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.
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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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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]
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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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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]
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Citations
Cites
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Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
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“(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
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The emerging role of aging in tumorigenesis
Wu, X., Wang, H., Liu, Y., & Hu, P. (2026) · Cell investigation. · doi:10.1016/j.clnves.2026.100093
Pallatt, S., Nambidi, S., Banerjee, A., & Pathak, S. (2026) · Cancer Reports · doi:10.1002/cnr2.70682
“Evidence supports a role for JAK/ STAT in maintaining, rather than initiating, SASP expression [66].”
Cellular Senescence in Oral Lichen Planus: Evidence, Limitations, and Future Perspectives
Falco, D. D., Lucchese, A., Pannone, G., & Petruzzi, M. (2026) · Immuno · doi:10.3390/immuno6030058
“However, this mechanism appears cell-and context-dependent and should not be considered a universal feature of senescence [27].”
Zhang, S., Ma, S., Li, H., Pang, Y., Dai, Y., Liu, X., Zhao, T., Liu, B., & Chen, H. (2026) · Journal of Dermatologic Science and Cosmetic Technology · doi:10.1016/j.jdsct.2026.100196
Djabali, K. (2026) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2026.112255
Bone Aging and Glycative Stress: Convergent and Divergent Mechanisms Driving Skeletal Deterioration
Peñarrubia, S., Martín‐Guerrero, E., Gortázar, A. R., & Ardura, J. A. (2026) · Cells · doi:10.3390/cells15181712
“The skeletal benefits observed following senescent cell targeting were attributable to decreased bone resorption, accompanied by maintained bone formation in trabecular bone and increased bone formation in cortical bone [29,98].”
Zhang, L., Yao, Y., & Chen, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1940235
Liu, H., & Lei, B. (2026) · Biogerontology · doi:10.1007/s10522-026-10508-y
“…r a p e u ti c b e n e fi t i n hu m a n s r e m a i n un t e s t e d Ruxolitinib, a JAK1/JAK2 inhibitor, alleviates SASP and frailty in aged mice (Xu et al. 2015), and the JAK-STAT pathway has been specifically implicated in SASP-mediated suppression of BMSC osteogenic differentiation in bone…”
Blanco, J. R., & Carnero, A. (2026) · Cancers · doi:10.3390/cancers18193084
“Pharmacological inhibition of JAK1/2 suppresses SASP production, reduces inflammatory signaling, and improves tissue function in experimental models of senescence [144,145].”
He, W., Liu, P., Kong, J., Wang, Q., Zhao, Y., & Xia, R. (2026) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl48959
Cellular senescence: six decades of discovery and reinvention
Klaver, M., Steeneken, L. S., Veeningen, N., Altulea, A., & Demaria, M. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00922-w
Cho, H.-J., Ryu, S. J., Kim, B. J., Hwang, J.-A., Yun, A., Kim, E.-C., Kim, J.-R., Park, T. J., Lee, S. B., Kim, Y. Z., et al. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119970
Senotherapeutic potential against xeroderma pigmentosum
王雪冰, Nishida, M., Yoshioka, A., Chung, C., Hashimoto, S., Tanizawa, H., Ohta, S., Noma, K.-I., & Fukumoto, T. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-05227-7
“Senomorphic agents have recently been shown to extend lifespan and reduce age-related inflammation [15, 27].”
Huang, J., Ji, L., Jin, H., Shi, Z., Song, X., Cai, Y., & Tong, X. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103398
Silencing without clearing: pharmacological modulation of the SASP in aging and disease
Fresser, L., Chrienová, Ž., Gebrt, J., Olekšák, P., Kuča, K., & Nepovimová, E. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1911529
“Ruxolitinib, FDA-approved drug for myelofibrosis (Lagoumtzi and Chondrogianni, 2021), prevented age-related adipose tissue loss, reduced lipotoxicity, improved insulin sensitivity, and enhanced physical performance in 22-month-old mice (Xu et al., 2015a; Xu et al., 2015b).”
Fang, H., Zhou, X., Liu, Y., Chen, W., Zhou, F., Zhou, H., Xiang, J., & Xiong, L. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1982491
Li, M., Yao, Y., Zhao, Y., Guo, Q., Li, C., Lv, C., Zhang, B., Li, J., & Zhao, H. (2026) · Biogerontology · doi:10.1007/s10522-026-10537-7
“Consequently, adipose tissue dysfunction is not restricted to local tissue impairment, but may also be linked to systemic frailty and broader organismal aging (Sanz-Ros et al. 2022; Xu et al. 2015).”
Saemann, L., Kozar, B., Pohl, S., Hoffmeister, A., Wernstedt, L., Gong, Y., Simm, A., & Szabo, G. B. (2026) · Frontiers in Transplantation · doi:10.3389/frtra.2026.1917058
“The senomorphic agent ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, blocks SASP secretion and may therefore be a protective agent for organ preservation (7, 8).”
Huang, D., Si, H., Jiao, X., Xuan, S., Yang, T., Ba, M., Qi, D., Pei, X., 卢丁丽, 黄深振, et al. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.12.73
Yang, Y., Chen, H., Yang, M., Li, H., Xu, W., Gong, H., Yang, Y., Mo, Y., Huang, N., Liu, J., et al. (2026) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-026-05788-4
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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