Association of CYP19 and ESR1 Pleiotropic Genes with Human Longevity

Rosa Maria Corbo, Laura Ulizzi, Lidia Positano, and Renato Scacchi

CNR Institute of Molecular Biology and Pathology, Rome, Italy. CORISA Consortium, Salerno, Italy.

Email: rosamaria.corbo@uniroma1.it

Aromatase (CYP19) and estrogen receptor-alpha (ESR1) are involved in the metabolism of estrogens, which have a relevant role in female and male aging. Moreover, due to their influence on fertility, both genes may be part of the longevity-fertility trade-off mechanism. In the same sample, we may infer that ESR1 genotypes could exert an antagonistic pleiotropic effect on longevity and fertility.

Key Words: ESR1, CYP19, Polymorphism, Longevity, Longevity-fertility trade-off.

Received June 24, 2010; Accepted August 16, 2010

Decision Editor: Rafael de Cabo, PhD


Research on the longevity-fertility trade-off in humans has nearly always been done using a historic demographic approach (11-12). Despite certain discrepancies in findings, there is evidence for a genetic basis for the longevity-fertility trade-off. Studies on pleiotropic genes have shown that some longevity candidate genes can influence reproductive function as well, thus exerting an action in different periods of life. 

Great efforts have been expended by researchers in the attempt to identify the genes involved in life-span determination (14). Variation in sex hormone (estrogens and androgens) level is a typical feature of aging but the possible impact on the human lifespan of genetic variation of the genes regulating sex hormone production and action has never been investigated before. As a starting point, we examined genes involved in estrogen metabolism. 

Estrogens play a critical role in physiology, bone and lipid metabolism, and maintenance and protection of the cardiovascular and nervous systems (5-7). More recently, similar estrogen functions have been identified in men as well (8). The drastic reduction in estrogen level at menopause marks the beginning of aging for women as it affects the multiple metabolic processes influenced by estrogen early in life. Although not so abrupt, the decline in estrogen is responsible for numerous signs of aging also in men (8). A further point of interest in examining estrogen metabolism genes is that, being involved in the determination of fertility, they could be part of the longevity-fertility trade-off mechanism.

It has been postulated that a trade-off between resources available for reproduction occurs on the one hand and a trade-off between maintenance and lifespan on the other. Because natural selection tends to favor an individual's reproductive ability over longevity, it is plausible that an antagonistic relationship exists between these two mechanisms.

CYP19 is expressed in the ovary and the placenta as well as in a number of extra-gonadal tissues (17). This suggests that CYP19, as it is involved in the production of estrogen, also participates with a regulatory role (17). Recently, CYP19 polymorphisms have been associated with various conditions such as breast cancer and Alzheimer's disease (18-23).

The ESR1 gene encodes for estrogen receptor-alpha (ER-alpha) which is found in all human reproductive tissues. It is expressed primarily with ER-beta encoded by the ESR2 gene on chromosome 14q23-24. ER-beta, co-expressed in a number of tissues including nervous tissue (17). This suggests that ESR1 may have a broader range of actions than previously thought.

Fertility rates were derived from responses to a questionnaire item asking about the number of children the participants reported they had had. The protocol for collection of biologic material for the scientific studies was approved by the institutional ethics committees. Informed consent was obtained from all participants.

Venous blood was drawn in ethylenediaminetetraacetic acid from all participants. Genomic DNA was extracted from whole blood according to the procedure described by Miller and colleagues (30). Two ESR1 polymorphisms (PvuII, or 401T/C, or rs2234693 and XbaI, or 354A/G, or rs9340799) were examined. Both polymorphisms are located in intron 1 of the ESR1 gene in the region of the transcription factor binding site and are closely linked (8). It has been speculated that they change the gene's enhancer activity. There are indications that support this hypothesis, especially for rs2234693 (31-32), although slight differences in enhancer activity were reported for rs9340799 as well (33). Both polymorphisms were genotyped according to the technique of Yaich and colleagues (34) with slight modifications. Specifically, a different primer couple was designed: 5'-AGGGTTATGTGGCA1.023.56, p=.039). ESR1 XX genotypes seem to have less influence on survival (adjusted OR=1.84, 95% confidence interval: 0.88-3.81, p=.10). No significant interaction of ESR1 and CYP19 genotypes with gender was observed. A comparison of the number of children associated with different CYP19 genotypes was performed using a nonparametric test (Kruskal-Wallis). Statistical analyses were performed using Statistix 8.0 analytical software.