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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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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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“Moreover, JAK/STAT pathway inhibitors have senomorphic effects by suppressing SASP gene expression in senescent preadipocytes and reduce inflammation in old mice (114) .”
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From Neuron‐Centric to Glia‐Centric: How Aging Glial Networks Drive Neurodegenerative Disease
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“Rafael Serafim Pinto: investigation, writing – original draft, writing Reduced senescent burden, reversed age-associated dysfunction, and produced long-lasting benefits in aging models (Amor et al. 2020, 2024) NKG2D- CAR-T cells Targets stress-induced NKG2D ligands broadly upregulated in senescent cells Selective elim…”
New Trends in Aging Drug Discovery
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“Inhibition of the JAK pathway by the JAK 1/2 inhibitor ruxolitinib (Figure 3) suppressed SASP production [44], alleviated age-related dysfunction in several mouse models [44,172], and reduced frailty in old age.”
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Cellular senescence: A novel therapeutic target for central nervous system diseases
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Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice.
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The Importance of Cellular Senescence in Frailty and Cardiovascular Diseases
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“The JAK inhibitor (JAKi) ruxolitinib suppresses components of the SASP, specifically IL-6, Il-8, and PAI-1 (457, 458), which are known to promote osteoclastogenesis and bone resorption (127).”
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“Moreover, studies have suggested that frailty phenotype can be a consequence of cellular senescence, possibly mediated by senescence-associated secretory phenotype, and chronic inflammation, and this mechanism might be reversed in pre-clinical models.(28,29) While many studies have focused on discovering molecular bio…”
BackgroundIdentification of a suitable endogenous control miRNA in bone aging and senescence
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“Drugs that target cellular senescence can have bene fi cial e ff ects in delaying aging and age-related diseases [76 – 78].”
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“Senescent fibroblasts and MSCs can also produce a range of pro‑inflammatory cytokines (7,8).”
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“Indeed, there is solid evidence from experimental aging models that senotherapeutics represent a powerful antiaging strategy in that it delays the onset of chronic diseases associated with aging, improves the function of organs, and extends healthspan (39–43).”
The senotherapeutic potential of phytochemicals for age-related intestinal disease
Costa, C. M., Pedrosa, S. S., Kirkland, J. L., Reis, F., & Madureira, A. R. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102619 · Cited by 18
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“Also, results of preclinical studies suggest that low-grade inflammation in older people can be reduced with JAK inhibitors [19, 20].”
Understanding the Impact of Obesity on Ageing in the Radiance of DNA Metabolism
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“In addition, resveratrol and metformin reduce the translocation of NF-kB, and other drugs Ruxolitinib and Momelotinib target the JAK/STAT receptor which leads to the inhibition of the SASP components in human preadipocytes (187, 188).”
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“In aged mice, inhibition of JAK pathways suppressed SASP and alleviate frailty (Xu et al., 2015).”
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Young at Gut—Turning Back the Clock with the Gut Microbiome
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Adipose tissue senescence: Biological changes, hallmarks and therapeutic approaches
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“Blocking the PD-1/PD-L1 interaction has been shown to reduce senescence markers in vitro and ameliorate senescence-associated phenotypes in vivo [64-66] .”
Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise
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“JAK inhibitors provide a second senomorphic approach, dampening SASP-driven inflammation and fibrosis by interrupting IL-1–NF-κ B–JAK/STAT signaling 257 .”
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“The SASP is widely believed to mediate many of the detrimental effects exerted by senescent cells, and consequently strategies have been devised to target it 10,11 .”
Cellular Senescence and Ageing
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A chronic wound model to investigate skin cellular senescence
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“Of note, it has also been shown that JAK inhibition suppressed SASP in human umbilical vein endothelial cells, and importantly, administration of JAK inhibitors to aged mice alleviated systemic inflammation and enhanced physical function (Xu et al., 2015).”
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“JAK inhibitors also substantially reduce age ‐ related syndromes in mice [83].”
Bone marrow fat: friend or foe in people with diabetes mellitus?
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“(94-97) Moreover, aged adipocytes show increased levels of p53, p21 and p16, and a decrease in SIRT-1 protein compared to younger cells.”
BackgroundThe immunometabolic roots of aging
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Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss
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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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