Red-Wine Gene Networks Linked to Exceptional Longevity in Humans

Abstract

Despite the health concerns regarding alcohol and its link to cancer, moderate consumption of red wine has been associated with healthy aging and longevity, defined as up to one drink per day for women and two drinks per day for men (approximately 142 mL or 5 oz per drink). Previous research has revealed the health benefits of red wine, particularly in relation to cardiovascular disease. However, the influence of genetic factors on these benefits remains to be elucidated. In this study, we explored genes linked to red wine and created a curated gene set that intersects with those related to centenarians, which are markers of exceptional longevity. By analyzing literature from over 190 databases, we identified and validated a curated list of 43 genes associated with red wine and centenarians. We conducted gene set enrichment analysis as well as enrichment analysis of diseases and their tissue distributions. The results suggest that these genes play a crucial role in stress response and apoptosis, which are essential for cell survival and renewal. Additionally, these genes were enriched in pathways associated with smooth muscle cell proliferation, neuroinflammation, nucleotide excision repair, and lipoprotein metabolism (false discovery rate, FDR < 3 × 10^-7). Gene set enrichment analysis indicated significant tissue distribution in the gastrointestinal, cardiovascular, and respiratory systems. Furthermore, the disease-gene enrichment analysis pointed to associations with diseases related to tissues and organs, including cardiovascular disease (heart disease and stroke), type 2 diabetes, gastrointestinal diseases and metabolic diseases, immune diseases, and cancer (FDR < 9.37 × 10^-6); notably, cardiovascular diseases, diabetes, and cancer are leading causes of death, suggesting that these genes may be protective against those diseases. Our review of the literature indicates that individuals who do not currently drink alcohol should not be encouraged to start. However, we propose that moderate consumption of red wine, especially for middle-aged to older adults after 40 years old, can provide significant health benefits due to its components and the positive effects of hormesis. Although further research is necessary to uncover additional genes, this study provides the first genetic overview of the health benefits of red wine, emphasizing its potential in supporting healthy aging and longevity.

Keywords: aging; alcohol; alternative medicine; catechins; centenarian; gallic acid; hormesis; longevity; polymorphism; polyphenol; red wine; resveratrol; rotundone.

Figure 1

Flow diagram of gene identification and analysis. Three types of analyses, including network topology analysis, over-representation analysis (ORA), and gene set enrichment analysis (GSEA), were performed. See text for details.

Figure 2

Nature of the genes associated with red wine and centenarians. (A). Network topology analysis of genes identified, showing a set of interactions within a single network. Seed genes (large gray nodes) represent the genes identified. Top-ranking neighbors (small gray nodes) represent the genes associated with the seed genes. (B). Network topology analysis of enriched GO terms (orange-pink, enriched GO terms; yellow, ancestors of the terms). The enriched GO terms are major categories that combine specific categories called ancestors of the terms, which can be summarized as two major categories: stress response (red circle) and cell death/ apoptosis (blue circle). (C). Over-presentation analysis (ORA) of the gene distributions, using gene ontology and the processes shown in the figure (red, biological category; cellular, cellular category; and green, molecular function categories). The numbers of each category are shown, and those with over 25 genes are listed in the text. Larger figures have been included.

Figure 3

ORA of disease and biological categories is presented. The top 10 disease categories are labeled and displayed in the box with their respective statistics. The biological categories are represented in the dot plot, which is labeled accordingly. They include five major groups: cell death/apoptosis (blue circle), stress response (red circle), metabolism (green circle), proliferation (purple circle), and inflammation (pale blue circle).

Figure 4

The GSEA result of the genes identified. (A). Biological ontology pathways, (B). Tissue expression profiles, and (C). Disease–gene association classifications. The top 10 categories were organized based on a similarity score of 0.8 or higher. A comprehensive discussion of the overall pathways is detailed in Section 4. Supplementary Material is available for a complete list of categories.

Figure 5

Summary of this study. (A). Organ systems, tissue expression enrichment, and biological enrichment are summarized. Most categories are included. Red wine is digested and absorbed in the digestive system, transported by the circulatory system, and exerts effects on various functions as indicated by the enrichment categories. See the discussion for risks of alcohol. (B). Disease association enrichment is organized into six groups (highlighted in yellow), including heart disease and stroke, immune disease, diabetes and gastrointestinal diseases, metabolic disease, cancer and neoplasm, tissue and other diseases (see also Table 1).