Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1.

Lifespan in Caenorhabditis elegans, Drosophila, and mice is regulated by conserved signaling networks, including the insulin/insulin-like growth factor 1 (IGF-1) signaling cascade and pathways depending on sirtuins, a family of NAD(+)-dependent deacetylases. Small molecules such as resveratrol are of great interest because they increase lifespan in many species in a sirtuin-dependent manner. However, no endogenous small molecules that regulate lifespan via sirtuins have been identified, and the mechanisms underlying sirtuin-dependent longevity are not well understood. Here, we show that in C. elegans, two endogenously produced small molecules, the dauer-inducing ascarosides ascr#2 and ascr#3, regulate lifespan and stress resistance through chemosensory pathways and the sirtuin SIR-2.1. Ascarosides extend adult lifespan and stress resistance without reducing fecundity or feeding rate, and these effects are reduced or abolished when nutrients are restricted. We found that ascaroside-mediated longevity is fully abolished by loss of SIR-2.1 and that the effect of ascr#2 requires expression of the G protein-coupled receptor DAF-37 in specific chemosensory neurons. In contrast to many other lifespan-modulating factors, ascaroside-mediated lifespan increases do not require insulin signaling via the FOXO homolog DAF-16 or the insulin/IGF-1-receptor homolog DAF-2. Our study demonstrates that C. elegans produces specific small molecules to control adult lifespan in a sirtuin-dependent manner, supporting the hypothesis that endogenous regulation of metazoan lifespan functions, in part, via sirtuins. These findings strengthen the link between chemosensory inputs and conserved mechanisms of lifespan regulation in metazoans and suggest a model for communal lifespan regulation in C. elegans.

Human intestinal fatty acid binding protein 2 expression is associated with fat intake and polymorphisms.

The intestinal fatty acid binding protein (FABP2) is involved in lipid metabolism whereby variations in the promoter (haplotypes A/B) and exon 2 (Ala54Thr) are associated with dyslipidemia and insulin resistance. To elucidate which factors determine FABP2 expression in human mucosa, we investigated the association between fat intake, genotypes, biochemical variables, and FABP2 expression. FABP2 gene expression was assessed in duodenal specimens from 100 participants who answered a FFQ and who were genotyped and characterized for traits of metabolic syndrome and further biochemical data. Homozygotes for haplotype A tended to have lower fat intake than B-allele carriers (P = 0.066). Searching for an explanation, we evaluated the orexigenic glucose-dependent insulinotropic polypeptide (GIP) in a subset from the Metabolic Intervention Cohort Kiel. AA homozygotes had lower postprandial GIP concentrations than BB homozygotes. Duodenal FABP2 expression was correlated with (n-3) fatty acid (FA) intake in AA homozygotes (r = 0.49; P = 0.021). It was higher in AA homozygotes than in B-allele carriers after adjustment for (n-3) FA intake (P = 0.049) and was negatively correlated with serum FFA (r = -0.41; P < 0.01). Our data indicate that FABP2 expression depends on (n-3) FA intake and FABP2 genotypes. FABP2 might be involved in regulating food intake and intestinal FA utilization.

Effect of quercetin on paraoxonase 2 levels in RAW264.7 macrophages and in human monocytes--role of quercetin metabolism.

There is increasing evidence that the intracellular antioxidant enzyme paraoxonase 2 (PON2) may have a protective function in the prevention of atherogenesis. An enhancement of PON2 activity by dietary factors including flavonoids is therefore of interest. In the present study we determined the effect of quercetin on paraoxonase 2 levels in cultured murine macrophages in vitro and in overweight subjects with a high cardiovascular risk phenotype supplemented with 150 mg quercetin/day for 42 days in vivo. Supplementation of murine RAW264.7 macrophages in culture with increasing concentrations of quercetin (1, 10, 20 micromol/L) resulted in a significant increase in PON2 mRNA and protein levels, as compared to untreated controls. Unlike quercetin, its glucuronidated metabolite quercetin-3-glucuronide did not affect PON2 gene expression in cultured macrophages. However the methylated quercetin derivative isorhamnetin enhanced PON2 gene expression in RAW264.7 cells to similar extent like quercetin. Although supplementing human volunteers with quercetin was accompanied by a significant increase in plasma quercetin concentration, dietary quercetin supplementation did not change PON2 mRNA levels in human monocytes in vivo. Current data indicate that quercetin supplementation increases PON2 levels in cultured monocytes in vitro but not in human volunteers in vivo.

Whole-grain consumption and transcription factor-7-like 2 ( TCF7L2) rs7903146: gene-diet interaction in modulating type 2 diabetes risk.

Whole grains are known to influence postprandial glucose response and insulin demand and are inversely associated with diabetes risk. Genetic variation of the transcription factor-7-like 2 encoding gene (TCF7L2) is assumed to promote an early insulin secretory defect and has been consistently attributed to the risk of developing type 2 diabetes. The present study examined the hypothesis that the protective effect of whole grains might be attenuated in the presence of the rs7903146 risk-conferring T-allele. We employed a case-cohort study of 2318 randomised individuals and 724 incident type 2 diabetes cases from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. Multivariate Cox regression was used to estimate relative risks of diabetes including product terms testing for the genotype-specific effect modification of dietary whole grain. Dietary intake of whole grains was assessed by a validated FFQ. The TCF7L2 rs7903146 T-allele was associated with type 2 diabetes (hazard ratio=1.51; 95 % CI 1.21, 1.87) and modified the inverse association between whole-grain intake and diabetes risk (P=0.016 for interaction). While whole-grain intake was inversely associated with diabetes risk among rs7903146 CC homozygote carriers (hazard ratio for 50 g portion per d=0.86; 95 % CI 0.75, 0.99), the T-allele negated the protective effect of whole-grain intake (hazard ratio among T-allele carriers for 50 g portion per d=1.08; 95 % CI 0.96, 1.23). These data provide evidence that the beneficial effect of whole-grain intake on diabetes risk is modified by TCF7L2 rs7903146.

Vitamin E dependent microRNA regulation in rat liver.

Dietary vitamin E (VE) is known to regulate gene expression by altering mRNA concentrations. Recently, microRNA (miRNA) have been discovered as a means of posttranscriptional gene regulation. Since the effect of VE on miRNA regulation is unknown, we fed rats for 6 months diets deficient or sufficient in VE and determined hepatic concentrations of miRNA involved in processes previously associated with VE (lipid metabolism, miRNA-122a; cancer and inflammation, miRNA-125b). VE-deficiency resulted in reduced concentrations of miRNA-122a and miRNA-125b. The findings of the present study demonstrate that differences in dietary VE may affect hepatic miRNA concentrations in vivo.

IGF-1 Gene Expression in Rat Colonic Mucosa After Different Exercise Volumes.

The evidence is increasing for a close link between the insulin/insulin-like growth factor (IGF) system and colon cancer prevention by physical exercise. To reveal exercise-induced alterations in colon mucosa, gene expression of IGF-1 and related genes and serum IGF-1 were investigated. Twenty male Wistar rats performed a 12 week voluntary exercise program. Nine rats served as the control group. Gene expression of IGF-1, IGF-1 receptor (IGF-1R) and IGF-binding protein 3 (IGF-BP3) were quantified by real-time RT-PCR. Circulating IGF-1 was analyzed exercise volume-dependent. Based on 3 distinguished groups with low (L-EX, <2629 m·night(-1)), medium (M-EX, 3003-7458 m·night(-1)) and high exercise volume (H-EX, >8314 m·night(-1)), we observed lower serum IGF-1 levels (P < 0.05) in all exercise groups as compared to the control group and IGF-1 levels declined proportional to the increase in exercise volume. A significant (p < 0.05) positive correlation was found between IGF-1 concentration and body mass (r = 0.50) and a significant negative correlation exists between body mass and exercise volume (r = -0.50). Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. Based on our data we propose that the exercise as well as the body mass reduction leads to a decrease in circulating IGF-1 and this might represent a prime link to colon cancer prevention. Key pointsThere were significantly lower serum IGF-1 levels in all exercise groups as compared to the control group.GF-1 levels declined proportional to the increase in exercise volume.A significant positive correlation was found between IGF-1 concentration and body mass and a significant negative correlation was found between body mass and exercise volume.Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed.

A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.

The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B-containing lipoproteins. Emerging evidence has indicated that the functional MTP exon polymorphism I128T is associated with dyslipidemia and other traits of the insulin-resistance syndrome, and the T128 variant seems to confer a reduced stability of MTP, resulting in reduced binding of LDL particles. The aim of the study was to elucidate the association of this MTP polymorphism with parameters of postprandial metabolism. A total of 716 male subjects from a postprandially characterized cohort (MICK) and a nested case-control study (EPIC) of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls were genotyped for the I128T exon polymorphism. In comparison to homozygote subjects of the wild allele, carriers of the less common allele of the MTP T128 genotype showed significantly lower postprandial insulin levels (P=0.017), lower diastolic blood pressure (P=0.049) and had a lower prevalence of impaired glucose metabolism and diabetes type 2 (P=0.03) in the MICK. Consistent with this, we found a lower incidence of type 2 diabetes in male subjects of the nested case-control study in the T128 genotype (P=0.007). These results suggest that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes and other parameters of the metabolic syndrome.