Results: To evaluate the involvement of the ESR1 and CYP19 polymorphisms in longevity, ESR1 and CYP19 genotype frequencies observed in the long-lived participants were compared with those observed in the participants who had died before the age of 90 years (controls). The results are reported in Table 1. In both the control and the long-lived groups, the genotype frequencies of ESR1 PvuII and XbaI polymorphisms agreed with those expected according to Hardy-Weinberg equilibrium. The ESR1*Pall allele frequencies in the controls and the long-lived were 0.488 and 0.528, respectively. The ESR1*X allele frequencies in the controls and in the long-lived were 0.488 and 0.543, respectively. Because of the proximity of the two ESR1 RFLPs, the linkage disequilibrium between them was analyzed. They were in strong linkage disequilibrium in both samples (p<.0001), with a tendency of the ESR1*P allele to be associated with ESR1*X and ESR1*p to be associated with ESR1*x. Consequently, as shown by the combined distribution of ESR1 genotypes (Table 1), more than 90% of ESR1 PP homozygotes of both groups were XX homozygotes as well. A comparison of genotype distributions between the long-lived and the controls (Table 1) shows that there was an excess of PP (29.6% vs. 18.8%, p=.08) and XX (27.7% vs. 20.0%, p=.22) genotypes in the long-lived versus the controls, although the comparisons (Pearson's goodness-of-fit chi-square) did not reach statistical significance.

To investigate the involvement of the two genes in polymorphisms on past fertility of the same sample population, ppxx genotypes were found to be associated with an above-average number of children among the men, whereas among the women, the difference in the number of children among the three genotypes was insignificant. The data on spontaneous abortions were not reported (Table 3).

Discussion: The aim was to avoid the cohort effect observed in studies on human longevity when the control sample is composed of younger participants belonging to birth cohorts that may have experienced different environmental effects from those experienced by older participants. Furthermore, using younger controls whose lifespan is unknown may introduce some bias. The present study shows that genes (and estrogen) are involved not only in reproduction but also in aging and that they may exert a pleiotropic action across the whole course of human life. The possible importance of these studies is that they may help to elucidate the aging process and to identify the proper strategies for slowing and/or mitigating its effects.

The ESR1 PvuII polymorphism seems to have a greater impact than XbaI on estrogen action, although the real impact of ESR1 polymorphisms on longevity is still unclear. It is surprising as estrogen influences various different physiological processes and is involved in the pathogenesis of many diseases of advanced age which, in turn, influence the lifespan of both men and women. In agreement with this observation, ESR1 and CYP19 genetic polymorphisms in relation to cardiovascular disease, Alzheimer's disease (5, 18-23, 25-27) have been reported.

Funding: This work was supported by the Italian National Research Council and La Sapienza University grants.This is not a complete sentence or text. Please provide the full text you want me to proofread and improve.