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.
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Senescent cells can directly cause insulin resistance by releasing SASP factors such as IL-6 and TNF-α.
“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]
The “Senescent Preadipocytes Develop a SASP” section reports increased secretion of IL-6 and increased TNF-α mRNA in senescent preadipocytes. The “Senescent Preadipocytes Induce Inflammation in Adjacent Cells” section shows that their conditioned medium induces inflammation, but the paper does not establish that these factors directly cause insulin resistance or demonstrate TNF-α secretion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAged 3xTg-AD male mice exhibit elevated plasma levels of known SASP factors, including IL-12, IL-10, IL-6, CXCL2, CXCL1, and G-CSF.
“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]
The sections “Senescent Preadipocytes Develop a SASP” and “Inhibition of JAK Suppresses the SASP in Senescent Preadipocytes” identify IL-6, CXCL-1, and G-CSF as SASP-associated factors. The citation is attached to the description of the factors, not the citing authors’ finding in 3xTg-AD mice. Our copy does not identify IL-12, IL-10, or CXCL2 as SASP factors, so it supports only part of the cited list (page numbers unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn aged mice, pharmacologic JAK inhibition suppresses adipose tissue and systemic inflammation markers and improves muscle strength, endurance, and coordination.
“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]
JAK inhibitors reduce frailty in aged mice.
“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 measuredOther inhibitors of proinflammatory signalling (e.g. JAK/STAT and p38) and antibodies targeting IL-6, IL-1 and TNFα might be potentially effective senomorphic drugs.
“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]
It is possible to modulate individual components of the SASP by inhibiting JAK1/2 and JAK2/STAT3.
“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]
Inhibition of pro-inflammatory JAK signalling in the same model attenuated pathogenesis by reducing monocyte infiltration to the lung.
“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]
Senomorphic treatment may require continuous administration and could disrupt tissue homeostasis due to SASP blockade.
“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]
Minimizing the SASP using JAK/STAT inhibition is very similar to eliminating or reducing senescent cell burden genetically or pharmacologically with senolytics.
“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]
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Cartwright, M. J., Schlauch, K. A., Lenburg, M. E., Tchkonia, T., Pirtskhalava, T., Cartwright, A., Thomou, T., & Kirkland, J. L. (2010) · The Journals of Gerontology Series A · doi:10.1093/gerona/glp213 · Cited by 87 · see citing works
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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 · see citing works
Self-citationCellular 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 · see citing works
Sarcopenia: 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 · see citing works
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 1,834 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 1,105 · see citing works
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 · see citing works
“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 · see citing works
Self-citationKalinkovich, A., & Livshits, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.008 · Cited by 882 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 648 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 559 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 529 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 448 · see citing works
“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 · see citing works
“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 403 · see citing works
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 · see citing works
Self-citationSenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 339 · see citing works
“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 · see citing works
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 313 · see citing works
“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 · see citing works
“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 · see citing works
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 323 · see citing works
“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 · see citing works
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 · see citing works
Targeting senescent cells in translational medicine
Pàez‐Ribes, M., González‐Gualda, E., Doherty, G. J., & Muñoz‐Espín, D. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201810234 · Cited by 289 · see citing works
“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 · see citing works
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 291 · see citing works
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 · see citing works
“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].”
BackgroundDiscovery 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 · see citing works
Lagoumtzi, S. M., & Chondrogianni, N. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.05.003 · Cited by 279 · see citing works
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 · see citing works
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 292 · see citing works
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 · see citing works
“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 270 · see citing works
Senescence in COPD and Its Comorbidities
Barnes, P. J. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034314 · Cited by 276 · see citing works
Farr, J. N., & Khosla, S. (2019) · Bone · doi:10.1016/j.bone.2019.01.015 · Cited by 263 · see citing works
“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 265 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 247 · see citing works
“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 · see citing works
“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 · see citing works
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 240 · see citing works
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 249 · see citing works
“…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 · see citing works
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 214 · see citing works
“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 211 · see citing works
“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 206 · see citing works
“(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 · see citing works
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 204 · see citing works
“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 206 · see citing works
“(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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 199 · see citing works
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 · see citing works
“, using INK-ATTAC mice) or pharmacologically with senolytic agents [4, 11, 13, 60].”
MethodSelf-citationSenotherapeutics for healthy ageing
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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 · see citing works
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 · see citing works
“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 185 · see citing works
Senescence as a therapeutic target in cancer and age-related diseases
McHugh, D., Durán, I., & Gil, J. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01074-4 · Cited by 199 · see citing works
“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 · see citing works
Angulo, J., Assar, M. E., & Rodríguez‐Mañas, L. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.06.001 · Cited by 185 · see citing works
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 · see citing works
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 · see citing works
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 181 · see citing works
Cellular senescence and the tumour microenvironment
Takasugi, M., Yoshida, Y., & Ohtani, N. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13268 · Cited by 178 · see citing works
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 176 · see citing works
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 175 · see citing works
“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
- 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
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- 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
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