Browse All / Modules / Inflammaging Module

Inflammaging Module

Immunology Aging Module inflammaging 3 disorders Pathograph 17
A conserved mechanism module for the intertwined hallmarks of aging (Lopez-Otin et al.) termed altered intercellular communication and chronic inflammation - together the phenomenon of "inflammaging": the chronic, low-grade, sterile systemic inflammation that develops with age in the absence of overt infection. Multiple age-associated stimuli converge to sustain it - the senescence-associated secretory phenotype (SASP), damage-associated molecular patterns from dysfunctional mitochondria, NLRP3 inflammasome activation, increased gut permeability and microbiota shifts, central obesity, immune dysregulation, and chronic infections. The resulting persistent cytokine milieu, propagated systemically through altered intercellular communication, is a highly significant risk factor for morbidity and mortality because most age-related diseases share an inflammatory pathogenesis. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific inflammatory driver and target tissue while preserving the conserved stimulus -> chronic-sterile-inflammation -> systemic-propagation -> age-related-morbidity chain.
⚙

Pathophysiology Nodes

4
4 shared nodes are defined in this module.
◉

Cell Types

0
No cell types are annotated for this module.
⇄

Biological Processes

3
Inflammatory Response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. Cytokine Production GO:0001816 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased Cytokine Production (GO:0001816). GO:0001816 is a biological process from the Gene Ontology. Cytokine-Mediated Signaling GO:0019221 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased Cytokine-Mediated Signaling (GO:0019221). GO:0019221 is a biological process from the Gene Ontology.
i

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "inflammaging#Chronic Low-Grade Sterile Inflammation"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context. The module captures the conserved inflammaging chain and its role as a shared risk substrate for age-related disease; it deliberately does NOT re-derive the SASP (see cellular_senescence) or adjudicate which upstream source dominates in a given disease. It is the systemic-inflammation convergence point downstream of cellular_senescence and mitochondrial_dysfunction. Key conformance target: "inflammaging#Chronic Low-Grade Sterile Inflammation". Two naked mole-rat models are attached under animal_models: the species itself as a comparative negative model for the outcome node, and the nmrHas2 transgenic mouse, which exports the naked mole-rat hyaluronan adaptation into a short-lived mammal and is the one intervention arm this module carries for the chain as a whole. Neither is a disease model, and conforming disorder entries do NOT inherit those links; the transfer question is recorded as a HUMAN_MODEL_MISMATCH discussion. One non-animal model is attached under experimental_models: a human cortical organoid microphysiological platform cocultured with primary monocytes from aged and young donors. It is the only model on this module that is entirely human, and it carries links across all four nodes, so it runs the stimulus-to-consequence chain in one system with donor age as the sole variable. Two limits bound every one of those links: the coculture is short, so it addresses the initiation of the chain and not the chronicity that defines inflammaging, and the responding organoid tissue is young by construction. Like the naked mole-rat models, it is not a disease model and conforming disorder entries do not inherit its links.
?

Discussions and Knowledge Gaps

6
The nmrHas2 mouse shows that naked mole-rat hyaluronan attenuates inflammaging and extends lifespan in a second species. Does that indicate a route that could be engaged in humans, or a result that depends on transgenic overexpression in the mouse?
HUMAN MODEL MISMATCH OPEN human_model_mismatch_nmrhas2_hyaluronan_transfer
Attached to: Chronic Low-Grade Sterile Inflammation Age-Related Morbidity and Mortality
This is the most direct intervention evidence attached to this module and also the easiest to over-read. The manipulation is transgenic overexpression of a foreign synthase, producing tissue hyaluronan levels that no dietary or pharmacological route reproduces, so the effect size is not a guide to what a human intervention would achieve. The authors themselves attribute the benefit to high-molecular-mass hyaluronan rather than to the naked mole-rat gene, which is the useful part of the finding - the effector is a polymer, not a species' allele - but it also means the result does not license reading nmrHas2 as a druggable target. Two further gaps sit between this model and human aging. Hyaluronan is already in wide clinical use as viscosupplementation and as a dermal filler, at routes and doses that do not produce sustained systemic high-molecular-mass tissue hyaluronan, so existing human exposure is not evidence about this mechanism either way. And part of the survival benefit in these mice ran through cancer resistance, which in the source species is a direct effect of the polymer on transformation rather than a consequence of reduced inflammation, so the lifespan result cannot be attributed to this module's chain without isolating the inflammatory arm.
Proposed experiments: Hyaluronan polymer size in human tissue across age Isolate the inflammatory arm of the nmrHas2 lifespan benefit
Do circulating inflammatory markers report biological age, or do they only track chronological age and disease burden?
KNOWLEDGE GAP OPEN knowledge_gap_inflammatory_markers_vs_chronological_age
Attached to: High-sensitivity C-reactive protein Circulating tumour necrosis factor Chronic Low-Grade Sterile Inflammation
This gap is deliberately attached to markers this module already curates, because it qualifies them rather than opposing them. The 2025 Delphi expert consensus recommends hsCRP and IL-6 as biomarkers of aging for intervention studies, yet hsCRP and TNF-alpha specifically failed to reach agreement that they predict biological age better than chronological age does. That is a narrower and more useful statement than "these markers are unvalidated": they are accepted as measures of the inflammatory state, and unresolved as measures of the rate of aging. A curator reading the readouts in this module should therefore treat the PROGNOSTIC links as claims about mortality risk in older adults, which is what the cited cohort evidence supports, and not as claims that the marker measures biological age. Resolving this needs longitudinal designs in which chronological age is held constant, not further cross-sectional association studies.
Which combination of markers best captures the inflammaging state, given that no single circulating analyte is expected to?
KNOWLEDGE GAP OPEN knowledge_gap_composite_vs_single_inflammaging_markers
Attached to: Chronic Low-Grade Sterile Inflammation
The module curates five markers as separate objects because that is what the schema represents well, but the field's own position is that composites outperform single analytes and that the right composite is unknown. The consensus statement labels this a research priority in as many words. This matters structurally for dismech and not only scientifically: a composite index is a model over features, not an analyte, so it does not fit the Biochemical class cleanly, and the same question arises for epigenetic clocks. The representation question is recorded in the decision register as "Computed indices and composite endpoints in aging biology" (docs/explanation/design-decisions.md section 12); consult it before proposing a schema change here. The gap is attached to the whole biochemical section rather than to any one marker because it is about the set.
For cf-mtDNA and agalactosylated IgG, can the marker be separated from the mechanism it reports on, and does that matter for their use as endpoints?
KNOWLEDGE GAP OPEN knowledge_gap_marker_or_driver_cfmtdna_iggg0
Attached to: Circulating cell-free mitochondrial DNA Agalactosylated IgG N-glycans (IgG-G0) Age-Associated Inflammatory Stimuli
Both markers are curated here with READOUT_OF or CORRELATES_WITH links, which deliberately assert observation rather than causation. But both are also pro-inflammatory in their own right: cf-mtDNA is a DAMP sensed by TLR9, NLRP3 and cGAS-STING, and IgG-G0 activates complement and Fc-gamma receptors. The open question is not whether they are markers, which is established, but what follows for their use as endpoints. If a marker is part of the mechanism, an intervention that lowers it may be acting on the disease process or may be acting only on the assay, and the two cannot be told apart by the marker moving. This is the specific form the general surrogate-endpoint problem takes in inflammaging, and it is why both are recorded as MONITORING or CANDIDATE_SURROGATE rather than as validated surrogates.
Which clinical endpoint are inflammaging biomarkers candidate surrogates for, and does any of them predict that endpoint well enough to shorten a trial?
KNOWLEDGE GAP OPEN knowledge_gap_surrogate_for_which_geroscience_endpoint
Attached to: Age-Related Morbidity and Mortality
A surrogate is only a surrogate for something. The markers in this module carry MONITORING and CANDIDATE_SURROGATE contexts, but dismech has no representation of the clinical endpoints they would stand in for, so the CANDIDATE_SURROGATE label currently points nowhere. The geroscience field has converged on three endpoint families, each with a flagship trial: disability-free survival, the composite of death, dementia and persistent physical disability used as the ASPREE primary endpoint; multimorbidity, the accumulation of new age-related diseases, which is the TAME design; and the deficit-accumulation frailty index, operationalized as a 36-item index in SPRINT and used in Look AHEAD. The TAME Biomarkers Workgroup states the purpose plainly, that biomarkers exist to show an intervention is engaging aging biology before enough clinical events accrue to power the trial, and its proposed panel overlaps this module directly at IL-6, CRP and the TNF receptors. What is not established is the step that makes a surrogate legitimate: that a treatment-induced change in the marker predicts a change in the endpoint. None of these markers has been qualified for that, and the FDA surrogate endpoint table curated in kb/surrogate_endpoints/ contains no aging row against which regulatory_endpoint_refs could be set.
Through which upstream action does metformin lower age-associated inflammation: autophagy, mitochondrial function, nutrient signalling, or something else?
KNOWLEDGE GAP OPEN knowledge_gap_metformin_mechanism_in_inflammaging
Attached to: Metformin (Anti-Inflammaging Pharmacotherapy) Chronic Low-Grade Sterile Inflammation
This edge targets inflammation itself, which is closer to an outcome than a mechanism, so it makes a weaker mechanistic claim than the other metformin edges. The open question is what lies between the drug and the reduced inflammation. The primary study behind the treatment found that metformin improved autophagy and mitochondrial function largely in parallel in T cells from older people, so its own data do not say which of the two carries the anti-inflammatory effect. The review that makes the geroscience case for the drug says its mechanisms in aging are not fully elucidated.
🧫

Experimental Models

1
Human cortical organoid microphysiological platform with aged-donor monocyte coculture CO_CULTURE namo:CoCulture
A human brain organoid microphysiological analysis platform used to ask whether an aged peripheral immune compartment is sufficient to drive an inflammatory, aging-associated state in young human neural tissue. Cortical organoids are grown in a 3D-printed scaffold device under rocking flow, which lets primary blood monocytes be perfused in and infiltrate the tissue non-invasively. Monocytes isolated from aged and from young human donors are then run against otherwise identical organoids. Aged-donor monocytes infiltrate more, raise aging-associated marker expression including p16 within the organoid, secrete more proinflammatory cytokine, and increase MCP-3 chemokine and prostaglandin E2 signaling; neurons next to the infiltrating cells take on an apoptotic morphology. Because donor age is the only variable separating the arms and no pathogen is present, the system isolates the module's chain from stimulus to tissue outcome in entirely human material.
Cortical organoid without monocytes (baseline) Young-donor primary monocyte coculture (comparator) Aged-donor primary monocyte coculture
cortical neuron CL:0010012 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses cortical neuron, annotated with cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology. primary classical blood monocyte CL:0000860 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses primary classical blood monocyte, annotated with classical monocyte (CL:0000860). CL:0000860 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Human cortical organoids differentiated from the WA01 human embryonic stem cell line, cocultured with classical monocytes isolated from the peripheral blood mononuclear cells of young and aged human donors, three donors per group. The abstract describes the donor groups as 20 to 30 years and over 60 years while the methods describe them as under 35 and over 65, so the exact stratification is stated inconsistently within the paper. The methods also list the THP-1 monocyte line, but it appears only in the cell-culture paragraph and underpins none of the reported comparisons, every one of which uses primary donor monocytes.
Culture
Cortical organoids confined in a 3D-printed tubular scaffold device under rocking flow, permitting perfusion and non-invasive infiltration of primary monocytes into the organoid over a coculture of roughly one to three days
Publication
PMID:35908805
Pathograph links
Age-Associated Inflammatory Stimuli partially recapitulates fidelity: moderate Immune-cell dysregulation is one of the stimulus classes this node enumerates, and here it is instantiated with monocytes taken from elderly humans rather than with a surrogate insult. Donor age is the only variable distinguishing the arms, so any difference is attributable to the aged state of the immune cells themselves. Those cells behave as an active stimulus and not merely a marker: they infiltrate the tissue more and raise aging-associated marker expression within it.
Limitations: Only one of the seven stimulus classes this node enumerates is represented; there is no senescent-cell SASP, mitochondrial DAMP, NLRP3, gut-permeability, obesity, or chronic-infection arm, so the model cannot speak to convergence across sources, which is the node's substantive claim. Three donors per group is a small sample for a phenotype with known inter-individual variability, and the paper states the donor age thresholds inconsistently between its abstract and its methods.
Readouts
Aged-monocyte infiltration and induction of aging-associated markers in the organoid
leukocyte chemotaxis GO:0030595 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on leukocyte chemotaxis (GO:0030595). GO:0030595 is a biological process from the Gene Ontology. cellular senescence GO:0090398 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology.
Direction: INCREASED
Interpretation: Measured against young-donor monocytes on identical organoids. Greater infiltration establishes that the aged cells engage the tissue, and the rise in aging-associated markers including p16 establishes that they change its state, which together is what qualifies them as a stimulus for this node rather than a bystander.
Evidence: 1
Evidence: 1
Chronic Low-Grade Sterile Inflammation partially recapitulates fidelity: moderate Aged-donor monocytes raise proinflammatory cytokine secretion, assayed as MCP-3, interleukin-1 beta and tumour necrosis factor alpha, in a system containing no pathogen. The sterility this node's name turns on is therefore a property of the experiment rather than an inference, and the elevation is referenced to young-donor cells in the same tissue, which is the comparison the human circulating-cytokine literature can only make across individuals.
Limitations: The coculture runs for roughly one to three days, so what is captured is an acute response, not the chronic persistence this node's definition rests on; nothing here shows the state is self-sustaining. Mediators are read in the organoid microenvironment rather than in circulation, so this is not the elevated-circulating-mediator measurement the node describes and it does not connect directly to the module's circulating IL-6, CRP or TNF biomarkers. The authors also note that their organoids derive from human embryonic stem cells with long telomeres and do not reflect the senescent phenotypes of an aged brain, so the responding tissue is young and any age-by-age interaction is missed.
Readouts
Proinflammatory cytokine secretion under aged-donor monocyte coculture
positive regulation of inflammatory response GO:0050729 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on positive regulation of inflammatory response (GO:0050729). GO:0050729 is a biological process from the Gene Ontology.
Direction: INCREASED
Interpretation: Cytokine concentrations were measured by ELISA for MCP-3, interleukin-1 beta and tumour necrosis factor alpha in coculture supernatant. The increase is relative to young-donor monocytes; per-analyte values are in the paper's figures, not in the sentences quoted here.
Evidence: 1
Evidence: 1
Systemic Propagation via Altered Intercellular Communication partially recapitulates fidelity: moderate Two separately sourced human compartments are joined here, and the inflammatory state moves between them: blood-derived monocytes act on neural parenchyma they did not originate in. The mediators are the ones this node names. Increased MCP-3 is a recruitment signal that draws further immune cells in, so the model captures the feed-forward character of the amplifier step and not only the presence of soluble mediators, and increased prostaglandin E2 signaling gives a second mediator axis alongside the cytokines.
Limitations: Propagation here is perfusion across a single device between one immune compartment and one target organ, so nothing demonstrates the body-wide distribution this node asserts. The authors also state that they presumed a compromised blood-brain barrier and that no functional barrier is incorporated, so the step where mediators or cells cross an intact barrier to reach a distant tissue is bypassed rather than modeled, which is the part of systemic propagation most likely to fail in vivo.
Readouts
MCP-3 chemokine and prostaglandin E2 signaling in aged-donor coculture
leukocyte chemotaxis GO:0030595 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on leukocyte chemotaxis (GO:0030595). GO:0030595 is a biological process from the Gene Ontology.
Direction: INCREASED
Interpretation: Both mediators are raised by aged-donor monocytes relative to young-donor cells. MCP-3 is read as the recruitment arm of the amplification loop, since its stated function here is to attract further immunocytes into the tissue.
Evidence: 1
Evidence: 1
Age-Related Morbidity and Mortality partially recapitulates fidelity: low The chain terminates in visible tissue damage: neurons adjacent to infiltrated aged monocytes take on an apoptotic morphology. That supplies a cellular endpoint for the consequence node from within the same experiment that produced the stimulus and the inflammation, which is what the module's animal and human evidence cannot do in one system.
Limitations: Fidelity is LOW because morbidity and mortality are organism-scale endpoints an organoid cannot reach, and no clinical, functional or survival outcome is measured. What is reported is apoptotic morphology in neurons near infiltrating cells, a qualitative morphological observation rather than quantified cell death or a dose-response, and it is spatially associated with infiltration rather than shown to be caused by the cytokines measured on the upstream node.
Readouts
Neuronal apoptotic morphology adjacent to infiltrated aged monocytes
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Direction: INCREASED
Interpretation: Read as a tissue-level surrogate for the consequence node, standing in for an organism-level outcome the system cannot produce. The observation is morphological and spatially local to infiltrating cells.
Evidence: 1
Evidence: 1
Notes
Typed CO_CULTURE rather than ORGAN_ON_CHIP deliberately, following the organoid-plus-immune-cell precedent in drug_induced_liver_injury. The platform is a device, so either value is defensible, but the enum is single-valued and what makes this model informative here is the aged-donor monocyte coculture, not the scaffold. The intestine-on-a-chip attached to gut_dysbiosis is typed ORGAN_ON_CHIP on the same reasoning inverted: there the oxygen-gradient device is the distinctive feature. The divergence between the two is intended. The first non-animal model on this module, and the only one of its models that is entirely human. It complements the two naked mole-rat entries under animal_models rather than duplicating them: those carry an intervention arm for the chain as a whole in a whole organism, while this one runs the stimulus-to-consequence chain in human tissue with donor age as the only variable. It does not resolve the HUMAN_MODEL_MISMATCH discussion this module records, which is about the naked mole-rat hyaluronan adaptation, and conforming disorder entries do not inherit these links. Two limits apply across every link. The coculture is short, so the model speaks to the initiation of the chain and not to its chronicity, which is the defining feature of inflammaging. The responding tissue is young by construction: the authors note their organoids derive from human embryonic stem cells with long telomeres and do not reflect the senescent phenotypes of an aged brain, so this system tests whether an aged immune compartment is sufficient to inflame young tissue, not how aged tissue and an aged immune system interact.
Evidence: 1
🐁

Animal Models

3
nmrHas2 transgenic mouse (naked mole-rat Has2 overexpression)
A transfer experiment rather than a disease model: the naked mole-rat Has2 gene was put into the mouse to ask whether the abundant high-molecular-mass hyaluronan associated with that species' cancer resistance and longevity carries a benefit into a short-lived mammal. It does. The most prominent change in these mice was attenuated inflammation across multiple tissues, alongside lower spontaneous and induced cancer incidence, extended lifespan and improved healthspan, which makes this the one intervention arm this module has for the inflammaging chain as a whole.
Species
Mouse
Genotype
Transgenic overexpression of naked mole-rat hyaluronic acid synthase 2 (nmrHas2)
Publication
PMID:37612507
Pathograph links
Chronic Low-Grade Sterile Inflammation rescues fidelity: moderate Raising tissue hyaluronan attenuates the central effector state of this module across multiple tissues, through direct immunoregulatory effects on immune cells, protection from oxidative stress, and improved gut barrier function during ageing - the last of which also acts on this module's upstream stimulus node.
Limitations: The manipulation is transgenic overexpression in mouse, so the effect size does not transfer directly to a physiological human range, and no human intervention data exist. The authors state the benefit is conferred by high-molecular-mass hyaluronan rather than by the naked mole-rat gene specifically, so this link supports hyaluronan as the effector and not the species' gene as such. Attenuated inflammation was measured transcriptionally across tissues; which of the three proposed routes dominates in which tissue is not resolved.
Readouts
Tissue inflammation during ageing
Direction: DECREASED
Interpretation: Reduction of the chronic sterile inflammatory state is the readout that grounds the rescue claim on this node.
Evidence: 1
Evidence: 1
Age-Related Morbidity and Mortality rescues fidelity: moderate The consequence node moves with the inflammatory state: nmrHas2 mice had lower spontaneous and induced cancer incidence, extended lifespan and improved healthspan, and their transcriptome shifted towards that of longer-lived species.
Limitations: Lifespan and cancer are the outcome measures; the causal path from attenuated inflammation to those outcomes is inferred from their co-occurrence in the same animals rather than isolated by blocking the inflammatory arm. Hyaluronan acts on cancer resistance directly in this species' biology, so part of the survival benefit may bypass this module's chain entirely.
Readouts
Lifespan
Direction: INCREASED
Interpretation: Longer life in the intervention arm than in wild-type littermates. The comparator is a normal mouse rather than a diseased one, so this is an extension past the baseline, not a return to it.
Evidence: 1
Spontaneous and induced cancer incidence
Direction: DECREASED
Interpretation: Lower tumour incidence is the morbidity half of this node's outcome, and moves in the opposite direction to lifespan, which is why it is a separate readout.
Evidence: 1
Naked mole-rat (Heterocephalus glaber) comparative longevity model
The source species for the transfer experiment above, curated here as the comparative negative model: a mammal in which the outcome node of this module is not reached over a lifespan above 30 years. Its abundant high-molecular-mass hyaluronan, over five times larger than the human or mouse polymer, is the specific adaptation that the nmrHas2 mouse tests.
Species
Naked mole-rat
Genotype
Wild type
Publication
PMID:29364116
Pathograph links
Age-Related Morbidity and Mortality fails to recapitulate fidelity: low Age-related morbidity and mortality, the conserved consequence of this module, are not observed: the age-specific hazard of death does not rise with age and fecundity is retained until death.
Limitations: The evidence is demographic and organism-level, from captive-colony records, and does not measure circulating inflammatory mediators across the naked mole-rat lifespan - so this species is not shown to lack inflammaging itself, only the morbidity endpoint this module attributes to it. The hyaluronan adaptation is a plausible but not established explanation for that endpoint, and the cited hyaluronan work characterises cancer resistance rather than age-related inflammation.
Evidence: 2
Spontaneously aging turquoise killifish immune system (Nothobranchius furzeri) Naturally short-lived vertebrate aging model
Killifish develop the inflammatory phenotype of aging spontaneously, without genetic sensitization or immune challenge, and do so within weeks. Old fish carry increased inflammation markers in the hematopoietic compartment and plasma; independently, aged killifish brain mounts a high inflammatory response with glial scarring after injury. Together these give the module both a systemic and a tissue-level reading in one short-lived vertebrate.
Species
Turquoise killifish (Nothobranchius furzeri)
Genotype
Wild type
Background
Young-adult versus old fish. Kidney marrow, the teleost hematopoietic organ, profiled by single-cell RNA sequencing, cytometry, and functional assays, with proteomic profiling of both marrow-derived cells and plasma; complementary brain-injury data from the dorsal telencephalon.
Publication
PMID:41862756
Pathograph links
Chronic Low-Grade Sterile Inflammation recapitulates fidelity: moderate Old killifish show increased inflammation markers in the absence of any infectious or experimental challenge, which is precisely the sterile, age-associated inflammatory state the module describes.
Limitations: The evidence is marker-level from transcriptomic and proteomic profiling rather than a panel of quantified circulating cytokines benchmarked against a clinical inflammaging signature, and killifish immune gene repertoires are not one-to-one orthologous with human ones. The measurement is cross-sectional between age groups. Whether the inflammation is causal for the functional decline that accompanies it is not established here.
Readouts
Inflammation markers in old kidney marrow and plasma
Inflammatory marker expression in kidney marrow cells and plasma proteome of old versus young-adult fish.
Direction: INCREASED
Interpretation: Elevated markers in both the hematopoietic compartment and the circulation is what makes this a systemic rather than a local inflammatory signal.
Evidence: 1
Acute-phase proteins in aged plasma
Core enrichment genes of the aged killifish plasma proteome, scored against young-adult plasma.
Direction: INCREASED
Interpretation: Complement proteins and coagulation factors are the specific circulating species behind the summary inflammation signal, and are the markers used for this purpose in other teleost models.
Evidence: 1
Inflammatory response and glial scarring in the aged injured brain
Inflammatory response and glial scar formation after stab-wound injury of the dorsal telencephalon in aged versus young killifish.
Direction: INCREASED
Interpretation: An exaggerated inflammatory response in aged neural tissue shows the module's node operating outside the hematopoietic compartment in the same species, and links it to a functional deficit.
Evidence: 1
Evidence: 1
Age-Related Morbidity and Mortality partially recapitulates fidelity: low The model reaches the module's terminal node at the level of organ morbidity rather than mortality: aged fish develop tissue fibrosis in the hematopoietic organ, detected by collagen staining and absent from young-adult fish, which the authors read as organ-specific inflammation.
Limitations: Fibrosis is organ morbidity, not mortality; no survival endpoint is tied to the inflammatory phenotype in this study, so the step from inflammation to mortality is not measured here and should not be read off this link. The histology arm is three young-adult and three aged fish, so the fibrosis result is a small-sample presence/absence contrast rather than a graded measurement, and it is confined to the kidney marrow.
Readouts
Tissue fibrosis in the aged hematopoietic organ
Collagen deposition in kidney marrow assessed by Sirius Red/Fast Green staining in three 7-week-old young-adult and three 16-week-old aged fish.
Direction: INCREASED
Interpretation: Fibrosis present only in aged tissue is a measured organ-level morbidity endpoint, which is what this link rests on in place of a survival result.
Evidence: 1
Evidence: 1
Curated as part of a tranche adding turquoise killifish models across the hallmarks-of-aging modules. The same study underpins the killifish model on the genomic_instability_aging module; that entry cites the DNA damage and repair findings, this one the inflammatory findings.
🧮

Computational Models

2
EpInflammAge Epigenetic-Inflammatory Clock MACHINE_LEARNING
Deep-learning model that predicts inflammatory-protein levels from DNA methylation and composes them into an age estimate, joining the epigenetic and inflammatory axes of ageing in a single predictor rather than treating them as separate biomarker families. Reported to associate with age-related disease states.
PMID:40650062
Pathograph links
Chronic Low-Grade Sterile Inflammation measures fidelity: moderate Gives the module's central effector node a quantitative human readout that does not require direct cytokine assay.
Age-Related Morbidity and Mortality partially recapitulates fidelity: moderate Relates the composite inflammatory-epigenetic state to age-associated disease.
Limitations: Predictive and correlational: it estimates inflammatory burden from methylation rather than measuring it, and asserts no mechanism connecting the two.
Because it derives inflammation from methylation, it is a shared readout with epigenetic_alterations and should not be treated as independent confirmation of either module.
Lewkiewicz2019 Naive T Cell Population and Diversity Aging Model SBML KINETIC
Mechanistic mathematical model of T cell population dynamics at the immunoclonal subpopulation level, formulated to give quantitative estimates of receptor diversity that full-organism experiments cannot measure directly. Diversity is defined in several ways according to the number of cells in a given immunoclone. The model attributes the age-related fall in diversity primarily to diminished thymic output of new T cells and the resulting loss of small immunoclones.
Repository ↗ PMID:31201663
Pathograph links
Age-Related Morbidity and Mortality partially recapitulates fidelity: moderate Models the loss of naive T cell receptor diversity that underlies age-associated susceptibility to novel infections and poor vaccine response.
Limitations: Captures the adaptive-immune (immunosenescence) arm of immune ageing, not the sterile inflammatory arm this module centres on. The two co-occur and are often conflated, but this model asserts nothing about the inflammatory mediators in the module's other nodes.
Included deliberately as the adaptive-immune counterpart: immunosenescence and inflammaging are distinct processes, and keeping the model's scope explicit prevents the module absorbing evidence that belongs to the other.
⌘

Module Collections

1
Hallmarks of Aging as Altered intercellular communication, Chronic inflammation
↗

Used By Disorder Entries

3
Hutchinson-Gilford Progeria Syndrome via ATM-NF-kB systemic inflammation → Chronic Low-Grade Sterile Inflammation
Ischemic Stroke via Chronic Low-Grade Systemic Inflammation → Chronic Low-Grade Sterile Inflammation
Sarcopenia via Chronic Low-Grade Inflammation → Chronic Low-Grade Sterile Inflammation
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.
Pathograph: causal mechanism network for Inflammaging Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
⚙

Pathophysiology

4
Age-Associated Inflammatory Stimuli
trigger
A diverse set of age-accumulating stimuli feed sterile inflammation: senescent-cell SASP, damage-associated molecular patterns from dysfunctional mitochondria, NLRP3 inflammasome activation, increased gut permeability and microbiota changes, central obesity, immune-cell dysregulation, and chronic infections. Regardless of the dominant source, these converge to drive a persistent inflammatory response.
Inflammatory Response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Downstream
  • Chronic Low-Grade Sterile Inflammation
Show evidence (1 reference)
PMID:30065258 SUPPORT Other
"Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic..."
Enumerates the conserved set of age-associated stimuli that drive inflammaging, the trigger modeled here. Evidence source is OTHER because this is a review.
Chronic Low-Grade Sterile Inflammation
central effector
The persistent stimuli establish a chronic, low-grade, sterile inflammatory state - elevated circulating inflammatory mediators without overt infection. This is the defining central effector of inflammaging and the conserved node that disease-specific inflammatory drivers converge upon.
Inflammatory Response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. Cytokine Production GO:0001816 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cytokine Production (GO:0001816). GO:0001816 is a biological process from the Gene Ontology.
Used by disorders
Hutchinson-Gilford Progeria Syndrome as ATM-NF-kB systemic inflammation
Ischemic Stroke as Chronic Low-Grade Systemic Inflammation
Sarcopenia as Chronic Low-Grade Inflammation
Downstream
  • Systemic Propagation via Altered Intercellular Communication
Show evidence (3 references)
PMID:24833586 SUPPORT Other
"Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging.""
Defines inflammaging as the chronic low-grade inflammation of human aging, the central effector modeled here. Evidence source is OTHER because this is a review.
PMID:30065258 SUPPORT Other
"Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death."
Characterizes inflammaging by elevated blood inflammatory markers and its link to morbidity, supporting this node. Evidence source is OTHER because this is a review.
PMID:32877690 SUPPORT Model Organism
"We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits."
Interventional support for this node running in the protective direction: lowering systemic inflammatory cytokines in aging mice compressed morbidity and extended lifespan, which is the causal prediction the inflammaging chain makes. Note the paper frames the IL-10 route as a proposal ("We propose"), so it is cited here for the cytokine-reduction and healthspan observation, not as a settled IL-10 mechanism. Evidence source is MODEL_ORGANISM (C57BL/6 mice).
Systemic Propagation via Altered Intercellular Communication
amplifier
The inflammatory state is propagated beyond its cells of origin through altered intercellular communication - circulating cytokines, chemokines, and other mediators acting at a distance. This systemic cytokine signaling is the amplifying step that converts local inflammatory sources into a body-wide aging phenotype, and is itself one of the enumerated hallmarks of aging.
Cytokine-Mediated Signaling GO:0019221 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cytokine-Mediated Signaling, annotated with cytokine-mediated signaling pathway (GO:0019221). GO:0019221 is a biological process from the Gene Ontology.
Downstream
  • Age-Related Morbidity and Mortality
Show evidence (1 reference)
PMID:36599349 SUPPORT Other
"We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular..."
Enumerates altered intercellular communication and chronic inflammation as hallmarks of aging, framing this systemic-propagation node. Evidence source is OTHER because this is a review.
💊

Treatments

2
Metformin (Anti-Inflammaging Pharmacotherapy)
Pharmacotherapy NCIT:C15986 NCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus.
Agent: metformin CHEBI:6801 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metformin (CHEBI:6801). CHEBI:6801 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Metformin is a biguanide whose geroprotective effects extend well beyond glucose lowering. In aged human CD4+ T cells it restores autophagy and mitochondrial bioenergetics, and by doing so suppresses the Th17-skewed cytokine profile that distinguishes older from younger donors. It is the agent of the TAME (Targeting Aging with MEtformin) trial and, in the geroscience prioritization of FDA-approved drugs by Kulkarni et al., ranks second of nine candidates (11/12). Represents the upstream metabolic-restoration design pattern for damping sterile inflammation, as opposed to blocking a single downstream cytokine.
Mechanism target:
INHIBITS Chronic Low-Grade Sterile Inflammation — Metformin suppresses the age-associated Th17 cytokine profile by restoring autophagy and mitochondrial bioenergetics in aged T cells, acting on the metabolic substrate of the chronic inflammatory state rather than on a single effector cytokine.
Evidence: 2
Senolytic Therapy (Dasatinib plus Quercetin)
Pharmacotherapy NCIT:C15986 NCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus.
Agent: dasatinib CHEBI:49375 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dasatinib, annotated with dasatinib (anhydrous) (CHEBI:49375). CHEBI:49375 is a therapeutic agent from Chemical Entities of Biological Interest. quercetin CHEBI:16243 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses quercetin (CHEBI:16243). CHEBI:16243 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Intermittent dasatinib plus quercetin (D+Q) selectively kills senescent cells by disabling their pro-survival networks, removing the SASP-secreting reservoir that is one of the principal stimuli feeding inflammaging. This is source control rather than cytokine blockade: the target is the cell that secretes the mediators, not the mediators themselves. Ranked seventh of nine (6/12) by Kulkarni et al., limited by the absence of clinical healthspan and mortality data rather than by weak preclinical evidence.
Mechanism target:
INHIBITS Age-Associated Inflammatory Stimuli — Eliminating senescent cells removes the SASP source that this node lists first among the stimuli feeding sterile inflammation, reducing frailty-related proinflammatory cytokine secretion at its origin.
INHIBITS Age-Related Morbidity and Mortality — Intermittent senolytic dosing in naturally aged mice improved physical function and survival, connecting removal of the senescent-cell stimulus to the morbidity and mortality outcome of this module.
Evidence: 2