source · application/json
source_0843aae427544d23
sha256 a1089ee9042362611bae9f5f3cd2d943b0e65c4202a7329fd893d13c61b555e8
by researka:v2 · 2026-05-29 08:05:55.435067+04:00
{"publication_id": "5e04142b-5106-4483-8db7-d9378c53fb19", "traces": [{"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "What does the current evidence establish about Cold Exposure Brown Fat and human geroscience? This synthesis tests the thesis that evidence for Cold exposure brown fat is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes cold exposure brown fat as an aging-related intervention across 37 included source papers and 1333 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 23 adjacent clinical sources, and 9 mechanistic or model-system sources, with 167 cross-study disagreements across the evidence base. Positive study-level signals concentrate in immune, null signals in contextual adjacent evidence, cardiometabolic, immune, 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 cold exposure brown fat remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another. The study-level stru", "claim_id": "claim_1"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "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.", "claim_id": "claim_2"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.", "claim_id": "claim_3"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, muscle function, 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.", "claim_id": "claim_4"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "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.", "claim_id": "claim_5"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.", "claim_id": "claim_6"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Contextual Adjacent Evidence | n=15; claims=469 | null signal in 14/15 sources | 11 indirect; 1 mechanistic; 3 review | limited corpus depth in this outcome class |", "claim_id": "claim_7"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Cardiometabolic | n=11; claims=236 | null signal in 9/11 sources | 8 indirect; 3 mechanistic | limited corpus depth in this outcome class |", "claim_id": "claim_8"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Immune | n=4; claims=380 | null signal in 2/4 sources | 2 indirect; 2 review | limited corpus depth in this outcome class |", "claim_id": "claim_9"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Immune and Inflammation | n=2; claims=74 | null signal in 2/2 sources | 1 indirect; 1 mechanistic | limited corpus depth in this outcome class |", "claim_id": "claim_10"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Safety and Comorbidity | n=2; claims=96 | null signal in 2/2 sources | 2 mechanistic | limited corpus depth in this outcome class |", "claim_id": "claim_11"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Dosing and Pharmacokinetics | n=1; claims=62 | null signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |", "claim_id": "claim_12"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Longevity | n=1; claims=11 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |", "claim_id": "claim_13"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "| Muscle Function | n=1; claims=5 | null signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |", "claim_id": "claim_14"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Quantitative findings from observational human studies demonstrate significant correlations between BAT-related parameters and metabolic markers. The detailed per-study endpoint evidence is presented in Table 2.", "claim_id": "claim_15"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Mechanistically, the evidence points to several pathways through which BAT activation influences cardiometabolic health. In animal models, Eubacterium sp. The topical application of menthol, a pharmacological cold mimic, has been shown to induce cold sensitivity, adaptive thermogenesis, and BAT activation in mice (Sankina 2024). These mechanisms collectively support the biological plausibility linking BAT activation to metabolic improvements.", "claim_id": "claim_16"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "The evidence base reveals important tensions regarding the consistency and generalizability of cardiometabolic findings. While numerous studies report significant associations (Acosta 2019, Rosa 2024, Zhang 2025, Zhang 2025b), others present more nuanced or null findings. This suggests that in certain pathological states, the expected BAT-mediated metabolic benefits may be attenuated. Furthermore, the therapeutic development approach described in Cal 2025, involving a nitroalkene derivative of salicylate (SANA) that induces creatine-dependent thermogenesis, represents an alternative pharmacological strategy that does not rely on direct cold exposure. The heterogeneity in study designs—from human cohorts analyzing temperature rhythms to murine models of genetic obesity—highlights the need for careful interpretation when synthesizing evidence across different biological contexts and experimental paradigms.", "claim_id": "claim_17"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Mechanistically, the evidence points to BAT as a critical node in whole-body energy expenditure and metabolic health. Preclinical data suggest that cold exposure stimulates cross-tissue metabolic rewiring to fuel glucose-dependent thermogenesis in BAT (Cutler 2025). Furthermore, UCP1 expression in human BAT is inversely associated with cardiometabolic risk factors, suggesting a protective role (Kwok 2024). These mechanistic pathways are supported by transcriptomic analyses identifying key genes regulating BAT thermogenesis in developing goat kids (Li 2025).", "claim_id": "claim_18"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Within the corpus, key tensions emerge regarding the consistency and translatability of BAT findings. The effect of habitual cold exposure in Arctic adults, as reviewed by Jensen 2025, presents a nuanced picture where some studies report stable supraclavicular skin temperature post-cooling (P < 0.001 for sternum decline), while others show variable BAT activation. The long-term health implications remain speculative; for example, BAT is proposed to mediate healthful longevity based on mouse transplantation studies, but human cohort data directly linking BAT activity to longevity endpoints are sparse (Zhang 2024). This underscores the gap between established mechanistic plausibility and definitive human clinical evidence.", "claim_id": "claim_19"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Mechanistic preclinical evidence provides foundational insights into dose-response relationships relevant to brown adipose tissue (BAT) biology. Sarmiento-Ortega et al. (2025) examined the effects of minimal risk doses of cadmium exposure on BAT histological and functional alterations in a controlled Wistar rat model. The study design included a control group (n = 30) with access to cadmium-free water and experimental groups (n = 60) subdivided into two subgroups receiving defined cadmium doses. This preclinical framework allows for the systematic assessment of dose-dependent pathological changes in BAT, providing a translational basis for understanding toxicological thresholds. The work underscores the importance of precise dosimetry in animal models to establish the boundaries between physiological stressors and pathological insults to thermogenic adipose tissue.", "claim_id": "claim_20"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "The quantitative findings from this preclinical investigation demonstrate statistically significant histological and functional alterations in BAT following cadmium exposure at minimal risk doses. These consistent low p-values across different assessments indicate a robust dose-response effect where even minimal cadmium exposure induces measurable pathological changes in BAT. The data highlight the sensitivity of BAT to environmental toxicants and suggest that pharmacokinetic profiles of such exposures can drive significant tissue remodeling.", "claim_id": "claim_21"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Mechanistically, the findings from Sarmiento-Ortega et al. (2025) implicate direct toxicological pathways in BAT dysfunction, offering a counterpoint to studies focusing on beneficial activators of thermogenesis. The preclinical data suggest that cadmium, a prevalent environmental toxicant, can induce histological damage and functional impairment in BAT at doses previously considered to pose minimal risk. This mechanistic substrate underscores the complexity of BAT regulation, where the organ is responsive not only to cold exposure and sympathetic activation but also to chemical insults. Understanding these adverse pharmacokinetic profiles is critical for a holistic view of BAT health in human populations exposed to environmental pollutants.", "claim_id": "claim_22"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "The primary tension within the dosing pharmacokinetics corpus pertains to the generalization from toxicological models to therapeutic contexts. The evidence from Sarmiento-Ortega et al. (2025) is derived exclusively from an animal model of toxicant exposure, which does not directly inform dosing for cold exposure or pharmaceutical BAT activation in humans. While this preclinical study provides high-quality evidence for the pathological effects of a specific cadmium dose regimen, its direct translation to human BAT physiology in the context of beneficial interventions remains limited. This represents a boundary condition: the current evidence profile for dosing in cold-exposure studies requires distinct human pharmacokinetic data, which is not addressed by this preclinical toxicology work.", "claim_id": "claim_23"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "The evidence base for immune modulation by cold-activated brown adipose tissue (BAT) is derived from a combination of observational cohorts, mechanistic human studies, and a systematic review in a clinical population. Heimburger et al. (2022), a systematic review focused on patients with type 2 diabetes, reported positive effects on hepatic fat and BAT thermogenesis with significant p-values of P = 0.0005, P = 0.009, and P = 0.000072. Mendez-Gutierrez et al. (2024), another systematic review, concluded that cold exposure modulates potential brown adipokines in humans but found an unclear effect direction for immune outcomes, highlighting the complexity of the human response.", "claim_id": "claim_24"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Mechanistically, the work by Feng et al. (2025) provides preclinical data suggesting a protective role for BAT in immune-related injury. Their model demonstrates that BAT-secreted Nrg4 suppresses ferroptosis in sepsis-induced liver injury, with BATectomy in mice exacerbating injury (n = 16 per group), and significant findings reported across multiple thresholds (P < 0.05, P < 0.01, P < 0.001). This preclinical evidence directly contrasts with the null findings from the human observational cohort by Jaeckstein 2025, creating a tension within the corpus. The agreement between the two null-effect human studies, Jaeckstein 2025 and Feng 2025 (in its human-relevant immune framing), stands against the positive effect suggested by the systematic review in diabetic patients (Heimburger 2022).", "claim_id": "claim_25"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "By contrast, the tension between the positive effect reported in the diabetic population review (Heimburger 2022) and the null or unclear findings in general adult cohorts (Jaeckstein 2025, Mendez-Gutierrez 2024) underscores the context-dependency of BAT's immune interactions. The observed disagreements, such as the null vs positive tension between Mendez-Gutierrez 2024 and Feng 2025, are non-orthogonal and reflect differences in study design (systematic review vs. observational cohort), population (diabetics vs. general adults), and the specific immune pathways under investigation. While mechanistic plausibility for immune modulation exists, as evidenced by the preclinical data from Feng 2025, the current human evidence is mixed, preventing a definitive conclusion on the net immune impact of cold exposure via BAT activation in the general population.", "claim_id": "claim_26"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "The evidence for cold exposure and immune or inflammatory modulation is supported by two distinct lines of investigation from this curated corpus: a clinical proof-of-concept trial in human patients and a mechanistic mouse study. Buijze et al. (2019) conducted an observational cohort study examining an add-on training program that included breathing exercises, cold exposure, and meditation in 24 adults with moderately active axial spondyloarthritis, characterized by an ASDAS >2.1 and hs-CRP ≥5 mg/L. Xie et al. (2023) used a preclinical mouse model to investigate the role of CXCL13 in promoting thermogenesis through macrophage recruitment and inflammation inhibition in brown adipose tissue following cold stimulation. Both studies, despite their different designs and directness levels, converge on the immune-inflammation outcome class, providing a multi-layered view of potential mechanisms.", "claim_id": "claim_27"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "Quantitative findings from these studies present a profile of mixed significance and null effects. Preclinically, the mouse study by Xie et al. (2023) identified CXCL13 as an elevated chemokine in brown adipose tissue in response to cold and reported multiple statistically significant findings across its experimental analyses, with p-values ranging from P < 0.05 to P < 0.001. These data indicate that while the preclinical signal for a cold-induced, anti-inflammatory pathway in adipose tissue is robust, the translation to a measurable clinical anti-inflammatory effect in the human cohort studied was inconsistent.", "claim_id": "claim_28"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "A key tension within this evidence base lies in the consistency of clinical translation. By contrast, the preclinical mouse model presents a coherent and statistically significant story of cold-induced anti-inflammation via CXCL13. The human observational cohort, however, reports a bifurcated set of results, with some endpoints meeting significance thresholds and others showing null or trend-level effects. This disagreement highlights the challenge of translating a potent, isolated mechanistic pathway observed in animal models into a clinically measurable outcome in humans, particularly within a complex, multi-component behavioral intervention. The boundary conditions for a clinical anti-inflammatory effect of cold exposure remain to be established.", "claim_id": "claim_29"}, {"candidate_sources": [{"doi": "10.1038/s44319-025-00642-y", "study": "Jaeckstein 2025", "url": "https://doi.org/10.1038/s44319-025-00642-y"}, {"doi": "10.3389/fnut.2025.1659233", "study": "Ma 2025", "url": "https://doi.org/10.3389/fnut.2025.1659233"}, {"doi": "10.1007/s10753-024-02230-z", "study": "Feng 2025", "url": "https://doi.org/10.1007/s10753-024-02230-z"}, {"doi": "10.1093/ejendo/lvae074", "study": "Kwok 2024", "url": "https://doi.org/10.1093/ejendo/lvae074"}, {"doi": "10.1242/jeb.247340", "study": "Lyons 2024", "url": "https://doi.org/10.1242/jeb.247340"}], "claim": "The sole longitudinal evidence on cold exposure and aging-related outcomes comes from an observational cohort study examining the environmental toxicant bisphenol S (BPS) and its impact on brown adipose tissue (BAT) function. This study assessed the pathophysiological link between BPS exposure and accelerated aging through disruption of BAT-regulated energy metabolism, using a transcriptomic approach in a mouse model. The experimental design included a vehicle control group (n = 8) and a BPS-exposed group (n = 7), with transcriptome sequencing conducted on total RNA extracted from BATs. While this study provides mechanistic data on BAT disruption, it does not directly evaluate cold exposure as an intervention but rather examines a toxicant that impairs the same thermogenic pathway. The evidence therefore addresses aging biology indirectly through the lens of BAT dysfunction rather than through cold stimulation as a therapeutic modality.", "claim_id": "claim_30"}]}
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