A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity

Bonafè, Massimiliano; Olivieri, Fabiola; Cavallone, Luca; Giovagnetti, Simona; Marchegiani, Francesca; Cardelli, Maurizio; Pieri, Carlo; Marra, Maurizio; Antonicelli, Roberto; Lisa, Rosamaria; Rizzo, Maria Rosaria; Paolisso, Giuseppe; Monti, Daniela; Franceschi, Claudio

doi:10.1002/1521-4141(200108)31:8<2357::aid-immu2357>3.0.co;2-x

Cited by 281 publications

(89 citation statements)

References 26 publications

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“…In this regard, we found that subjects homozygous for the IL-6 −174 GG polymorphism had higher plasma levels of IL-6 than carriers of allele C at position −174 [12]. Independent studies found that high IL-6 levels are the major predictor of disability and mortality in the elderly [18].…”

Section: 'Inflammaging'mentioning

confidence: 75%

“…As a result of a variety of experimental data on the absolute numbers and percentages of T and B lymphocyte subsets (naïve, memory and effector cells) [5], natural killer cell numbers and activity [5], autoantibodies (organ-and non-organ-specific) [6,7], complement components and activity [8], number and function of haemopoietic progenitors (CD34 + cells) [9], and cytokine production and polymorphisms [interleukin-1 (IL-1), IL-3, IL-6, IL-7, IL-8, IL-10, stem cell factor, granulocyte/macrophage colony-stimulating factor, tumour necrosis factor α, interferon γ ] [9][10][11][12], among others, we arrived at the general conclusion that immunosenescence represents a complex remodelling, whereby some parameters decrease with age while others increase or remain unchanged [13][14][15][16]. Remodelling suggests that not only a loss of function, but also complex changes in immune function, occur with age.…”

Section: Immunosenescence As Remodellingmentioning

confidence: 99%

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Centenarians as a model for healthy aging

Franceschi

Bonafè

2003

Biochemical Society Transactions

325

186

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For over 10 years we have studied centenarians as a model to address the biological basis of aging and longevity, with particular attention to immunology and genetics. The most important findings can be summarized as follows. (i) Human immunosenescence represents a complex remodelling, whereby clonotypical immunity deteriorates, while ancestral, innate immunity is largely preserved. (ii) Continuous exposure to antigens causes a lifelong, chronic antigenic stress, which is responsible, together with the involution of the thymus, for the accumulation of memory/effector T cells and the exhaustion of naïve T cells. (iii) Aging is characterized by a peculiar chronic inflammatory status that we propose to call 'inflammaging', which appears to be under genetic control, is detrimental for longevity and is more evident in men than in women. Inflammaging, i.e. the up-regulation of a variety of anti-stress responses at the cellular and molecular level, is the consequence of the ability of the body to adapt to and counteract the effects of a variety of stressors, which causes the accumulation of molecular and cellular scars. Inflammaging is considered the common and most important driving force of age-related pathologies, such as neurodegeneration, atherosclerosis, diabetes and sarcopenia, among others, all of which share an inflammatory pathogenesis. (iv) Possible strategies to counteract the major effects of immunosenescence and inflammaging, such as the systematic reduction of the lifelong antigenic load, the elimination of chronic infections, thymic rejuvenation and preventative treatment with anti-inflammatory drugs in people with a pro-inflammatory genotype, are envisaged.

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Section: 'Inflammaging'mentioning

confidence: 75%

Section: Immunosenescence As Remodellingmentioning

confidence: 99%

Centenarians as a model for healthy aging

Franceschi

Bonafè

2003

Biochemical Society Transactions

325

186

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“…First, there is strong evidence that IL-6 levels increase with age [19], and some studies have evaluated alterations in the frequency of IL-6 SNPs with age [20,21]. Moreover, IL-6 and insulin action have had conflicting results in different tissues (organs), such as adipose tissue, skeletal muscle, and liver [22].…”

Section: Discussionmentioning

confidence: 99%

Association between interleukin-6 receptor gene variations and atherosclerotic lipid profiles among young adolescents in Taiwan

et al. 2011

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BackgroundTo analyze the potential genetic associations between four polymorphisms of interleukin-6 receptor (IL-6R) gene and atherosclerotic lipid profiles among young adolescents in Taiwan.MethodsUsing data from the Taipei Children Heart Study-II - a cross-sectional survey in 2003. After multi-stage sampling, we selected 418 boys and 441 girls with an average age of 13.1 years. We genotyped the subjects for four IL-6R gene polymorphisms (rs4845617 G/A, rs4845623 A/G, rs8192284 A/C, and rs2229238 C/T) using a TaqMan 5' nuclease assay. Lipid profiles, including total cholesterol (CHOL), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) were measured using standard methods. We also calculated CHOL/HDL-C ratio, LDL-C/HDL-C ratio, and TG/HDL-C ratio as atherosclerotic indexes.ResultsIL-6R rs8192284 A/C and rs2229238 C/T variants showed strong associations with high TG (additive model, OR = 1.58, 95%CI: 1.05-2.37; OR = 1.55, 95%CI: 1.04-2.29, respectively), low HDL-C (additive model, OR = 1.57, 95%CI: 1.03-2.39; OR = 1.68, 95%CI: 1.12-2.52, respectively), and high CHOL/HDL-C (additive model, OR = 1.68, 95%CI: 1.08-2.61, OR = 1.82, 95%CI: 1.18-2.79, respectively) in girls. We inferred five common haplotypes using rs4845617 G/A, rs4845623 A/G, and rs2229238 C/T (GAC, GAT, GGC, AAC, and AAT). In girls, the AAT haplotype was associated with a significant risk of high TG, low HDL-C, high CHOL/HDL-C, and abnormal lipid levels (high TG or low HDL-C) when compared with the GAC haplotype (OR range = 3.08-4.40, all p < 0.05).ConclusionThe IL-6R rs8192284 A/C and rs2229238 C/T variants are associated with dyslipidemia in girls, but not in boys. The AAT haplotype of the IL-6R gene (rs4845617 G/A, rs4845623 A/G, and rs2229238 C/T) may play an important role in the pathogenesis of dyslipidemia and atherosclerosis in girls.

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“…Considering the poorer prognosis of males and their higher IL-6 blood levels, Bonafè et al investigated 700 subjects aged 60–110 years, including 323 centenarians [69]. The authors showed that the IL-6 promoter genetic variability at the −174 C/G locus and its effect on IL-6 serum levels clearly influenced longevity in homozygous men.…”

Section: Reviewmentioning

confidence: 99%

Sex and inflammation in respiratory diseases: a clinical viewpoint

et al. 2013

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This review discusses sex differences in the prognosis of acute or chronic inflammatory diseases. The consequences of severe inflammation vary in relation to sex, depending on illness duration. In the majority of acute diseases, males present higher mortality rates, whereas continuous chronic inflammation associated with tissue damage is more deleterious in females. The recruitment of cells, along with its clinical expression, is more significant in females, as reflected by higher inflammatory markers. Given that estrogens or androgens are known to modulate inflammation, their different levels in males and females cannot account for the sexual dimorphism observed in humans and animals from birth to death with regard to inflammation. Numerous studies evaluated receptors, cytokine production, and clinical outcomes in both animals and humans, revealing that estrogens clearly modulate the immune response, but the results are contradictory and difficult to link to hormone concentrations. Even in prepubescent children, the presentation of acute pneumonia or chronic diseases mimics the adult pattern. Several genes located on the X chromosome have been shown to encode molecules involved in inflammation. Moreover, 10% to 15% of the genes from silenced X chromosome may escape inhibition. Females are also a mosaic of cells with genes from either paternal or maternal X chromosome. Therefore, polymorphism of X-linked genes would result in the presence of two cell populations with distinct regulatory arsenals, providing females with greater diversity to fight against infectious challenges, in comparison with the uniform cell populations in hemizygous males. The similarities observed between males and Turner syndrome patients using an endotoxin stimulation model support the difference in gene expression between monosomy and disomy for the X chromosome. Considering the enhanced inflammation in females, cytokine production may be assumed to be higher in females than males. Even if all results are not clear-cut, nonetheless, many studies have reported higher cytokine levels in both male humans and animals than in females. High IL-6 levels in males correlated with poorer prognosis and shorter longevity. A sound understanding of the basic regulatory mechanisms responsible for these gender differences may lead to new therapeutic targets.

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A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity

Cited by 281 publications

References 26 publications

Centenarians as a model for healthy aging

Centenarians as a model for healthy aging

Association between interleukin-6 receptor gene variations and atherosclerotic lipid profiles among young adolescents in Taiwan

Sex and inflammation in respiratory diseases: a clinical viewpoint

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