Low insulin resistance and preserved b-cell function contribute to human longevity but are not associated with TH±INS genes Giuseppe Paolisso a, * , Michelangela Barbieri a , Maria Rosaria Rizzo a , Carlo Carella b , Mario Rotondi b , Massimiliano Bonafe Á c , Claudio Franceschi c , Giuseppina Rose d , Giovanna De Benedictis d a Department of Geriatric Medicine and Metabolic Diseases, Servizio di Astanteria Medica, IV Divisione di Medicina Interna, University of Naples, Piazza Miraglia 2, I-80138 Naples, Italy b Institute of Endocrinology, University of Naples, Naples, Italy c Department of Experimental Pathology, University of Bologna, Bologna, Italy d Department of Cell Biology, University of Calabria, Rende, Italy Received 12 April 2001; received in revised form 6 July 2001; accepted 10 July 2001 Abstract 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 b-cell function in centenarians C). We analyzed age-related trajectories of IR and b-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 b-cell function relevant to TH-STR and INS-FokI polymorphisms were estimated in C. Both IR and b-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 b-cell function 26:1 ^ 8:5 vs 55:4 ^ 16; p , 0:001 than nC. In nC, but not in C, IR and b-cell function correlated with the main anthropometric and metabolic confounders. Nevertheless, signi®cant allele average effects by TH-STR and INS- FokI polymorphisms on IR and b-cell function were not observed in C. In conclusion, C has a lower degree of IR and a preserved b-cell function in comparison to nC, but the cause of such metabolic differences, which are likely does not lie in this genomic region. q 2001 Elsevier Science Inc. All rights reserved. Keywords: Human longevity; Centenarians; Glucose metabolism; TH±INS genes 1. Introduction Advancing age is associated with impaired glucose handling  Paolisso et al., 1999), which is mainly due to an age-related raise in insulin resistance, not fully compensated by a suf®cient b-cell function Chen et al., 1985). Such age related metabolic changes are the key risk factors for non-insulin dependent diabetes mellitus Lillioja et al., 1993; Pimenta et al., 1995; Haffner et al., 1995), and associated with a variety of intermediate phenotypes hypertension, athero- sclerosis, obesity) strongly affecting morbidity, disability and mortality among elderly Harris et al., 1987; Wilson et al., 1986; Wingard et al., 1990). Thus, Experimental Gerontology 37 2001) 149±156 0531-5565/01/$ - see front matter q 2001 Elsevier Science Inc. All rights reserved. PII: S0531-556501)00148-6 www.elsevier.com/locate/expgero * Corresponding author. Tel.: 139-81-5665016; fax: 139-81- 5665051. E-mail address: gpaoliss@tin.it G. Paolisso).