{"publication_id":"f2d5e407-7f5f-4de0-8775-b05423c0edb8","content_hash":"sha256:80a51d3249f12f18f1015512d81324cc371fc893e69e9881d5863ce3be41bd6f","nodes":[{"id":"f2d5e407-7f5f-4de0-8775-b05423c0edb8","type":"publication","title":"Adjacent Evidence Brief: Young plasma — full paper"},{"id":"claim_1","type":"claim","text":"This synthesis tests the thesis that evidence for Young plasma is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 13/17 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_3","type":"claim","text":"This paper synthesizes evidence on Young plasma across 17 included source papers and 474 high-confidence extracted claims."},{"id":"claim_4","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 9 adjacent clinical sources, and 8 mechanistic or model-system sources, with 7 cross-study disagreements across the evidence base."},{"id":"claim_5","type":"claim","text":"Positive study-level signals are summarized in the longevity outcome class; null signals are summarized in the mechanism, contextual adjacent evidence, immune and inflammation, safety and comorbidity, and skeletal, fracture, and bone outcome classes; negative signals are not the dominant direction in any outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_6","type":"claim","text":"The conclusion is that Young plasma should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_7","type":"claim","text":"This manuscript is reported as a Thin-corpus 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-young_plasma_parabiosis-v06-DAILY-2026-06-24T11-35-39Z-R3`."},{"id":"claim_8","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_9","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_10","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (contextual adjacent evidence, immune and inflammation, longevity, mechanism, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_11","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_12","type":"claim","text":"| Evidence group | Study-design signal | n | Example sources | Interpretation boundary |"},{"id":"claim_13","type":"claim","text":"| Preclinical rodent n=8 | animal/preclinical experiment | 8 | Habibi 2024: Effect of Young Plasma Therapy on Cognition, Oxidative Stress, miRNA-134, BDNF, ; Zhao 2020: Young blood plasma reduces Alzheimer’s disease-like brain pathologies and amelio; Li 2022: Young plasma reverses anesthesia and surgery-induced cognitive impairment in age | Preclinical rows support mechanism only; they do not establish human efficacy. |"},{"id":"claim_14","type":"claim","text":"| Other/unclear species n=6 | unclear or mixed design | 6 | Ceylani 2023: The rejuvenating influence of young plasma on aged intestine; Baba 2025: Therapeutic potential of young plasma in reversing age-related liver inflammatio; Yuan 2019: Young plasma ameliorates aging-related acute brain injury after intracerebral he | Unclear rows are retained only as bounded contextual evidence. |"},{"id":"claim_15","type":"claim","text":"| Cell/in vitro n=1 | cell or ex vivo model | 1 | Chen 2024: Small extracellular vesicles from young plasma reverse age-related functional de | Cell-model rows are mechanistic context, not organism-level efficacy evidence. |"},{"id":"claim_16","type":"claim","text":"| Human n=1 | observational/donor or cohort evidence | 1 | Muraglia 2024: A simple cell proliferation assay and the inflammatory protein content show sign | Human observational rows are interpreted as association or feasibility evidence. |"},{"id":"claim_17","type":"claim","text":"In animal/preclinical evidence, substantive evidence synthesis: The manifest includes 17 retained sources, 0 direct-source row(s), and directional coding across null=13, positive=3, unclear=1. Representative source-level signals are: Zhao 2020: outcome=Mechanism; direction=positive; directness=mechanistic; tier=C1; claims=48; Yuan 2019: outcome=Longevity; direction=positive; directness=indirect; tier=B2; claims=31; Chiavellini 2024: outcome=Mechanism; direction=positive; directness=mechanistic; tier=C1; claims=19; O 2026: outcome=Immune and Inflammation; direction=unclear; directness=review; tier=B1; claims=1; Chen 2024: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; claims=76; Habibi 2024: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1; claims=51; Ceylani 2023: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; claims=36; Li 2022: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1; claims=34. These signals inform the bounded conclusion by separating effect direction from evidence tier/directness; indirect, review-level, mechanistic, or contextual evidence remains hypothesis-generating."},{"id":"claim_18","type":"claim","text":"In animal/preclinical evidence, key findings from source synthesis: First, the strongest positive or favorable signals are treated as narrow source-level signals, not broad clinical proof (Zhao 2020: outcome=Mechanism; direction=positive; directness=mechanistic; tier=C1; claims=48; Yuan 2019: outcome=Longevity; direction=positive; directness=indirect; tier=B2; claims=31; Chiavellini 2024: outcome=Mechanism; direction=positive; directness=mechanistic; tier=C1; claims=19). Second, negative, mixed, unclear, or no-directional-signal rows are given equal interpretive weight (O 2026: outcome=Immune and Inflammation; direction=unclear; directness=review; tier=B1; claims=1; Chen 2024: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; claims=76; Habibi 2024: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1; claims=51). Third, the bounded conclusion follows from the balance of source direction, outcome class, evidence tier, and directness rather than from source count alone."},{"id":"claim_19","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_20","type":"claim","text":"| Contextual Adjacent Evidence | n=4; claims=134 | no extracted directional signal in 4/4 sources | 4 indirect | limited corpus depth in this outcome class |"},{"id":"claim_21","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_22","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_23","type":"claim","text":"5 included sources were assigned to this outcome class. Directional coding: null=3, positive=2. Directness coding: mechanistic=5."},{"id":"claim_24","type":"claim","text":"4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: indirect=4."},{"id":"claim_25","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2."},{"id":"claim_26","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_27","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, mechanistic=1."},{"id":"claim_28","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_29","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_30","type":"claim","text":"In animal/preclinical evidence, several outcome domains are supported by only a single source in the corpus, which means within-corpus replication is impossible. Chen 2024 stands alone on small extracellular vesicles as the active fraction; Yuan 2019 alone reports young plasma effects on intracerebral-hemorrhage acute brain injury; Parker 2020 is the only human safety-tolerability record of plasma infusions in a neurodegenerative population (Parkinson's Disease); and Li 2025 is the sole entry on osteogenic differentiation and osteoporosis-relevant endpoints. Because the corpus contains no second study addressing any of these endpoints, the direction and magnitude of effect on each cannot be triangulated, and a reader should treat these single-source signals as hypothesis-generating only."},{"id":"source_1","type":"source","study":"Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism","year":2024,"doi":"10.1038/s43587-024-00612-4","url":"https://doi.org/10.1038/s43587-024-00612-4","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"},{"id":"source_2","type":"source","study":"Effect of Young Plasma Therapy on Cognition, Oxidative Stress, miRNA-134, BDNF, CREB, and SIRT-1 Expressions and Neuronal Survey in the Hippocampus of Aged Ovariectomized Rats with Alzheimer’s","year":2024,"doi":"10.3390/brainsci14070656","url":"https://doi.org/10.3390/brainsci14070656","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"},{"id":"source_3","type":"source","study":"Young blood plasma reduces Alzheimer’s disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice","year":2020,"doi":"10.1186/s13195-020-00639-w","url":"https://doi.org/10.1186/s13195-020-00639-w","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"},{"id":"source_4","type":"source","study":"The rejuvenating influence of young plasma on aged intestine","year":2023,"doi":"10.1111/jcmm.17926","url":"https://doi.org/10.1111/jcmm.17926","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"},{"id":"source_5","type":"source","study":"Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity","year":2022,"doi":"10.3389/fnagi.2022.996223","url":"https://doi.org/10.3389/fnagi.2022.996223","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"},{"id":"source_6","type":"source","study":"Therapeutic potential of young plasma in reversing age-related liver inflammation via modulation of NLRP3 inflammasome and necroptosis","year":2025,"doi":"10.1007/s10522-025-10260-9","url":"https://doi.org/10.1007/s10522-025-10260-9","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"},{"id":"source_7","type":"source","study":"Chronic stress-induced anxiety-like behavior, hippocampal oxidative, and endoplasmic reticulum stress are reversed by young plasma transfusion in aged adult rats","year":2024,"doi":"10.22038/IJBMS.2023.72437.15754","url":"https://doi.org/10.22038/IJBMS.2023.72437.15754","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"},{"id":"source_8","type":"source","study":"Rejuvenating the gut: young plasma therapy improves cell proliferation, IGF-I and IGF-IR expression, and immune defense in aged male rats jejunum","year":2025,"doi":"10.1007/s10522-025-10204-3","url":"https://doi.org/10.1007/s10522-025-10204-3","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"},{"id":"source_9","type":"source","study":"Young Plasma Attenuated Chronic Kidney Disease Progression after Acute Kidney Injury by Inhibiting Inflammation in Mice","year":2023,"doi":"10.14336/AD.2023.1230","url":"https://doi.org/10.14336/AD.2023.1230","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"},{"id":"source_10","type":"source","study":"Young plasma attenuates cognitive impairment and the cortical hemorrhage area in cerebral amyloid angiopathy model mice","year":2021,"doi":"10.21037/atm-20-8008","url":"https://doi.org/10.21037/atm-20-8008","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"},{"id":"source_11","type":"source","study":"Young Plasma Rejuvenates Blood DNA Methylation Profile, Extends Mean Lifespan, and Improves Physical Appearance in Old Rats","year":2024,"doi":"10.1093/gerona/glae071","url":"https://doi.org/10.1093/gerona/glae071","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"},{"id":"source_12","type":"source","study":"Safety of Plasma Infusions in Parkinson's Disease","year":2020,"doi":"10.1002/mds.28198","url":"https://doi.org/10.1002/mds.28198","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"},{"id":"source_13","type":"source","study":"A simple cell proliferation assay and the inflammatory protein content show significant differences in human plasmas from young and old subjects","year":2024,"doi":"10.3389/fbioe.2024.1408499","url":"https://doi.org/10.3389/fbioe.2024.1408499","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"},{"id":"source_14","type":"source","study":"Exosomes from young plasma stimulate the osteogenic differentiation and prevent osteoporosis via miR-142-5p","year":2025,"doi":"10.1016/j.bioactmat.2025.03.012","url":"https://doi.org/10.1016/j.bioactmat.2025.03.012","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"},{"id":"source_15","type":"source","study":"Young plasma transfer enhances antioxidant defense and preserves structural integrity in aged lung tissue.","year":2026,"doi":"10.1093/gerona/glag007","url":"https://doi.org/10.1093/gerona/glag007","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"},{"id":"source_16","type":"source","study":"Young plasma ameliorates aging-related acute brain injury after intracerebral hemorrhage","year":2019,"doi":"10.1042/BSR20190537","url":"https://doi.org/10.1042/BSR20190537","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"},{"id":"source_17","type":"source","study":"Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy","year":2018,"doi":"10.1111/acel.12708","url":"https://doi.org/10.1111/acel.12708","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"},{"id":"source_18","type":"source","study":"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_19","type":"source","study":"**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.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_20","type":"source","study":"**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.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_21","type":"source","study":"**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.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_22","type":"source","study":"Perera 2006","year":null,"doi":"10.1111/j.1532-5415.2006.00701.x","url":"https://doi.org/10.1111/j.1532-5415.2006.00701.x","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":"citation"},{"id":"source_23","type":"source","study":"Bohannon 1997","year":null,"doi":"10.1093/ageing/26.1.15","url":"https://doi.org/10.1093/ageing/26.1.15","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":"citation"},{"id":"source_24","type":"source","study":"Ioannidis 2005","year":null,"doi":"10.1371/journal.pmed.0020124","url":"https://doi.org/10.1371/journal.pmed.0020124","population":"not 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