Gender-Specific Association Between FSHR and PPARG Common Variants and Human Longevity

Rosa Maria Corbo, Alessandro Pinto, and Renato Scacchi

Abstract

Men and women have different life expectancies. Not unexpectedly, several genes involved in lifespan determination have been found to influence the probability of achieving longevity differently in men and women. This investigation examines the association between longevity and polymorphisms of follicle-stimulating hormone receptor (FSHR, Asn680Ser polymorphism) and peroxisome proliferator-activated receptor gamma (PPARG, Pro12Ala polymorphism), two genes that previous investigations suggested may exert a gender-specific influence on human longevity. A sample of 277 individuals (mean age, 82.9 ± 5.7 years) was recruited in 2000. Based on mortality data collected in 2009, the sample was divided into two groups of subjects surviving over 90 years (long-lived) or not (controls). The frequency of the FSHR 680 Ser/Ser genotype was significantly higher in the sample of long-lived women compared to controls, indicating that the FSHR 680 Ser/Ser genotype may favor survival to more than 90 years of age only in women (odds ratio [OR] = 4.21; 95% confidence interval [CI], 1.10-16.10, p = 0.036). In contrast, the frequency of the PPARG Pro/Ala genotype was significantly higher in the sample of male subjects who died before 90 years of age than in the long-lived, suggesting that carrying the PPARG Pro/Ala genotype may prevent the attainment of advanced age only in men (OR = 0.13; 95% CI, 0.02-0.79; p = 0.03). We then searched the literature for studies reporting a differential role for the genetic component in male and female longevity. To do this, we selected longevity genes with a gender-specific effect. A review of the studies showed that genetic factors tend to have a greater relevance in determining longevity in men than in women. The possible impact of this phenomenon is discussed.

Introduction

Men and women have different life expectancies, which can be traced back across populations at least to the 18th century. Epidemiological data indicate that the higher mortality of men for all leading causes of death, including accidents and such diseases as cancer or heart disease, influenza, and pneumonia, could account for this gender gap in aging. This widespread phenomenon led researchers to investigate the extent to which human aging and longevity depend on genetic factors. Numerous studies using animal models (Caenorhabditis elegans, Drosophila melanogaster) have helped to identify longevity genes in the strict sense, i.e., those belonging to pathways that delay the onset and/or reduce the rate of aging (e.g., stress resistance and oxidative damage or inflammation or DNA repair). Studies on human longevity have suggested that some polymorphic genes may influence lifespan through their association with common disease.

Not unexpectedly, among the various genetic factors involved in lifespan determination, some have been found to have a gender-specific effect, influencing the probability of achieving longevity differently between men and women.

In this study, we investigated the possible association between longevity and follicle-stimulating hormone receptor (FSHR) and peroxisome proliferator-activated receptor gamma (PPARG), two genes that could have a gender-specific influence on human longevity. The FSHR gene (OMIM 136435), located on chromosome 2p21, encodes the receptor of follicle-stimulating hormone (FSH), a gonadotropin essential for normal reproductive function in males and females. It is a member of the hypothalamic-pituitary-gonadal axis that regulates the production of sex steroids, including estrogen. Its action is mediated by the FSH receptor, a member of the family of G protein-coupled receptors, located on the surface of Sertoli cells in the testis and the granulosa cells in the ovary.

Much research has gone into attempts to clarify to what extent human aging and longevity are dependent on genetic factors. Numerous studies using animal models (Caenorhabditis elegans, Drosophila melanogaster) have helped to identify longevity genes in the strict sense, i.e., those belonging to pathways that delay the onset and/or reduce the rate of aging (e.g., stress resistance and oxidative damage or inflammation or DNA repair). Studies on human longevity have suggested that some polymorphic genes may influence lifespan through their association with common disease.

Results