RESUMEN
Current literature indicates that abrogation of the IGF-I response pathway affects longevity in Caenorhabditis elegans, and that the down-regulation of IGF-I gene expression is associated with an extension of the life span in mice. In this paper we tested the hypothesis that polymorphic variants of IGF-I response pathway genes, namely IGF-IR (IGF-I receptor; G/A, codon 1013), PI3KCB (phosphoinositol 3-kinase; T/C, -359 bp; A/G, -303 bp), IRS-1 (insulin receptor substrate-1; G/A, codon 972), and FOXO1A (T/C, +97347 bp), play a role in systemic IGF-I regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF-IR have low levels of free plasma IGF-I and are more represented among long-lived people. Moreover, genotype combinations at IGF-IR and PI3KCB genes affect free IGF-I plasma levels and longevity. These findings represent the first indication that free IGF-I plasma levels and human longevity are coregulated by an overlapping set of genes, contributing to the hypothesis that the impact of the IGF-I/insulin pathway on longevity is a property that has been evolutionarily conserved throughout the animal kingdom.
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , Longevidad/genética , Fosfatidilinositol 3-Quinasas/genética , Polimorfismo Genético , Receptor IGF Tipo 1/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Proteínas de Unión al ADN/genética , Evolución Molecular , Femenino , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead , Frecuencia de los Genes , Genotipo , Humanos , Insulina/metabolismo , Masculino , Persona de Mediana Edad , Factores de Transcripción/genéticaRESUMEN
The human forkhead box O1A (FOXO1A) gene belongs to the human forkhead gene family and acts downstream of the human insulin signalling pathway. In this study, polymorphisms of the Intron I of FOXO1A gene were studied in Italian healthy people and insulin resistant subjects. No significant association between the germ-line variability in the Intron I of FOXO1A and insulin resistance was observed. Interestingly, during the study, a new 39-bp sequence insertion polymorphism in Intron I of FOXO1A gene was described. The polymorphism was found to co-segregate in a co-dominant Mendelian fashion and to be present in an ethnically distinct population (Greeks). A BLAST search showed that the sequence shares 100% identity with a mtDNA (mitochondrial DNA) sequence coding for the ATP synthase 8 (ATPase8) and ATP synthase 6 (ATPase6) genes. Hence, FOXO1A Intron I is a polymorphic nuclear region involved in the exchange of DNA material between mitochondrial and genomic DNA, which is a well-established mechanism of evolutionary change in eukaryotes.
Asunto(s)
ADN Mitocondrial/genética , Proteínas de Unión al ADN/genética , Intrones/genética , Mutagénesis Insercional , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Adenosina Trifosfatasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , ADN/química , ADN/genética , Análisis Mutacional de ADN , Femenino , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Resistencia a la Insulina/genética , Italia , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Linaje , Eliminación de SecuenciaRESUMEN
In this study, we analysed the polymorphic variants of IL-1alpha (C-T transition at position -889), IL-1beta (C-T transition at position -511) and IL-1 receptor antagonist (Ra) (86-bp repeated sequence in intron 2) in 1131 subjects (453 females and 678 males) from Northern and Central Italy, including 134 centenarians, to evaluate whether IL-1 cluster alleles might be differently represented in people selected for longevity. In addition, IL-1Ra and IL-1beta plasma levels were quantified by ELISA in 130 randomly selected subjects. No significant differences in the genotype and allele frequency distributions were observed between young, elderly and centenarian subjects. IL-1Ra plasma levels showed an age-related increase, whereas IL-1beta plasma levels did not show any detectable age-related trend. Neither IL-1Ra nor IL-1beta plasma levels showed any relationship with genotypes of the three IL-1 genes. These results suggest that no one particular polymorphism in the IL-1 gene cluster yields an advantage for survival in the last decades of life, and that the age-related increase in plasma levels of IL-1Ra seems not to be genetically regulated but a likely safeguard mechanism to buffer the age-associated increased inflammatory state.
Asunto(s)
Interleucina-1/genética , Longevidad/genética , Longevidad/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/inmunología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Interleucina-1/sangre , Italia , Masculino , Persona de Mediana Edad , Familia de Multigenes , Polimorfismo Genético , Distribución AleatoriaRESUMEN
In the present investigation we analysed Interleukin 6 (IL-6) in vitro production by Epstein-Barr virus (EBV)-immortalized B lymphocytes established from 43 subjects, 15 young people and 28 elderly people, including 18 centenarians, after 3, 6, 9, 24, 48 and 72 h of culture. The subjects were genotypized for the C to G transition at nucleotide -174 of IL-6 gene promoter (-174 C/G) and were classified as C allele carriers (C+) and non-carriers (C-). We found that: (i) the interindividual difference in in vitro IL-6 production was wider in elderly individuals in respect to young individuals, leading to different coefficient of variation in the two groups; (ii) the -174 C/G polymorphism had an age-related effect on IL-6 in vitro production. Only among C- people, cells from elderly subjects produced significant higher level of IL-6 than cells from young subjects. These data are consistent with our previous results regarding the IL-6 serum levels in a large group of people of different age, including centenarians. Thus, the EBV-immortalized B lymphocytes can be considered a useful in vitro model for studying the genetic control of IL-6 production and its changes with age.
Asunto(s)
Envejecimiento/genética , Envejecimiento/inmunología , Linfocitos B/fisiología , Interleucina-6/genética , Interleucina-6/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Transformada , Femenino , Genotipo , Herpesvirus Humano 4/genética , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
IL-6 in vitro production, as well as the serum/plasma concentration of the cytokine, increase with age. In the present investigation, a total of 62 individuals (31 males and 31 females), aged from 29 to 93 years of age (mean age of males: 60.4 years; mean age of females: 59.4 years) were assessed for IL-6 plasma concentration, and for IL-6 in vitro production, using supernatants of 4h cultured adherent peripheral blood mononuclear cells (aPBMC). The subjects were examined for a C to G transition at nucleotide -174 of the IL-6 gene promoter (-174 C/G locus), and were classified as C allele carriers (C+) or non-carriers (C-). We found that: (i) aPBMC from C+ individuals produced smaller amounts of IL-6 in vitro than C- individuals; (ii) IL-6 production by aPBMC increased with age in C+ but not in C- subjects; (iii) there was no correlation between IL-6 plasma levels and in vitro IL-6 production by aPBMC; (iv) IL-6 C+ individuals had lower plasma levels than C- individuals, and this phenomenon was significant only in men. On the whole our data indicate that the production of IL-6 is genetically controlled and age- and gender-dependent.