Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Longevity medicine:upskilling the physicians of tomorrow

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Equol-Stimulated Mitochondrial Reactive Oxygen Species Activate Endothelial Nitric Oxide Synthase and Redox Signaling in Endothelial Cells:Roles for F-Actin and GPR30

We reported previously that dietary isoflavones modulate arterial blood pressure in vivo and that the daidzein metabolite equol rapidly activates endothelial NO synthase (eNOS) via Akt and extracellular signal–regulated kinase 1/2– dependent signaling. In this study, we report the first evidence in human endothelial cells that acute stimulation of mitochondrial superoxide generation by equol (100 nmol/L) is required for eNOS activation. Scavengers of superoxide (superoxide dismutase and manganese [III] tetrakis[1-methyl-4-pyridyl]porphyrin) abrogated equol stimulated Akt and eNOS phosphorylation, and the mitochondrial complex I inhibitor rotenone inhibited Akt, extracellular signal–regulated kinase 1/2, and eNOS phosphorylation, as well as NO-mediated increases in intracellular cGMP. Equol also induced rapid alterations in F-actin fiber distribution, with depolymerization of F-actin with cytochalasin D abrogating equol-stimulated mitochondrial superoxide generation. Treatment of cells with pertussis toxin or inhibition of GPR30/epidermal growth factor receptor kinase transactivation prevented equol-induced activation of extracellular signal–regulated kinase 1/2 via c-Src, Akt, and eNOS. Moreover, inhibition of epidermal growth factor receptor kinase activation with AG-1478 abrogated equol-stimulated mitochondrial reactive oxygen species generation and subsequent kinase and eNOS activation. Our findings suggest that equol-stimulated mitochondrial reactive oxygen species modulate endothelial redox signaling and NO release involving transactivation of epidermal growth factor receptor kinase and reorganization of the F-actin cytoskeleton. Identification of these novel actions of equol may provide valuable insights for therapeutic strategies to restore endothelial function in cardiovascular disease

Endothelial dysfunction and reduced antioxidant protection in an animal model of the developmental origins of cardiovascular disease

Endothelial dysfunction underlies cardiovascular disease (CVD) in humans and is reported in animal models of developmental origins of such disease. We have investigated whether impaired antioxidant defences and NO generation underlie the genesis of endothelial dysfunction and operate as part of the normal processes of developmental plasticity regulating the induction of phenotype in the offspring. Female Wistar rats were fed either a control (C, 18% protein) or protein-restricted (PR, 9% protein) diet throughout pregnancy. Dams and pups were returned to standard laboratory chow post partum. In male offspring, PR resulted in a reduced endothelial responsiveness to acetylcholine (P &lt; 0.05) in resistance arteries, with vascular remodelling evident from a reduction in smooth muscle content. mRNA expression of endothelial NO synthase (eNOS) was increased (P &lt; 0.05) but there was no change in mRNA levels of manganese superoxide dismutase (MnSOD) or glutamate cysteine ligase (GCL) expression. Interestingly, expression of the antioxidant enzyme haem oxygenase-1 (HO-1) was reduced in the liver (P &lt; 0.05). Female PR offspring also showed a reduced endothelial responsiveness but exhibited no changes in expression of eNOS, iNOS, soluble guanylate cyclase (sGC) or antioxidant genes. Thus, in this model of the developmental origins of CVD, the structure and function of resistance arteries in offspring is altered in complex ways which cannot simply be explained by attenuation in vascular eNOS or in antioxidant protection afforded by GCL or MnSOD. The dysfunction in male offspring may partially be counteracted by an up-regulation of eNOS expression; however, PR does lead to reduced HO-1 expression in these offspring, which may affect both their growth and vascular function. Our findings have established that PR induces significant phenotypic changes in male offspring that may be indicative of an adaptive response during development<br/

In utero protein restriction leads to a down-regulation of antioxidant gene expression in adult male offspring

In rats, restriction of dietary protein during pregnancy leads to raised blood pressure, impaired vasodilatation (Brawley et al. 2003) and increased oxidative damage (increased protein carbonyl concentration) (Langley-Evans et al. 2005) in the male offspring. The aim of the present study was to assess mRNA expression of three key endothelial antioxidant genes, heme oxygenase-1 (HO-1), glutamate cysteine ligase (GCL) and manganese superoxide dismutase (Mn-SOD), as well as, endothelial nitric oxide synthase (eNOS), in the liver and mesenteric arteries of adult male offspring of protein-restricted rat dams. Pregnant Wistar rats (240 g) were fed either a control diet (C; 18% casein, n = 6) or a protein-restricted diet (PR; 9% casein, n = 6) throughout gestation from conception. At 120 days of age, male offspring were culled and liver and small mesenteric arteries (~250 µm diameter and ~12 arteries per animal) were removed and snap frozen in liquid nitrogen. RNA was extracted and mRNA levels of HO-1, GCL, MnSOD and eNOS were measured using quantitative real-time PCR and normalised with respect to 28S RNA (Mahn et al. 2005). Data are presented as mean ± SEM, and differences assessed by two-way analysis of variance (ANOVA) with significance accepted at p&lt;0.05. The mRNA expression of all three antioxidant genes was reduced in the livers of the PR compared to C male offspring (HO-1: C; 1807 ± 439, n = 11, PR; 424 ± 109, n = 11, p = 0.006, GCL: C; 120 ± 16, n = 11, PR; 70 ± 11, n = 11, p = 0.016, MnSOD: C; 1544 ± 189, n = 11, PR; 1044 ± 101, n = 12, p = 0.027, figures expressed as gene mRNA relative to 28s RNA). Expression in the mesenteric arteries followed the same trend, being reduced by 14% for HO-1, 36% for MnSOD and 36% for GCL but did not reach significance for any of the three genes. The eNOS mRNA expression was not significantly different between the two groups in either tissue type. These findings demonstrate that the previously observed oxidative damage in the offspring of in utero protein-restricted rats (Langley-Evans et al. 2005) may be in part due to a reduced antioxidant enzyme defence. Diminished antioxidant defences may also account for the previously observed vascular dysfunction in the mesenteric arteries due to a nitric oxide–reactive oxygen species imbalance in the PR offspring