Low insulin resistance and preserved beta-cell function contribute to human longevity but are not associated with TH-INS genes.

Tyrosine Hydroxylase (TH) and Insulin (INS) genes lie extremely close in the 11p15.5 chromosomal region. An STR marker of the TH gene had revealed this locus associated with longevity. Thus, it seemed of interest to investigate the association between the TH-STR and INS gene variability (FokI-RFLP) with a phenotypic trait, such as the degree of insulin resistance (IR) and beta-cell function in centenarians (C). We analyzed age-related trajectories of IR and beta-cell function in a large sample (n=466) of individuals whose age ranged from 28 to more than 100 years; furthermore, allele average effects on IR and beta-cell function relevant to TH-STR and INS-FokI polymorphisms were estimated in C. Both IR and beta-cell function increased with advancing age and declined in subjects older than 90 years (p for trend <0.001). C had lower IR (1.5+/-0.7 vs. 3.9+/-1.7, p<0.001) and beta-cell function (26.1+/-8.5 vs. 55.4+/-16, p<0.001) than nC. In nC, but not in C, IR and beta-cell function correlated with the main anthropometric and metabolic confounders. Nevertheless, significant allele average effects by TH-STR and INS-FokI polymorphisms on IR and beta-cell function were not observed in C. In conclusion, C has a lower degree of IR and a preserved beta-cell function in comparison to nC, but the cause of such metabolic differences, which are likely does not lie in this genomic region.