By the concordance of the present data with the analogous data reported for the HLA-DR locus, which is in linkage disequilibrium with the (A/C)110 polymorphism (Cascino et al. 1993a,b). Indeed, a female-specific association has been reported between some alleles of the HLA-DR locus and longevity (Ivanova et al. 1998). These results clearly indicate that the chromosomal region surrounding HLA-DR and HSP70-1 loci harbors variants that can affect human longevity. The (A/C)110 polymorphism of HSP70-1 may be one of the variants that play this role in the above chromosomal region. The (A/C)110 marker lies in HSF1-HSE binding domain of HSP70-1 (Abravayata et al. 1991). Although this polymorphism was reported not to affect either HSE-HSF binding or hsp70 protein synthesis (Favatier et al. 1999), the possibility that allele (A)110 and allele (C)110 may have slightly different binding efficiency in very old organisms is a reasonable hypothesis. In fact, from a biological point of view, aging is a stressful condition which implies a profound reshaping of most physiological functions (Franceschi et al. 2000c). Allele (A)110 may have lower efficiency than allele (C)110 in coping with such a stressful condition, which is also accompanied byFavatier F, Jacquier-Sarlin MR, Swierczewski E and Polla - Polymorphism in the regulatory sequence of the human hsp gene does not affect heat shock factor binding or shock protein synthesis. Cell Mol Life Sci: Feder ME and Hofmann GE - Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol: Franceschi C, Valensin S, Bonafe M, Paolisso G, Yashin AI, Monti D and De Benedictis G (a) The network and the remodeling theories of aging: historical background and new perspective. Exp Gerontol: Franceschi C, Motta L, Valensin S and the Italian Multicenter on Centenarians (b) Do men and women follow different trajectories to reach extreme longevity? Aging Clin Exp Res: Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca Ottaviani E and De Benedictis G (c) Inflamm-aging: evolutionary perspective on immunosenescence. Ann N Y Acad Sci USA: Garasto S, Rose G, Derango F, Berardelli M, Corsonello A, Feraco E, Mari V, Maletta R, Bruni A, Franceschi C, Carotenuto L and De Benedictis G - The study of APOA,APOC  and variability in healthy ageing people reveals another paradox in the oldest old subjects. Ann Hum Genet: Gutsmann-Conrad A, Heydari AR, You S and Richardson A - The expression of heat shock protein decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp Cell Res: Ivanova R, Fhenon N, Lepage V, Charron D, Vicaut E and Schachter F - HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity. Hum Mol Genet: On the other hand, it is intriguing to note that HSF-1 is under positive regulation by estrogen hormones (Yang et al. 1995; Knowlton and Sun 2001), and this is in line with the different effects of (A/C)110 alleles in the two genders. It is worth noticing, however, that a variety of genes affecting longevity in a sex-specific way have been reported, both for humans (Ivanova et al. 1998; Tan et al. 2001; De Luca et al. 2001; Bonafe et al. 2001; Lio et al. 2002) and model organisms (Jackson et al. 2002; Leips and Mackay 2002). Since the present study is a cross-sectional one, mortality of genotypes may depend on the birth year of the cohort for oldest-old people (De Benedictis et al. 2001). If this were the case, the (A/C)110 polymorphism may affect survival in historically specific environments, rather than longevity. In any case, the study carried out in a well-defined and homogeneous population has shown that the allele (A)110 of the HSP70-1 gene, which is a strong candidate for affecting lifespan on the basis of studies in model organisms, is unfavorable to longevity in women. physiology. Annu Rev Physiol: Franceschi C, Valensin S, Bonafe M, Paolisso G, Yashin AI, Monti D and De Benedictis G (a) The network and the remodeling theories of aging: historical background and new perspective. Exp Gerontol: Franceschi C, Motta L, Valensin S and the Italian Multicenter Study on Centenarians (b) Do men and women follow different trajectories to reach extreme longevity? Aging Clin Exp Res: Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E and De Benedictis G (c) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci USA: Garasto S, Rose G, Derango F, Berardelli M, Corsonello A, Feraco E, Mari V, Maletta R, Bruni A, Franceschi C, Carotenuto L and De Benedictis G - The study of APOA,APOC and APOA variability in healthy aging people reveals another paradox in the oldest old subjects. Ann Hum Genet: Gutsmann-Conrad A, Heydari AR, You S and Richardson A - The expression of heat shock protein decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp Cell Res: Ivanova R, Fhenon N, Lepage V, Charron D, Vicaut E and