The G/C₉₁₅ polymorphism of transforming growth factor β1 is associated with human longevity: a study in Italian centenarians

Abstract

SummarySequence variations in a variety of pro-or anti-inflammatory cytokine genes have been found to influence successful aging and longevity. Because of the role played by the transforming growth factor β β β β 1 (TGF-β β β β 1) cytokine in inflammation and regulation of immune responses, the variability of the TGF-β β β β 1 gene may affect longevity by playing a role in inflamm-aging. Two polymorphisms, G/ A − − − − 800 and C/T − − − − 509 , located in the 5′ ′ ′ ′ region, and two missense polymorphisms, T/C 869 and G/C 915 which change (Leu > Pro) 10 and (Arg > Pro) 25 , respectively, located in the signal peptide, were analysed in 419 subjects from Northern and Central Italy, including 172 centenarians and 247 younger controls. In addition, the effects of the TGF-β β β β 1 genetic variability on plasma levels of the biologically active form (naturally processed) of this cytokine were studied in 143 randomly selected subjects, including 73 centenarians. Significant differences were found at the +915 site as far as the C allele and GC genotype were concerned, both of them being lower in centenarians than in young controls ( P = 0.034 and 0.028, respectively), but none of the other tested genetic variants was significantly different between centenarians and controls. Moreover, a particular haplotype combination (G − − − − 800 /C − − − − 509 /C 869 /C 915 ) was notably lower in centenarians than in younger individuals ( P = 0.007). Finally, active TGF-β β β β 1 plasma levels were significantly increased in the elderly group, but no relationship with TGF-β β β β 1 genotypes was observed. These results suggest that, at least in this population, the variability of the TGF-β β β β 1 gene influences longevity and that the age-related increase in plasma levels of active TGF-β β β β 1 seems not to be genetically regulated.

Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

“…Recently, polymorphisms in a TGF-β binding protein (LTBP) and a TGF-β coreceptor (betaglycan) were found to associate with distinct COPD-related subphenotypes (31,36). Although a connection between TGF-β polymorphisms and serum levels was initially presumed based on a few publications, subsequent studies in larger and more heterogeneous populations have not consistently shown this association (37)(38)(39)(40). Immunohistochemical studies of COPD lung specimens show evidence of enhanced TGF-β signaling predominantly in the airway compartment (41)(42)(43).…”

Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis

“…55,56 In fact, metformin treatment extends life span in the nematode Caenorhabditis elegans and in rodents. [57][58][59][60] We now propose that metformin, by weakening the ability of TGFb signaling to fully induce mesenchymal cell states in a variety of pathological processes including fibrosis, sclerosis and malignant progression (and likely by reducing TGFb-regulated inflammation and immune responsesinflamm-aging), [61][62][63] may provide an attractive therapeutic means to interfere with various age-related chronic diseases, thus molecularly behaving as a bona fide anti-aging modality. .…”

Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

“…Another cytokine gene often suggested is the transforming growth factor beta 1 gene (TGFβ1), which is involved, among others, in regulation of cellular proliferation and differentiation. In TGFβ1, the +915 polymorphism (rs1800471) and a haplotype including rs1800471 have been reported to be of relevance for longevity (Carrieri et al 2004).…”