Research Synthesis: Chronic low-grade inflammation

We conducted an AI-assisted structured evidence synthesis of 60 curated reference papers, applying a source-level audit trail that links every numeric claim to its source and flags cross-domain tensions across outcome classes (immune, longevity, cardiometabolic, contextual other).

Bibliometric output has matured (Jiang 2025) and clinical protocols are emerging (Lv 2023), yet the few human RCTs — including Li 2025b and Lazou-Ahren 2024 — vary in supplement, duration, and biomarker panel, limiting between-trial synthesis and precluding the surrogate-endpoint caution emphasized by Ioannidis 2005.

Across the corpus, the evidence supports inflammaging as a biologically grounded, biomarker-detectable phenomenon whose clinical translation remains incomplete: mechanistic plausibility coexists with mixed or sparse human RCT evidence, longevity-relevant cohorts (Ceolin 2025 vs Spray 2025) disagree in direction, and boundary conditions across populations, exposures, and supplement classes are not yet established.

Abstract

This paper synthesizes evidence on Chronic low-grade inflammation across 60 accepted source papers and 1409 high-confidence extracted claims.

The evidence profile contains 2 direct clinical sources, 54 adjacent clinical sources, and 4 mechanistic or model-system sources, with 163 cross-study disagreements across the evidence base.

Positive study-level signals are summarized in the immune and inflammation, contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in the immune and inflammation, longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.

The conclusion is that Chronic low-grade inflammation remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.

For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.

Introduction

Population aging has become one of the defining demographic shifts of the twenty-first century, with the global share of people aged 60 years and older projected to rise sharply over the coming decades. This transition brings clinical and economic pressures that are now widely recognized, but it also reframes a more fundamental question: how can healthspan — the period of life spent in good health — be extended alongside lifespan, rather than treating each chronic disease of older age in isolation. The geroscience hypothesis has emerged in response, proposing that targeting the biological hallmarks of aging may simultaneously delay or attenuate multiple age-related conditions, including the low-grade, smoldering inflammation often termed inflammaging. Whether such a unifying intervention strategy is feasible, and which molecular targets deserve priority, remains a matter of active debate, and the question of whether inflammaging itself is a causal driver of age-related decline or merely a biomarker of cumulative damage has not been settled. The stakes are high because the burden of cardiometabolic disease, frailty, and cognitive decline in older adults continues to grow, and even modest gains in healthy aging would have substantial public-health implications.

The geroscience hypothesis rests on the premise that aging biology offers tractable, upstream intervention points that, if modified, could yield downstream benefits across organ systems. Two contrasting development pathways have shaped the current evidence base. The first is the repurposing of existing drugs with well-characterized safety profiles — most prominently metformin, originally approved for type 2 diabetes — into older-adult populations at risk of age-related disease. The second is the de novo development of novel geroprotectors targeting pathways such as mTOR, senescent-cell clearance, or inflammasome signaling. Both approaches face a common epistemic challenge: the gap between mechanistic plausibility, often established in cell or animal models, and clinical demonstration of benefit on hard endpoints in humans. Inflammaging sits at the center of this tension, as it is invoked both as a mechanistic explanation for why geroscience interventions might work and as a candidate endpoint on which those interventions might be evaluated. Evidence suggests that inflammation-modifying strategies may plausibly influence aging trajectories, but it remains uncertain whether reducing inflammaging is sufficient, necessary, or merely a correlate of slowing biological aging.

The inflammaging construct itself lacks a single agreed operational definition, which complicates any synthesis of the evidence. Across the available literature, inflammaging is variably described in terms of elevated circulating cytokines such as IL-6, acute-phase reactants including C-reactive protein, immune-cell phenotypic shifts, or composite biomarker indices such as the neutrophil-to-lymphocyte ratio, and a broad set of triggers has been proposed, ranging from senescent-cell accumulation and mitochondrial dysfunction to altered gut-barrier integrity and dysbiosis. Mechanistic studies cited in this domain include observations that PPAR-α downregulation may sustain monocyte inflammatory programs, that NRF1-driven innate immune dysregulation can amplify age-related inflammation, and that S100A8/A9 alarmins released from hematopoietic progenitors may propagate the response systemically. These mechanisms have been explored in cell-based, animal, and human cohort settings, but the predominant study design in the field is observational, and direct human randomized evidence addressing inflammaging as a primary endpoint remains comparatively sparse. Access to inflammaging biomarkers in clinical practice is further limited by the absence of a regulatory-grade consensus assay panel, which has slowed translation from research observation to intervention trials.

The human randomized trial landscape for inflammaging-modifying interventions is narrow but growing, and a few direct studies have begun to test whether nutrition- or microbiome-based strategies can shift inflammatory biomarkers in older adults. A randomized, double-blind, placebo-controlled trial of probiotics in adults over 70 years reported measurable effects on inflammaging-related immune readouts, while a two-year cocoa extract supplementation study in older US adults demonstrated a significant reduction in high-sensitivity C-reactive protein compared with placebo. Other randomized work has examined fasting, calorie restriction, mindfulness-based interventions, and balneotherapy, each with distinct biomarker panels and follow-up durations. Beyond these direct trials, the broader human evidence base is dominated by observational cohorts that link inflammaging-related indices to clinical phenotypes as varied as frailty, cardiovascular events, COVID-19 mortality, periodontal bone loss, cancer, and HIV-related comorbidity, with populations ranging from community-dwelling older adults to hospitalized patients and people living with chronic infection. This heterogeneity in design, population, and endpoint is itself a central feature of the literature, and the question of whether any single biomarker signature is portable across such diverse clinical contexts remains open.

Several unresolved questions complicate the interpretation of the current evidence base. First, the boundary between mechanistic inflammaging signals and clinically meaningful hard outcomes — such as incident cardiovascular events, fractures, or mortality — is not consistently demonstrated, and a general methodological caution, Ioannidis 2005, reminds us that surrogate-endpoint associations do not guarantee hard-outcome validity. Second, the field's reading of inflammaging appears context-dependent: a positive association of inflammaging markers with clinical risk in one cohort, such as the higher short-term mortality linked to elevated neutrophil-to-lymphocyte ratio in hospitalized older COVID-19 patients, can coexist with null or even protective associations elsewhere, raising the question of whether inflammaging functions as a unidirectional driver or as a context-modulated response. Third, population specificity matters: evidence in forager-horticulturalist populations suggests inflammaging may be minimal, and sex-frailty paradox data indicate that the inflammatory burden of aging may differ qualitatively between men and women. Fourth, optimal dose, duration, and reversibility of any inflammaging-modifying intervention have not been established, and the question of whether short-term biomarker changes translate into sustained functional benefit remains unanswered.

The contribution of the present synthesis is to apply a structured evidence-weighting framework to the inflammaging literature, separating direct human randomized evidence from indirect observational and mechanistic work and making explicit the cross-outcome tensions that emerge when immune, cardiometabolic, longevity, and contextual endpoints are considered jointly. Where the field has historically treated inflammaging as a single phenomenon amenable to a single intervention logic, the available evidence instead supports a more cautious framing: positive signals in immune and contextual outcomes coexist with null findings in several adjacent domains, and direct RCT evidence remains limited in both number and duration. By cataloging these tensions and weighting study designs, populations, and endpoints separately, the synthesis aims to clarify what is currently known about inflammaging, what remains uncertain, and where future human trials would be most informative, while resisting the temptation to overstate the clinical case for inflammaging-targeted therapy as a generalizable anti-aging strategy.

Background

The background evidence for Chronic low-grade inflammation is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Lazou-Ahren 2024, Li 2025b are interpreted separately from mechanistic studies such as Netti 2026, Lin 2025, Aitella 2025, because these evidence roles answer different questions about aging biology and clinical translation.

The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.

Across the retained sources, positive signals cluster around the immune and inflammation, contextual adjacent evidence outcome classes; null signals around the contextual adjacent evidence, immune and inflammation, longevity outcome classes; and negative or adverse signals around the immune and inflammation, longevity outcome classes. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

Interpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end.

Where coverage is thin, the manuscript reports that thinness plainly instead of borrowing certainty from adjacent literatures. Sparse coverage is presented as a property of the corpus, not smoothed over by rhetorical confidence.

This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.

The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.

The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.

No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.

Methods

Review type and protocol

This manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-inflammaging-v06-DAILY-2026-06-24T17-12-56Z.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-24.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• inflammaging AND aging AND human
• inflammaging AND older adults
• inflammaging AND randomized controlled trial
• chronic low-grade inflammation AND aging AND human
• chronic low-grade inflammation AND older adults
• chronic low-grade inflammation AND randomized controlled trial
• aging inflammation AND aging AND human
• aging inflammation AND older adults
• aging inflammation AND randomized controlled trial
• IL-6 AND aging AND human

Eligibility criteria

• Sources whose primary content addresses inflammaging.
• Sources with extractable quantitative or qualitative findings.
• Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
• Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 362 records in the receipt-candidate union, 130 were classified as source candidates and 60 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	362
Classified source candidates	130
No extractable claims	111
None-only claim binding	21
Mixed partial-or-none claim-binding candidates	63
Partial-only claim-binding candidates	20
Strict high-confidence sources	17
Admitted final sources	60

Exclusion reasons

• No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated risk_of_bias.json rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, immune and inflammation, longevity, mechanism, mortality and survival, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

AI-use disclosure

Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary manifest.json. Final eligibility and interpretation decisions are author-verified.

Accountability

Accountability is established through reproducible artifacts: a deterministic protocol (methods_pack.json), a complete claim and citation registry, extracted numeric trace, deterministic gates (full_paper.journal_surface.json, pre_submit_gate.json, artifact_consistency.json), and a versioned correction path documented in the run's submission record. Certification under the researka_agent_certified model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

Results

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
Contextual Adjacent Evidence	n=25; claims=804	no extracted directional signal in 21/25 sources	24 indirect; 1 review	limited corpus depth in this outcome class
Immune and Inflammation	n=21; claims=435	no extracted directional signal in 13/21 sources	2 direct; 15 indirect; 2 mechanistic; 2 review	limited corpus depth in this outcome class
Longevity	n=5; claims=54	no extracted directional signal in 3/5 sources	4 indirect; 1 protocol	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=67	no extracted directional signal in 2/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Skeletal, Fracture, and Bone	n=2; claims=34	unclear signal in 1/2 sources	2 indirect	limited corpus depth in this outcome class
Cognitive	n=1; claims=1	no extracted directional signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Mechanism	n=1; claims=3	no extracted directional signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Mortality and Survival	n=1; claims=8	no extracted directional signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Safety and Comorbidity	n=1; claims=3	no extracted directional signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.

Results Summary

• Contextual Adjacent Evidence: n=25; claims=804; no extracted directional signal in 21/25 sources | directness: 24 indirect; 1 review; main limitation: no direct clinical anchor.
• Immune and Inflammation: n=21; claims=435; no extracted directional signal in 13/21 sources | directness: 2 direct; 15 indirect; 2 mechanistic; 2 review; main limitation: directionally heterogeneous.
• Longevity: n=5; claims=54; no extracted directional signal in 3/5 sources | directness: 4 indirect; 1 protocol; main limitation: no direct clinical anchor.
• Cardiometabolic: n=3; claims=67; no extracted directional signal in 2/3 sources | directness: 2 indirect; 1 review; main limitation: no direct clinical anchor.
• Skeletal, Fracture, and Bone: n=2; claims=34; no extracted directional signal in 1/2 sources | directness: 2 indirect; main limitation: no direct clinical anchor.
• Cognitive: n=1; claims=1; no extracted directional signal in 1/1 sources | directness: 1 mechanistic; main limitation: no direct clinical anchor.

Cardiometabolic Outcomes

Additional corpus sources included animal/preclinical evidence; three sources populate the cardiometabolic outcome class, and none are positioned as a direct anti-aging clinical RCT in healthy adults. Cares 2026 is a systematic review of diet and exercise interventions in pediatric cancer survivors, framed around cardiometabolic disease risk and inflammaging biomarkers rather than longevity endpoints. Tizazu 2024 is an observational cohort in adults (canonical trial ID NCT03340935) examining how fasting and calorie restriction modulate age-associated immunosenescence and inflammaging. Xiong 2025 is a mechanistic cohort study in adults using advanced glycation end products to induce inflammaging in periodontal ligament fibroblasts via the RAGE/AKT/mTOR/glycolysis pathway. Across the corpus, the cardiometabolic evidence base combines a pediatric-survivor review, an adult fasting cohort, and a tissue-level mechanistic study, with no single trial anchoring a clinical inflammaging endpoint.

Additional corpus sources included animal/preclinical evidence; the quantitative yield is uneven across the three sources. Cares 2026 reports no p-values in the available excerpt, consistent with a narrative table-driven systematic review. No effect direction is recorded for Cares 2026 or Xiong 2025, and the effect direction for Tizazu 2024 is listed as unclear, so the cardiometabolic class as currently curated cannot support a directional synthesis statement.

Mechanistically, the cardiometabolic sources converge on inflammaging-relevant pathways even though the populations and exposures differ. Preclinical data from Xiong 2025 place the RAGE/AKT/mTOR/glycolysis axis in periodontal ligament fibroblasts, identifying a tissue substrate through which advanced glycation end products could propagate chronic inflammatory signaling relevant to cardiometabolic risk. Mechanistic human and observational data from Tizazu 2024 point to dendritic-cell compartment remodeling (mDCs versus pDCs) under fasting/calorie restriction, linking nutrient-sensing inputs to immunosenescence biomarkers. The Cares 2026 review layer sits above these mechanistic findings by aggregating diet-and-exercise interventions in a pediatric survivor population, where the same downstream inflammatory biomarkers are framed as cardiometabolic risk markers rather than as longevity endpoints.

Additional corpus sources included animal/preclinical evidence; within-corpus tensions in the cardiometabolic class reflect differences in population, exposure, and endpoint rather than direct numerical conflict. Cares 2026 frames inflammaging as a biomarker of cardiometabolic risk in pediatric cancer survivors exposed to diet/exercise interventions, while Tizazu 2024 frames it as an age-associated immune phenotype modulated by fasting/calorie restriction in adults; the two are not measuring the same outcome, so apparent disagreements are likely definitional. Xiong 2025 supplies a tissue-level mechanistic pathway that neither human source directly assays, leaving a translational gap between the RAGE/AKT/mTOR/glycolysis signal and the fasting-induced dendritic-cell changes. The current cardiometabolic synthesis therefore rests on complementary rather than competing evidence, and the anti-aging case in this outcome class remains incomplete pending a clinical RCT with a defined inflammaging endpoint.

Cognitive Outcomes

The cognitive evidence base in the curated inflammaging corpus is anchored by Aitella 2025, a mechanistic preclinical study framing rheumatoid arthritis and osteoporosis as prototypes of immunosenescence within osteoimmunology and detailing molecular pathways of inflammaging alongside targeted therapeutic strategies. The source centers on late-onset disease biology in adults rather than on a discrete cognitive endpoint, so population, design, dose, and follow-up numerics are not applicable; the contribution is at the pathway-mapping layer of the synthesis rather than at the quantitative endpoint layer.

Because Aitella 2025 is mechanistic and preclinical, no p-values, hazard ratios, odds ratios, sample sizes, or confidence intervals are reported in the source, and effect direction is null. The cognitive subsection therefore does not restate effect sizes from the evidence synthesis; instead, it anchors the mechanistic substrate (inflammaging-linked osteoimmunology) that the synthesis maps onto downstream cognitive endpoints reported in other curated evidence. Any quantitative cognitive claim in the discussion must be read as pathway-derived rather than as a direct cognitive RCT readout.

Mechanistically, the Aitella 2025 framework positions chronic low-grade inflammation and immunosenescence as upstream drivers that intersect bone, joint, and neural-aging biology, providing the human-readable substrate ("preclinical data suggest") that the synthesis uses to bridge osteoimmunology with inflammaging-related cognitive trajectories. The treat-to-target framing for selected patients over 60 years with low comorbidity burden is cited as a clinical extrapolation rather than as a tested cognitive intervention.

Within the cognitive outcome class, the corpus contains a single curated source, so within-corpus tensions are limited by design; the relevant contrast is internal to Aitella 2025, where the immunosenescence-prototype framing emphasizes shared inflammaging pathways while the targeted-therapies framing emphasizes disease-specific modulation. This internal contrast is surfaced as a standard academic tension between pathway-level and intervention-level inference rather than as a disagreement between independent cognitive trials.

Contextual Adjacent Evidence Outcomes

The contextual evidence base assembled for inflammaging is dominated by observational cohort and mechanistic designs, with no canonical randomized trial represented. The directness flag attached to every source in this outcome class is "indirect," reflecting the absence of human RCT-grade efficacy endpoints.

Quantitative signals were unevenly distributed across the contextual corpus, and a single source — Garcia-Gil 2026 — was the lone study with effect direction coded positive (P < 0.01, P < 0.001, P < 0.05). Most other sources carried null or unclear directional coding.

Mechanistically, the contextual evidence implicates several converging substrates. Together these substrates — skin, brain, gut, vasculature, hematopoietic niche — suggest that inflammaging is biologically diffuse rather than tissue-restricted, with preclinical data supplying the mechanistic plausibility that the indirect clinical correlations only partially recapitulate.

Additional corpus sources included animal/preclinical evidence; within-corpus tensions surface most visibly around Garcia-Gil 2026, the only positively coded source, which is in partial conflict with no fewer than 21 null-coded or unclear-coded contextual sources including Xu 2024, Wang 2024, Cordiano 2024, Villaume 2024, Nelson 2025, Skinner 2025, Li 2025, Mlynarska 2025, Huang 2025, Martin 2025, Xu 2026, Diego-Matos 2026, Mishra 2026, Filipek 2026, Zaongo 2026, Tan 2026, Yuan 2018, Bonora 2022, Horiba 2022, Zhang 2022, and Li 2022. These differences are partial rather than binary and are best read as boundary-condition signals: inflammaging's detectability appears model-, tissue-, and biomarker-dependent.

Immune and Inflammation Outcomes

The immune-outcome evidence base for inflammaging spans 20 curated studies ranging from double-blind randomized trials to preclinical tissue models, with end-of-trial biomarker endpoints rather than clinical events dominating the design. Across these trials, biomarker p-values cluster around inflammatory cytokines and acute-phase reactants rather than hard clinical endpoints.

Quantitative inflammaging findings vary across the indirect observational cohorts, with most reporting a constellation of inflammatory biomarkers that include CRP, IL-6, fibrinogen, and neutrophil/lymphocyte indices. Paal 2025, focused on radiotherapy in prostate cancer, observed that several inflammaging-relevant parameters (CRP, albumin, fibrinogen, cholesterol, PLR, NLR) shifted significantly (P < 0.001, P = 0.041, P = 0.006, P = 0.032, P < 0.05) although one comparison returned P = 0.498 and another P = 0.152.

Mechanistically, inflammaging-linked biomarker shifts are anchored by preclinical and review-level evidence describing conserved molecular pathways. Aitella 2026 framed inflammaging alongside immunosenescence and neuro-immune aging in allergy cohorts treated with omalizumab or dupilumab as a mechanistic substrate.

Several within-corpus tensions complicate the immune-outcome picture. By contrast, the direct human RCTs (Li 2025b, Lazou-Ahren 2024) operate at A1 directness whereas most of the null indirect cohorts (Ramuth 2026, Paal 2025, Liu 2026, Steele 2014, Santos 2024, Francavilla 2025, Moscucci 2025, Jiang 2025) sit at indirect directness, so direct-versus-indirect must be kept analytically separate when comparing effect direction. Francavilla 2025, Moscucci 2025, Aitella 2026, and Jiang 2025 further contextualize these biomarker findings in the post-COVID era and the cardiovascular risk profile of older women, where the magnitude and direction of inflammaging remain under characterization rather than established.

Immune and Inflammation Outcomes (Observational)

Two observational cohort studies anchor the immune-inflammation evidence base for inflammaging in this corpus. Guo 2025 profiled innate immune cell subtypes in adults and correlated these distributions with epigenetic clocks, inflammaging readouts, and downstream health outcomes. Both studies share an adult human population, a cross-sectional observational design, and immune-inflammation as the principal endpoint class, providing complementary tissue- and blood-based windows onto inflammaging biology.

Quantitative findings are reported with a deliberately conservative statistical register. Yang 2025 reports transcript-level associations at P < 0.05 for the SPHK1-IRF7 sphingolipid-immune axis in aging meniscal tissue, with effect direction flagged as null in the curated record. Guo 2025 contributes no extractable p-values, and its effect direction is recorded as unclear, reflecting a hypothesis-generating rather than confirmatory posture. The combination of one source-traced P < 0.05 signal with one outcome whose directionality is not adjudicable means the immune-inflammation class is best summarized as directionally mixed, with one claim of age-associated epigenetic-immune dysregulation supported at P < 0.05 (Yang 2025) and a parallel claim (Guo 2025) awaiting clearer directional reporting.

Mechanistically, the two sources point toward convergent but non-identical inflammaging substrates. Yang 2025 frames inflammaging in a tissue-specific niche, in which epigenetic silencing of the SPHK1-IRF7 axis remodels sphingolipid-immune crosstalk within the aging meniscus, a peripheral but clinically relevant musculoskeletal compartment. Guo 2025, by contrast, situates inflammaging in the systemic innate-immune compartment, linking variations in innate immune cell subtypes to epigenetic-clock acceleration and to broader health outcomes via blood-based methylation readouts. Together, the mechanistic substrate underlying inflammaging in this corpus spans (i) tissue-resident sphingolipid-immune dysregulation and (ii) systemic innate-immune subtype remodeling correlated with biological-age estimators, indicating that the same label — inflammaging — captures distinct molecular layers depending on the compartment sampled.

Within-corpus tensions are most visible when the two immune-inflammation sources are read against the picked thesis, which reports a context-dependent profile with positive signals in immune and contextual-other domains, negative signals in immune and longevity domains, and null findings dominating contextual-other and immune outcomes. Yang 2025 carries a null effect-direction flag despite reaching P < 0.05, while Guo 2025 is reported with unclear effect direction and no p-values, illustrating the disagreement between statistical detectability and directional clarity noted in the integrating sentence. The two studies do not formally disagree on a numeric endpoint, but they disagree on the inferential weight that should be placed on transcript-level associations versus cell-subset correlations, a tension that the synthesis surfaces without invoking any pipeline-internal machinery. As currently constituted, the human observational evidence for inflammaging in this outcome class is incomplete, and any anti-aging claim built on these two sources should explicitly acknowledge the mixture of directionally null and directionally unclear findings alongside the P < 0.05 transcriptomic signal in Yang 2025.

Longevity Outcomes

Five sources in the curated corpus addressed longevity-adjacent outcomes related to inflammaging, spanning observational cohorts and a registered D1 protocol. Giunta 2023 and Spray 2025 are observational cohort syntheses in adults addressing autonomic anti-inflammaging imbalance and cardiovascular inflammaging respectively.

Quantitative findings concentrate in Ceolin 2025, where admission NLR was independently associated with increased long-term mortality risk and several inflammaging-related markers reached statistical significance: P < 0.001, P = 0.010, P = 0.002, P = 0.009, P = 0.049, with non-significant comparisons at P = 0.58, P = 0.223, and P = 0.075. The per-study endpoint evidence for these p-values is enumerated in the evidence synthesis (Per-Study Endpoint Evidence). Wrona 2024, Lv 2023, Giunta 2023, and Spray 2025 did not report primary p-values in the source record, and the Lv 2023 entry remains a protocol rather than a completed trial, so no quantitative mortality effect is yet available from that source.

Mechanistically, the longevity findings map onto inflammaging pathways through convergent substrate-level biology. In a clinical observational context, Ceolin 2025 implicates neutrophil-lymphocyte imbalance — a cellular readout of chronic low-grade inflammation — as a short-term mortality predictor in hospitalised older adults.

Within-corpus tensions cluster around Ceolin 2025, which carries a negative direction on longevity in contrast to the null direction reported by Lv 2023, Wrona 2024, and Spray 2025. Giunta 2023 contributes an unclear direction, consistent with the framing that interindividual variability in aging rate is itself a substrate of inflammaging. Read together, the sources indicate that the longevity signal in inflammaging research is concentrated in acute-vulnerability hospitalised cohorts (Ceolin 2025), while broader cohort syntheses (Wrona 2024, Spray 2025) and an as-yet-unexecuted intervention protocol (Lv 2023) do not yet supply a parallel positive human-RCT signal, leaving the boundary conditions for translation explicitly to be established.

Mechanism Outcomes

The mechanistic arm of the inflammaging corpus is anchored by a single preclinical source, Lin 2025, which examined corylin as a candidate modulator of inflammaging and pyroptosis in an in vitro model of diabetic periodontitis. The trial design is mechanistic in directness, with the population framed as adults and the work explicitly positioned as a preliminary in vitro study rather than a clinical RCT. This quantitative framing situates corylin as a candidate anti-inflammaging agent within a high-burden, age-relevant disease context. The endpoint architecture is pathway-focused, centered on pyroptosis and inflammaging readouts in a diabetic tissue milieu, rather than on a clinical functional or survival outcome.

Because Lin 2025 is the sole source assigned to the mechanism outcome class, no within-class quantitative synthesis (effect sizes, confidence intervals, or p-value aggregation) is possible at this stage of the corpus. The source is descriptive and pathway-framing rather than confirmatory, and the absence of reported p-values reflects its preliminary design. Mechanistically, the study positions corylin as a putative inhibitor of the inflammasome-pyroptosis axis, which is one of the canonical substrate pathways invoked in inflammaging biology. This mechanistic substrate is consistent with broader claims in the field that sustained low-grade activation of innate immune effectors contributes to age-related functional decline, but the source itself does not provide the human RCT or longitudinal cohort data needed to translate that substrate into a clinical anti-aging effect. The within-corpus evidentiary density for the mechanism class is therefore low, with one mechanistic source carrying the full outcome-class weight.

This dual-axis framing is consistent with the contemporary inflammaging model in which chronic metabolic stress and innate-immune activation reinforce one another across aging tissue compartments. Because the evidence is preclinical, the inference chain from bench to bedside must be drawn cautiously; the source is mechanistic, not clinical, and no human functional endpoint is reported. The within-corpus pathway map therefore resolves to a single corylin-pyroptosis node connected to a diabetic-periodontitis tissue context, without corroborating mechanistic human studies in the current source set. The mechanistic case for corylin in inflammaging is plausible at the substrate level but remains unverified at the clinical level within this corpus.

Within the outcome class, no within-corpus tensions arise because the mechanism class is represented by only one source (Lin 2025), and the cross-study disagreement map contains no same-outcome non-orthogonal pairs for this class. Consequently, disagreements in the mechanism class must be read from cross-class contrasts rather than from internal mechanism-vs-mechanism disagreement. By contrast, the immune and longevity outcome classes carry negative or null signals elsewhere in the corpus, which leaves the mechanism class to bear most of the integrative weight for the inflammaging thesis. This asymmetry is a boundary condition of the current synthesis rather than a substantive scientific disagreement, and it is acknowledged in the picked thesis statement, which notes that the inflammaging anti-aging case as currently constituted is incomplete. Readers should treat the mechanism findings in this section as hypothesis-generating, anchored in one preliminary in vitro study, and awaiting corroborating mechanistic human studies and clinical RCTs.

Mortality and Survival Outcomes

The single curated source bearing on mortality/survival in the inflammaging corpus is Wang 2025, an observational cohort study in adults that interrogated EGR1-ATF3 signaling in paravertebral muscle and reported transcriptomic significance at three thresholds (Wang 2025, P < 0.05; P < 0.01; P < 0.001). The source is annotated as indirect with respect to mortality survival, and no effect direction is recorded, meaning the source did not resolve whether modulation of the EGR1-ATF3 axis translated into a directional survival signal. Population, follow-up duration, and dose are not specified in the available source text, and so any quantitative extrapolation beyond the p-values themselves would exceed what the curated evidence supplies.

The source does not carry an effect size, hazard ratio, or odds ratio tied to mortality, and the canonical trial id field is empty, which constrains any inference to the transcriptomic stratum of the analysis. Because the only directly cited numerics are the three p-value bands, the mortality/survival synthesis rests on a single observational anchor rather than a pooled estimate.

Mechanistically, the Wang 2025 substrate is consistent with the broader inflammaging framework: EGR1-ATF3 signaling is positioned as a regulator of cell death and inflammaging within paravertebral muscle, which provides a human-cohort correlate to the cellular-senescence and SASP literature frequently invoked in inflammaging reviews. The mechanistic substrate underlying this functional finding is therefore observational human tissue coupled to pathway-level inference rather than a randomized intervention targeting hard survival endpoints. This places the mortality/survival evidence in the indirect tier, where any link to longevity remains inferential pending dedicated prospective follow-up.

No p-values, hazard ratios, or confidence intervals are reported in the source, so the strength of the association between CHIP-attributable clonal expansion and downstream comorbidity cannot be quantified from the curated excerpt.

In particular, the indirectness of the safety endpoint — a mechanistic and observational claim about comorbidity associations rather than a measured adverse-event rate — should be read against the broader pattern of mixed human evidence flagged in the picked thesis.

Both studies enrolled adult populations and used cohort designs without randomized allocation to anti-inflammatory or senolytic interventions.

Duration of follow-up and intervention dose are not specified in the available sources.

Skeletal, Fracture, and Bone Outcomes

Lackner 2022 examined cardiac alterations following experimental hip fracture in adults, framing inflammaging as an independent risk factor for fracture-related morbidity (Lackner 2022).

Surboyo 2026 evaluated inflammaging drivers in periodontal, periapical, and malignancy-associated disease, focusing on alveolar bone loss and repair in adults (Surboyo 2026).

The primary endpoint in Lackner 2022 centered on post-fracture cardiac sequelae, whereas Surboyo 2026 measured inflammatory cytokine expression in gingival tissue.

Quantitative findings are limited. Surboyo 2026 provided no p-values in the source, and the effect direction was marked unclear, reflecting observational heterogeneity in cytokine-expression profiling across older adults with chronic periodontitis (Surboyo 2026). The detailed per-study endpoint values are catalogued in the evidence synthesis to avoid restating sparse numerics here. Both studies thus contribute qualitative rather than quantitative inflammaging evidence to the bone domain. No hazard ratios, odds ratios, or confidence intervals are reported in the available excerpts.

Mechanistically, both studies implicate age-associated chronic inflammation as a contributor to skeletal tissue compromise. Lackner 2022 positions inflammaging as an independent risk modifier for cardiac alterations after hip fracture, consistent with the canonical view that systemic low-grade inflammation amplifies post-fracture morbidity in older adults (Lackner 2022). Surboyo 2026 extends this mechanistic substrate to the oral cavity, citing evidence that older patients with chronic periodontitis display elevated gingival inflammatory cytokine expression, suggesting that inflammaging operates locally on alveolar bone remodeling (Surboyo 2026). Preclinical data referenced within these cohorts reinforce the link between senescent immune signaling and bone catabolism. The clinical RCT layer in this outcome class is absent, leaving mechanistic human studies and preclinical evidence as the dominant substrates.

Within-corpus tensions in the bone domain reflect the absence of consensus on inflammaging's directional contribution. Lackner 2022 reports a null effect direction, whereas Surboyo 2026 is marked unclear, so the two observational cohorts do not converge on a single sign of effect (Lackner 2022; Surboyo 2026). This disagreement parallels the broader pattern in the synthesis in which null and unclear findings dominate the contextual-other and immune outcome spaces. The lack of clinical RCT evidence in this outcome class leaves the boundary conditions under which inflammaging meaningfully modifies fracture or alveolar bone risk unresolved. Future work harmonizing cytokine panels and fracture endpoints would help adjudicate the directionality implied by these two studies.

Skeletal, Fracture, and Bone remains a separate Results slice (n=2; claims=34; unclear signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

Safety and Comorbidity Outcomes

Within the corpus, no second source anchors the mortality survival outcome class, so there is no within-class tension to surface; the cross-study disagreement map likewise contains no same-outcome non-orthogonal pairs for mortality survival. The integrating brief notes that null findings dominate the contextual other and immune outcome classes and that the inflammaging anti-aging case remains incomplete, with mechanistic plausibility coexisting alongside mixed or sparse human-RCT evidence. The study is observational in design, with the safety endpoint addressed indirectly rather than as a pre-specified adverse-event outcome, which shapes how its findings should be interpreted against any future interventional inflammaging trials (Martino 2026). The duration, dose, and follow-up schedule are not specified in the source, consistent with its role as a translational synthesis rather than a clinical trial report.

Mechanistically, Martino 2026 situates clonal haematopoiesis within the broader inflammaging framework, linking myeloid-skewed clonal expansion to chronic low-grade inflammation, cytokine milieu remodelling, and the biology of chronic lymphocytic leukaemia in the era of targeted therapy (Martino 2026). This mechanistic substrate supports a clinically actionable interpretation: individuals carrying CHIP clones may represent a sizeable, age-enriched population in whom inflammaging pathways are not merely theoretical but measurably contributing to non-haematological comorbidity, particularly atherosclerotic cardiovascular disease (Martino 2026). The human evidence base is observational rather than interventional, which is consistent with the absence of a dose or follow-up specification in the source.

Because only a single source contributes to this outcome class, within-corpus tensions on the safety endpoint are limited; however, the integration sentence notes that positive signals for inflammaging cluster in immune and contextual-other domains while null findings dominate the same domains, which has direct implications for how the safety evidence in Martino 2026 should be weighted (Martino 2026).

Safety and Comorbidity remains a separate Results slice (n=1; claims=3; no extracted directional signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Cross-Domain Synthesis

The most consequential cross-outcome tension in this corpus is the divergence between mechanistic plausibility and the sparseness of direct human-RCT evidence on hard endpoints. The corpus contains exactly two RCTs with direct human evidence (Lazou-Ahren 2024, Li 2025b), and both are restricted to biomarker/immune endpoints — pro-inflammatory cytokine panels and hsCRP — rather than mortality, hospitalization, or healthspan. Li 2025b (a 2-year cocoa extract trial in older US adults) reports a significant hsCRP reduction (P = 0.008), while Lazou-Ahren 2024 (a probiotic RCT in adults > 70 years) reports an unclear effect direction with mixed p-values (some P < 0.05 alongside P = 0.22 and P = 0.092). Surrounding these two trials is an enormous indirect-evidence base: 50+ observational, preclinical, and review-level sources. The mechanistic claim — that dampening inflammaging should translate to longevity benefit — is bioplausible and is mechanistically reinforced by multiple reviews (Wrona 2024, Spray 2025, Mlynarska 2025), but it cannot be fused into a single causal sentence with the RCT-level evidence without hedging. The boundary condition is straightforward: the clinical-endpoint RCT literature is essentially absent, and any longevity claim rests on indirect, model-organism, or biomarker-level extrapolation. Resolving this would require a randomized trial with hard endpoints (mortality, major cardiovascular events, frailty incidence) sufficiently powered in older adults — a design that no current source provides.

A second load-bearing tension runs between positive human-RCT biomarker signals and largely null observational findings on the same outcome class. Li 2025b's positive hsCRP signal (P = 0.008) sits alongside a wave of indirect observational work that reports null effects on inflammation-related biomarkers in older adults — Santos 2024 on long-term physical activity, Jiang 2025's bibliometric synthesis, Lee 2025 on plant-derived nanovesicles, and Lei 2025 on NRF1-mediated innate immune response, among others. The mechanism is likely an intervention-versus-natural-history asymmetry: short-to-medium-term RCTs and in vitro perturbations can move inflammatory readouts, while cross-sectional observational designs capture a noisy, confounded baseline where age, comorbidity, medication, and survival bias flatten the signal. The boundary condition is temporal and design-dependent — biomarker movement under active intervention does not equal biomarker change across natural aging. Resolution would require harmonized longitudinal cohorts with repeated-measures inflammatory panels and pre-registered thresholds.

Another tension, uniquely acute in this corpus, is the disagreement on whether inflammaging is even a robust, generalizable phenomenon in humans. The mechanistic reading here is that acute inflammatory triggers (infection, radiation, injury) produce transient, sometimes paradoxically protective immune remodeling that does not align with the slow, chronic inflammaging construct. The boundary condition is one of context: chronic low-grade inflammaging in community-dwelling older adults may behave very differently from acute inflammatory stress in hospitalized or treated populations. Resolution would require prospective cohorts that explicitly separate baseline inflammaging trajectory from acute inflammatory events, with the two never collapsed into a single exposure variable.

Another tension, central to the paper's overall argument, is the surrogate-endpoint versus hard-outcome gap, which the methodologically cautious reader must keep separate (Ioannidis 2005). The corpus's evidence is overwhelmingly concentrated on surrogate and contextual endpoints: in vitro Nrf2/HO-1 modulation (Garcia-Gil 2026), exoproteome complement deactivation (Mishra 2026), S100A8/A9 alarmins (Bonora 2022), NLR and PLR ratios (Ceolin 2025, Paal 2025), methylation-clock feature rectification (Skinner 2025), and peritumoral immune remodeling (Netti 2026). The few proxies for hard outcomes that do appear — Ceolin 2025's mortality endpoint, Wang 2025's EGR1-ATF3 mortality signal, Lackner 2022's hip-fracture cardiac alterations, Surboyo 2026's alveolar bone loss — are themselves indirect, observational, and largely null. The boundary condition is that improvements in any of these surrogate biomarkers, including hsCRP, IL-6, NLR, and SASP factors, are not equivalent to demonstrated gains in healthspan, disability-free survival, or mortality. Indeed, the same caution that Ioannidis 2005 articulated for surrogates in cardiovascular and metabolic trials applies here. What would resolve this is a trial designed with a hard clinical primary endpoint (e. For example, major adverse cardiovascular events, incident frailty, or mortality) and an inflammaging biomarker as a pre-specified secondary mediator, with formal mediation analysis linking the two — a design absent from this corpus.

A fifth and final tension, often underweighted, is the cross-species generalizability of the inflammaging construct itself. The boundary condition is that inflammaging is plausibly a human-, environment-, and exposure-specific phenomenon rather than a pan-mammalian aging program. Resolving this would require harmonized wild and captive mammalian cohorts with the same inflammatory biomarker panel — a near-absent design in the current evidence base.

Boundary-condition synthesis

Interpreting the cross-domain evidence requires treating each domain as part of a boundary-condition map rather than as a single pooled effect. Direct human findings set the clinical perimeter; mechanistic findings explain plausible pathways; indirect findings identify where transfer across populations, time horizons, or measurement systems remains uncertain. This separation is important because evidence can be valid within one outcome domain while remaining weak support for another. The synthesis therefore gives priority to source-traced clinical findings when making patient-facing claims, uses mechanistic evidence to explain why effects might diverge, and treats discordance as a signal about applicability rather than as a reason to average unlike endpoints together.

Cross-domain interpretation compares outcome classes and identifies where signals converge or diverge. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation separates direct clinical findings from mechanistic and adjacent evidence, preserving uncertainty where endpoint, population, comparator, or follow-up differs. This conservative boundary keeps the scientific question visible without inserting unsupported numeric detail or stronger causal language than the retained evidence allows. Where studies point in different directions, the synthesis treats that disagreement as information about design and applicability rather than as noise. The key question becomes which population, intervention schedule, comparator, and endpoint layer would be required for the claim to survive a prospective test. This preserves the practical implication for readers: favorable signals can justify targeted follow-up, while unresolved tradeoffs still limit broad clinical or public-health recommendations.## Endpoint-Sensitivity Framework

We operationalize an Endpoint-Sensitivity framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.

The included evidence base contains direct, indirect, mechanistic evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.

The framework is useful here because the matrix contains mechanism-vs-clinical, null-vs-positive, null-vs-negative tensions that can otherwise be mistaken for simple inconsistency.

A falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.

This is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.

Discussion

Thesis: Across the 60-paper inflammaging corpus, direct human RCT evidence for immune-biomarker modulation exists but is narrow in endpoint scope, while the broader inflammaging portfolio is dominated by indirect observational, mechanistic, and preclinical signals whose effect directions and outcome classes are genuinely mixed, so the inflammaging anti-aging case is best read as mechanistically plausible yet clinically underdetermined, not as a settled or refuted claim. The thesis is falsifiable: it would be refuted by replicated, hard-outcome RCTs (e. For example, mortality, incident frailty, cardiovascular events) showing consistent inflammaging-mediated benefit in pre-frail or older adults, with effect sizes that survive adjustment for baseline inflammation, sex, and comorbidity. The corpus supports a position stronger than "context-dependent" boilerplate: the convergent signal is that inflammaging biomarkers — CRP, IL-6, NLR, fibrinogen, sCD14, LPS — are reproducibly elevated in older and clinically vulnerable populations, but interventions that move these biomarkers have not yet been shown to move hard outcomes. We interpret the evidence as consistent with inflammaging as a measurable, modifiable biological state, while remaining cautious about claims of durable clinical translation. This distinction is the load-bearing reason the thesis is qualified rather than declarative.

Threat 1: The direct RCT evidence base is too thin to ground durable claims. These two studies are the only source-anchored evidence where the design, endpoint, and direction meet the bar for direct human evidence on inflammaging biomarkers, and even they disagree on effect direction (unclear vs positive). A second reading of the corpus is therefore possible: the inflammaging anti-aging case may be no more than a small, inconsistent, biomarker-level literature, and any broader claim is overreach. We acknowledge that the body of direct human evidence is insufficient to claim either benefit or harm on hard clinical endpoints, and we treat the mechanistic consensus (Franceschi and others) as a hypothesis generator, not a conclusion.

Threat 2: Cross-domain tensions are pervasive and risk spurious fusion. The corpus also contains null vs positive conflicts between Garcia-Gil 2026 (positive on contextual other, in vitro Nrf2/HO-1 modulation) and roughly twenty indirect observational and review sources reporting null contextual other effects (Mlynarska 2025, Mishra 2026, Yuan 2018, Bonora 2022, Horiba 2022, Zhang 2022, Li 2022, Xu 2024, Wang 2024, Cordiano 2024, Villaume 2024, Nelson 2025, Skinner 2025, Huang 2025, Martin 2025, Xu 2026, Diego-Matos 2026, Filipek 2026, Zaongo 2026, Tan 2026). Naive pooling across these designs would inflate certainty; one reading is that the field has not yet converged on what "inflammaging reduction" means across tissues and species. We therefore recommend that future syntheses stratify by design, tissue, and species rather than aggregate effect signs.

Threat 3: The human longevity and mortality signal is genuinely mixed and likely population- and biomarker-specific. This mixture of directions is most parsimoniously explained as population specificity: acutely ill hospitalised older adults (Ceolin 2025) are not interchangeable with community-dwelling Bolivian foragers (Aronoff 2025) or with mechanistic preclinical models (Lin 2025 corylin, Yuan 2018 hAAT, Lee 2025 PgELNs). We interpret this as evidence that inflammaging is real and measurable, but that its clinical translation depends on baseline inflammatory load, comorbidity, and biological age. Translation to clinical practice therefore warrants further trials, not adoption.

Threat 4: The mechanistic-versus-clinical pipeline has a major indirectness gap that the matrix flags repeatedly. The two direct RCTs (Lazou-Ahren 2024, Li 2025b) sit on immune outcomes, yet the corpus also includes mechanism-level claims about longevity, cardiometabolic risk, skeletal/bone outcomes, cognitive outcomes, and safety/comorbidity — all of which the matrix flags as mechanism vs clinical at severity 3. Surrogate-endpoint reasoning is precisely where the Ioannidis 2005 caution applies: a surrogate association does not guarantee hard-outcome validity. We interpret the recurrence of this gap as the single most important methodological limitation of the inflammaging literature, and we recommend that any future claim of clinical benefit be paired with explicit hard-endpoint adjudication (incident frailty, cardiovascular events, mortality) rather than biomarker movement alone.

Threat 5: Endpoint, species, and age heterogeneity make a single effect estimate implausible. Cole 2026 in particular reports minimal evidence of inflammaging in naturalistic chimpanzee populations, which is interpretively important because it qualifies the universality of the inflammaging construct across the primate lineage. We therefore suggest that any future meta-analysis adopt a stratified-by-population design, since pooled effect sizes across such heterogeneous groups would have low interpretive value and could mislead clinical decision boundaries.

Resolution criteria: The threats above would be settled by a small, deliberate set of study designs. First, a population-stratified prospective cohort enrolling acutely ill (Ceolin 2025 phenotype), community-dwelling, and forager-horticulturalist (Aronoff 2025 phenotype) groups with harmonised biomarker panels, to test the population-specificity hypothesis directly. Second, an ancillary mechanistic arm on a subset of trial participants linking biomarker movement to single-cell and epigenetic endpoints (Skinner 2025, Guo 2025) so that surrogate-to-hard-outcome inference (Ioannidis 2005) is no longer speculative. Until such trials are reported, the inflammaging anti-aging case remains to be determined, and the evidence supports inflammaging as a measurable state, not yet as a clinical target.

Limitations

Verification note: Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

The curated corpus does not contain any long-term mortality or hard cardiovascular endpoint randomized trial of an inflammaging-targeted intervention in generally healthy community-dwelling older adults. As a result, any cross-paper claim that inflammaging modification prolongs survival or reduces hard events lacks an in-corpus RCT source and must be treated as hypothesis-generating, consistent with the surrogate-endpoint caution articulated in Ioannidis 2005.

Several clinically relevant inflammaging claims in the corpus are supported by only a single source, leaving them unreplicated within this evidence base. Single-source claims of this kind cannot be checked for direction-of-effect stability and should be interpreted as illustrative rather than confirmed.

The enrolled populations skew toward narrow demographic and clinical strata, constraining external validity. Almost no source reports an inflammaging intervention in generally healthy mid-life adults free of chronic disease, so the headline findings should not be extrapolated to that population.

Additional corpus sources included animal/preclinical evidence; the endpoint scope of the corpus is heavily weighted toward circulating inflammatory biomarkers, in-vitro readouts, and tissue-level mechanistic markers rather than functional or patient-important outcomes. Directness is largely indirect or mechanistic: the immune class is dominated by indirect observational cohorts (e. For example, Ramuth 2026, Santos 2024, Wang 2021, Liu 2026), and the longevity class is largely populated by indirect, narrative, or protocol-stage sources (Wrona 2024, Spray 2025, Giunta 2023, Lv 2023). Consequently, inflammaging-biomarker effects reported in the corpus cannot be mapped onto the standard functional geriatric endpoints that clinicians use.

The gap between mechanistic plausibility and clinical evidence is particularly wide for several domain-relevant claims. Lin 2025 (in-vitro diabetic periodontitis), Aitella 2025 (preclinical rheumatoid arthritis and osteoporosis), Aitella 2026 (preclinical allergy biology), Netti 2026 (clear cell renal cell carcinoma peritumoral tissue), and Wang 2021 (monocyte PPAR-α downregulation) all generate mechanism-grade support for inflammaging but report no human clinical endpoint. Because the corpus supplies mechanistic and disease-specific indirect evidence but lacks general-population or hard-endpoint human RCT data, the clinic-ready translation of any inflammaging-targeted intervention is not supported by this evidence base.

Conclusion

Across the corpus, the 60 sources evaluated in this synthesis support an integrating position that the inflammaging construct, as currently operationalised, is mechanistically plausible but clinically incomplete: positive signals appear chiefly in immune and contextual biomarker outcomes (e. For example, Garcia-Gil 2026 and Aronoff 2025), negative signals cluster on immune and longevity outcomes (notably Paal 2025, Ceolin 2025), and null or mixed findings dominate the remaining outcome classes, with Cole 2026, Steele 2014, and Li 2022 returning non-significant results on key comparators. These findings, layered atop 163 non-orthogonal cross-domain tensions, indicate that the inflammaging anti-aging case as currently constituted remains to be confirmed in adequately powered trials with pre-registered longevity or functional endpoints.

Additional corpus sources included animal/preclinical evidence; what the current evidence does and does not support for clinical practice requires careful boundary-drawing. For drugs, compounds, or supplements with putative anti-inflammaging properties — including metformin, doxycycline (Li 2022), alpha-1 antitrypsin (Yuan 2018), vitamin E-loaded dialysers (Sepe 2019), pomegranate extract (Cordiano 2024), fucoxanthin combinations (Garcia-Gil 2026), and 2-O-methylmagnolol (Huang 2025b) — the appropriate clinical posture is that off-label geroprotective use remains to be confirmed pending further trials with hard endpoints, and any such use outside of registered protocols cannot currently be justified by the evidence base.

A defensible next study should pre-specify which endpoint layer it intends to test, align intervention exposure with that endpoint, and report functional or safety tradeoffs with the same visibility as benefit signals. Agreement across mechanistic, intermediate, functional, and hard-clinical layers would support stronger inference than any isolated signal; disagreement across those layers should be treated as a design problem rather than averaged into a single geroprotective claim.

What This Synthesis Adds

This synthesis maps 60 included sources on Inflammaging across 10 outcome classes and 163 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

Across 60 curated reference papers, the evidence base for inflammaging shows a context-dependent profile. Positive signals appear in: immune, contextual other. Negative signals appear in: immune, longevity. Null findings dominate: contextual other, immune. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The inflammaging anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

The strongest unresolved contrast is the disagreement between Paal 2025 and Aronoff 2025 on immune and inflammation (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Cares 2026, Alp 2025, Aronoff 2025) emphasize convergent signals on Inflammaging. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	5	negative, null, unclear	conflict-resolution gap
cardiometabolic	0	3	null, unclear	direct interventional hard-endpoint gap
cognitive	0	1	null	direct interventional hard-endpoint gap
mechanism	0	1	null	direct interventional hard-endpoint gap
contextual adjacent evidence	0	25	null, positive, unclear	conflict-resolution gap
immune and inflammation	2	17	mixed, negative, null, positive, unclear	conflict-resolution gap
immune and inflammation	0	2	null, unclear	direct interventional hard-endpoint gap
mortality and survival	0	1	null	direct interventional hard-endpoint gap
safety and comorbidity	0	1	null	direct interventional hard-endpoint gap
skeletal, fracture, and bone	0	2	null, unclear	direct interventional hard-endpoint gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: conflict-resolution gap	0 direct and 5 indirect sources; direction profile: negative, null, unclear
P2	cardiometabolic: direct interventional hard-endpoint gap	0 direct and 3 indirect sources; direction profile: null, unclear
P3	cognitive: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null
P4	mechanism: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null
P5	contextual adjacent evidence: conflict-resolution gap	0 direct and 25 indirect sources; direction profile: null, positive, unclear

Next-Study Design Recommendation

The next high-yield study for Inflammaging should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.

Evidence Snapshot

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

Load-Bearing Included Studies

• Lazou-Ahren 2024; tier=A1; directness=direct; endpoint=immune; direction=unclear; representative statistic=P = 0.01.
• Li 2025b; tier=A1; directness=direct; endpoint=immune; direction=positive; representative statistic=P = 0.008.
• Cares 2026; tier=B1; directness=review; endpoint=cardiometabolic; direction=null.
• Alp 2025; tier=B1; directness=review; endpoint=immune; direction=null.
• Aronoff 2025; tier=B1; directness=review; endpoint=immune; direction=positive; representative statistic=P < 0.01.
• Li 2022; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.
• Paal 2025; tier=B2; directness=indirect; endpoint=immune; direction=negative; representative statistic=P < 0.001.
• Garcia-Gil 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.001.
• Steele 2014; tier=B2; directness=indirect; endpoint=immune; direction=null; representative statistic=P = 0.052.
• Ceolin 2025; tier=B2; directness=indirect; endpoint=longevity; direction=negative; representative statistic=P < 0.001.

Source Classification Map

Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.

• Additional corpus sources included animal/preclinical evidence; Lazou-Ahren 2024: outcome=immune; directness=direct; tier=A1; direction=unclear; claims=31.
• Li 2025b: outcome=immune; directness=direct; tier=A1; direction=positive; claims=6.
• Cares 2026: outcome=cardiometabolic; directness=review; tier=B1; direction=null; claims=31.
• Alp 2025: outcome=immune; directness=review; tier=B1; direction=null; claims=4.
• Aronoff 2025: outcome=immune; directness=review; tier=B1; direction=positive; claims=2.
• Li 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=344.
• Paal 2025: outcome=immune; directness=indirect; tier=B2; direction=negative; claims=88.
• Garcia-Gil 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=positive; claims=86.
• Steele 2014: outcome=immune; directness=indirect; tier=B2; direction=null; claims=57.
• Ceolin 2025: outcome=longevity; directness=indirect; tier=B2; direction=negative; claims=49.
• Cole 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=46.
• Ramuth 2026: outcome=immune; directness=indirect; tier=B2; direction=null; claims=45.
• Mishra 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=39.
• Bonora 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=38.
• Li 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=38.
• Wang 2021: outcome=immune; directness=indirect; tier=B2; direction=null; claims=37.
• Xu 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=37.
• Lackner 2022: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=31.
• Tizazu 2024: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=29.
• Arosio 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=27.
• Santos 2024: outcome=immune; directness=indirect; tier=B2; direction=null; claims=27.
• Diego-Matos 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=26.
• Zhang 2025: outcome=immune; directness=indirect; tier=B2; direction=null; claims=25.
• Lei 2025: outcome=immune; directness=indirect; tier=B2; direction=null; claims=23.
• Sepe 2019: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=21.
• Huang 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.
• Nelson 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.
• Yuan 2018: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=16.
• Horiba 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.
• Yang 2025: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=14.
• Cordiano 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13.
• Liu 2026: outcome=immune; directness=indirect; tier=B2; direction=null; claims=13.
• Martin 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12.
• Guo 2025: outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=10.
• Huang 2025b: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=9.
• Mlynarska 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=9.
• Wang 2025: outcome=mortality survival; directness=indirect; tier=B2; direction=null; claims=8.
• Xiong 2025: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=7.
• Xu 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4.
• Jiang 2025: outcome=immune; directness=indirect; tier=B2; direction=null; claims=3.

Classification Criteria

• Outcome class is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
• Directness is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
• Directional signal is counted within the assigned outcome class only. A no extracted directional signal cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
• Evidence tier follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

Load-Bearing Tensions

• Additional corpus sources included animal/preclinical evidence; severity 5 disagreement: Paal 2025 vs Aronoff 2025; Paal 2025 reports negative effect on immune; Aronoff 2025 reports positive on the same outcome — direct conflict
• Severity 4 null vs negative: Lv 2023 vs Ceolin 2025; Ceolin 2025 (negative on longevity) vs Lv 2023 (null on longevity) — partial conflict
• Severity 4 null vs negative: Wrona 2024 vs Ceolin 2025; Ceolin 2025 (negative on longevity) vs Wrona 2024 (null on longevity) — partial conflict
• Severity 4 null vs negative: Santos 2024 vs Paal 2025; Paal 2025 (negative on immune) vs Santos 2024 (null on immune) — partial conflict
• Severity 4 null vs negative: Paal 2025 vs Zhang 2025; Paal 2025 (negative on immune) vs Zhang 2025 (null on immune) — partial conflict
• Severity 4 null vs negative: Paal 2025 vs Jiang 2025; Paal 2025 (negative on immune) vs Jiang 2025 (null on immune) — partial conflict
• Severity 4 null vs negative: Paal 2025 vs Francavilla 2025; Paal 2025 (negative on immune) vs Francavilla 2025 (null on immune) — partial conflict
• Severity 4 null vs negative: Paal 2025 vs Lee 2025; Paal 2025 (negative on immune) vs Lee 2025 (null on immune) — partial conflict

References

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• Paal 2025. Radiotherapy and inflammaging: the influence of prostate cancer radiotherapy on systemic inflammation. World Journal of Urology, 2025. DOI: 10.1007/s00345-024-05409-z. PMID: 39692768.
• Garcia-Gil 2026. Morin and Morin Semicarbazone Combined with Fucoxanthin Have Potential Anti-Inflammaging Effects Through Modulation of Nrf2/HO-1 System in UVB-Exposed HaCaT Keratinocytes. Antioxidants, 2026. DOI: 10.3390/antiox15050599. PMID: 42193222.
• Steele 2014. Contribution of Intestinal Barrier Damage, Microbial Translocation and HIV-1 Infection Status to an Inflammaging Signature. PLoS ONE, 2014. DOI: 10.1371/journal.pone.0097171. PMID: 24819230.
• Ceolin 2025. Neutrophil-to-lymphocyte ratio as a sex-specific predictor of short-term mortality in hospitalised older adults with COVID-19: a pragmatic biomarker of inflammaging in acute vulnerability. Immunity & Ageing: I & A, 2025. DOI: 10.1186/s12979-025-00548-2. PMID: 41462275.
• Cole 2026. Minimal Evidence of Inflammaging in Naturalistic Chimpanzee Populations. American Journal of Biological Anthropology, 2026. DOI: 10.1002/ajpa.70211. PMID: 41657073.
• Ramuth 2026. New insights into the association between cardiometabolic index with metabolic profile, nutritional status, and inflammaging in older adults. Frontiers in Aging, 2026. DOI: 10.3389/fragi.2025.1699767. PMID: 41602164.
• Mishra 2026. Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging. Nature Aging, 2026. DOI: 10.1038/s43587-026-01107-0. PMID: 41974968.
• Li 2025. Bottom-up engineering of the nucleus pulposus using a photocrosslinkable decellularized matrix hydrogel attenuates inflammaging and enhances microtissue-mediated regeneration. Materials Today Bio, 2025. DOI: 10.1016/j.mtbio.2025.102347. PMID: 41104045.
• Bonora 2022. Hematopoietic progenitor cell liabilities and alarmins S100A8/A9‐related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults. Aging Cell, 2022. DOI: 10.1111/acel.13545. PMID: 35166014.
• Xu 2026. The alteration of bile acids and gut microbiota is associated with intestinal barrier dysfunction and inflammaging in human. Frontiers in Aging, 2026. DOI: 10.3389/fragi.2026.1741360. PMID: 42064446.
• Wang 2021. Programmed PPAR-α downregulation induces inflammaging by suppressing fatty acid catabolism in monocytes. iScience, 2021. DOI: 10.1016/j.isci.2021.102766. PMID: 34286232.
• Lazou-Ahren 2024. Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. Probiotics and Antimicrobial Proteins, 2024. DOI: 10.1007/s12602-024-10310-7. PMID: 38896223.
• Cares 2026. Diet and Exercise Interventions in Pediatric Cancer Survivors and Effects on Cardiometabolic Disease Risk and Inflammaging Biomarkers: A Systematic Review. Advances in Nutrition, 2026. DOI: 10.1016/j.advnut.2026.100605. PMID: 41692128.
• Lackner 2022. Cardiac alterations following experimental hip fracture - inflammaging as independent risk factor. Frontiers in Immunology, 2022. DOI: 10.3389/fimmu.2022.895888. PMID: 36131923.
• Tizazu 2024. Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging. Aging Medicine, 2024. DOI: 10.1002/agm2.12342. PMID: 39234195.
• Santos 2024. Long-Term Physical Activity Mitigates Inflammaging Progression in Older Adults Amidst the COVID-19 Pandemic. International Journal of Environmental Research and Public Health, 2024. DOI: 10.3390/ijerph21111425. PMID: 39595692.
• Arosio 2025. Inflammaging and the sex-frailty paradox. Aging Clinical and Experimental Research, 2025. DOI: 10.1007/s40520-025-03181-7. PMID: 41055841.
• Diego-Matos 2026. Gut-heart immuno-metabolic disruption associated with inflammaging and subclinical coronary artery disease in people with HIV on antiretroviral therapy. Immunity & Ageing: I & A, 2026. DOI: 10.1186/s12979-026-00566-8. PMID: 42046076.
• Zhang 2025. Protective effects of Rosa roxburghii Tratt. extract against UVB-induced inflammaging through inhibiting the IL-17 pathway. Scientific Reports, 2025. DOI: 10.1038/s41598-025-92559-8. PMID: 40064976.
• Netti 2026. Molecular Remodeling of Peritumoral Tissue in Clear Cell Renal Cell Carcinoma: Insights into Inflammaging and Prognostic Markers. Cancers, 2026. DOI: 10.3390/cancers18030414. PMID: 41681886.
• Lei 2025. NRF1-mediated innate immune response drives inflammaging. Nature Communications, 2025. DOI: 10.1038/s41467-025-66368-6. PMID: 41381492.
• Sepe 2019. Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging. BMC Nephrology, 2019. DOI: 10.1186/s12882-019-1585-6. PMID: 31729973.
• Nelson 2025. The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation. JCI Insight, 2025. DOI: 10.1172/jci.insight.187271. PMID: 40036082.
• Huang 2025. Spatiotemporal mapping reveals Ccl8 hi macrophages as key drivers of testicular inflammaging. Clinical and Translational Medicine, 2025. DOI: 10.1002/ctm2.70527. PMID: 41251087.
• Yuan 2018. Anti‐inflammaging effects of human alpha‐1 antitrypsin. Aging Cell, 2018. DOI: 10.1111/acel.12694. PMID: 29045001.
• Yang 2025. Epigenetic silencing of SPHK1-IRF7 axis drives inflammaging in age-related meniscus degeneration via sphingolipid-immune dysregulation. Journal of Orthopaedic Surgery and Research, 2025. DOI: 10.1186/s13018-025-06518-0. PMID: 41419949.
• Horiba 2022. IL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin. JID Innovations, 2022. DOI: 10.1016/j.xjidi.2022.100112. PMID: 35521044.
• Cordiano 2024. Pomegranate ( Punica granatum L.) Extract Effects on Inflammaging. Molecules, 2024. DOI: 10.3390/molecules29174174. PMID: 39275022.
• Liu 2026. Interferon-related inflammaging links epigenetic age acceleration to multimorbidity. Cell Genomics, 2026. DOI: 10.1016/j.xgen.2026.101218. PMID: 41999740.
• Martin 2025. Age-related nigral downregulation of the Parkinson’s risk factor FAM49B primes human microglia for inflammaging. NPJ Aging, 2025. DOI: 10.1038/s41514-025-00296-z. PMID: 41419490.
• Guo 2025. Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes. Advanced Science, 2025. DOI: 10.1002/advs.202505922. PMID: 40862296.
• Huang 2025b. 2-O-methylmagnolol mitigates the generation of reactive oxidative stress and inflammaging in human gingival epithelial cells and fibroblasts with advanced glycation end products stimulation. Journal of Dental Sciences, 2025. DOI: 10.1016/j.jds.2025.04.022. PMID: 40654450.
• Mlynarska 2025. Inflammaging and Senescence-Driven Extracellular Matrix Remodeling in Age-Associated Cardiovascular Disease. Biomolecules, 2025. DOI: 10.3390/biom15101452. PMID: 41154680.
• Wang 2025. Targeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging. Biological Research, 2025. DOI: 10.1186/s40659-025-00634-1. PMID: 40722201.
• Xiong 2025. Advanced glycation end products induce inflammaging in periodontal ligament fibroblasts through RAGE/AKT/mTOR/glycolysis pathway. Acta Odontologica Scandinavica, 2025. DOI: 10.2340/aos.v84.44581. PMID: 40839341.
• Li 2025b. Effects of 2-year cocoa extract supplementation on inflammaging biomarkers in older US adults: findings from the COcoa Supplement and Multivitamin Outcomes Study randomised clinical trial. Age Ageing, 2025. DOI: 10.1093/ageing/afaf269. PMID: 40966617.
• Xu 2024. Identification of crucial inflammaging related risk factors in multiple sclerosis. Frontiers in Molecular Neuroscience, 2024. DOI: 10.3389/fnmol.2024.1398665. PMID: 38836117.
• Alp 2025. Balneotherapy as a potential immunomodulator in inflammaging. Clin Rheumatol, 2025. DOI: 10.1007/s10067-025-07708-1. PMID: 41062894.
• Jiang 2025. Global research trends in inflammaging from 2005 to 2024: a bibliometric analysis. Frontiers in Aging, 2025. DOI: 10.3389/fragi.2025.1554186. PMID: 40276724.
• Lin 2025. Corylin ameliorates inflammaging and pyroptosis in diabetic periodontitis: A preliminary in vitro study. Journal of Dental Sciences, 2025. DOI: 10.1016/j.jds.2025.02.014. PMID: 40654439.
• Martino 2026. Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy. Clinical and Translational Medicine, 2026. DOI: 10.1002/ctm2.70633. PMID: 41793184.
• Surboyo 2026. Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair. Journal of Bone and Mineral Metabolism, 2026. DOI: 10.1007/s00774-026-01706-2. PMID: 41706167.
• Wang 2024. The infrapatellar fat pad in inflammaging, knee joint health, and osteoarthritis. NPJ Aging, 2024. DOI: 10.1038/s41514-024-00159-z. PMID: 39009582.
• Wrona 2024. The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience. Frontiers in Aging, 2024. DOI: 10.3389/fragi.2024.1490302. PMID: 39478807.
• Skinner 2025. DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging. GeroScience, 2025. DOI: 10.1007/s11357-024-01460-1. PMID: 39825170.
• Lee 2025. Photinia glabra -derived exosome-like nanovesicles mitigate skin inflammaging via dual regulation of inflammatory signaling and calcium homeostasis. Nanomedicine, 2025. DOI: 10.1080/17435889.2025.2572991. PMID: 41088925.
• Zaongo 2026. Bridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence. Frontiers in Immunology, 2026. DOI: 10.3389/fimmu.2026.1792954. PMID: 42273671.
• Tan 2026. Inflammaging and the role of micronutrients as immunomodulators: a pathway to healthy aging. Immunity & Ageing: I & A, 2026. DOI: 10.1186/s12979-026-00569-5. PMID: 42057125.
• Zhang 2022. A Novel Strategy to Model Age-Related Cancer for Elucidation of the Role of Th17 Inflammaging in Cancer Progression. Cancers, 2022. DOI: 10.3390/cancers14215185. PMID: 36358603.
• Aronoff 2025. Inflammaging is minimal among forager-horticulturalists in the Bolivian Amazon. Proc Biol Sci, 2025. DOI: 10.1098/rspb.2025.1111. PMID: 40829666.
• Lv 2023. The effect of the mindfulness-based interventions on inflammaging: Protocol for a systematic review and meta-analysis. PLOS ONE, 2023. DOI: 10.1371/journal.pone.0284228. PMID: 37027447.
• Giunta 2023. Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies. GeroScience, 2023. DOI: 10.1007/s11357-023-00947-7. PMID: 37821752.
• Villaume 2024. Pathogenesis and inflammaging in myelodysplastic syndromes. Haematologica, 2024. DOI: 10.3324/haematol.2023.284944. PMID: 39445405.
• Spray 2025. Cardiovascular inflammaging: Mechanisms, consequences, and therapeutic perspectives. Cell Reports Medicine, 2025. DOI: 10.1016/j.xcrm.2025.102264. PMID: 40782796.
• Aitella 2025. Rheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies. International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26199268. PMID: 41096536.
• Francavilla 2025. Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges. Chemmedchem, 2025. DOI: 10.1002/cmdc.202400672. PMID: 39651728.
• Aitella 2026. Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies. International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27031206. PMID: 41683635.
• Moscucci 2025. Inflammaging and Cardiovascular Risk in Old Women. High Blood Pressure & Cardiovascular Prevention, 2025. DOI: 10.1007/s40292-025-00758-1. PMID: 41366614.
• Filipek 2026. Inflammaging and Senescence-Associated Secretory Phenotype (SASP) in Psoriasis – A Narrative Review of Potential Mechanisms and Anti-Inflammaging Strategies. Psoriasis: Targets and Therapy, 2026. DOI: 10.2147/PTT.S598115. PMID: 42232205.

Background References

Canonical reference values and methodological references cited in prose. Each entry's citation_token appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).

• Ioannidis 2005. Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.