"Cold activates a BH2 metabolic network promoting longevity and proteostasis" - Logical Review & Gap Analysis

An independent logical review of Lee et al., Nature (2026), https://doi.org/10.1038/s41586-026-11152-9, which proposes that cold activates a muscle-derived BH2/BH4/tyrosine network extending lifespan and preserving proteostasis in C. elegans. Based on the article, Extended Data, Reporting Summary, Peer Review File and Supplementary Tables 1–7 (Table 8 structure only), the report: Restates the paper's reasoning chain and claims, preserving the authors' level of certainty. Lists limitations acknowledged by the authors or left only partly resolved in peer review. Identifies 7 methodological gaps (e.g., CAT-4→BH2/BH4 not measured under CAT-4 manipulation; inter-tissue transport inferred genetically; tyrosine not measured in the pathway; thermodynamic-compensation vs. active-program readings; limited generalisability). Adds 3 high-level checking notes (replicate consistency, proteomics thresholds, metabolite effect sizes) plus minor checks. Rates confidence per claim (High to Not yet verified). Net: the cold-lifespan phenomenon in worms and a partial requirement for muscle CAT-4 are well supported; downstream links are mostly inferred from consistent genetic interventions rather than direct metabolite measurements. Important notes "Lifespan extension" here refers only to one narrow laboratory result in C. elegans (shift from 20 °C to 15 °C after development). It does not mean that lower environmental temperature extends lifespan in general, or in humans or mammals, and it is not health advice. Not medical guidance. The paper tested BH2 and tyrosine only in worms and cultured cells. No safety, dose or efficacy data exist for humans. Do not self-administer or self-experiment with cold exposure, tyrosine, BH2, BH4 (sapropterin) or related compounds based on this report or the paper. The reviewer accepts no responsibility for misinterpretation. Limits: the reviewer is not a domain specialist, did not re-run raw data, and lacked Supplementary Fig. 1 and Source data. AI tools assisted drafting and cross-checking. This report does not replace formal peer review. Keywords: peer review; logical review; gap analysis; Section Zero; scientific methodology; Caenorhabditis elegans; cold temperature; longevity; ageing; proteostasis; dihydrobiopterin (BH2); tetrahydrobiopterin (BH4); GCH1/CAT-4; tyrosine; PAH-1; inter-tissue signalling; protein aggregation; causal inference; reproducibility