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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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Frailty syndrome: A target for functional nutrients?
Davinelli, S., Corbi, G., & Scapagnini, G. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111441 · Cited by 38
Madani, A. Y., Majeed, Y., Abdesselem, H., Agha, M. V., Vakayil, M., Sukhun, N. K. A., Halabi, N. M., Kumar, P., Hayat, S., Elrayess, M. A., et al. (2021) · Antioxidants · doi:10.3390/antiox10020334 · Cited by 37
“Emerging evidence has shown that the clearance of senescent cells in adipose tissue by pharmacogenetic approaches enhanced adipogenesis and metabolic function in obese animal models [19].”
BackgroundHames, K. C., Morgan-Bathke, M. E., Harteneck, D. A., Zhou, L., Port, J. D., Lanza, I. R., & Jensen, M. D. (2017) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.116.148114 · Cited by 40
Self-citationWang, Y., Wang, Y., Yang, M., & Ma, X. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111191 · Cited by 34
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Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep
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“Targeting senescent cells using senolytic drugs/agents has been shown to improve SASP and frailty and to enhance metabolic function in aged mice [37,38].”
BackgroundIacobini, C., Vitale, M., Haxhi, J., Menini, S., & Pugliese, G. (2024) · Cells · doi:10.3390/cells13090763 · Cited by 42
“Thus, SASP plays a role in the development of localized and systemic chronic low-grade inflammation, known as inflammaging, through autocrine and paracrine mechanisms [182–184].”
BackgroundAging human abdominal subcutaneous white adipose tissue at single cell resolution
Whytock, K. L., Divoux, A., Sun, Y., Pino, M. F., Yu, G., Jin, C. A., Robino, J. J., Plekhanov, A., Varlamov, O., Smith, S. R., et al. (2024) · Aging Cell · doi:10.1111/acel.14287 · Cited by 39
Enhancing immunity during ageing by targeting interactions within the tissue environment
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Senotherapy: growing old and staying young?
Schmitt, R. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1972-4 · Cited by 36
“Treatment of old mice with a selective JAK1/2 inhibitor resulted in decreased tissue inflammation and enhanced physical activity [62].”
BackgroundDietary Phytochemicals that Can Extend Longevity by Regulation of Metabolism
Shen, J., Shan, J., Zhong, L., Liang, B., Zhang, D., Li, M., & Tang, H. (2022) · Plant Foods for Human Nutrition · doi:10.1007/s11130-021-00946-z · Cited by 38
“Senescent cells can release factors, such as proinflammatory cytokines and chemokines, to healthy cells nearby, and therefore cause the local and systemic dysfunction [46].”
BackgroundAging, senescence, and cutaneous wound healing—a complex relationship
O’Reilly, S., Markiewicz, E., & Idowu, O. C. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1429716 · Cited by 41
Treating age-related multimorbidity: the drug discovery challenge
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Biological Aspects of Inflamm-Aging in Childhood Cancer Survivors
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Context‐dependent roles of cellular senescence in normal, aged, and disease states
Moiseeva, V., Cisneros, A., Cobos, A. C., Tarrega, A. B., Oñate, C. S., Perdiguero, E., Serrano, A. L., & Muñoz‐Cánoves, P. (2023) · The FEBS Journal · doi:10.1111/febs.16573 · Cited by 34
Tindle, C., Fonseca, A. G., Taheri, S., Katkar, G. D., Lee, J., Maity, P., Sayed, I. M., Ibeawuchi, S.-R., Vidales, E., Pranadinata, R. F., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101748 · Cited by 33
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“…the SCs by inhibiting NF-κ B, the janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, the serine/threonine protein kinase mTOR, mitochondrial complex-1-related or 4-related targets, or other pathways involved in the induction and maintenance of the SASP [40–43].”
Mikuła‐Pietrasik, J., Uruski, P., Pakuła, M., Maksin, K., Szubert, S., Woźniak, A., Naumowicz, E., Szpurek, D., Tykarski, A., & Książek, K. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.06.015 · Cited by 33
“The effect of autologous and cancer-derived CM or exogenous HGF on the activation of signaling pathways associated with cellular senescence (AKT, JAK1, JNK, PI3K, NF-κB, and p38 MAPK) was analyzed using specific ELISA-based kits purchased from Active Motif (Carlsbad, CA, USA) as per manufacturer's instructions.”
MethodCho, S., Kim, A. Y., Kim, J., Choi, D. H., Son, E., & Shin, D. W. (2019) · British Journal of Dermatology · doi:10.1111/bjd.17824 · Cited by 35
TGF‑β induces periodontal ligament stem cell senescence through increase of ROS production
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“cellular senescence can be induced by various stimuli and stressors, including dna damage, metabolic insults, oxidative stresses, oncogene activation and epigenetic changes (16-18).”
BackgroundTherapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy?
van Schaik, T., Chen, K., & Shah, K. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.678562 · Cited by 37
Senescent cells and SASP in cancer microenvironment: New approaches in cancer therapy
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Targeting the hallmarks of aging to improve influenza vaccine responses in older adults
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“Interestingly, JAK-STAT inhibitors decrease the senescence associated secretory phenotype (SASP), which is directly related to inflammaging in aged mice [93].”
BackgroundTargeting senescent cells for the treatment of age-associated diseases
Suda, M., Tchkonia, T., Kirkland, J. L., & Minamino, T. (2024) · The Journal of Biochemistry · doi:10.1093/jb/mvae091 · Cited by 38
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“Senescent cells may have the ability to evade immune cells, leading to their accumulation; however, the specific mechanism is still unclear [36, 37].”
Noncanonical Wnt5a signaling regulates tendon stem/progenitor cells senescence
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“The JAK–STAT signaling is one of the important intracellular pathways, which is frequently activated in senescent stem cell [27, 39].”
BackgroundWang, P., Konja, D., Singh, S., Zhang, B., & Wang, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25041978 · Cited by 37
“Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice [192].”
BackgroundSenescence and SASP Are Potential Therapeutic Targets for Ischemic Stroke
Ouvrier, B., Ismael, S., & Bix, G. J. (2024) · Pharmaceuticals · doi:10.3390/ph17030312 · Cited by 32
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Linking skeletal muscle aging with osteoporosis by lamin A/C deficiency
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“Targeting senescent cells or inhibiting the production of the proinflammatory SASP of senescent cells was reported to markedly improved bone mass and microarchitecture in trabecular and cortical bone in old mice [35,68,69].”
BackgroundHan, X., Zhang, T., Zhang, X., Zhang, R., Lao, K., Mi, Y., & Gou, X. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111347 · Cited by 33
Ding, X., Ma, X., Meng, P., Yue, J., Li, L., & Xu, L. (2024) · Clinical Interventions in Aging · doi:10.2147/cia.s447514 · Cited by 33
“61 The high glucose and fat environment in diabetic patients has been identified as the main cause of cellular senescence.”
BackgroundPhospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease
Beaulieu, D., Attwe, A., Breau, M., Lipskaia, L., Marcos, É., Born, E., Huang, J. L., Abid, S., Dérumeaux, G., Houssaini, A., et al. (2021) · European Respiratory Journal · doi:10.1183/13993003.00752-2020 · Cited by 32
Promises and challenges of senolytics in skin regeneration, pathology and ageing
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Self-citationTherapeutic Antiaging Strategies
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Apoptosis signal-regulating kinase 1 promotes inflammation in senescence and aging
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“Previous studies have shown that pharmacological inhibition of NF-κ B and other SASP drivers ameliorates ataxia, glomerulosclerosis, osteoporosis, and frailty 40 – 43 .”
Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation
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“179 In senescent cells and aged adipose tissue, heightened JAK/STAT activation under mechanical imbalance exacerbates pro-inflammatory responses and impairs cellular homeostasis.”
InfluentialMixing old and young: enhancing rejuvenation and accelerating aging
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“Activin A, which is also closely related to myostatin and GDF11, can be secreted by senescent cells and can bind to the same receptor (20).”
BackgroundSelf-citationMorsiani, C., Terlecki‐Ζaniewicz, L., Skalicky, S., Bacalini, M. G., Collura, S., Conte, M., Sevini, F., Garagnani, P., Salvioli, S., Hackl, M., et al. (2021) · Aging Cell · doi:10.1111/acel.13409 · Cited by 29
“SOCS1, known as suppressor of cytokine signaling, acts via the JAK/STAT pathway inhibiting JAK directly, and senescenceassociated secretory phenotype (SASP) can be suppressed by inhibiting the JAK pathway in senescent cells (Xu et al., 2015).”
Background
Metadata
- Authors
- Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K., & Kirkland, J. L.
- Affiliations
- Mayo Clinic (US)
- Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-11-02
- Volume
- 112
- Issue
- 46
- Pages
- E6301-10
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4655580
- OpenAlex
- W1932046626
- Cited by
- 915
- References
- 68
- Citations by year
- 2026: 104 · 2025: 110 · 2024: 112 · 2023: 98 · 2022: 110 · 2021: 115 · 2020: 72 · 2019: 70 · 2018: 59 · 2017: 30 · 2016: 33 · 2015: 1
- FWCI
- 30.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- HHS | NIH | National Institute on Aging (AG041122, AG013925)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- JAK inhibition, cellular senescence, senescence-associated secretory phenotype, frailty, aging, age-related inflammation, adipose tissue, preadipocytes, macrophage migration, conditioned medium, endothelial cells, physical function, JAK inhibitors
- MeSH terms
- Adipose Tissue, Animals, Cell Movement, Extracellular Matrix, Humans, Macrophages, Signal Transduction, Cellular Senescence, Adipocytes, RNA, Small Interfering, Mice, Janus Kinases, Human Umbilical Vein Endothelial Cells
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