Discussion

During the last 20 years, the rs1042522 has been extensively studied and numerous findings have been proven to be effective and relevant for some pathogenetic mechanisms underlying common phenotypes and life- threatening diseases. However, its role in aging and longevity still raises several questions and conflicting results. Here, we provide novel evidence for rs1042522 in longevity; in the Central Italy population, we studied, that the TP53*P72 allele influences negatively female life expectancy. We did not detect any association of rs1042522 with longevity in men, a finding consistent with previous studies conducted in Italian (cross-sectional study) and Ashkenazi (case– control) populations (7,8). In contrast to our results, the follow-up study on the cohort of 9,219 participants aged 20–95 years from the Danish general population by Ørsted and colleagues (9) demonstrated an increased frequency of P*/P* homozygotes and the TP53*P72 allele with increasing age toward 90 years. A similar result was obtained in the prospective Leiden 85-plus follow-up study that reported a 1.41-fold increase in survival of carriers of the P*/P* genotype compared with R*/R* carriers (p = .032 [10]). However, contrary to the study of Ørsted and colleagues (9), no survival benefit was noticed for the R*/P* genotype, survival being 0.95-fold lower (p = .550 [10]). Both the longitudinal studies (9,10) used gender- adjusted hazard ratios, whereas the Italian cross-sectional study (7) was conducted on the whole population enrolled without stratifying by gender.

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Results

The allele and genotype frequency distributions of the rs1042522 were compared among the age classes, men and women separately (Table 1). No significant deviation from Hardy–Weinberg Equilibrium expectation was detected among the gender-specific age classes. The genotype dis- tribution and the allele frequency in Age Class 1 (women + men) are comparable to that previously reported for Italian population (p > .205 [6]). Therefore, the sample can be con- sidered a representative sample of the continental Italian population. The rs1042522 affects female longevity, show- ing significant associations in Comparison 2 (Age Class 3 vs Age Class 2) under both additive (common oR 0.574; p = .006] and dominant (oR 0.513; 95% ci 0.317–0.830; p = .006) genetic models (Table 1). The P72* allele is sig- nificantly underrepresented in Age Class 3 only in women (Comparison 2: allele, oR 0.575; 95% ci 0.381–0.866; p = .008).

As the GD method requires the assumption of domi- nance of an allele upon the other, a P72* > R72* dominant relationship was assumed. Figure 1 shows the maximum likelihood estimates of the survival functions of TP53*P72 carriers (P*/P* plus P*/R* participants (blue curve) and of R*/R* participants (red curve), compared with the general Italian population (green curve). Panel A shows the female population, whereas panel B shows the male one.

It has been suggested that the different rs1042522 fre- quencies between young and long-living people observed in different populations can be explained by hypothesizing that TP53 genotypes may differently predispose to diverse age- related diseases. Thus, the genotype frequencies observed in centenarians (or long-living people) could be the result of a population-specific balancing between opposite ten- dencies toward an increased or decreased risk of different life-threatening diseases (cancer, cardiovascular diseases, etc.). Furthermore, the presence of different study designs (from case–control to prospective follow-up) is remark- able. Therefore, when interpreting the results obtained to date, one must take into account the advantages and pitfalls of each methodological approach used. It is also notewor- thy that rs1042522 heterozygotes show opposite mortality risk in the two prospective follow-up studies conducted in Dutch and in Danish populations (9,10).

In women, the survival curve of P72* carriers shows a prevalent best survival chance along the most part of life, respect the survival of noncarriers. The difference between survival curves is not significant, so we cannot reject the null hypothesis that the survival functions of carriers (SA(x)), noncarriers (SB(x)), and the female population (S(x)), are equal (p = .115). However, around 85 years of age, in women, we observe a crossing of the survival curves, suggesting that carrying the allele P72* is disadvan- tageous after this age.

The analysis of the differences between the survival esti- mations age by age showed that the age of intersection is x = 82 years. Indeed, the frequency of allele P72* carriers is 53% in the age class 18–82 years (154 carriers and 133 noncarriers), whereas it is reduced to 40% in the age class 83–106 years (114 carriers and 168 noncarriers), and the