It has been suggested that the different rs1042522 frequencies 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 tendencies 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 remarkable. Therefore, when interpreting the results obtained to date, one must take into account the advantages and pitfallsThe GD approach allows identification of favorable or unfavorable alleles/genotypes for longevity at different ages, without introducing arbitrary age classes. It also takes into account cohort effects in mortality changes (15). The approach determines the age at which a genotype affects survival chance, revealing sex-specific allelic effects and possibly pleiotropic effects of an allele during an individual's life (15).

A significant element contributing to the gender-specific association detected here is the estrogen hormone. A strong relationship between estrogen signaling and the estrogen receptor with p53 has been documented, where ER and p53 physically interact, leading to inhibition of p53 function in cell culture and xenograft models (26). Thus, it is conceivable that in women, the inhibition of p53 function can be stronger than in men, especially in TP53*P allele carriers, leading to a significant impairment of apoptotic mechanisms. This event may be associated with an increased risk of cancer, immune senescence, and autoimmunity (27). In this context, it is remarkable that women display an increased risk for autoimmune diseases compared to men (28).

Several suggestions can be made about the gender-specific association of TP53*P72 allele with life expectancy. First, we have to take into account the difference between the two polymorphic p53 variants: the P72 is weaker than the R72 variant in inducing apoptosis and suppressing cellular transformation but appears to be better at initiating senescence and cell cycle arrest (17,18). There is a specific effect of p53 on lifespan (19); modulating p53 has tissue- and stage-specific consequences (19). Ubiquitous overexpression of p53 in adults shortens lifespan in females but slightly increases lifespan in males (20), whereas neuronal expression of the same construct extends lifespan in females and decreases lifespan in males (21). Overexpressing p53 in larval stages is sufficient to extend adult lifespan in both sexes but in a dose-dependent manner, where strong expression is deleterious for lifespan, whereas moderate-to-weak overexpression increases lifespan (20). 

Extensive research over the past two decades has placed p53 at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs. Thus, it is becoming increasingly clear that the opposing effects of various components of the p53 signaling network must be carefully balanced to correctly regulate p53 function and induce the appropriate cellular response (29,30). Under normal conditions, p53 is expressed at a low level and has a short half-life. When cells are exposed to a stressful environment, p53 is activated, resulting in transcriptional regulation of many target genes, including the MDM2 gene. A reduced MDM2-mediated degradation of p53R72 variant compared with p53P72 variant was recently reported (31). Notably, a single nucleotide polymorphism in the MDM2 promoter (SNP309), leading to elevated MDM2 expression and attenuated efficiency of the p53 pathway, is regulated by estrogen signaling (32-34). Interestingly, SNP309 (G/G) seems to have a more significant effect on accelerating tumor formation in a gender-specific (women) and hormonal-dependent manner (35-37). Also, recent results suggest the possibility that SNP309 G allele may contribute to gender-specific tumorigenesis through further elevating the MDM2 levels and disrupting the p53MDM2 oscillation (38). Indeed, a gender-specific gene-gene interaction between the two polymorphisms was found in nonoropharyngeal cancer, where the youngest age at onset was observed in female patients with the combined MDM2 SNP309 G/G and TP53 codon 72 P*/P* genotypes (39). In breast cancer, homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53*P72 carriers (25).

In conclusion, the discrepancies among the results obtained on rs1042522 for longevity in different populations could result from the pleiotropic effects of p53 and the potential ethnic variation of its functional variants. The gender-specific association of rs1042522 with life expectancy clearly claims for future investigations. Manipulating p53 expression in mouse models in p53 dose-specific, mouse tissue-specific, developmental stages specific, and sex-specific manners may further shed light on the role of p53 in aging and longevity in mammals (5). Thus, only a wider analysis of genetic and environmental factors influencing the p53 pathway could definitively address the role of p53 protein in human longevity.

Funding: This work was supported by the Italian Ministry for University, Scientific Research and Technology (PRIN 2008prot. 20089MANHH_002).

References:

Donehower LA. p53: guardian AND suppressor of longevity? Exp Gerontol.; 41(2006): 1212-7.