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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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“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]
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“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]
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“Furthermore, JAK inhibitors alleviated frailty in aged mice99.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [99]
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“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]
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“Activin A, as well as other SASP factors such as IL-6 and TNFa, can also directly impede insulin sensitivity in neighboring cells [34] and attract immune cells that further promote insulin resistance.”
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InfluentialFunctional conservation in genes and pathways linking ageing and immunity
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“…demonstrated that inhibition of the SASP in cancer, aging, and other models is beneficial (Bussian et al., 2018; Chandra et al., 2020; Chang et al., 2016; Demaria et al., 2017; Jeon et al., 2017; Justice et al., 2019; Perrott et al., 2017; Suvakov et al., 2019; Wiley et al., 2018; Xu et al., 2015).”
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“Since this initial discovery, key findings have been reported by several laboratories establishing that reducing the burden of senescent cells in old mice extends healthspan by, for example, improving measures of metabolic dysfunction,((168)) hepatic steatosis,((169)) vascular dysfunction/ cardiovascular disease,((170…”
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“Chronic in fl ammation contributes to the age-associated condition of frailty, which has been alleviated in aged mice following treatment with anti-in fl ammatory agents such as JAK1/2 inhibitors 111 .”
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“Other senomorphics, like JAK inhibitors, target cytokine signaling cascades to diminish the pro-inflammatory environment created by senescent cells (Valenzuela 2022; Xu et al. 2016; Xu et al. 2015).”
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“Thus, targeting the Janus kinase pathway might also be a promising strategy for agerelated diseases [139].”
Calorie restriction reduces biomarkers of cellular senescence in humans
Aversa, Z., White, T. A., Heeren, A. A., Hulshizer, C. A., Saul, D., Zhang, X., Molina, A. J. A., Redman, L. M., Martin, C. K., Racette, S. B., et al. (2023) · Aging Cell · doi:10.1111/acel.14038 · Cited by 66
“…advancing age and, through the secretion of bioactive molecules collectively referred as senescence-associated secretory phenotype (SASP) (Coppé et al., 2010), can exert local and systemic deleterious effects such as contributing to chronic inflammation (Acosta et al., 2013; Xu et al., 2015, 2018).”
BackgroundSelf-citationSenescence: A DNA damage response and its role in aging and Neurodegenerative Diseases
Shreeya, T., Ansari, M. S., Kumar, P., Saifi, M., Shati, A. A., Alfaifi, M. Y., & Elbehairi, S. E. I. (2024) · Frontiers in Aging · doi:10.3389/fragi.2023.1292053 · Cited by 72
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“A plethora of pathways and proteins has been implicated with inflammatory molecule secretion in senescent cells, for example, NF-κB, mTOR, and JAK [27, 34].”
BackgroundKhalil, R., Diab‐Assaf, M., & Lemaître, J.-M. (2023) · Cells · doi:10.3390/cells12060915 · Cited by 68
“Inhibition of JAK/STAT signaling by ruxolitinib is able to repress C/EBPβ transcriptional activity, reducing systemic inflammation and ameliorating fitness in old mice [92,167].”
BackgroundAdipose tissue, immune aging, and cellular senescence
Frasca, D., & Blomberg, B. B. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00812-1 · Cited by 72
Chae, J., Jang, H., Son, C., Park, C., Choi, H., Jin, S., Lee, H., Lee, H., Ryu, J., Kim, N., et al. (2021) · GeroScience · doi:10.1007/s11357-021-00457-4 · Cited by 64
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Innate immunosensing of DNA in cellular senescence
Glück, S., & Ablasser, A. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.013 · Cited by 62
Adipose tissue aging is regulated by an altered immune system
Zhang, Y.-X., Ou, M.-Y., Yang, Z.-H., Sun, Y., Li, Q.-F., & Zhou, S.-B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1125395 · Cited by 62
Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart
Nicin, L., Wagner, J. U. G., Luxán, G., & Dimmeler, S. (2021) · FEBS Letters · doi:10.1002/1873-3468.14234 · Cited by 67
Kidney Aging and Chronic Kidney Disease
Zhang, Y., Chen, Y., & Li, X. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126585 · Cited by 72
“The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays a crucial role in regulating SASP production; targeting JAK/STAT with inhibitors emerges as an appealing strategy for senomorphic intervention [175].”
BackgroundSenescence and tissue fibrosis: opportunities for therapeutic targeting
O’Reilly, S., Tsou, P., & Varga, J. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.05.012 · Cited by 67
Positive and negative effects of cellular senescence during female reproductive aging and pregnancy
Velarde, M. C., & Menon, R. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0018 · Cited by 65
Cellular Senescence and Senotherapies in the Kidney: Current Evidence and Future Directions
Docherty, M. H., Baird, D., Hughes, J., & Ferenbach, D. A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00755 · Cited by 66
Mbara, K. C., Devnarain, N., & Owira, P. M. O. (2022) · Pharmaceutical Medicine · doi:10.1007/s40290-022-00444-w · Cited by 47
Cellular Senescence in Human Skin Aging: Leveraging Senotherapeutics
Wyles, S. P., CARRUTHERS, J. D. A., Dashti, P., Yu, G., Yap, J. Q., Gingery, A., Tchkonia, T., & Kirkland, J. L. (2023) · Gerontology · doi:10.1159/000534756 · Cited by 67
“Senomodi fi ers or senomorphics are drugs that suppress the adverse effects of senescent cells without directly clearing them, such as JAK inhibitors [101] or rapamycin [102].”
BackgroundSelf-citationCellular Senescence Affects Cardiac Regeneration and Repair in Ischemic Heart Disease
Yan, C., Xu, Z.-M., & Huang, W. (2021) · Aging and Disease · doi:10.14336/ad.2020.0811 · Cited by 61
Chen, M., Xiao, L., Dai, G.-C., Lu, P., Zhang, Y., Li, Y., Ni, M., & Rui, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.650250 · Cited by 64
Kim, H., Jang, J., Song, M. J., Park, C., Lee, D. H., Lee, S., & Chung, J. H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113034 · Cited by 64
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Self-citationThe Jekyll and Hyde of Cellular Senescence in Cancer
Demirci, D., Dayanc, B., Mazi, F. A., & Şentürk, Ş. (2021) · Cells · doi:10.3390/cells10020208 · Cited by 62
Senescence under appraisal: hopes and challenges revisited
Davan-Wetton, C. S. A., Pessolano, E., Perretti, M., & Montero‐Melendez, T. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03746-x · Cited by 61
Alveolar type 2 epithelial cell senescence and radiation-induced pulmonary fibrosis
Zhou, S., Zhu, J., Zhou, P., & Gu, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.999600 · Cited by 58
“When IR causes AT2 cell senescence, SASP can promote the EMT of AT2 cells to generate fibroblasts and myofibroblasts; On the other hand, SASP activates and multiplies fibroblasts; SASP also acts on myofibroblasts to induce senescence and aggravate inflammatory responses; these lead to excessive proliferation and abnor…”
BackgroundIntegrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence
Kalinin, A., Zubkova, E., & Menshikov, M. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417423 · Cited by 62
“This alleviates both systemic and local inflammation in adipose tissue in old mice [44].”
BackgroundMicroRNAs are critical regulators of senescence and aging in mesenchymal stem cells
Potter, M. L., Hill, W., Isales, C. M., Hamrick, M. W., & Fulzele, S. (2020) · Bone · doi:10.1016/j.bone.2020.115679 · Cited by 59
“Consistent with this finding, suppression of the SASP has been shown to alleviate frailty in aged mice (45).”
BackgroundAntiaging Strategies and Remedies: A Landscape of Research Progress and Promise
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Senescence as a molecular target in skin aging and disease
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Self-citationEnergetic interventions for healthspan and resiliency with aging
Huffman, D. M., Schafer, M. J., & LeBrasseur, N. K. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.05.012 · Cited by 54
Self-citationThe impact of cellular senescence in human adipose tissue
Nerstedt, A., & Smith, U. (2023) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-023-00769-4 · Cited by 60
Calorie restriction protects neural stem cells from age-related deficits in the subventricular zone
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“Cellular senescence is a phenomenon by which cellular division ceases in the aged organism, and is modifiable in laboratory models [20].”
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“A growing amount of evidence indicates that chronic inflammation accelerates senescence, while inflammation-deletion delays senescence [15, 28, 34].”
Zhang, W., Xu, M., Chen, F., Su, Y., Yu, M., Xing, L., Chang, Y. E., & Yan, T. (2023) · Experimental Neurology · doi:10.1016/j.expneurol.2023.114474 · Cited by 54
Self-citationTranslating the Biology of Aging into New Therapeutics for Alzheimer's Disease: Senolytics
Rießland, M., & Orr, M. E. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.104 · Cited by 58
“Interestingly, inhibition of JAK/STAT signaling by ruxolitinib suppressed C/EBP β transcriptional activity, leading to a reduction in systemic inflammation by SASP repression and improvement in fitness in elderly mice (94).”
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“Removal of senescent cells in adipose tissue delays the fat loss and its related metabolic dysfunctions in the aging mouse models (6,7).”
BackgroundAdipose Tissue Aging and Metabolic Disorder, and the Impact of Nutritional Interventions
Wang, X., Xu, M., & Li, Y. (2022) · Nutrients · doi:10.3390/nu14153134 · Cited by 56
“Experiments have confirmed that targeted elimination of senescent cells in mouse adipose tissue can significantly improve adipose tissue dysfunction [44,52], and inhibition of SASP production by JAK/STAT inhibitors, l-carnitine and other drugs can relieve chronic inflammation and weakness in elderly mice [53,54].”
BackgroundSelf-citationRole of Senescent Cells in Cutaneous Wound Healing
Andrade, A. M., Sun, M., Gasek, N. S., Hargis, G. R., Sharafieh, R., & Xu, M. (2022) · Biology · doi:10.3390/biology11121731 · Cited by 56
“Furthermore, these cells produce a typically pro-inflammatory secretome referred to as the senescence associated secretory phenotype (SASP), which possesses corresponding complexity [2,4,8,11,12].”
BackgroundSelf-citationAging and Mesenchymal Stem Cells: Therapeutic Opportunities and Challenges in the Older Group
Chen, H., Liu, O., Chen, S., & Zhou, Y. (2021) · Gerontology · doi:10.1159/000516668 · Cited by 52
The senescence-associated secretory phenotype: Fueling a wound that never heals
Pulido, T., Velarde, M. C., & Alimirah, F. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111561 · Cited by 54
Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging
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Age‐associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis
Song, J., Farris, D. M., Ariza, P., Moorjani, S., Varghese, M., Blin, M. G., Chen, J., Tyrrell, D. J., Zhang, M., Singer, K., et al. (2023) · Aging Cell · doi:10.1111/acel.13783 · Cited by 50
“These results are consistent with the prior notion that aging increases senescence within adipose tissue (Liu et al., 2020; Ou et al., 2022; Tchkonia et al., 2010; Xu et al., 2015).”
ResultGeroprotectors: A role in the treatment of frailty
Trendelenburg, A., Scheuren, A. C., Potter, P. K., Müller, R., & Bellantuono, I. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.03.002 · Cited by 52
Liang, Y., Su, W., & Wang, F. (2023) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s408765 · Cited by 61
MDSCs, ageing and inflammageing
Pawelec, G., Picard, E., Bueno, V., Verschoor, C. P., & Ostrand‐Rosenberg, S. (2021) · Cellular Immunology · doi:10.1016/j.cellimm.2021.104297 · Cited by 50
Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
Rysanek, D., Vašicová, P., Kolla, J. N., Sedlák, D., Anděra, L., Bártek, J., & Hodný, Z. (2022) · Aging · doi:10.18632/aging.204207 · Cited by 48
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
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