Associations Between Genetic Variants of the Taste Receptors, TAS1R2, TAS1R3, TAS2R38, and CD36 and Human Longevity

Background/Objectives: Taste receptors are expressed in the oral cavity and numerous extra-oral tissues, where they use a universal chemical language. In this wide contest, taste receptors modulate feeding behavior, maintain metabolic balance and physiological homeostasis potentially contributing to exceptional longevity. Genetic variants of these receptors are associated with their sensitivity or expression. Methods: We evaluated differences in genotype and allele frequencies at the TAS1R2, TAS1R3, TAS2R38, and CD36 single gene polymorphism (SNPs) and their associations with BMI in two genetically and environmentally distinct Sardinian populations: a cohort of near-centenarian participants (LBZ) and a control cohort (CYME). The associations between the SNPs, BMI, and gender were also analyzed. Results: Significant differences were observed in the genotype and allele distributions of the TAS1R3, TAS2R38, and CD36 SNPs. In the LBZ cohort, specific genotypes such as TAS1R3 CC, TAS2R38 PAV/PAV, and CD36 GG were most frequent contributing to favorable phenotypes, whereas these genotypes showed no effect in the more heterogeneous urban CYME population. The TAS1R2, TAS1R3, TAS2R38, and CD36 variants modulated BMI in an environmental- and sex-dependent manner. Conclusions: These results underscore the importance of integrating genetic screening into nutritional and metabolic health assessments, considering sex and environmental context in gene–phenotype associations, suggesting that BMI may not be a universal health metric, especially in genetically unique or long-lived populations. These results contribute to the expanding understanding of taste receptors as multifunctional chemosensors, with roles extending beyond gustatory perception to influence systemic physiology, energy balance, and potentially contributing to longevity-associated phenotypes.