Metabolic gene polymorphisms and p53 mutations in healthy centenarians and younger controls

L. Gaspari, P. Pedotti, M. Bonafè, C. Franceschi, D. Marinelli, D. Mari, S. Garte, and E. Taioli* conducted a study to gain insights into the genetic mechanisms of aging by examining the frequency of polymorphisms in phase I and phase II genes and several p53 germline mutations in a group of 66 nonagenarians and centenarians in good health and a sample of 150 young healthy volunteers of the same ethnic group.

The researchers discovered a statistically significant difference in the frequency of the GSTT1 deletion and the p53 genotypes between the two groups. The absence of any p53 polymorphisms and GSTT1 deletion and the simultaneous presence of the three p53 polymorphisms and GSTT1 deletion were much more common in young subjects than in centenarians (41.5% vs 26.9% and 8.8% vs 3.8%, respectively).

One hypothesis for this difference is that individuals with both GSTT1 deletion and p53 polymorphisms may accumulate carcinogens, have reduced DNA repair ability, and are therefore more vulnerable to cancer. Another possible explanation is that metabolic genes and p53 affect pathways related to cell aging and death, so certain composite genetic patterns may serve as a generic mechanism to protect against aging and not just chronic diseases.

Longevity is likely related to a complex genetic trait as well as environmental exposures.

Keywords: aging, molecular epidemiology, chronic diseases.

Introduction

Centenarians who reach the extreme limit of human life in good health are an excellent example of successful aging. It is possible that they managed to avoid age-related diseases due to optimal environmental conditions, good lifestyle habits, and genetically determined resistance against age-associated diseases (Johnson 1997). Recently, research has suggested a possible antagonism between living a long life and developing cancer (Leroi et al. 2003).

Individual susceptibility to environmental carcinogens and toxicants is influenced by genetic differences. Many enzymes are involved in the metabolism of and endogenous carcinogens. These enzymes are the products of two major families: phase I (such as the CYP family) and phase II (such as the GST, NAT EH families). Polymorphisms in these genes are very common in the population (Garte et al. 2001) and are associated with various types of cancer (DErrico et al. 1999). In a previous study, we found a significant increase in homozygous deletion of the GSTT1 gene in Italian nonagenarians compared with young healthy subjects (Taioli et al. 2001).

The homozygous CYP1A1 Msp1 restriction fragment length polymorphism (RFLP) has been found to affect levels of expression of the gene (Garte et al. 2003) and has been shown to be associated with lung cancer in Europeans (Vineis et al. 2003). The heterozygote polymorphism has no phenotypic effect.

p53 is a nuclear protein that plays a major role in tumour suppression via its involvement in multiple pathways, including apoptosis, cell cycle regulation and arrest, cellular transcriptional control, and DNA repair. The p53 gene is located on chromosome 17p13 and is one of the most commonly mutated genes in different types of human cancer (Hollstein et al. 1991). Besides germline mutations as the basis of the rare familial Li-Fraumeni syndrome (Law et al. 1991), other more common polymorphisms have been found in this gene: in codon 72 in exon 4, a G0C transversion leads to an arginine (Arg) to proline (Pro) change (Miller et al. 2002); in intron 6, there is an Msp1 RFLP consisting of either six or eight variable bases (McDaniel et al. 1991), and a 16 bp duplication has been described in intron 3 (Lazar et al. 1993). These polymorphisms have been associated with lung cancer (Birgander et al. 1995, Biros et al. 2001), breast cancer (Sjalander et al. 1996, Wang-Gohrke et al. 2002), ovarian cancer (Wang- Gohrke et al. 1999), and bladder cancer (Biro et al. 2000). A previous study showed no differences in genotype frequency between healthy centenarians and controls (Bonafè et al. 1999).

Two studies on lung cancer looked at the combined effect of both p53 codon 72 polymorphism and GSTs polymorphisms. Both studies showedthe centenarians were born, compared to the present time. Therefore, it is possible that the observed differences in genotype frequencies are due to environmental exposures that occurred many years ago and have since changed. Nevertheless, our findings suggest that certain combinations of genotypes may play a role in determining longevity and susceptibility to cancer. Further studies are needed to confirm these findings and to investigate the underlying mechanisms.This population was younger and more active than nowadays. Our study included a large number of female centenarians whose reproductive lives included more children than younger females. This could be a contributing factor to longevity. Metabolic gene polymorphisms and p53 mutations in healthy centenarians. Another possible explanation for our findings is that metabolic genes and p53 act on pathways related to cell aging and death. It is known that p53 acts on apoptosis and cell senescence. The accumulation of oxidative processes, such as those found in the presence of deletion of the GST genes, could increase the mechanisms of cell senescence and death associated with p53 polymorphisms. In this case, certain composite genetic patterns would represent a generic mechanism of protection against aging, not just against the development of chronic diseases. Since cancer is not the only disease responsible for short survival, the genes included in our study could also be relevant to other diseases.