Hypothesis-Generating Brief: Immune senescence

Hypothesis-Generating Brief: Immune senescence

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.

Methods

Review type and protocol

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.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-23.

Search strategy

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

• immunosenescence AND aging AND human
• immunosenescence AND older adults
• immunosenescence AND randomized controlled trial
• immune senescence AND aging AND human
• immune senescence AND older adults
• immune senescence AND randomized controlled trial
• T cell senescence AND aging AND human
• T cell senescence AND older adults
• T cell senescence AND randomized controlled trial
• vaccine response AND aging AND human

Eligibility criteria

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

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 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.

source admission funnel

Admission bucket	n
Receipt candidate union	424
Classified source candidates	155
No extractable claims	115
None-only claim binding	38
Mixed partial-or-none claim-binding candidates	89
Partial-only claim-binding candidates	22
Strict high-confidence sources	5
Admitted final sources	46

Exclusion reasons

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

Data items

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

Risk-of-bias appraisal

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

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, 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.

AI-use disclosure

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

Accountability

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

Results

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.

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
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
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
Longevity	n=4; claims=27	no extracted directional signal in 3/4 sources	4 indirect	limited corpus depth in this outcome class
Cardiometabolic	n=2; claims=38	no extracted directional signal in 2/2 sources	2 indirect	limited corpus depth in this outcome class
Frailty	n=2; claims=18	no extracted directional signal in 2/2 sources	1 direct; 1 indirect	limited corpus depth in this outcome class
Cognitive	n=1; claims=1	no extracted directional signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Safety and Comorbidity	n=1; claims=88	no extracted directional signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.

Contextual Adjacent Evidence Outcomes

18 included sources were assigned to this outcome class. Directional coding: null=18. Directness coding: indirect=16, review=2.

Immune Outcomes

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.

3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.

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.

Longevity Outcomes

4 included sources were assigned to this outcome class. Directional coding: null=3, unclear=1. Directness coding: indirect=4.

Cardiometabolic Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.

Frailty Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: direct=1, indirect=1.

Cognitive Outcomes

1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1.

Safety Comorbidity Outcomes

1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.

Limitations

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

The 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.

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.

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).

Hard 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.

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.

Conclusion

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.

What This Synthesis Adds

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.

Across 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.

The 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.

This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	4	null, unclear	direct interventional hard-endpoint gap
cardiometabolic	0	2	null	direct interventional hard-endpoint gap
cognitive	0	1	null	direct interventional hard-endpoint gap
frailty	1	1	null	replication gap
contextual adjacent evidence	0	18	null	direct interventional hard-endpoint gap
immune and inflammation	1	14	null, positive, unclear	conflict-resolution gap
safety and comorbidity	0	1	null	direct interventional hard-endpoint gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: direct interventional hard-endpoint gap	0 direct and 4 indirect sources; direction profile: null, unclear
P2	cardiometabolic: direct interventional hard-endpoint gap	0 direct and 2 indirect sources; direction profile: null
P3	cognitive: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null
P4	frailty: replication gap	1 direct and 1 indirect sources; direction profile: null
P5	contextual adjacent evidence: direct interventional hard-endpoint gap	0 direct and 18 indirect sources; direction profile: null

Next-Study Design Recommendation

The 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.

Evidence Snapshot

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

Load-Bearing Included Studies

• Additional corpus sources included animal/preclinical evidence; Rastgoo 2025; tier=A1; directness=direct; endpoint=immune; direction=null.
• Zhong 2025; tier=A1; directness=direct; endpoint=frailty; direction=null.
• Xiao 2023; tier=B2; directness=indirect; endpoint=safety comorbidity; direction=null.
• Li 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.
• Jin 2025; tier=B2; directness=indirect; endpoint=immune; direction=unclear; representative statistic=P < 0.001.
• Lupoae 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.
• Anaya 2026; tier=B2; directness=indirect; endpoint=immune; direction=null; representative statistic=P = 0.06.
• Ventura 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.
• Tizazu 2024; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null.
• Bashir 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.

Source Classification Map

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

• 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.
• 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.
• 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.
• 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.
• Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=54.
• 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.
• Biological age and immunosenescence in Colombian centenarians: outcome=immune; directness=indirect; tier=B2; direction=null; claims=38.
• Immunosenescence Profile Is Associated With Increased Susceptibility to Severe COVID ‐19: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=33.
• Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=29.
• 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.
• 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.
• 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.
• Age-related changes in circulating immune factors reveal biomarkers of immunosenescence: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=23.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Aging, inflammaging and immunosenescence as risk factors of severe COVID-19: outcome=longevity; directness=indirect; tier=B2; direction=unclear; claims=11.
• 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.
• Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=9.
• The pathophysiological mechanisms of immunosenescence in coronary artery disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.
• Deciphering Immunosenescence From Child to Frailty: Transcriptional Changes, Inflammation Dynamics, and Adaptive Immune Alterations: outcome=frailty; directness=indirect; tier=B2; direction=null; claims=8.
• 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.
• 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.
• 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.
• Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma: outcome=immune; directness=indirect; tier=B2; direction=null; claims=5.
• 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.
• Age Versus Immunity: Dietary Influences on Immunosenescence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=3.
• HIV infection and immunosenescence: challenges and intervention strategies: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=3.
• Red ginseng extract enhances mitochondrial function and alleviates immunosenescence in T cells: outcome=immune; directness=indirect; tier=B2; direction=positive; claims=2.
• Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=2.
• The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=2.
• Bridging aging and colorectal cancer: synergistic roles of inflammaging and immunosenescence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2.
• Multivariate analysis of immunosenescence data in healthy humans and diverse diseases: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1.
• Immunosenescence and susceptibility to respiratory viruses: a state-of-the-art review: outcome=immune; directness=indirect; tier=B2; direction=null; claims=1.
• Inflammaging and Immunosenescence in the Post‐COVID Era: Small Molecules, Big Challenges: outcome=immune; directness=indirect; tier=B2; direction=null; claims=1.
• Insights into tumor vaccines for elderly individuals in the context of immunosenescence: outcome=immune; directness=indirect; tier=B2; direction=null; claims=1.
• “Immunopause” no more: exercise to counter immunosenescence in aging: outcome=immune; directness=indirect; tier=B2; direction=unclear; claims=1.

Classification Criteria

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

Load-Bearing Tensions

• Severity 4 null vs positive: Valentino 2024 vs Lee 2025; Lee 2025 (positive on immune) vs Valentino 2024 (null on immune) — partial conflict
• Severity 4 null vs positive: Khoury 2025 vs Lee 2025; Lee 2025 (positive on immune) vs Khoury 2025 (null on immune) — partial conflict
• Severity 4 null vs positive: Cevirgel 2025 vs Lee 2025; Lee 2025 (positive on immune) vs Cevirgel 2025 (null on immune) — partial conflict
• Severity 4 null vs positive: Coelho 2025 vs Lee 2025; Lee 2025 (positive on immune) vs Coelho 2025 (null on immune) — partial conflict
• Severity 4 null vs positive: Lee 2025 vs Li 2025; Lee 2025 (positive on immune) vs Li 2025 (null on immune) — partial conflict
• Severity 4 null vs positive: Lee 2025 vs Francavilla 2025; Lee 2025 (positive on immune) vs Francavilla 2025 (null on immune) — partial conflict
• Severity 4 null vs positive: Lee 2025 vs Fragkou 2026; Lee 2025 (positive on immune) vs Fragkou 2026 (null on immune) — partial conflict
• Severity 4 null vs positive: Lee 2025 vs Anaya 2026; Lee 2025 (positive on immune) vs Anaya 2026 (null on immune) — partial conflict

Additional 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.

References

• 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.
• 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.
• 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.
• 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.
• Lupoae 2026. Predictors of Severe Herpes Zoster: Contributions of Immunosenescence, Metabolic Risk, and Lifestyle Behaviors. Diseases, 2026. DOI: 10.3390/diseases14010026. PMID: 41590241.
• Anaya 2026. Biological age and immunosenescence in Colombian centenarians. NPJ Aging, 2026. DOI: 10.1038/s41514-026-00340-6. PMID: 41735334.
• Ventura 2025. Immunosenescence Profile Is Associated With Increased Susceptibility to Severe COVID ‐19. Aging Cell, 2025. DOI: 10.1111/acel.70077. PMID: 40388115.
• Tizazu 2024. Fasting and calorie restriction modulate age‐associated immunosenescence and inflammaging. Aging Medicine, 2024. DOI: 10.1002/agm2.12342. PMID: 39234195.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
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• 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.
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Background References

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

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