{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"bd88fdac-646d-49da-ad47-a3e928cc057a","name":"Hypothesis-Generating Brief: Immune senescence — full paper","doi":"10.17605/OSF.IO/F3P6E","doi_status":"minted","osf_url":"https://osf.io/f3p6e/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_393b468290ee4f10/chain","content_hash":"sha256:24b09388eccfb1eee347273a3bbd8ed1c19934abfff799cefa1917cfc63e20bd","provenance_passport":{"publication_id":"bd88fdac-646d-49da-ad47-a3e928cc057a","submission_id":"6c9d2c5a-4a4e-489e-80e6-f51407ff1911","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:24b09388eccfb1eee347273a3bbd8ed1c19934abfff799cefa1917cfc63e20bd","persistent_identifiers":{"doi":"10.17605/OSF.IO/F3P6E","osf_url":"https://osf.io/f3p6e/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"unavailable","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_393b468290ee4f10","dw_chain_url":"https://provenance.researka.org/artifacts/claim_393b468290ee4f10/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"bd88fdac-646d-49da-ad47-a3e928cc057a","object_type":"publication","parent_object_id":"6c9d2c5a-4a4e-489e-80e6-f51407ff1911","title":"Hypothesis-Generating Brief: Immune senescence — full paper","body_markdown":"# Hypothesis-Generating Brief: Immune senescence — full paper\n\n## Abstract\n\nThis paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims.\n\nThe evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that Immune senescence 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.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Evidence brief. 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-immunosenescence-v06-DAILY-2026-06-23T04-08-56Z`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-23.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `immunosenescence AND aging AND human`\n- `immunosenescence AND older adults`\n- `immunosenescence AND randomized controlled trial`\n- `immune senescence AND aging AND human`\n- `immune senescence AND older adults`\n- `immune senescence AND randomized controlled trial`\n- `T cell senescence AND aging AND human`\n- `T cell senescence AND older adults`\n- `T cell senescence AND randomized controlled trial`\n- `vaccine response AND aging AND human`\n\n### Eligibility criteria\n- Sources whose primary content addresses immunosenescence.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe 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 424 records in the receipt-candidate union, 155 were classified as source candidates and 46 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.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 424 |\n| Classified source candidates | 155 |\n| No extractable claims | 115 |\n| None-only claim binding | 38 |\n| Mixed partial-or-none claim-binding candidates | 89 |\n| Partial-only claim-binding candidates | 22 |\n| Strict high-confidence sources | 5 |\n| Admitted final sources | 46 |\n\n### Exclusion reasons\n- 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.\n\n### Data items\nThe 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.\n\n### Risk-of-bias appraisal\nRisk-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.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, frailty, immune and inflammation, longevity, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource 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.\n\n### Accountability\nAccountability 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.\n\n## Results\n\n**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.\n\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=18; claims=286 | no extracted directional signal in 18/18 sources | 16 indirect; 2 review | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=18; claims=292 | no extracted directional signal in 14/18 sources | 1 direct; 15 indirect; 2 mechanistic | limited corpus depth in this outcome class |\n| Longevity | n=4; claims=27 | no extracted directional signal in 3/4 sources | 4 indirect | limited corpus depth in this outcome class |\n| Cardiometabolic | n=2; claims=38 | no extracted directional signal in 2/2 sources | 2 indirect | limited corpus depth in this outcome class |\n| Frailty | n=2; claims=18 | no extracted directional signal in 2/2 sources | 1 direct; 1 indirect | limited corpus depth in this outcome class |\n| Cognitive | n=1; claims=1 | no extracted directional signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |\n| Safety and Comorbidity | n=1; claims=88 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n18 included sources were assigned to this outcome class. Directional coding: null=18. Directness coding: indirect=16, review=2.\n\n### Immune Outcomes\n\n15 included sources were assigned to this outcome class. Directional coding: null=11, positive=1, unclear=3. Directness coding: direct=1, indirect=12, mechanistic=2.\n\n3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.\n\nEvidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.\n\n### Longevity Outcomes\n\n4 included sources were assigned to this outcome class. Directional coding: null=3, unclear=1. Directness coding: indirect=4.\n\n### Cardiometabolic Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.\n\n### Frailty Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: direct=1, indirect=1.\n\n### Cognitive Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1.\n\n### Safety Comorbidity Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe corpus contains no long-term, hard-outcome randomized trial in non-diabetic older adults, and the absence of such evidence is a primary boundary on every cross-domain inference. Ioannidis 2005 underscores the risk that surrogate-endpoint RCTs in this corpus (e. For example, Rastgoo 2025's senescent-cell and SA-β-gal readouts) may not translate to clinical benefit, and that caveat applies to most of the headline conclusions.\n\nSeveral clinically prominent outcomes are touched by only a single source, so any conclusion that names those outcomes cannot be replicated inside the corpus. The lymphocyte-to-monocyte ratio / HFpEF longevity signal rests on Cai 2026 alone; the BC02-adjuvanted VZV-gE vaccine claim of overcoming age-related immune limitation rests on Li 2026 alone; the senolytic Agrimonia pilosa pilot in middle-aged humans rests on Shimizu 2025 alone; and the centenarian immune-profiling data rest on Anaya 2026. When a single observational cohort or preclinical study is the entire evidence base for a claim, the point estimate carries an unreplicated, design-specific uncertainty, and the synthesis cannot adjudicate between chance, confounding, and a true effect. The -type null vs positive tension on the immune outcome class (Lee 2025 positive vs. Khoury 2025 / Cevirgel 2025 / Coelho 2025 / Fragkou 2026 / Anaya 2026 null) compounds this risk, because there is no within-corpus independent dataset that resolves which direction generalizes.\n\nAdditional corpus sources included animal/preclinical evidence; external validity is bounded by the populations the trials and cohorts actually enrolled. Geographically, the corpus is concentrated in Chinese (Xiao 2023, Chen 2026, Li 2026, Li 2026b, Zhong 2025, Zhang 2026, Zhang 2024, He 2025, Reina-Alfonso 2026), Brazilian (Ventura 2025, Coelho 2025, Dema 2025, Francavilla 2025), and Bulgarian (Nikolova 2025) cohorts, with single-country representation from Colombia (Anaya 2026) and Italy (Valentino 2024, Aitella 2025, Aitella 2026).\n\nHard clinical endpoints — incident infection, hospitalization, cardiovascular events, cancer incidence, and all-cause mortality — are rarely the measured outcome. As a result, the corpus cannot answer whether any of the candidate interventions (vitamin D + NAC in Rastgoo 2025, Agrimonia pilosa in Shimizu 2025, red ginseng in Lee 2025, tai chi in Zhong 2025) reduces the hard outcomes that motivate clinical interest in immunosenescence, and any quantitative claim to the contrary exceeds the sources.\n\nSeveral clinically actionable claims are supported only by mechanistic or preclinical evidence, with no within-corpus human-RCT bridge. Lee 2025 reports a positive in-vitro T-cell mitochondrial effect, but is not an in-human trial of clinical benefit. Without a within-corpus human RCT that tests a mechanistically nominated intervention on a hard endpoint, the immunosenescence anti-aging case as currently constituted remains incomplete, and the boundary conditions for translation — age stratum, comorbidity profile, baseline immune fitness — are not established by the available evidence.\n\n## Conclusion\n\nFor Immune senescence, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 46 included sources on Immunosenescence across 8 outcome classes and 96 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.\n\nAcross 46 curated reference papers, the evidence base for immunosenescence shows a context-dependent profile. Positive signals appear in: immune. Null findings dominate: contextual other. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The immunosenescence 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.\n\nThe strongest unresolved contrast is the null vs positive between Valentino 2024 and Lee 2025 on immune and inflammation (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nThis 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.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 4 | null, unclear | direct interventional hard-endpoint gap |\n| cardiometabolic | 0 | 2 | null | direct interventional hard-endpoint gap |\n| cognitive | 0 | 1 | null | direct interventional hard-endpoint gap |\n| frailty | 1 | 1 | null | replication gap |\n| contextual adjacent evidence | 0 | 18 | null | direct interventional hard-endpoint gap |\n| immune and inflammation | 1 | 14 | null, positive, unclear | conflict-resolution gap |\n| safety and comorbidity | 0 | 1 | null | direct interventional hard-endpoint gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: null, unclear |\n| P2 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n| P3 | cognitive: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P4 | frailty: replication gap | 1 direct and 1 indirect sources; direction profile: null |\n| P5 | contextual adjacent evidence: direct interventional hard-endpoint gap | 0 direct and 18 indirect sources; direction profile: null |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Immunosenescence 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 12 months; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Additional corpus sources included animal/preclinical evidence; Rastgoo 2025; tier=A1; directness=direct; endpoint=immune; direction=null.\n- Zhong 2025; tier=A1; directness=direct; endpoint=frailty; direction=null.\n- Xiao 2023; tier=B2; directness=indirect; endpoint=safety comorbidity; direction=null.\n- Li 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.\n- Jin 2025; tier=B2; directness=indirect; endpoint=immune; direction=unclear; representative statistic=P < 0.001.\n- Lupoae 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Anaya 2026; tier=B2; directness=indirect; endpoint=immune; direction=null; representative statistic=P = 0.06.\n- Ventura 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Tizazu 2024; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null.\n- Bashir 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial: outcome=immune; directness=direct; tier=A1; direction=null; claims=25.\n- A randomized controlled trial to assess the efficacy of standardized tai chi in prefrail older adults with immunosenescence: design and protocol: outcome=frailty; directness=direct; tier=A1; direction=null; claims=10.\n- Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor: outcome=safety comorbidity; directness=indirect; tier=B2; direction=null; claims=88.\n- BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=55.\n- Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=54.\n- Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=48.\n- Biological age and immunosenescence in Colombian centenarians: outcome=immune; directness=indirect; tier=B2; direction=null; claims=38.\n- Immunosenescence Profile Is Associated With Increased Susceptibility to Severe COVID ‐19: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=33.\n- Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=29.\n- The impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=28.\n- Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=27.\n- CD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults: outcome=immune; directness=indirect; tier=B2; direction=null; claims=26.\n- Age-related changes in circulating immune factors reveal biomarkers of immunosenescence: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=23.\n- Living in endemic area for infectious diseases is associated to differences in immunosenescence and inflammatory signatures: outcome=immune; directness=indirect; tier=B2; direction=null; claims=17.\n- Differential associations of anti-cytomegalovirus antibodies and soluble CD14 levels with immunosenescence in people living with HIV on long term antiretroviral therapy: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.\n- MAM‐STAT3‐Driven Mitochondrial Ca +2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=16.\n- Immunosenescence and cytomegalovirus-associated immune signatures on severe acute respiratory syndrome coronavirus 2 booster responses: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=16.\n- Enhancing flu vaccine responses in older adults: preliminary insights from the ISOLDA study on immunosenescence and antioxidant and anti-inflammatory approaches: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.\n- Lymphocyte-To-Monocyte Ratio is Partially Mediated in Age-Related Cardiovascular Mortality in HFpEF: Immunosenescence, Inflamm-Aging, and Longevity: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=13.\n- Aging, inflammaging and immunosenescence as risk factors of severe COVID-19: outcome=longevity; directness=indirect; tier=B2; direction=unclear; claims=11.\n- Immunosenescence and its impact on ischemic stroke risk and outcomes in older adults: a systematic review: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=10.\n- Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=9.\n- The pathophysiological mechanisms of immunosenescence in coronary artery disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.\n- Deciphering Immunosenescence From Child to Frailty: Transcriptional Changes, Inflammation Dynamics, and Adaptive Immune Alterations: outcome=frailty; directness=indirect; tier=B2; direction=null; claims=8.\n- Immunosenescence is a therapeutic target for frailty in older adults: a narrative review: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=7.\n- Aging-associated transcriptional programs in T cells signify constituents of TGF-β signaling for immunosenescence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma: outcome=immune; directness=indirect; tier=B2; direction=null; claims=5.\n- Gene Expression Changes as Biomarkers of Immunosenescence in Bulgarian Individuals of Active Age: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4.\n- Age Versus Immunity: Dietary Influences on Immunosenescence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=3.\n- HIV infection and immunosenescence: challenges and intervention strategies: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=3.\n- Red ginseng extract enhances mitochondrial function and alleviates immunosenescence in T cells: outcome=immune; directness=indirect; tier=B2; direction=positive; claims=2.\n- Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=2.\n- The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=2.\n- Bridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2.\n- Multivariate analysis of immunosenescence data in healthy humans and diverse diseases: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1.\n- Immunosenescence and susceptibility to respiratory viruses: a state-of-the-art review: outcome=immune; directness=indirect; tier=B2; direction=null; claims=1.\n- Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges: outcome=immune; directness=indirect; tier=B2; direction=null; claims=1.\n- Insights into tumor vaccines for elderly individuals in the context of immunosenescence: outcome=immune; directness=indirect; tier=B2; direction=null; claims=1.\n- “Immunopause” no more: exercise to counter immunosenescence in aging: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=1.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **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.\n- **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.\n- **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.\n\n### Load-Bearing Tensions\n\n- Severity 4 null vs positive: Valentino 2024 vs Lee 2025; Lee 2025 (positive on immune) vs Valentino 2024 (null on immune) — partial conflict\n- Severity 4 null vs positive: Khoury 2025 vs Lee 2025; Lee 2025 (positive on immune) vs Khoury 2025 (null on immune) — partial conflict\n- Severity 4 null vs positive: Cevirgel 2025 vs Lee 2025; Lee 2025 (positive on immune) vs Cevirgel 2025 (null on immune) — partial conflict\n- Severity 4 null vs positive: Coelho 2025 vs Lee 2025; Lee 2025 (positive on immune) vs Coelho 2025 (null on immune) — partial conflict\n- Severity 4 null vs positive: Lee 2025 vs Li 2025; Lee 2025 (positive on immune) vs Li 2025 (null on immune) — partial conflict\n- Severity 4 null vs positive: Lee 2025 vs Francavilla 2025; Lee 2025 (positive on immune) vs Francavilla 2025 (null on immune) — partial conflict\n- Severity 4 null vs positive: Lee 2025 vs Fragkou 2026; Lee 2025 (positive on immune) vs Fragkou 2026 (null on immune) — partial conflict\n- Severity 4 null vs positive: Lee 2025 vs Anaya 2026; Lee 2025 (positive on immune) vs Anaya 2026 (null on immune) — partial conflict\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Shete 2024, Padhiar 2024, Aiello 2025, Tizazu 2022, Seah 2026, Lai 2025, Bie 2025, Jia 2022, Danilowska 2025, Jin 2025b, Theodorakis 2024, Wrona 2024, Zaongo 2026, Ane-Kouri 2025, Yang 2025, Sun 2025.\n## References\n\n- **Xiao 2023.** _Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor._ Immunity & Ageing : I & A, 2023. DOI: 10.1186/s12979-023-00364-6. PMID: 37501123.\n- **Chen 2026.** _Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway._ Immunity & Ageing : I & A, 2026. DOI: 10.1186/s12979-026-00560-0. PMID: 41630039.\n- **Li 2026.** _BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models._ Human Vaccines & Immunotherapeutics, 2026. DOI: 10.1080/21645515.2026.2617728. PMID: 41575203.\n- **Jin 2025.** _Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity._ Cell Reports Medicine, 2025. DOI: 10.1016/j.xcrm.2025.102484. PMID: 41406938.\n- **Lupoae 2026.** _Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors._ Diseases, 2026. DOI: 10.3390/diseases14010026. PMID: 41590241.\n- **Anaya 2026.** _Biological age and immunosenescence in Colombian centenarians._ NPJ Aging, 2026. DOI: 10.1038/s41514-026-00340-6. PMID: 41735334.\n- **Ventura 2025.** _Immunosenescence Profile Is Associated With Increased Susceptibility to Severe COVID ‐19._ Aging Cell, 2025. DOI: 10.1111/acel.70077. PMID: 40388115.\n- **Tizazu 2024.** _Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging._ Aging Medicine, 2024. DOI: 10.1002/agm2.12342. PMID: 39234195.\n- **Bashir 2026.** _The impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells._ Pituitary, 2026. DOI: 10.1007/s11102-025-01632-y. PMID: 41524828.\n- **Shimizu 2025.** _Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study._ Nutrients, 2025. DOI: 10.3390/nu17040667. PMID: 40004995.\n- **Cevirgel 2025.** _CD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults._ Immunity & Ageing : I & A, 2025. DOI: 10.1186/s12979-025-00504-0. PMID: 40055790.\n- **Rastgoo 2025.** _Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1570441. PMID: 40421021.\n- **Zhang 2026.** _Age-related changes in circulating immune factors reveal biomarkers of immunosenescence._ Frontiers in Medicine, 2026. DOI: 10.3389/fmed.2026.1729112. PMID: 41658615.\n- **Shete 2024.** _Differential associations of anti-cytomegalovirus antibodies and soluble CD14 levels with immunosenescence in people living with HIV on long term antiretroviral therapy._ Immunity & Ageing : I & A, 2024. DOI: 10.1186/s12979-024-00491-8. PMID: 39709460.\n- **Coelho 2025.** _Living in endemic area for infectious diseases is associated to differences in immunosenescence and inflammatory signatures._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1547854. PMID: 40165959.\n- **Padhiar 2024.** _MAM‐STAT3‐Driven Mitochondrial Ca +2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients._ Advanced Science, 2024. DOI: 10.1002/advs.202407398. PMID: 39661729.\n- **Reina-Alfonso 2026.** _Immunosenescence and cytomegalovirus-associated immune signatures on severe acute respiratory syndrome coronavirus 2 booster responses._ The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2026. DOI: 10.1093/gerona/glag095. PMID: 41999211.\n- **Aiello 2025.** _Enhancing flu vaccine responses in older adults: preliminary insights from the ISOLDA study on immunosenescence and antioxidant and anti-inflammatory approaches._ Immunity & Ageing : I & A, 2025. DOI: 10.1186/s12979-025-00506-y. PMID: 40140897.\n- **Cai 2026.** _Lymphocyte-To-Monocyte Ratio is Partially Mediated in Age-Related Cardiovascular Mortality in HFpEF: Immunosenescence, Inflamm-Aging, and Longevity._ Reviews in Cardiovascular Medicine, 2026. DOI: 10.31083/RCM45403. PMID: 41789332.\n- **Tizazu 2022.** _Aging, inflammaging and immunosenescence as risk factors of severe COVID-19._ Immunity & Ageing : I & A, 2022. DOI: 10.1186/s12979-022-00309-5. PMID: 36369012.\n- **Zhong 2025.** _A randomized controlled trial to assess the efficacy of standardized tai chi in prefrail older adults with immunosenescence: design and protocol._ BMC Complementary Medicine and Therapies, 2025. DOI: 10.1186/s12906-024-04732-7. PMID: 39754159.\n- **Seah 2026.** _Immunosenescence and its impact on ischemic stroke risk and outcomes in older adults: a systematic review._ Frontiers in Aging Neuroscience, 2026. DOI: 10.3389/fnagi.2026.1776458. PMID: 41878309.\n- **Dema 2025.** _Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence._ Aging Cell, 2025. DOI: 10.1111/acel.14491. PMID: 39894902.\n- **Lai 2025.** _Deciphering Immunosenescence From Child to Frailty: Transcriptional Changes, Inflammation Dynamics, and Adaptive Immune Alterations._ Aging Cell, 2025. DOI: 10.1111/acel.70082. PMID: 40285422.\n- **Bie 2025.** _The pathophysiological mechanisms of immunosenescence in coronary artery disease._ Frontiers in Cell and Developmental Biology, 2025. DOI: 10.3389/fcell.2025.1686947. PMID: 41133221.\n- **Jia 2022.** _Immunosenescence is a therapeutic target for frailty in older adults: a narrative review._ Annals of Translational Medicine, 2022. DOI: 10.21037/atm-22-4405. PMID: 36388790.\n- **He 2025.** _Aging-associated transcriptional programs in T cells signify constituents of TGF-β signaling for immunosenescence._ BMC Biology, 2025. DOI: 10.1186/s12915-025-02484-5. PMID: 41398262.\n- **Li 2026b.** _Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways._ Aging Cell, 2026. DOI: 10.1111/acel.70548. PMID: 42169620.\n- **Khoury 2025.** _Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26031258. PMID: 39941028.\n- **Nikolova 2025.** _Gene Expression Changes as Biomarkers of Immunosenescence in Bulgarian Individuals of Active Age._ Biomedicines, 2025. DOI: 10.3390/biomedicines13030721. PMID: 40149697.\n- **Danilowska 2025.** _Age Versus Immunity: Dietary Influences on Immunosenescence._ Journal of Clinical Medicine, 2025. DOI: 10.3390/jcm14238313. PMID: 41375615.\n- **Jin 2025b.** _HIV infection and immunosenescence: challenges and intervention strategies._ BMC Medicine, 2025. DOI: 10.1186/s12916-025-04545-6. PMID: 41331594.\n- **Theodorakis 2024.** _Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors._ Microorganisms, 2024. DOI: 10.3390/microorganisms12102052. PMID: 39458361.\n- **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.\n- **Lee 2025.** _Red ginseng extract enhances mitochondrial function and alleviates immunosenescence in T cells._ Journal of Ginseng Research, 2025. DOI: 10.1016/j.jgr.2025.05.004. PMID: 40843013.\n- **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.\n- **Zhang 2024.** _Impact and potential value of immunosenescence on solid gastrointestinal tumors._ Frontiers in Immunology, 2024. DOI: 10.3389/fimmu.2024.1375730. PMID: 39007138.\n- **Valentino 2024.** _The role of autoantibodies in bridging obesity, aging, and immunosenescence._ Immunity & Ageing : I & A, 2024. DOI: 10.1186/s12979-024-00489-2. PMID: 39616399.\n- **Ane-Kouri 2025.** _Multivariate analysis of immunosenescence data in healthy humans and diverse diseases._ Frontiers in Aging, 2025. DOI: 10.3389/fragi.2025.1568034. PMID: 40308557.\n- **Yang 2025.** _Nanoparticle-mediated delivery of herbal-derived natural products to modulate immunosenescence-induced drug resistance in cancer therapy: a comprehensive review._ Frontiers in Oncology, 2025. DOI: 10.3389/fonc.2025.1567896. PMID: 40356750.\n- **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.\n- **Li 2025.** _Insights into tumor vaccines for elderly individuals in the context of immunosenescence._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1660874. PMID: 41132679.\n- **Francavilla 2025.** _Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges._ Chemmedchem, 2025. DOI: 10.1002/cmdc.202400672. PMID: 39651728.\n- **Sun 2025.** _“Immunopause” no more: exercise to counter immunosenescence in aging._ Immunity & Ageing : I & A, 2025. DOI: 10.1186/s12979-025-00549-1. PMID: 41275232.\n- **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.\n- **Fragkou 2026.** _Immunosenescence and susceptibility to respiratory viruses: a state-of-the-art review._ European Respiratory Review, 2026. DOI: 10.1183/16000617.0248-2025. PMID: 41813014.\n\n### Background References\n\n*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).*\n\n- **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.\n","metadata":{"abstract":"This paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Immune senescence 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.","article_type":"evidence_map","counts":{"retrieved_count":46,"selected_count":46,"review_like_count":2,"primary_like_count":44,"year_start":2022,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper-live","integrity":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"public_visibility":"listed","source_submission_id":"6c9d2c5a-4a4e-489e-80e6-f51407ff1911","submission_identity_key":"sha256:d1ea2ebb09ee9197ae1a563b574c4951344d9830f6308be4d66c6daa2a1fe4a1","submission_payload_hash":"sha256:10bb5dac0926aa7d35bc9e8a651fbd66a36313cca3faea3fad6b1e04754ec268","content_hash":"sha256:24b09388eccfb1eee347273a3bbd8ed1c19934abfff799cefa1917cfc63e20bd","source_citation_hash":"sha256:aac4e9357829a12d2bb14825dec513ea2b60ab865443c6817423757e11d3b9c4","author_signature":"sha256:24b09388eccfb1eee347273a3bbd8ed1c19934abfff799cefa1917cfc63e20bd","run_id":"synthesis-immunosenescence-v06-DAILY-2026-06-23T04-08-56Z","topic":"immunosenescence","domain_slug":"longevity","category":"longevity","identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/F3P6E","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"f3p6e","osf_url":"https://osf.io/f3p6e/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"f3p6e","url":"https://osf.io/f3p6e/","doi":"10.17605/OSF.IO/F3P6E"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"MiniMax-M3|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_auth_source":"oauth_agent_token","dw_artifact_id":"claim_393b468290ee4f10","dw_chain_url":"https://provenance.researka.org/artifacts/claim_393b468290ee4f10/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_393b468290ee4f10/chain","dw_source_artifact_id":"source_f2e6318846a94631","dw_input_artifact_ids":["source_9980fc3353714cfb","source_f7ff2af580c949f8","source_2e8a4f4cb8164b76","source_b861ca5d7944420a","source_4a82bc6243594eb0","source_f18f482dff5d40ba"],"dw_step_id":"step_d577dfe3a94043e9","dw_step_hash":"182575b5e5907b5db30296a98b75cd0f8f06c5ea82a64e41deeeda7fb6b9f5c5","dw_status":"registered","sha256":"sha256:228b8f1b1720d06f376712c5f6654faf04f97db0c475ef62e73f32498bd3e35e"},"created_at":"2026-06-23T08:25:53.250355+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"bd88fdac-646d-49da-ad47-a3e928cc057a","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Immune senescence 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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"This paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"The evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"Positive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The conclusion is that Immune senescence 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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"This manuscript is reported as a Evidence brief. 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-immunosenescence-v06-DAILY-2026-06-23T04-08-56Z`.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, frailty, immune and inflammation, longevity, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"| Contextual Adjacent Evidence | n=18; claims=286 | no extracted directional signal in 18/18 sources | 16 indirect; 2 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"18 included sources were assigned to this outcome class. Directional coding: null=18. Directness coding: indirect=16, review=2.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"15 included sources were assigned to this outcome class. Directional coding: null=11, positive=1, unclear=3. Directness coding: direct=1, indirect=12, mechanistic=2.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"4 included sources were assigned to this outcome class. Directional coding: null=3, unclear=1. Directness coding: indirect=4.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: direct=1, indirect=1.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"The corpus contains no long-term, hard-outcome randomized trial in non-diabetic older adults, and the absence of such evidence is a primary boundary on every cross-domain inference. Ioannidis 2005 underscores the risk that surrogate-endpoint RCTs in this corpus (e. For example, Rastgoo 2025's senescent-cell and SA-β-gal readouts) may not translate to clinical benefit, and that caveat applies to most of the headline conclusions.","citation_support":[{"source_id":"source_12","study":"Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial","doi":"10.3389/fimmu.2025.1570441","url":"https://doi.org/10.3389/fimmu.2025.1570441","support_kind":"cited_as_match","cited_as":"Rastgoo 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Immunosenescence is an important factor in the impaired immune response in older adults and plays a significant role in the development of biological aging. Targeting immunosenescence could present a novel pharmacological approach to mitigating aging and age-related diseases. We aimed to investigate the effect of N-acetylcysteine (NAC) and vitamin D (Vit-D) on the senescence of peripheral blood mononuclear cells (PBMCs). METHOD: This randomized clinical trial was conducted on older adults with Vit-D deficiency. Eligible participants were randomly assigned to one of four groups to receive either (A) 1000 IU of Vit-D daily (D1) (B), 1000 IU of Vit-D plus 600 mg of NAC daily (D1N) (C), 5000 IU of Vit-D daily (D5), or (D) 5000 IU of Vit-D plus 600 mg of NAC daily (D5N) for 8 weeks. Senescence-associated beta-galactosidase (SA-β-gal) staining, expression of senescence-related genes, and serum inflammatory factors were measured at baseline and after 8 weeks."}],"candidate_sources":[]},{"claim_id":"claim_26","claim":"Several clinically prominent outcomes are touched by only a single source, so any conclusion that names those outcomes cannot be replicated inside the corpus. The lymphocyte-to-monocyte ratio / HFpEF longevity signal rests on Cai 2026 alone; the BC02-adjuvanted VZV-gE vaccine claim of overcoming age-related immune limitation rests on Li 2026 alone; the senolytic Agrimonia pilosa pilot in middle-aged humans rests on Shimizu 2025 alone; and the centenarian immune-profiling data rest on Anaya 2026. When a single observational cohort or preclinical study is the entire evidence base for a claim, the point estimate carries an unreplicated, design-specific uncertainty, and the synthesis cannot adjudicate between chance, confounding, and a true effect. The -type null vs positive tension on the immune outcome class (Lee 2025 positive vs. Khoury 2025 / Cevirgel 2025 / Coelho 2025 / Fragkou 2026 / Anaya 2026 null) compounds this risk, because there is no within-corpus independent dataset that resolves which direction generalizes.","citation_support":[{"source_id":"source_3","study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","support_kind":"cited_as_match","cited_as":"Li 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group."},{"source_id":"source_6","study":"Biological age and immunosenescence in Colombian centenarians","doi":"10.1038/s41514-026-00340-6","url":"https://doi.org/10.1038/s41514-026-00340-6","support_kind":"cited_as_match","cited_as":"Anaya 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Biological aging and immunosenescence are central to longevity, yet their interplay in centenarians remains unclear. We conducted a cross-sectional study in 160 Colombian centenarians to examine associations between biological age (PhenoAge), immunosenescence and age-related clinical variables. Cytokine profiling (n = 114) and lymphocyte immunophenotyping (n = 42) were assessed. It was observed that better QoL and well-being were significantly associated with lower biological age, while depressive symptoms, prior tobacco use, elevated levels of RANTES and G-CSF as well as a distinct CD8+ T cell phenotype including greater CD27- CD28+ central memory, effector memory, and KLRG1- CD57+ terminally differentiated effector memory T cells (TEMRA), and fewer KLRG1+ CD57+ TEMRA cells were linked to higher biological age. Centenarians were classified into three categories: vigorous (10%), resilient (46.25%), and vulnerable (43.75%). Cytokine levels were similar across the groups. These findings challenge the notion of immunosenescence in centenarians and highlight the value of translational research in geroscience."},{"source_id":"source_10","study":"Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study","doi":"10.3390/nu17040667","url":"https://doi.org/10.3390/nu17040667","support_kind":"cited_as_match","cited_as":"Shimizu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"OBJECTIVES: To assess the effects of agrimol-containing Agrimonia pilosa Ledeb. extract (APE) for senescent immune cell removal in middle-aged Japanese adults with immunosenescence. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, parallel-group study was conducted in Japan between June 2023 and April 2024. PARTICIPANTS: 110 individuals aged 40-59, selected based on CD8+ T cells with highly-expressing-senescence-associated-β-galactosidase (SA-βGal). INTERVENTION: Participants were randomly assigned to receive 50 mg APE containing 0.2 mg of agrimols or a placebo for eight consecutive weeks. MEASUREMENTS: The primary endpoint was the change in the proportion of CD8+ T cells with high SA-βGal expression at 8 weeks of intake from the baseline. The secondary endpoints included the proportion of CD4+ T cells with high SA-βGal expression, CD4+ and CD8+ T cell subsets, and the ratio of various immune cells. RESULTS: Of the 635 subjects screened, 110 with immunosenescence were included in this study. In total, 55 participants in the placebo group and 53 in the APE group completed the intervention."},{"source_id":"source_11","study":"CD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults","doi":"10.1186/s12979-025-00504-0","url":"https://doi.org/10.1186/s12979-025-00504-0","support_kind":"cited_as_match","cited_as":"Cevirgel 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: The T cell compartment undergoes significant age-related changes, contributing to the decline of the adaptive immune system and increasing the risk of suboptimal antibody responses to vaccines in older adults. To better understand the association between T cell phenotypes and vaccine responsiveness, we conducted an in-depth analysis of CD4+, CD8+, and γδ + T cells on VITAL cohort participants who are low or high responders to multiple vaccines (influenza, pneumococcal, and SARS-CoV-2). RESULTS: Using spectral cytometry and FlowSOM, we identified detailed phenotypes of naïve, regulatory, and terminally differentiated T cells. We observed that the percentages of CD31 + naïve CD4+, CD31 + naïve CD8+, and CD38 + naïve CD8 + T cells were significantly lower in low vaccine responders. Notably, CD31 + naïve T cell subsets showed a stronger correlation with immune entropy, a measure of cumulative immune system perturbations, than with age itself. CONCLUSIONS: These findings suggest that subsets of naïve cells could be associated with weak vaccine responsiveness and immunosenescence."},{"source_id":"source_14","study":"Living in endemic area for infectious diseases is associated to differences in immunosenescence and inflammatory signatures","doi":"10.3389/fimmu.2025.1547854","url":"https://doi.org/10.3389/fimmu.2025.1547854","support_kind":"cited_as_match","cited_as":"Coelho 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Research on aged individuals from developed countries show that lifestyle factors such as diet, physical activity, stress, smoking, and sleep quality impact aging. However, other relevant factors may influence aging in less-studied populations, such as Brazilian cohorts. This study aimed to analyze immunosenescence profile of individuals living in an endemic area for several infectious diseases in Brazil. We showed that these individuals exhibited accelerated epigenetic aging and increased production of IL-12p70, IL-17A, and IL-9. Production of inflammatory mediators IL-12p70, IL-6, IL-1β, IL-2, and IL-1ra in individuals with flu-like symptoms and those with COVID-19 was higher among residents in endemic areas than in residents from a control non-endemic area. Furthermore, residents of the endemic area had a more prominent inflammatory profile during viral infection and a different pattern of plasma mediators when compared to residents of a non-endemic area. Our data suggests that these two cohorts had specific immune signatures regardless of the presence or the type of infection at study."},{"source_id":"source_19","study":"Lymphocyte-To-Monocyte Ratio is Partially Mediated in Age-Related Cardiovascular Mortality in HFpEF: Immunosenescence, Inflamm-Aging, and Longevity","doi":"10.31083/RCM45403","url":"https://doi.org/10.31083/RCM45403","support_kind":"cited_as_match","cited_as":"Cai 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is recognized as an aging-related clinical syndrome with high mortality, from which systemic inflammation could represent a primary culprit. Thus, this study aimed to evaluate the association between the lymphocyte-to-monocyte ratio (LMR), a systemic inflammation marker, and clinical outcomes, and to explore the mediation effect of the LMR in the relationship between age and mortality for HFpEF. METHODS: Participants in the Real-world Data of Cardiometabolic ProtEcTion trial (RED-CARPET) trial were categorized into tertiles based on the recorded LMRs. We employed Cox regression analyses to explore the relationship between the LMR and mortality, as well as mediation analyses to determine whether the LMR serves as a mediator between aging and mortality. RESULTS: A total of 1274 inpatients with HFpEF were enrolled between May 2015 and December 2023. After a median follow-up period of 4.9 years, there were 166 recorded deaths, of which 82 were due to cardiovascular causes. In the third model, each one-unit increase in standard deviation (SD) for age was correlated with a 1."}],"candidate_sources":[]},{"claim_id":"claim_27","claim":"Additional corpus sources included animal/preclinical evidence; external validity is bounded by the populations the trials and cohorts actually enrolled. Geographically, the corpus is concentrated in Chinese (Xiao 2023, Chen 2026, Li 2026, Li 2026b, Zhong 2025, Zhang 2026, Zhang 2024, He 2025, Reina-Alfonso 2026), Brazilian (Ventura 2025, Coelho 2025, Dema 2025, Francavilla 2025), and Bulgarian (Nikolova 2025) cohorts, with single-country representation from Colombia (Anaya 2026) and Italy (Valentino 2024, Aitella 2025, Aitella 2026).","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"Several clinically actionable claims are supported only by mechanistic or preclinical evidence, with no within-corpus human-RCT bridge. Lee 2025 reports a positive in-vitro T-cell mitochondrial effect, but is not an in-human trial of clinical benefit. Without a within-corpus human RCT that tests a mechanistically nominated intervention on a hard endpoint, the immunosenescence anti-aging case as currently constituted remains incomplete, and the boundary conditions for translation — age stratum, comorbidity profile, baseline immune fitness — are not established by the available evidence.","citation_support":[{"source_id":"source_34","study":"Red ginseng extract enhances mitochondrial function and alleviates immunosenescence in T cells","doi":"10.1016/j.jgr.2025.05.004","url":"https://doi.org/10.1016/j.jgr.2025.05.004","support_kind":"cited_as_match","cited_as":"Lee 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Mitochondrial function is essential for immune cell regulation, and its decline is linked to aging and chronic diseases. Impaired activity contributes to inflammation and reduced immunity. This study explores Red ginseng extract (RGE)'s potential in enhancing mitochondrial function and immune cell viability, offering benefits in mitigating immunosenescence. METHODS: T cells and macrophages from young (12-week-old) and aged (20-month-old) mice were treated with RGE to assess mitochondrial function and cell viability. Flow cytometry evaluated immune cell populations and cytokine expression in splenocytes, while single cell transcriptomics analyzed RGE-induced transcriptional changes in T cells and macrophages. RESULTS: RGE treatment improved mitochondrial oxygen consumption rate and glycolytic function in CD4 + and CD8 + T cells from both young and old mice, though effects were more pronounced in young cells. In aged mice, RGE administration resulted in higher proportions of naive T cells and reduced expression of senescence and exhaustion markers."}],"candidate_sources":[]},{"claim_id":"claim_29","claim":"For Immune senescence, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"This synthesis maps 46 included sources on Immunosenescence across 8 outcome classes and 96 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.","citation_support":[],"candidate_sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships.","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"bd88fdac-646d-49da-ad47-a3e928cc057a","content_hash":"sha256:24b09388eccfb1eee347273a3bbd8ed1c19934abfff799cefa1917cfc63e20bd","nodes":[{"id":"bd88fdac-646d-49da-ad47-a3e928cc057a","type":"publication","title":"Hypothesis-Generating Brief: Immune senescence — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Immune senescence 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."},{"id":"claim_2","type":"claim","text":"This paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims."},{"id":"claim_3","type":"claim","text":"The evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base."},{"id":"claim_4","type":"claim","text":"Positive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_5","type":"claim","text":"The conclusion is that Immune senescence 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."},{"id":"claim_6","type":"claim","text":"This manuscript is reported as a Evidence brief. 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-immunosenescence-v06-DAILY-2026-06-23T04-08-56Z`."},{"id":"claim_7","type":"claim","text":"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."},{"id":"claim_8","type":"claim","text":"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."},{"id":"claim_9","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, frailty, immune and inflammation, longevity, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_10","type":"claim","text":"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."},{"id":"claim_11","type":"claim","text":"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."},{"id":"claim_12","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_13","type":"claim","text":"| Contextual Adjacent Evidence | n=18; claims=286 | no extracted directional signal in 18/18 sources | 16 indirect; 2 review | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_15","type":"claim","text":"18 included sources were assigned to this outcome class. Directional coding: null=18. Directness coding: indirect=16, review=2."},{"id":"claim_16","type":"claim","text":"15 included sources were assigned to this outcome class. Directional coding: null=11, positive=1, unclear=3. Directness coding: direct=1, indirect=12, mechanistic=2."},{"id":"claim_17","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3."},{"id":"claim_18","type":"claim","text":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim."},{"id":"claim_19","type":"claim","text":"4 included sources were assigned to this outcome class. Directional coding: null=3, unclear=1. Directness coding: indirect=4."},{"id":"claim_20","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2."},{"id":"claim_21","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: direct=1, indirect=1."},{"id":"claim_22","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1."},{"id":"claim_23","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_24","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_25","type":"claim","text":"The corpus contains no long-term, hard-outcome randomized trial in non-diabetic older adults, and the absence of such evidence is a primary boundary on every cross-domain inference. Ioannidis 2005 underscores the risk that surrogate-endpoint RCTs in this corpus (e. For example, Rastgoo 2025's senescent-cell and SA-β-gal readouts) may not translate to clinical benefit, and that caveat applies to most of the headline conclusions."},{"id":"claim_26","type":"claim","text":"Several clinically prominent outcomes are touched by only a single source, so any conclusion that names those outcomes cannot be replicated inside the corpus. The lymphocyte-to-monocyte ratio / HFpEF longevity signal rests on Cai 2026 alone; the BC02-adjuvanted VZV-gE vaccine claim of overcoming age-related immune limitation rests on Li 2026 alone; the senolytic Agrimonia pilosa pilot in middle-aged humans rests on Shimizu 2025 alone; and the centenarian immune-profiling data rest on Anaya 2026. When a single observational cohort or preclinical study is the entire evidence base for a claim, the point estimate carries an unreplicated, design-specific uncertainty, and the synthesis cannot adjudicate between chance, confounding, and a true effect. The -type null vs positive tension on the immune outcome class (Lee 2025 positive vs. Khoury 2025 / Cevirgel 2025 / Coelho 2025 / Fragkou 2026 / Anaya 2026 null) compounds this risk, because there is no within-corpus independent dataset that resolves which direction generalizes."},{"id":"claim_27","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; external validity is bounded by the populations the trials and cohorts actually enrolled. Geographically, the corpus is concentrated in Chinese (Xiao 2023, Chen 2026, Li 2026, Li 2026b, Zhong 2025, Zhang 2026, Zhang 2024, He 2025, Reina-Alfonso 2026), Brazilian (Ventura 2025, Coelho 2025, Dema 2025, Francavilla 2025), and Bulgarian (Nikolova 2025) cohorts, with single-country representation from Colombia (Anaya 2026) and Italy (Valentino 2024, Aitella 2025, Aitella 2026)."},{"id":"claim_28","type":"claim","text":"Several clinically actionable claims are supported only by mechanistic or preclinical evidence, with no within-corpus human-RCT bridge. Lee 2025 reports a positive in-vitro T-cell mitochondrial effect, but is not an in-human trial of clinical benefit. Without a within-corpus human RCT that tests a mechanistically nominated intervention on a hard endpoint, the immunosenescence anti-aging case as currently constituted remains incomplete, and the boundary conditions for translation — age stratum, comorbidity profile, baseline immune fitness — are not established by the available evidence."},{"id":"claim_29","type":"claim","text":"For Immune senescence, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_30","type":"claim","text":"This synthesis maps 46 included sources on Immunosenescence across 8 outcome classes and 96 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."},{"id":"source_1","type":"source","study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","year":2023,"doi":"10.1186/s12979-023-00364-6","url":"https://doi.org/10.1186/s12979-023-00364-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Xiao 2023","excerpt":"BACKGROUND: Older adults are more vulnerable to seasonal influenza than younger adults. The immune responses of older persons to the influenza vaccine are usually poorer than those of young individuals, which is hypothesized due to immunosenescence. We conducted a study to evaluate the immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4) in a total of 167 young (< 65 years, n = 79) and older (≥ 65 years, n = 88) adults from October 2021 to March 2022 in Tianjin, China. A single dose was administered to all participants. Blood samples were collected and strain-specific hemagglutination inhibition (HAI) antibody titers were measured before and 21 to 28 days after vaccination. Safety information was also collected for 28 days and 6 months after vaccination. Differences in immunogenicity and safety were compared between young and old age groups, and multivariate logistic regression was used to estimate the effect of age and other factors on HAI antibody responses. RESULTS: Overall, geometric mean titers (GMTs) against all four vaccine strains in older adults were lower than those in the young, whereas the seroconversion rates (SCRs) were similar."},{"id":"source_2","type":"source","study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway","year":2026,"doi":"10.1186/s12979-026-00560-0","url":"https://doi.org/10.1186/s12979-026-00560-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism. METHODS: Nineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy."},{"id":"source_3","type":"source","study":"BC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models","year":2026,"doi":"10.1080/21645515.2026.2617728","url":"https://doi.org/10.1080/21645515.2026.2617728","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026","excerpt":"After infection with the varicella-zoster virus (VZV), the virus becomes latent in the sensory ganglia. Immune senescence may lead to its reactivation, resulting in herpes zoster (HZ). The limited immunogenicity of current vaccines in elderly populations remains a significant challenge for prevention and control. This study investigated the immune-enhancing effects of the novel compound adjuvant BC02 on a recombinant VZV glycoprotein E (gE) subunit vaccine in a serum-positive elderly mouse model. A seropositive state was simulated through pre-immunization with the Oka strain of VZV, and the impacts of vaccines with various adjuvant formulations on humoral and cellular immunity in aged mice were systematically compared. Results demonstrated that the number of gE-specific IFN-γ- and IL-2-secreting cells induced by the BC02-adjuvanted vaccine (gE+BC02-1) increased 11.8- and 5.7-fold compared to the single-adjuvant group, significantly enhancing the multifunctionality of CD4+ T cells. The neutralizing antibody titer reached 1:122, comparable to that of the commercial vaccine Shingrix®, while the ratio of memory T/B cells was markedly higher than in the control group."},{"id":"source_4","type":"source","study":"Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity","year":2025,"doi":"10.1016/j.xcrm.2025.102484","url":"https://doi.org/10.1016/j.xcrm.2025.102484","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025","excerpt":"The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67 + immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3 + immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals."},{"id":"source_5","type":"source","study":"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors","year":2026,"doi":"10.3390/diseases14010026","url":"https://doi.org/10.3390/diseases14010026","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lupoae 2026","excerpt":"BACKGROUND: Herpes zoster (HZ) represents a substantial public health concern among aging populations, yet regional variability in clinical patterns and risk determinants remains insufficiently documented. In southeastern Romania, epidemiological data are limited, and the combined influence of demographic, behavioral, and metabolic factors on disease severity has not been systematically evaluated. METHODS: We performed a retrospective observational study including 100 consecutive patients diagnosed with HZ between 2019 and 2023 in a dermatology department in southeastern Romania. Demographic characteristics, lifestyle behaviors, anthropometric status, clinical manifestations, and outcomes were extracted from medical records. Associations between categorical variables were assessed using Chi-square tests and Cramer's V, while interaction patterns were explored through log-linear modeling. Heatmaps were generated in Python (version 3.10) using the Matplotlib library (version 3.7.1) to visualize distribution patterns and subgroup relationships."},{"id":"source_6","type":"source","study":"Biological age and immunosenescence in Colombian centenarians","year":2026,"doi":"10.1038/s41514-026-00340-6","url":"https://doi.org/10.1038/s41514-026-00340-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Anaya 2026","excerpt":"Biological aging and immunosenescence are central to longevity, yet their interplay in centenarians remains unclear. We conducted a cross-sectional study in 160 Colombian centenarians to examine associations between biological age (PhenoAge), immunosenescence and age-related clinical variables. Cytokine profiling (n = 114) and lymphocyte immunophenotyping (n = 42) were assessed. It was observed that better QoL and well-being were significantly associated with lower biological age, while depressive symptoms, prior tobacco use, elevated levels of RANTES and G-CSF as well as a distinct CD8+ T cell phenotype including greater CD27- CD28+ central memory, effector memory, and KLRG1- CD57+ terminally differentiated effector memory T cells (TEMRA), and fewer KLRG1+ CD57+ TEMRA cells were linked to higher biological age. Centenarians were classified into three categories: vigorous (10%), resilient (46.25%), and vulnerable (43.75%). Cytokine levels were similar across the groups. These findings challenge the notion of immunosenescence in centenarians and highlight the value of translational research in geroscience."},{"id":"source_7","type":"source","study":"Immunosenescence Profile Is Associated With Increased Susceptibility to Severe COVID ‐19","year":2025,"doi":"10.1111/acel.70077","url":"https://doi.org/10.1111/acel.70077","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ventura 2025","excerpt":"In this study, we tested the hypothesis that the immunosenescence profile could account for the disproportional susceptibility of the elderly to severe forms of COVID-19. The immunological profiles of volunteers residing in endemic and non-endemic areas for chronic infectious diseases were analyzed at the early stage of SARS-CoV-2 infection. A unique signature of inflammatory plasma mediators was identified in COVID-19 volunteers when compared to individuals with other flu-like syndromes. COVID-19 severity correlated with high levels of inflammatory mediators; among them, CXCL9, a serum marker of aging. Patients who progressed to hospitalization displayed high frequencies of CD8 + and CD4 + T cells expressing exhaustion and senescence markers and showed reduced and more mature B cell repertoires, which are typical of senescence. They also had an acceleration of epigenetic age measured by DNA methylation. Therefore, severe COVID-19 correlated with phenotypic, functional, and epigenetic features of accelerated immunosenescence at the onset of infection."},{"id":"source_8","type":"source","study":"Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging","year":2024,"doi":"10.1002/agm2.12342","url":"https://doi.org/10.1002/agm2.12342","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Tizazu 2024","excerpt":"Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored."},{"id":"source_9","type":"source","study":"The impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells","year":2026,"doi":"10.1007/s11102-025-01632-y","url":"https://doi.org/10.1007/s11102-025-01632-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Bashir 2026","excerpt":"PURPOSE: Immunosenescence is a gradual decline in immune function, leading to increased susceptibility to infections and autoimmune conditions. Growth hormone (GH) has been shown to have an effect on both immune function and aging. In fact, the absence of GH-induced intracellular signaling can slow the aging process, as demonstrated by the longest-lived laboratory mouse (GH receptor gene disrupted or GHR-/- mice). Because GH receptors (GHR) are expressed in B and T cells, and these cells undergo age-related changes that impact immune function, we hypothesized that decreased GH action protects from immunosenescence. To validate this hypothesis, this study aimed to characterize differences in B cell and T cell populations within the lymphoid organs of aged female GHR-/- mice (24 months of age) compared to wild-type controls. METHODS: B and T cell populations in mouse blood, spleen, thymus, and bone marrow (BM) were analyzed by multicolor flow cytometry."},{"id":"source_10","type":"source","study":"Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study","year":2025,"doi":"10.3390/nu17040667","url":"https://doi.org/10.3390/nu17040667","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Shimizu 2025","excerpt":"OBJECTIVES: To assess the effects of agrimol-containing Agrimonia pilosa Ledeb. extract (APE) for senescent immune cell removal in middle-aged Japanese adults with immunosenescence. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, parallel-group study was conducted in Japan between June 2023 and April 2024. PARTICIPANTS: 110 individuals aged 40-59, selected based on CD8+ T cells with highly-expressing-senescence-associated-β-galactosidase (SA-βGal). INTERVENTION: Participants were randomly assigned to receive 50 mg APE containing 0.2 mg of agrimols or a placebo for eight consecutive weeks. MEASUREMENTS: The primary endpoint was the change in the proportion of CD8+ T cells with high SA-βGal expression at 8 weeks of intake from the baseline. The secondary endpoints included the proportion of CD4+ T cells with high SA-βGal expression, CD4+ and CD8+ T cell subsets, and the ratio of various immune cells. RESULTS: Of the 635 subjects screened, 110 with immunosenescence were included in this study. In total, 55 participants in the placebo group and 53 in the APE group completed the intervention."},{"id":"source_11","type":"source","study":"CD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults","year":2025,"doi":"10.1186/s12979-025-00504-0","url":"https://doi.org/10.1186/s12979-025-00504-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Cevirgel 2025","excerpt":"BACKGROUND: The T cell compartment undergoes significant age-related changes, contributing to the decline of the adaptive immune system and increasing the risk of suboptimal antibody responses to vaccines in older adults. To better understand the association between T cell phenotypes and vaccine responsiveness, we conducted an in-depth analysis of CD4+, CD8+, and γδ + T cells on VITAL cohort participants who are low or high responders to multiple vaccines (influenza, pneumococcal, and SARS-CoV-2). RESULTS: Using spectral cytometry and FlowSOM, we identified detailed phenotypes of naïve, regulatory, and terminally differentiated T cells. We observed that the percentages of CD31 + naïve CD4+, CD31 + naïve CD8+, and CD38 + naïve CD8 + T cells were significantly lower in low vaccine responders. Notably, CD31 + naïve T cell subsets showed a stronger correlation with immune entropy, a measure of cumulative immune system perturbations, than with age itself. CONCLUSIONS: These findings suggest that subsets of naïve cells could be associated with weak vaccine responsiveness and immunosenescence."},{"id":"source_12","type":"source","study":"Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial","year":2025,"doi":"10.3389/fimmu.2025.1570441","url":"https://doi.org/10.3389/fimmu.2025.1570441","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Rastgoo 2025","excerpt":"BACKGROUND: Immunosenescence is an important factor in the impaired immune response in older adults and plays a significant role in the development of biological aging. Targeting immunosenescence could present a novel pharmacological approach to mitigating aging and age-related diseases. We aimed to investigate the effect of N-acetylcysteine (NAC) and vitamin D (Vit-D) on the senescence of peripheral blood mononuclear cells (PBMCs). METHOD: This randomized clinical trial was conducted on older adults with Vit-D deficiency. Eligible participants were randomly assigned to one of four groups to receive either (A) 1000 IU of Vit-D daily (D1) (B), 1000 IU of Vit-D plus 600 mg of NAC daily (D1N) (C), 5000 IU of Vit-D daily (D5), or (D) 5000 IU of Vit-D plus 600 mg of NAC daily (D5N) for 8 weeks. Senescence-associated beta-galactosidase (SA-β-gal) staining, expression of senescence-related genes, and serum inflammatory factors were measured at baseline and after 8 weeks."},{"id":"source_13","type":"source","study":"Age-related changes in circulating immune factors reveal biomarkers of immunosenescence","year":2026,"doi":"10.3389/fmed.2026.1729112","url":"https://doi.org/10.3389/fmed.2026.1729112","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zhang 2026","excerpt":"BACKGROUND: Immunosenescence, characterized by the decline and restructuring of immune system components with age, affects both innate and adaptive immunity. The predictive value of soluble factors in immunosenescence remains unclear. OBJECTIVE: To investigate the predictive value of sCD28 (Soluble CD28), sCD40L (CD40 Ligand), sCD25 (Soluble CD25), IL-6 (Interleukin-6) and sPD-1 (Soluble Programmed Cell Death Protein 1) for immunosenescence in a general population, to evaluate their diagnostic potential using ROC curve analysis, including both individual and combined detection efficacy. METHODS: We analyzed 131 healthy individuals across four age groups: young (≤44 years, n = 34), middle-aged (45-60 years, n = 31), young-old (61-70 years, n = 38), and older (>70 years, n = 28). Serum levels of sCD28, sCD40L, sCD25, IL-6, and sPD-1 were measured using ELISA. Baseline characteristics and correlations were analyzed using SPSS 25.0. ROC analysis was performed to assess diagnostic potential, with a focus on both individual markers and the combined detection of sPD-1, IL-6, and sCD28. RESULTS: sPD-1, IL-6, and sCD28 levels positively correlated with age ( p < 0.05)."},{"id":"source_14","type":"source","study":"Living in endemic area for infectious diseases is associated to differences in immunosenescence and inflammatory signatures","year":2025,"doi":"10.3389/fimmu.2025.1547854","url":"https://doi.org/10.3389/fimmu.2025.1547854","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Coelho 2025","excerpt":"Research on aged individuals from developed countries show that lifestyle factors such as diet, physical activity, stress, smoking, and sleep quality impact aging. However, other relevant factors may influence aging in less-studied populations, such as Brazilian cohorts. This study aimed to analyze immunosenescence profile of individuals living in an endemic area for several infectious diseases in Brazil. We showed that these individuals exhibited accelerated epigenetic aging and increased production of IL-12p70, IL-17A, and IL-9. Production of inflammatory mediators IL-12p70, IL-6, IL-1β, IL-2, and IL-1ra in individuals with flu-like symptoms and those with COVID-19 was higher among residents in endemic areas than in residents from a control non-endemic area. Furthermore, residents of the endemic area had a more prominent inflammatory profile during viral infection and a different pattern of plasma mediators when compared to residents of a non-endemic area. Our data suggests that these two cohorts had specific immune signatures regardless of the presence or the type of infection at study."},{"id":"source_15","type":"source","study":"Differential associations of anti-cytomegalovirus antibodies and soluble CD14 levels with immunosenescence in people living with HIV on long term antiretroviral therapy","year":2024,"doi":"10.1186/s12979-024-00491-8","url":"https://doi.org/10.1186/s12979-024-00491-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Shete 2024","excerpt":"BACKGROUND: People living with HIV (PLHIV) demonstrate accelerated aging and immunosenescence in spite of immune-restoration following long-term antiretroviral treatment (ART). Low level inflammation leading to inflammaging plays an important role in mediating premature immunosenescence. Ongoing viral replication, antiretrovirals and subclinical infections with the common viruses like Cytomegalovirus (CMV) are known to induce inflammaging. However such data is scarce in India where persistent low level inflammation is common in general population due to various subclinical infections. Hence we conducted a study to determine the extent of immunosenescence in asymptomatic PLHIV on long term ART in comparison with their age-matched controls. RESULTS: The study was conducted in asymptomatic virally suppressed PLHIV on ART for more than 5 years [n = 70, M: F = 36:34] and HIV uninfected controls [n = 68, M: F = 31:37] belonging to the age-group of 40-55 years. Blood samples were collected for assessing levels of immunosenescence markers on CD4 T cells by flow cytometry and anti-CMV antibodies as well as soluble CD14 (sCD14) levels by ELISA."},{"id":"source_16","type":"source","study":"Immunosenescence and cytomegalovirus-associated immune signatures on severe acute respiratory syndrome coronavirus 2 booster responses","year":2026,"doi":"10.1093/gerona/glag095","url":"https://doi.org/10.1093/gerona/glag095","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Reina-Alfonso 2026","excerpt":"Aging remodels antiviral immunity, yet its influence on responses to repeated mRNA vaccination is not fully defined. We evaluated humoral and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific T-cell responses in 41 adults-stratified by age (<50 vs. ≥60 years), sex, prior SARS-CoV-2 infection, and cytomegalovirus (CMV) serostatus-before and after a fourth dose of the bivalent BNT162b2 vaccine. Anti-RBD IgG titers increased in nearly all participants, with no measurable impact of age, sex, infection history, or CMV status, and baseline titers predicted post-booster antibody levels. In contrast, cellular immunity showed clear heterogeneity across aging-related variables. Although the booster enhanced IFN-γ production and reduced TNF-α-associated inflammatory activity at the cohort level, older adults and males exhibited significantly lower post-boost frequencies of IFN-γ-producing CD4+ T cells. Prior SARS-CoV-2 infection was associated with attenuated CD4+ recall responses, whereas infection-naïve and female participants showed the strongest functional gains. Immunosenescence markers were associated with reduced cellular responsiveness."},{"id":"source_17","type":"source","study":"MAM‐STAT3‐Driven Mitochondrial Ca +2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients","year":2024,"doi":"10.1002/advs.202407398","url":"https://doi.org/10.1002/advs.202407398","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Padhiar 2024","excerpt":"Individuals with homozygous laminA/C p.R527C mutations manifest a severe form of Mandibuloacral dysplasia-(MAD) and exhibit overlapping progeroid symptoms, for which the underlying molecular pathology remains unknown. Herein, it is shown that MAD patients achieved inflammaging with different pro-inflammatory cytokines compared to progeria-(HGPS) patient. Characterization of MAD iPSC-derived Mesenchymal stem cells (MAD-iMSC) uncovers deregulated mitochondrial Ca +2 as the primary cause of inflammaging, mediated through inflammasome formation rather than the cGAS-STING pathway. Moreover, MAD-iMSCs extracellular vesicles (EVs) can also upregulate mitochondrial Ca +2 in healthy cells. This deregulated Ca +2 homeostasis is indirectly mediated by mitochondrial calcium mediator, signal transducer, and activator of transcription-3 (STAT3), situated on the mitochondrial associated membrane (MAM). Inflammaging is mitigated by various FDA-approved MAM-STAT3 upstream inhibitors, such as (Tocilizumab) or by correcting R527C mutation with CRISPR/CAS9."},{"id":"source_18","type":"source","study":"Enhancing flu vaccine responses in older adults: preliminary insights from the ISOLDA study on immunosenescence and antioxidant and anti-inflammatory approaches","year":2025,"doi":"10.1186/s12979-025-00506-y","url":"https://doi.org/10.1186/s12979-025-00506-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Aiello 2025","excerpt":"Aging is frequently characterized by an inadequate primary vaccine response, likely due to immunosenescence and inflamm-aging, a low-level, chronic inflammatory state. Both aspects increase the susceptibility of older adults to viral and bacterial infections, resulting in a higher frequency and severity of infectious diseases. In this preliminary study, a cohort of 52 individuals was recruited and divided into two groups: young (age range 21-35) and older adults (> 60 years old). Peripheral blood mononuclear cells (PBMCs) were collected before (time 0, T0) and after (time 1, T1) the immunization with a tetravalent influenza vaccine. Then, T cell immunophenotyping analysis was conducted to investigate how aging and influenza vaccination influence T cell responses. Additionally, the anti-inflammatory and antioxidant effects of oleuropein (OLE), a secoiridoid extracted from extra virgin olive oil, alone or in combination with BIRB 796, a potent inhibitor of p38 MAPK, were explored to enhancing the impact of influenza virus on T cell activation, aiming to identify potential alternatives or complementary strategies to improve traditional flu-vaccine formulations."},{"id":"source_19","type":"source","study":"Lymphocyte-To-Monocyte Ratio is Partially Mediated in Age-Related Cardiovascular Mortality in HFpEF: Immunosenescence, Inflamm-Aging, and Longevity","year":2026,"doi":"10.31083/RCM45403","url":"https://doi.org/10.31083/RCM45403","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Cai 2026","excerpt":"BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is recognized as an aging-related clinical syndrome with high mortality, from which systemic inflammation could represent a primary culprit. Thus, this study aimed to evaluate the association between the lymphocyte-to-monocyte ratio (LMR), a systemic inflammation marker, and clinical outcomes, and to explore the mediation effect of the LMR in the relationship between age and mortality for HFpEF. METHODS: Participants in the Real-world Data of Cardiometabolic ProtEcTion trial (RED-CARPET) trial were categorized into tertiles based on the recorded LMRs. We employed Cox regression analyses to explore the relationship between the LMR and mortality, as well as mediation analyses to determine whether the LMR serves as a mediator between aging and mortality. RESULTS: A total of 1274 inpatients with HFpEF were enrolled between May 2015 and December 2023. After a median follow-up period of 4.9 years, there were 166 recorded deaths, of which 82 were due to cardiovascular causes. In the third model, each one-unit increase in standard deviation (SD) for age was correlated with a 1."},{"id":"source_20","type":"source","study":"Aging, inflammaging and immunosenescence as risk factors of severe COVID-19","year":2022,"doi":"10.1186/s12979-022-00309-5","url":"https://doi.org/10.1186/s12979-022-00309-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Tizazu 2022","excerpt":"Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by having a heterogeneous disease course, ranging from asymptomatic and mild symptoms to more severe and critical cases. In most cases the severity of COVID-19 is related to host factors, especially deregulation of the immune response in patients. Even if COVID-19 indiscriminately affects individuals of different age group, ethnicity and economic status; most severe cases and disproportional mortality occur in elderly individuals. This point out that aging is one risk factor for unfavourable clinical outcomes among COVID-19 patients. The biology of aging is a complex process; Aging can alter the structure and function of cells, tissues, and organs resulting in impaired response to stress. Alongside with other systems, the immune system is also affected with the aging process. Immunosenescence is an age associated change in the immune system that affects the overall response to immunological challenges in the elderly."},{"id":"source_21","type":"source","study":"Immunosenescence and its impact on ischemic stroke risk and outcomes in older adults: a systematic review","year":2026,"doi":"10.3389/fnagi.2026.1776458","url":"https://doi.org/10.3389/fnagi.2026.1776458","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Seah 2026","excerpt":"BACKGROUND: Age is a major risk factor for ischemic stroke (IS), with immunosenescence-age-related immune system dysfunction - contributing to worse outcomes. Immunosenescence impairs immune responses, heightens inflammation, and increases susceptibility to infections, all of which affect stroke prognosis. This review investigates the association between immunosenescence, immune cell dysfunction, and IS risk and outcomes. METHODS: A systematic review was conducted to identify cohort studies examining immunosenescence in IS patients aged 60 and above. Databases PubMed and Embase were searched up to 10 August 2024. Studies were included if they analyzed immune cell markers or inflammatory markers in relation to IS risk or outcomes. A total of 11 studies met the inclusion criteria. RESULTS: Elevated inflammatory markers such as interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), and Th17 cells were significantly associated with poorer stroke outcomes. Studies indicated an imbalance between pro-inflammatory Th17 cells and regulatory T cells (Treg) post-stroke."},{"id":"source_22","type":"source","study":"A randomized controlled trial to assess the efficacy of standardized tai chi in prefrail older adults with immunosenescence: design and protocol","year":2025,"doi":"10.1186/s12906-024-04732-7","url":"https://doi.org/10.1186/s12906-024-04732-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zhong 2025","excerpt":"BACKGROUND: Frailty is a common geriatric syndrome worldwide, and its early identification and intervention have important clinical significance. Resistance training has been recommended as an efficient means to combat loss of muscle strength and mass; however, it is often not a prioritized option for older adults. Tai chi is a well-known traditional Chinese exercise that has a beneficial impact on physical performance, balance ability, metabolism, and immune function. AIMS: With the newly emerged concept of muscle-immune homeostasis, this study focused on determining the efficacy of tai chi prefrail older adults who develop immunosenescence. Furthermore, the proper timing of the exercise regimen for maximizing the therapeutic effect of tai chi has also been explored. METHODS: This 12-week, multicenter, randomized controlled trial (RCT) was conducted with participants between 60 and 75 years of age. A total of 144 prefrail participants were included in this study and were randomized (1:1:1:1) to four groups: (1) a control group with only health education, (2) a morning tai chi group, (3) a morning resistance training group, and (4) an afternoon tai chi group."},{"id":"source_23","type":"source","study":"Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence","year":2025,"doi":"10.1111/acel.14491","url":"https://doi.org/10.1111/acel.14491","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Dema 2025","excerpt":"The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system."},{"id":"source_24","type":"source","study":"Deciphering Immunosenescence From Child to Frailty: Transcriptional Changes, Inflammation Dynamics, and Adaptive Immune Alterations","year":2025,"doi":"10.1111/acel.70082","url":"https://doi.org/10.1111/acel.70082","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lai 2025","excerpt":"Aging induces significant alterations in the immune system, with immunosenescence contributing to age-related diseases. Peripheral blood mononuclear cells (PBMCs) offer a convenient and comprehensive snapshot of the body's immune status. In this study, we performed an integrated analysis of PBMCs using both bulk-cell and single-cell RNA-seq data, spanning from children to frail elderlies, to investigate age-related changes. We observed dynamic changes in the PBMC transcriptome during healthy aging, including dramatic shifts in inflammation, myeloid cells, and lymphocyte features during early life, followed by relative stability in later stages. Conversely, frail elderly individuals exhibited notable disruptions in peripheral immune cells, including an increased senescent phenotype in monocytes with elevated inflammatory cytokine expression, heightened effector activation in regulatory T cells, and functional impairment of cytotoxic lymphocytes. Overall, this study provides valuable insights into the complex dynamics of immunosenescence, elucidating the mechanisms driving abnormal inflammation and immunosuppression in frailty."},{"id":"source_25","type":"source","study":"The pathophysiological mechanisms of immunosenescence in coronary artery disease","year":2025,"doi":"10.3389/fcell.2025.1686947","url":"https://doi.org/10.3389/fcell.2025.1686947","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Bie 2025","excerpt":"Coronary artery disease (CAD) is the most common coronary heart disease, characterized by the accumulation of atherosclerotic plaques in the coronary arteries, which supply oxygen and nutrients to the heart. The National Health and Nutrition Examination Survey (NHANES) reported that between 2011 and 2014, the prevalence of coronary artery disease was higher in men (30.6%) than in women (21.7%) aged ≥80 years. In the ARIC (Atherosclerosis Risk in Communities) study, the incidence of myocardial infarction (MI) was higher in black individuals compared to white individuals among those aged 65-84 years. Immunosenescence plays a pivotal role in its onset and progression. Immunosenescence is a complex process involving organ remodeling and cellular regulation, leading to a decline in immune function and reduced responses to infection and vaccination in older adults. By driving dysfunction in multiple immune cell populations-including T cells, B cells, and macrophages-immunosenescence promotes chronic inflammation, vascular injury, and the advancement of atherosclerotic plaques."},{"id":"source_26","type":"source","study":"Immunosenescence is a therapeutic target for frailty in older adults: a narrative review","year":2022,"doi":"10.21037/atm-22-4405","url":"https://doi.org/10.21037/atm-22-4405","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Jia 2022","excerpt":"BACKGROUND AND OBJECTIVE: Aging refers to a progressive decrease in functional performance, leading to increased mortality risk. At present, life expectancy is increasing worldwide and is expected to exceed 80 years by 2040. However, this increase in life expectancy also indicates a rise in the incidence and prevalence of diseases, such as cardiovascular, neurological, musculoskeletal, and oncological diseases, which are associated with aging. The exact underlying mechanisms of aging remain unknown, and whether it is a programmed process or the consequence of an accumulation of stress events remains unclear. Thus, more scientific research is needed to improve the management of complex and frail patients. METHODS: Several databases were searched with the following key words: immunosenescence, inflamm-aging, frailty, sarcopenia and skeletal muscle, etc. KEY CONTENT AND FINDINGS: Skeletal muscle is the core phenotype of frailty and sarcopenia. Immune aging and skeletal muscle decline interplay with each other and form a vicious circle. Maintaining muscle health is beneficial for immune function and delays the onset of frailty."},{"id":"source_27","type":"source","study":"Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways","year":2026,"doi":"10.1111/acel.70548","url":"https://doi.org/10.1111/acel.70548","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2026b","excerpt":"Aging significantly impairs vaccine efficacy in older adults, driven by immunosenescence, inflammaging, and disruptions in the gut microbiota-mTOR-immune axis. This review synthesizes current evidence on how aging alters vaccine-induced immune responses through the interplay of gut microbiota dysbiosis and dysregulated mTOR signaling. Age-related microbial diversity declines and reduced short-chain fatty acid (SCFA) production exacerbate inflammation, while heightened mTOR activity suppresses autophagy, promotes pro-inflammatory states, and impairs T/B cell function, collectively diminishing antibody production and immune memory formation. We highlight the bidirectional interaction between SCFAs and mTOR, where SCFAs mitigate mTOR overactivation to enhance immune regulation, and mTOR dysregulation further aggravates microbial dysbiosis, forming a vicious cycle. Critically, this review systematically stratifies the evidence, distinguishing preclinical mechanistic insights from correlative human data. Animal and human studies suggest that targeting this axis-via mTOR inhibitors, probiotics, or dietary interventions-holds promise for improving vaccine responses in the elderly."},{"id":"source_28","type":"source","study":"Aging-associated transcriptional programs in T cells signify constituents of TGF-β signaling for immunosenescence","year":2025,"doi":"10.1186/s12915-025-02484-5","url":"https://doi.org/10.1186/s12915-025-02484-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"He 2025","excerpt":"BACKGROUND: Immunosenescence, particularly the altered ratio of naïve and memory T cells, contributes to a diminished immune reserve and impaired adaptive immunity in aging and frail populations. The role of TGF-β signaling pathway-a critical hallmark of organismal senescence and T-cell exhaustion-in terminally differentiated effector memory T (Temra) cells remains elusive. We devised single-cell and bulk-cell RNA sequencing (RNA-seq) datasets to identify age-group-specific transcriptional regulatory networks in T cells and elucidate the roles of TGF-β signaling constituents associated with immunosenescence in Temra. RESULTS: Analysis of scRNA-seq data from peripheral T cells across healthy human age groups revealed young-specific regulons controlled by FOXP1, TCF7, LEF1, and IKZF1 and old-specific regulons governed by EOMES, TBX21, RUNX3, and NFATC2. Transcription factor (TF)-binding-motif enrichment analysis implicated TGF-β signaling pathway components ZEB2 and TGFBR3 as pivotal target genes coregulated by multiple TFs, potentially facilitating T-cell terminal differentiation and exhaustion."},{"id":"source_29","type":"source","study":"Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma","year":2025,"doi":"10.3390/ijms26031258","url":"https://doi.org/10.3390/ijms26031258","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Khoury 2025","excerpt":"Localized scleroderma (LS) is an autoimmune, fibrotic skin disease that is thought to be triggered by environmental factors. Recent evidence from systemic autoimmune diseases proposed that the induction of immunosenescence may link environmental triggers with autoimmunity development. We aimed to explore the inflammatory signature in juvenile LS and investigate the presence of DNA instability and immunosenescence using publicly available transcriptomic data. High-throughput RNA sequencing data from 28 juvenile LS and 10 healthy controls were analyzed. Unsupervised clustering, pathway analyses, cell-type enrichment, fusion analyses, and immunosenescence gene set enrichment were performed. IFN and Type 1/2/3 pathways were upregulated in clinically active and histologically inflammatory LS. Type 2 inflammatory signature in both inflammatory and fibrotic LS was demonstrated by enriched genes, pathways, and deconvolution analyses (eosinophils). Features of genotoxic stress signals manifesting as DNA instability genes, pathways, and fusion events as well as mitochondrial dysfunction were demonstrated for the first time in LS. Features of immunosenescence (e.g."},{"id":"source_30","type":"source","study":"Gene Expression Changes as Biomarkers of Immunosenescence in Bulgarian Individuals of Active Age","year":2025,"doi":"10.3390/biomedicines13030721","url":"https://doi.org/10.3390/biomedicines13030721","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Nikolova 2025","excerpt":"Background/Objectives: Immunosenescence implies innate and adaptive immunity dysfunction, which naturally occurs with aging. It is a complex multifactorial process which can be triggered by either genetic changes, immune changes or both. Numerous research studies have shown that the process of senescence goes alongside chronic immune activation. The purpose of this study is to analyze the changes in the expression of genes associated with adaptive and innate immune responses in order to identify reliable biomarkers for immune aging. Methods : For that aim, 55 clinically healthy individuals of active age (21-65 years) were distributed based on immunophenotyping in two groups, with and without signs of premature senescence. A gene expression analysis was subsequently made on those two groups, and the differentially expressed genes were presented and interpreted. Results : Altogether, forty-eight (48) genes exhibited differential expression between the two groups, most of which showed up-regulation (45) (fold change more than 2), and only three were down-regulated (fold change less than -2). The highest positive fold change showed IL-1β (10.76), BCL6 (13.25) and CCL4 (15."},{"id":"source_31","type":"source","study":"Age Versus Immunity: Dietary Influences on Immunosenescence","year":2025,"doi":"10.3390/jcm14238313","url":"https://doi.org/10.3390/jcm14238313","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Danilowska 2025","excerpt":"Background : Immunosenescence, or the age-related weakening of the immune system, leads to greater susceptibility to chronic diseases, infections, and metabolic disorders. This process involves changes in the number and function of lymphocytes, increased levels of inflammatory markers, and modifications to the gut microbiome. In recent years, increasing importance has been placed on diet-both functional, rich in bioactive ingredients, and conventional, often pesticide-laden-as a factor modulating immune system aging. Methods : This paper provides a literature review on the effects of dietary components on immunosenescence. Results from 2010 to 2025 and from clinical and experimental studies on substances such as curcumin, butyrate, vitamin D3, omega-3 fatty acids, and conventional products containing pesticides were analyzed. Their impact on the microbiome, intestinal barrier integrity, inflammatory biomarkers, and the overall immune response was considered. Results : Numerous beneficial effects of functional foods were identified. Curcumin increases microbiota diversity and lowers C-Reactive Protein (CRP) and Tumor Necrosis Factor α (TNF-α) levels."},{"id":"source_32","type":"source","study":"HIV infection and immunosenescence: challenges and intervention strategies","year":2025,"doi":"10.1186/s12916-025-04545-6","url":"https://doi.org/10.1186/s12916-025-04545-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jin 2025b","excerpt":"BACKGROUND: Antiretroviral therapy has extended the life expectancy of people with HIV (PWH), leading to a rapidly expanding ageing population of PWH worldwide, including in low- and middle-income countries. The interaction between ageing and chronic HIV infection is closely associated with immunosenescence, and PWH are widely regarded as a model of accelerated immune ageing. Immunosenescence, characterized by a progressive decline in immune function and increased susceptibility to infections, contributes to a higher burden of age-related comorbidities and cancers, posing a major long-term health challenge for this population. MAIN BODY: The main focus of this review is on immunosenescence-related phenotypic and functional alterations in innate immune cells in PWH, including natural killer cells, monocytes, macrophages, and dendritic cells."},{"id":"source_33","type":"source","study":"Bridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence","year":2026,"doi":"10.3389/fimmu.2026.1792954","url":"https://doi.org/10.3389/fimmu.2026.1792954","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zaongo 2026","excerpt":"Colorectal cancer (CRC) is one of the most commonly occurring malignancies worldwide, with incidence and mortality rising sharply in older adults. While aging is increasingly recognized as a key risk factor for CRC, the fundamental immunological mechanisms which underlie this risk remain incompletely understood. Two interconnected processes, namely inflammaging and immunosenescence, appear central to this association. On the one hand, inflammaging, which is characterized by chronic low-grade inflammation in older individuals, fosters a tumor-promoting microenvironment through oxidative stress, genomic instability, and persistent cytokine activation. On the other hand, immunosenescence diminishes immune surveillance, reducing the clearance of premalignant cells and weakening responses to tumor progression and therapy. Together, these processes create an immunological framework that predisposes the aging colon to malignant transformation. This review synthesizes current knowledge of the cellular and mechanistic impacts of inflammaging and immunosenescence in CRC pathogenesis, highlighting their roles in shaping disease susceptibility in the elderly."},{"id":"source_34","type":"source","study":"Red ginseng extract enhances mitochondrial function and alleviates immunosenescence in T cells","year":2025,"doi":"10.1016/j.jgr.2025.05.004","url":"https://doi.org/10.1016/j.jgr.2025.05.004","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lee 2025","excerpt":"BACKGROUND: Mitochondrial function is essential for immune cell regulation, and its decline is linked to aging and chronic diseases. Impaired activity contributes to inflammation and reduced immunity. This study explores Red ginseng extract (RGE)'s potential in enhancing mitochondrial function and immune cell viability, offering benefits in mitigating immunosenescence. METHODS: T cells and macrophages from young (12-week-old) and aged (20-month-old) mice were treated with RGE to assess mitochondrial function and cell viability. Flow cytometry evaluated immune cell populations and cytokine expression in splenocytes, while single cell transcriptomics analyzed RGE-induced transcriptional changes in T cells and macrophages. RESULTS: RGE treatment improved mitochondrial oxygen consumption rate and glycolytic function in CD4 + and CD8 + T cells from both young and old mice, though effects were more pronounced in young cells. In aged mice, RGE administration resulted in higher proportions of naive T cells and reduced expression of senescence and exhaustion markers."},{"id":"source_35","type":"source","study":"Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors","year":2024,"doi":"10.3390/microorganisms12102052","url":"https://doi.org/10.3390/microorganisms12102052","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Theodorakis 2024","excerpt":"The process of aging leads to a progressive decline in the immune system function, known as immunosenescence, which compromises both innate and adaptive responses. This includes impairments in phagocytosis and decreased production, activation, and function of T- and B-lymphocytes, among other effects. Bacteria exploit immunosenescence by using various virulence factors to evade the host's defenses, leading to severe and often life-threatening infections. This manuscript explores the complex relationship between immunosenescence and bacterial virulence, focusing on the underlying mechanisms that increase vulnerability to bacterial infections in the elderly. Additionally, it discusses how machine learning methods can provide accurate modeling of interactions between the weakened immune system and bacterial virulence mechanisms, guiding the development of personalized interventions. The development of vaccines, novel antibiotics, and antivirulence therapies for multidrug-resistant bacteria, as well as the investigation of potential immune-boosting therapies, are promising strategies in this field."},{"id":"source_36","type":"source","study":"The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience","year":2024,"doi":"10.3389/fragi.2024.1490302","url":"https://doi.org/10.3389/fragi.2024.1490302","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wrona 2024","excerpt":"As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function."},{"id":"source_37","type":"source","study":"Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies","year":2026,"doi":"10.3390/ijms27031206","url":"https://doi.org/10.3390/ijms27031206","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Aitella 2026","excerpt":"With the global increase in population aging, allergic diseases in older adults are becoming an increasingly relevant clinical and public health challenge. Age-related molecular and cellular alterations significantly affect the pathophysiology, clinical manifestations, diagnosis, and management of major allergic diseases in the elderly. This review focuses on immunosenescence in major allergic conditions, including asthma, chronic urticaria and angioedema, dermatitis, food and drug allergies, and hymenoptera venom hypersensitivity. Particular emphasis is placed on molecular mechanisms underlying immune aging, such as inflammaging, dysregulation of innate and adaptive immune responses, epithelial barrier dysfunction, microbiota alterations, neuro-immune interactions, and age-related comorbidities. Sex-related differences in immune responses are also addressed, together with current diagnostic and therapeutic strategies, including the opportunities and limitations of biologic therapies in aging populations."},{"id":"source_38","type":"source","study":"Immunosenescence and susceptibility to respiratory viruses: a state-of-the-art review","year":2026,"doi":"10.1183/16000617.0248-2025","url":"https://doi.org/10.1183/16000617.0248-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fragkou 2026","excerpt":"The global rise in the older population poses novel challenges in healthcare systems. Ageing is associated with immunosenescence, a progressive decline and remodelling of the immune system, and with inflammageing, a chronic, low-grade inflammatory process. Both states are associated with increased susceptibility to infections and adverse outcomes, especially in the context of infections. In this review, we examine the molecular and cellular pathophysiological mechanisms of immunosenescence and inflammageing that predispose older adults to increased morbidity and mortality from respiratory viral infections. We also outline the clinical implications of the ageing immune system, along with the most up-to-date evidence on possible biomarkers, preventative measures and treatment options aimed at mitigating the effects of immunosenescence on the vulnerability of older adults in respiratory viral infections."},{"id":"source_39","type":"source","study":"Multivariate analysis of immunosenescence data in healthy humans and diverse diseases","year":2025,"doi":"10.3389/fragi.2025.1568034","url":"https://doi.org/10.3389/fragi.2025.1568034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ane-Kouri 2025","excerpt":"INTRODUCTION: Immunosenescence is a dynamic process, where both genetic and environmental factors account for the substantial inter-individual variability. This paper integrates all the data on immunosenescence markers generated in our laboratory and describes the differences and/or similarities between individuals based on their biological conditions (immunosenescence markers) and their associations with chronological age and health status. MATERIALS AND METHODS: The dataset consisted of immunological data from healthy donors, centenarians, patients diagnosed with chronic kidney disease, COVID-19 and non-small cell lung cancer (NSCLC), treatment-naïve or treated with platinum-based chemotherapy. To determine whether there are groups of immunologically different individuals despite their age or clinical condition, cluster analysis was performed. Canonical discriminant analysis was performed to determine which variables characterize each cluster. RESULTS: There are differences in the expression of immunosenescence markers between healthy subjects and patients diagnosed with different pathological conditions, regardless of their age."},{"id":"source_40","type":"source","study":"Nanoparticle-mediated delivery of herbal-derived natural products to modulate immunosenescence-induced drug resistance in cancer therapy: a comprehensive review","year":2025,"doi":"10.3389/fonc.2025.1567896","url":"https://doi.org/10.3389/fonc.2025.1567896","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Yang 2025","excerpt":"Immunosenescence, the age-associated decline of the immune system, is pivotal in fostering drug resistance within the tumor microenvironment (TME). The accumulation of senescent immune cells and the release of pro-inflammatory senescence-associated secretory phenotype (SASP) factors create a milieu that supports tumor survival and undermines therapeutic efficacy. Traditional cancer treatments often fail to address this underlying issue, leading to suboptimal outcomes. This article proposes an innovative strategy to overcome immunosenescence-induced drug resistance through the nanoparticle-mediated delivery of herbal-derived natural products (HDNPs), which possess senolytic and immunomodulatory properties capable of clearing senescent cells and rejuvenating immune function. Nanoparticle delivery systems enhance these compounds' stability, bioavailability, and targeted delivery to the TME and senescent immune cells. By harnessing the synergistic effects of HDNPs and nanotechnology, this approach offers a novel and multifaceted solution to drug resistance in cancer therapy."},{"id":"source_41","type":"source","study":"Rheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies","year":2025,"doi":"10.3390/ijms26199268","url":"https://doi.org/10.3390/ijms26199268","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Aitella 2025","excerpt":"Immunosenescence refers to the set of immunoendocrinological alterations underlying the progressive decline in innate and adaptive immune function that occurs with aging. It is closely linked to the concept of inflammaging, a state of low-grade chronic systemic inflammation that contributes to age-related diseases. In the elderly, key features of diseases such as rheumatoid arthritis, particularly in its elderly onset form, and senile osteoporosis are characterized by a decline in sex hormones and the immunoregulatory IL-2; an increase in serum autoantibodies and pro-inflammatory mediators such as TNF-α, IL-6; and upregulation of bone-related factors RANKL, DKK1, and sclerostin, including the dysregulation of the IL-33/IL-31 axis. The aim of this review is to examine the key molecular pathways of immunosenescence in osteoimmunology, as well as the potential for therapeutic modulation of inflammaging through biologic and target synthetic disease-modifying antirheumatic drugs, denosumab and romosozumab, with particular attention to their management in elderly patients."},{"id":"source_42","type":"source","study":"Insights into tumor vaccines for elderly individuals in the context of immunosenescence","year":2025,"doi":"10.3389/fimmu.2025.1660874","url":"https://doi.org/10.3389/fimmu.2025.1660874","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Li 2025","excerpt":"The global burden of cancer is increasing tremendously, particularly among individuals aged 60 years and older, and has emerged as a critical public health concern. Cancer vaccine-induced immunity can recognize and eliminate tumor cells with high specificity and low toxicity. Nevertheless, immunosenescence increases the risk and severity of cancers in elderly individuals while impairing vaccine-induced immunity. Furthermore, much oncology research has predominantly focused on adults, often neglecting the potential contributions of aging individuals to tumor progression. Elucidating the interactions between the immunosenescent microenvironment and tumorigenesis can inspire the development of more effective cancer vaccines tailored to the characteristics of elderly individuals, thereby alleviating the global cancer burden. In this review, we analyze how the immunosenescent microenvironment impacts tumor development and summarize existing strategies aimed at enhancing cancer vaccine efficacy, drawing inspiration from insights into immunosenescence. We believe that this review will inspire efforts toward creating individualized cancer vaccines for the elderly."},{"id":"source_43","type":"source","study":"Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges","year":2025,"doi":"10.1002/cmdc.202400672","url":"https://doi.org/10.1002/cmdc.202400672","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Francavilla 2025","excerpt":"Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress."},{"id":"source_44","type":"source","study":"“Immunopause” no more: exercise to counter immunosenescence in aging","year":2025,"doi":"10.1186/s12979-025-00549-1","url":"https://doi.org/10.1186/s12979-025-00549-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sun 2025","excerpt":"The global demographic shift towards an aging population has amplified the public health challenge posed by immunosenescence, a progressive remodeling of the immune system that compromises host defenses. This age-related decline is characterized by a reduction in adaptive immunity, marked by a diminished pool of naïve T-cells and an increased susceptibility to infections and poor vaccine responses. Simultaneously, it is defined by a paradoxical state of chronic low-grade inflammation, or \"inflammaging,\" which accelerates age-related pathologies. This review posits \"immunopause\" as a conceptual framework for a state of severe immune decline, a state often viewed as an inevitable consequence of aging. However, the evidence synthesized herein challenges this view by positioning physical exercise as a potent, non-pharmacological intervention capable of countering this process. The report systematically reviews the cellular, molecular, and systemic mechanisms through which exercise exerts its beneficial effects, including the rejuvenation of T-cell repertoires, the regulation of cytokine networks, and the modulation of multi-organ axes involving myokines and the gut microbiome."},{"id":"source_45","type":"source","study":"Impact and potential value of immunosenescence on solid gastrointestinal tumors","year":2024,"doi":"10.3389/fimmu.2024.1375730","url":"https://doi.org/10.3389/fimmu.2024.1375730","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zhang 2024","excerpt":"Solid gastrointestinal tumors often respond poorly to immunotherapy for the complex tumor microenvironment (TME), which is exacerbated by immune system alterations. Immunosenescence is the process of increased diversification of immune genes due to aging and other factors, leading to a decrease in the recognition function of the immune system. This process involves immune organs, immune cells, and the senescence-associated secretory phenotype (SASP). The most fundamental change is DNA damage, resulting in TME remodeling. The main manifestations are worsening inflammation, increased immunosuppressive SASP production, decreased immune cell antitumor activity, and the accumulation of tumor-associated fibroblasts and myeloid-derived suppressor cells, making antitumor therapy less effective. Senotherapy strategies to remove senescent cells and block key senescence processes can have synergistic effects with other treatments. This review focuses on immunoenescence and its impact on the solid TME. We characterize the immunosenescent TME and discuss future directions for antitumor therapies targeting senescence."},{"id":"source_46","type":"source","study":"The role of autoantibodies in bridging obesity, aging, and immunosenescence","year":2024,"doi":"10.1186/s12979-024-00489-2","url":"https://doi.org/10.1186/s12979-024-00489-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Valentino 2024","excerpt":"Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood. Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance."}],"edges":[{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_1","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_2","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_3","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_4","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_5","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_6","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_7","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_8","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_9","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_10","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_11","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_12","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_13","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_14","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_15","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_16","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_17","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_18","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_19","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_20","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_21","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_22","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_23","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_24","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_25","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_26","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_27","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_28","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_29","type":"contains_claim"},{"from":"bd88fdac-646d-49da-ad47-a3e928cc057a","to":"claim_30","type":"contains_claim"}],"screening":{"identified":46,"screened":46,"excluded":0,"included":46,"included_or_retained":46,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"46 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"bd88fdac-646d-49da-ad47-a3e928cc057a","screening":{"identified":46,"screened":46,"excluded":0,"included":46,"included_or_retained":46,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"46 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["This paper synthesizes evidence on Immune senescence across 46 accepted source papers and 750 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 41 adjacent clinical sources, and 3 mechanistic or model-system sources, with 96 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the immune and inflammation outcome class, null signals in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Immune senescence 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.","The conclusion is that Immune senescence 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.","Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","Several clinically actionable claims are supported only by mechanistic or preclinical evidence, with no within-corpus human-RCT bridge. Lee 2025 reports a positive in-vitro T-cell mitochondrial effect, but is not an in-human trial of clinical benefit. Without a within-corpus human RCT that tests a mechanistically nominated intervention on a hard endpoint, the immunosenescence anti-aging case as currently constituted remains incomplete, and the boundary conditions for translation — age stratum, comorbidity profile, baseline immune fitness — are not established by the available evidence.","For Immune senescence, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\n\"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nKaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBC02-adjuvanted varicella-zoster virus glycoprotein E subunit vaccine overcomes immunosenescence to induce robust neutralizing antibodies and multifunctional T-cell immunity in seropositive aged murine models,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPhysical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBiological age and immunosenescence in Colombian centenarians,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImmunosenescence Profile Is Associated With Increased Susceptibility to Severe COVID ‐19,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFasting and calorie restriction modulate age‐associated immunosenescence and inflammaging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Preliminary Data on the Senolytic Effects of Agrimonia pilosa Ledeb. Extract Containing Agrimols for Immunosenescence in Middle-Aged Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCo-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAge-related changes in circulating immune factors reveal biomarkers of immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLiving in endemic area for infectious diseases is associated to differences in immunosenescence and inflammatory signatures,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDifferential associations of anti-cytomegalovirus antibodies and soluble CD14 levels with immunosenescence in people living with HIV on long term antiretroviral therapy,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImmunosenescence and cytomegalovirus-associated immune signatures on severe acute respiratory syndrome coronavirus 2 booster responses,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMAM‐STAT3‐Driven Mitochondrial Ca +2 Upregulation Contributes to Immunosenescence in Type A Mandibuloacral Dysplasia Patients,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEnhancing flu vaccine responses in older adults: preliminary insights from the ISOLDA study on immunosenescence and antioxidant and anti-inflammatory approaches,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Lymphocyte-To-Monocyte Ratio is Partially Mediated in Age-Related Cardiovascular Mortality in HFpEF: Immunosenescence, Inflamm-Aging, and Longevity\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Aging, inflammaging and immunosenescence as risk factors of severe COVID-19\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImmunosenescence and its impact on ischemic stroke risk and outcomes in older adults: a systematic review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nA randomized controlled trial to assess the efficacy of standardized tai chi in prefrail older adults with immunosenescence: design and protocol,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDisease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Deciphering Immunosenescence From Child to Frailty: Transcriptional Changes, Inflammation Dynamics, and Adaptive Immune Alterations\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe pathophysiological mechanisms of immunosenescence in coronary artery disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImmunosenescence is a therapeutic target for frailty in older adults: a narrative review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nImmunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAging-associated transcriptional programs in T cells signify constituents of TGF-β signaling for immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMarkers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGene Expression Changes as Biomarkers of Immunosenescence in Bulgarian Individuals of Active Age,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAge Versus Immunity: Dietary Influences on Immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHIV infection and immunosenescence: challenges and intervention strategies,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRed ginseng extract enhances mitochondrial function and alleviates immunosenescence in T cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImmunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImmunosenescence and susceptibility to respiratory viruses: a state-of-the-art review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMultivariate analysis of immunosenescence data in healthy humans and diverse diseases,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNanoparticle-mediated delivery of herbal-derived natural products to modulate immunosenescence-induced drug resistance in cancer therapy: a comprehensive review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRheumatoid Arthritis and Osteoporosis as Prototypes of Immunosenescence in Osteoimmunology: Molecular Pathways of Inflammaging and Targeted Therapies,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nInsights into tumor vaccines for elderly individuals in the context of immunosenescence,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n“Immunopause” no more: exercise to counter immunosenescence in aging,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nImpact and potential value of immunosenescence on solid gastrointestinal tumors,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"The role of autoantibodies in bridging obesity, aging, and immunosenescence\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"bd88fdac-646d-49da-ad47-a3e928cc057a","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Immunogenicity and safety of quadrivalent influenza vaccine among young and older adults in Tianjin, China: implication of immunosenescence as a risk factor","doi":"10.1186/s12979-023-00364-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy 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