Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans
Open accessAbstract
Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. Baseline pSTAT levels tracked with circulating levels of C-reactive protein (CRP), and we derived a cytokine response score that negatively correlates with measures of cardiovascular disease, specifically diastolic dysfunction and atherosclerotic burden, outperforming CRP. Thus, we identified an immunological link between inflammation, decreased cell responsiveness in the JAK-STAT pathway, and cardiovascular aging. Targeting chronic inflammation may ameliorate this deficiency in cellular responsiveness and improve cardiovascular function.
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The primary outcome, cytokine response score difference from baseline to end of intervention, was not significant in either arm.
“The primary outcome of cytokine response score (Shen-Orr et al., 2016) difference from baseline to end of intervention was not significant for either arm of the study (Table S4), nor were race or gender significant covariates.”
From Gut-microbiota-targeted diets modulate human immune status (2021) · cites this paper as Shen-Orr et al., 2016
Race and gender were not significant covariates in the primary outcome analysis.
“The primary outcome of cytokine response score (Shen-Orr et al., 2016) difference from baseline to end of intervention was not significant for either arm of the study (Table S4), nor were race or gender significant covariates.”
From Gut-microbiota-targeted diets modulate human immune status (2021) · cites this paper as Shen-Orr et al., 2016
Systemic chronic inflammation can impair normal immune function, increasing susceptibility to infections and tumors and reducing vaccine response.
“SCI can also impair normal immune function, leading to increased susceptibility to infections and tumors and a poor response to vaccines22–25.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [22]
Elevated SCI can produce low-grade continuous activation of pathways like JAK-STAT in leukocytes, which weakens the acute response of immune cells from older adults with chronic inflammation to various stimuli, because phosphorylation of these proteins increases less after stimulation.
“elevated SCI can lead to a basal low-grade constitutive activation of various signaling pathways, such as the Janus kinase/signal transducers and activators of transcription (JAK–STAT) system in leukocytes, which results in a weakened acute response to multiple stimuli in immune cells from older adults with chronic inflammation due to reduced fold-increase in the levels of phosphorylation of these”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [22]
Increased proinflammatory cytokines or danger signals cause constitutive low-level engagement of JAK-STAT, MyD88, NF-κB and inflammasome signalling, producing high basal activation but impaired responses to further stimulation.
“The increased presence of proinflammatory cytokines or danger signals leads to constitutive low-level engagement of immune cell signaling events such as JAK-STAT, MyD88, NF-κB, and inflammasomes, resulting in high basal activation but impaired immune cell responses to further cytokine and pattern recognition receptor (PRR) stimulation17,18.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [17]
Many immune cell subsets become hyporesponsive to acute challenges with age.
“Thus, many immune cell subsets become hyporesponsive to acute challenges as we age17,19-25.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [17]
In older humans, elevated baseline phosphorylation of STAT proteins in T cells distinguishes healthy ageing from unhealthy ageing subjects based on cardiovascular ageing phenotypes.
“mTOR has also been shown to regulate STAT signaling175, and studies in older humans show that the elevation in baseline phosphorylation of STAT proteins in T cells distinguishes healthy ageing from unhealthy ageing subjects based on cardiovascular ageing phenotypes17.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [17]
Lack of early type I IFN responses during severe COVID-19, compounded with JAK/STAT hyporesponsiveness of aged immune cells, could facilitate early viral replication and overburden the immune system in early elderly responses to SARS-CoV-2.
“A lack of early type I IFN responses during severe COVID-19, compounded with the JAK/STAT hyporesponsiveness of aged immune cells17, could facilitate early viral replication and overburden the immune system in early elderly responses to SARS-CoV-2 invasion.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [17]
Inflammatory markers are at least partly responsible for reduced JAK-STAT response to cytokine stimulations in various leukocyte populations.
“inflammatory markers have been shown to be, at least in part, responsible for a reduced JAK–STAT response to cytokine stimulations in various leukocyte populations in our previous studies of aging28.”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [28]
Sustained levels of inflammatory mediators lead to nonfunctional constitutive phosphorylation of signaling pathways with saturation of phosphorylation sites, resulting in lowered δ phosphorylation and dampened immune response.
“we show that sustained levels of inflammatory mediators lead to nonfunctional constitutive phosphorylation of signaling pathways with saturation of phosphorylation sites in signaling proteins (such as the JAK–STAT system), which results in a lowered δ phosphorylation in response to acute stimuli and subsequent dampening of the immune response to infections or vaccination28.”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [28]
The pro-inflammatory environment may cause blunted T cell responses to cytokines in older individuals, possibly through induction of negative regulatory pathways.
“the pro-inflammatory environment may be responsible for the blunted response of T cells from older individuals to cytokines, as shown by in vitro studies, possibly due to the induction of negative regulatory pathways”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Shen-Orr et al., 2016
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- Authors
- Shen-Orr, S. S., Furman, D., Kidd, B. A., Hadad, F., Lovelace, P., Huang, Y.-W., Rosenberg-Hasson, Y., Mackey, S., Grisar, F. A. G., Pickman, Y., Maecker, H. T., Chien, Y.-H., Dekker, C. L., Wu, J. C., Butte, A. J., & Davis, M. M.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Butte, Atul J.
- Davis, Mark M.
- ORCID
- Venue
- Cell Systems
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 3
- Issue
- 4
- Pages
- 374-384.e4
- ISSN
- 2405-4712 (ISSN-L)
- PMC
- PMC5358544
- OpenAlex
- W2531162495
- Cited by
- 154
- References
- 53
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 12 · 2023: 18 · 2022: 21 · 2021: 20 · 2020: 16 · 2019: 18 · 2018: 12 · 2017: 6 · 2016: 1
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Systems (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (HHSN272201200028C, U19AI090019, U19AI057229)
- National Center for Research Resources (UL1RR025744)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- JAK/STAT signaling, chronic inflammation, aging, cardiovascular aging, cytokine responsiveness, T cells, STAT phosphorylation, C-reactive protein, interleukin-6, interferon-alpha, IL-21, interferon-gamma, diastolic dysfunction, atherosclerosis, cardiovascular risk, immunosenescence
- MeSH terms
- Aging, Cardiovascular Diseases, Humans, Inflammation, Interferon-gamma, Phosphorylation, Risk Factors, Signal Transduction, Cytokines, STAT Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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