https://www.mdpi.com/2218-273X/15/10/1414
Summary
- What it asks: whether genes linked to red wine overlap with genes linked to exceptional human longevity (centenarians).
- How it’s done: the authors query GeneCards (aggregating >190 databases) for genes associated with “red wine” and with “centenarian(s)”, manually vet the hits, and end with 43 genes in the intersection. They then run STRING (GSEA) and WebGestalt (ORA/topology) to see what pathways/tissues/diseases these genes enrich.
- Main findings: enrichment for pathways related to stress responses, apoptosis/cell death, neuroinflammation, nucleotide-excision repair, and lipoprotein metabolism (very low FDRs), with tissue enrichment in GI, cardiovascular, and respiratory systems. Disease enrichment highlights cardiovascular disease, type 2 diabetes, metabolic and immune diseases, and cancer.
- Controls & caveats (from the paper): a “white wine + centenarian” search returned no human genes (used as a negative control). The authors also report a 40% overall false-positive rate across initial hits during validation, note that their gene list is likely incomplete, and discuss method limitations of ORA/GSEA/topology analyses.
- Take-home message they offer: they argue this is a first genetic overview connecting moderate red-wine–linked genes with longevity genes, and (despite acknowledging alcohol risks) suggest moderate red wine intake (esp. >40 y) may support healthy aging via hormesis and polyphenols.
What’s novel
- A curated “red-wine ∩ centenarian” gene set (43 genes). Prior work often looked at single compounds (e.g., resveratrol) or single outcomes; this paper explicitly intersects wine-linked genes with centenarian genes and then maps networks.
- Network-level framing (STRING/WebGestalt topology with neighbor expansion) rather than only listing genes or single pathways.
- Transparency about text-mining error (reporting ~40% false positives in initial hits) and a small “AI chatbot” sanity-check—unusual elements in curation papers.
Critique (strengths & limitations)
Strengths
- Clear, reproducible pipeline (search terms, platforms, FDR thresholds) with open access to the supplement.
- Cross-checking limitations (false-positive accounting; method comparison table) are candidly stated.
Limitations / concerns
- Ascertainment & circularity. Using keyword hits in GeneCards biases toward already popular targets (SIRT1, FOXO, APOE-adjacent, etc.). Intersecting two literature-biased lists can preferentially recover widely studied “longevity usual suspects,” not necessarily wine-specific biology. A true negative control would need matched search intensity—not “white wine,” which simply has less mechanistic literature.
- From association to recommendation. The paper moves from in silico enrichment to a population guidance flavor (“moderate intake after 40 may be beneficial”). That leap conflicts with public-health consensus that no level of alcohol is safe for cancer risk (WHO/IARC; UK CMOs), and that perceived cardioprotection often collapses after confounding correction. Mechanistic enrichment ≠ causal benefit of drinking.
- Dose and bioavailability mismatch. Much of the mechanistic wine literature involves polyphenols at supra-physiologic doses or their metabolites (sulfates/glucuronides) rather than parent compounds at levels from 1–2 glasses. A 2024 clinical review concludes no conclusive clinical efficacy for resveratrol despite vast promise.
- Pathway generality. Enrichments like “response to stimulus,” “apoptotic process,” and broad disease categories are non-specific and show up for many curated lists. The study also expands networks with nearest neighbors, inflating pathway coverage and potentially overstating specificity to red wine.
- Evidence cherry-picking risk. The narrative emphasizes studies suggesting neutral/beneficial cancer associations with red wine, but large public-health bodies emphasize dose-dependent cancer risk from any alcohol (no safe threshold). This tension is not fully reconciled.
Context to balance the claims
- There are small controlled human data showing short-term gene-expression shifts (e.g., SIRT1, CAT, MnSOD, p53 up in PBMCs after 14 days of moderate red wine in cloistered nuns) and lifespan extension in Drosophila—but these are tiny, short, and not clinical-endpoint trials.
- Importantly, dealcoholized red wine lowers blood pressure more than alcoholic red wine in crossover trials—implicating polyphenols rather than ethanol (argues against needing alcoholic “hormesis”).
Bottom line
The paper offers a literature-curated gene set linking red-wine–studied genes with centenarian genes and shows broad, plausible longevity-adjacent pathways. That’s hypothesis-generating, not proof that drinking red wine extends human lifespan or reduces disease. Given strong population-level evidence that any alcohol increases cancer risk, the safest translational angle is to test non-alcoholic polyphenol sources (or dealcoholized wine) in well-powered, preregistered studies using physiologic doses, objective exposure biomarkers, and causal designs (e.g., Mendelian randomization) before making consumption recommendations.
Sources
Primary article: Lacayo et al. 2025, Biomolecules (open-access full text & methods).
Key context: WHO/IARC & UK CMO alcohol guidance; resveratrol clinical review; small controlled wine studies; dealcoholized wine RCTs.