander effect contributes to the accumulation of senescent cells in vivo
da Silva, P. F. L., Ogrodnik, M., Kucheryavenko, O., Glibert, J., Miwa, S., Cameron, K., Ishaq, A., Saretzki, G., Nagaraja‐Grellscheid, S., Nelson, G., et al. (2019) · Aging Cell · doi:10.1111/acel.12848 · Cited by 247
“inflammation in old mice (Jurk et al., 2014; Xu et al., 2015), we found no evidence for increased abundance of SASP cytokines at protein level in old muscle (Supporting information Figure S1D).”
BackgroundSelf-citationSmall molecule compounds that induce cellular senescence.
Petrova, N. V., Velichko, A. K., Razin, S. V., & Kantidze, O. L. (2016) · Aging Cell · doi:10.1111/acel.12518 · Cited by 240
Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation
Perner, F., Perner, C., Ernst, T., & Heidel, F. H. (2019) · Cells · doi:10.3390/cells8080854 · Cited by 248
“Moreover, administration of a JAK1/2 inhibitor to aged mice for 10 weeks reduced inflammation and alleviated frailty [115].”
BackgroundInhibition of IL-11 signalling extends mammalian healthspan and lifespan
Widjaja, A. A., Lim, W.-W., Viswanathan, S., Chothani, S., Corden, B., Dasan, C. M., Goh, J. W. T., Lim, R., Singh, B. K., Tan, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07701-9 · Cited by 238
“The pro-inflammatory signalling factors NF-κB and JAK–STAT3 are specifically implicated in ageing and JAK inhibitors can alleviate age-related dysfunction 2,20,21 .”
BackgroundMolecular mechanisms of renal aging
Schmitt, R., & Melk, A. (2017) · Kidney International · doi:10.1016/j.kint.2017.02.036 · Cited by 235
Obesity and aging: Molecular mechanisms and therapeutic approaches
Santos, A. L., & Sinha, S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101268 · Cited by 249
Aging in the dermis: Fibroblast senescence and its significance
Zhang, J., Yu, H., Man, M., & Hu, L. (2023) · Aging Cell · doi:10.1111/acel.14054 · Cited by 258
“…factors controlling SASP secretion include p53, NF-κ B, CCAAT/ enhancer-binding protein beta (C/EBP β ), Janus kinase-signal transducer and activator of transcription (JAK–STAT), and GATA binding protein 4 (GATA4) (Huggins et al., 2013; Kang et al., 2015; Salminen et al., 2012; Xu et al., 2015).”
BackgroundBiology of premature ageing in survivors of cancer
Cupit-Link, M. C., Kirkland, J. L., Ness, K. K., Armstrong, G. T., Tchkonia, T., LeBrasseur, N. K., Armenian, S. H., Ruddy, K. J., & Hashmi, S. K. (2017) · ESMO Open · doi:10.1136/esmoopen-2017-000250 · Cited by 214
Self-citationNKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., Zhang, X., Liu, N., Yan, L., Deng, Y., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.add1951 · Cited by 217
“Given that age-dependent loss of adipose tissue is a widely used marker inversely correlated with aging in rodents (5, 29, 30), we examined IAT histology, adipocyte size, and abdominal adipose tissue volume to assess the aging-associated alterations in mice.”
BackgroundSenotherapeutics: emerging strategy for healthy aging and age-related disease
Kim, E.-C., & Kim, J. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.1.293 · Cited by 217
“senoinflammation, alleviated age-related tissue dysfunction, and enhanced physical function in old mice (55).”
BackgroundPapatheodoridi, A., Chrysavgis, L., Koutsilieris, M., & Chatzigeorgiou, A. (2019) · Hepatology · doi:10.1002/hep.30834 · Cited by 210
“(61) Of note, the presence of DNA in the cytoplasm, especially under tumorigenic conditions, may act as a senescence-initiating signal, and the process depends on a cytoplasmic DNA–sensing pathway, composed of the nucleotidyl transferase cyclic GMP-AMP synthase (cGAS) and the adaptor protein stimulator of interferon g…”
BackgroundInfluentialSASP: Tumor Suppressor or Promoter? Yes!
Rao, S. G., & Jackson, J. G. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.001 · Cited by 206
Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases
Wang, Y., Boerma, M., & Zhou, D. (2016) · Radiation Research · doi:10.1667/rr14445.1 · Cited by 218
“It was recently reported that using RNAi or JAK inhibitors to target the JAK pathway suppressed development of SASP in human umbilical vein endothelial cells and human preadipocytes after exposure to radiation (102).”
BackgroundBone Aging, Cellular Senescence, and Osteoporosis
Pignolo, R. J., Law, S. F., & Chandra, A. (2021) · JBMR Plus · doi:10.1002/jbm4.10488 · Cited by 217
“(178) The JAK inhibitor (JAKi) ruxolitinib suppresses components of the SASP, particularly IL-6, Il-8, and PAI-1,(179,180) which are known to be important for osteoclastogenesis and bone resorption.”
BackgroundHan, Y., & Kim, S. Y. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00906-w · Cited by 201
Cellular Senescence and Inflammaging in Age-Related Diseases
Olivieri, F., Prattichizzo, F., Grillari, J., & Balistreri, C. R. (2018) · Mediators of Inflammation · doi:10.1155/2018/9076485 · Cited by 200
“symptoms and amelioration of dysglycemia in old mice [36].”
BackgroundStrategies targeting cellular senescence
Ovadya, Y., & Krizhanovsky, V. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95149 · Cited by 200
“JAK1/2 inhibitors, such as the FDA-approved drug ruxolitinib, can reduce systemic inflammation and improve fitness in aged mice (92).”
BackgroundTherapeutic interventions for aging: the case of cellular senescence
Soto-Gamez, A., & Demaria, M. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.01.004 · Cited by 192
Cellular Senescence in Postmitotic Cells: Beyond Growth Arrest
Sapieha, P., & Mallette, F. A. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.03.003 · Cited by 193
Roles of extracellular vesicles in the aging microenvironment and age‐related diseases
Yin, Y., Chen, H., Wang, Y., Zhang, L., & Wang, X. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12154 · Cited by 205
Reducing Senescent Cell Burden in Aging and Disease
Pignolo, R. J., Passos, J. F., Khosla, S., Tchkonia, T., & Kirkland, J. L. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.03.005 · Cited by 177
“, using INK-ATTAC mice) or pharmacologically with senolytic agents [4, 11, 13, 60].”
MethodSelf-citationSenotherapeutics for healthy ageing
Niedernhofer, L. J., & Robbins, P. D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.44 · Cited by 190
Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis
Stojanović, S. D., Fiedler, J., Bauersachs, J., Thum, T., & Sedding, D. G. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz919 · Cited by 188
The Signaling of Cellular Senescence in Diabetic Nephropathy
Xiong, Y., & Zhou, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7495629 · Cited by 185
“SASP blockade would be another attractive treatment option [214, 215].”
BackgroundAdvances in Understanding of the Role of Lipid Metabolism in Aging
Chung, K. W. (2021) · Cells · doi:10.3390/cells10040880 · Cited by 191
Senescence as a therapeutic target in cancer and age-related diseases
McHugh, D., Durán, I., & Gil, J. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01074-4 · Cited by 197
“156) or JAK inhibitors 157 , suppress the inflammatory SASP and ameliorate the outcome of senescence-induced diseases (Fig.”
Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds
Wilkinson, H. N., & Hardman, M. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00773 · Cited by 173
Angulo, J., Assar, M. E., & Rodríguez‐Mañas, L. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.06.001 · Cited by 195
Anti-senescence compounds: A potential nutraceutical approach to healthy aging
Gurău, F., Baldoni, S., Prattichizzo, F., Espinosa, E., Amenta, F., Procopio, A. D., Albertini, M. C., Bonafè, M., & Olivieri, F. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.05.001 · Cited by 179
Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce
Li, Q., Hagberg, C. E., Silva Cascales, H., Lang, S., Hyvönen, M. T., Salehzadeh, F., Chen, P., Alexandersson, I., Terezaki, E., Harms, M. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01501-8 · Cited by 178
Osteocytes in bone aging: Advances, challenges, and future perspectives
Cui, J., Shibata, Y., Zhu, T., Zhou, J. M., & Zhang, J. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101608 · Cited by 185
Cellular senescence and the tumour microenvironment
Takasugi, M., Yoshida, Y., & Ohtani, N. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13268 · Cited by 190
Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs
Kudlová, N., Sanctis, J. B. D., & Hajdúch, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084168 · Cited by 186
Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing
Burton, D. G. A., & Faragher, R. (2018) · Biogerontology · doi:10.1007/s10522-018-9763-7 · Cited by 181
“As an example of the potential benefits, findings from one study suggested that inhibition of senescent secretome in mice reduces frailty in old age (Xu et al. 2015b).”
BackgroundInfluential
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
