Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Assessment of sella turcica area and skeletal maturation patterns of children with unilateral cleft lip and palate.

OBJECTIVES: The aim of this case-control study was to assess sella turcica area and skeletal maturity in children with unilateral cleft lip and palate (UCLP) and compare with those of non-cleft children. SETTING AND SAMPLE POPULATION: A total of 85 UCLP patients aged 7.5-17.08 years (Group 1: age 7-11 years, Group 2: age 11-14 years and Group 3: age 14-18 years) were compared with 85 control subjects without clefts who were divided into similar age groups. MATERIALS AND METHODS: Hand-wrist radiographs and cervical vertebra maturation stages (CVMS) were used to evaluate growth. Lateral cephalograms were traced, and reference points of sella were determined. Sella turcica area was measured using a digital planimeter. RESULTS: Comparison of overall growth on hand-wrist radiographs revealed no significant difference between cleft and non-cleft subjects. However, according to the chronological age groups, Group 1-UCLP showed statistically significant delay in skeletal maturation when compared with the age-matched control subjects (P = .05). This difference was due to the delay among male subjects (P = .05). As for CVMS, more significant maturation delay was observed in Group 1-UCLP (P = .001) and was attributable to both male and female subjects (P = .05). Comparison of sella turcica area showed no significant difference between UCLP patients and controls. CONCLUSION: Although children with CLP showed significant delay in growth when they are younger compared with the non-cleft children, sella turcica area measurements were similar for individuals in both groups.

The effects of forskolin and rolipram on cAMP, cGMP and free fatty acid levels in diet induced obesity.

Obesity is a major health problem. We investigated the effects of forskolin and rolipram in the diet of animals in which obesity had been induced. We used 50 female albino Wistar rats that were assigned randomly into five groups as follows: group 1, control; group 2, high fat diet; group 3, high fat diet + forskolin; group 4, high fat diet + rolipram; and group 5, high fat diet + rolipram + forskolin. The rats were fed for 10 weeks and rolipram and forskolin were administered during last two weeks. The animals were sacrificed and blood samples were obtained. Serum cAMP, cGMP and free fatty acids (FFA) levels were measured using ELISA assays. We also measured weight gain during the 10 week period. cAMP and FFA levels of groups 3, 4 and 5 were significantly higher than those of groups 1 and 2. We found no significant differences in serum cGMP levels among the groups. The weight gain in groups 3, 4 and 5 was significantly less than for group 2. We also found that the weight gain in group 5 was significantly less than in groups 3 and 4. We found that both forskolin and rolipram stimulated lipolysis and inhibited body weight increase by increasing cAMP levels. Also, combination therapy using the two agents may be more effective in preventing diet induced obesity than either agent alone. We found also that these agents did not effect cellular cGMP levels in diet induced obesity.

A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease.

Obesity and the associated pathologies including dyslipidemia, insulin resistance, type 2 diabetes, and cardiovascular disease constitute a major threat to global human health. Yet, the genetic factors that differentially predispose individuals to this cluster of pathologies are unclear. The fatty acid-binding protein aP2 is a cytoplasmic lipid chaperon expressed in adipocytes and macrophages. Mice with aP2 deficiency are partially resistant to obesity-induced insulin resistance and type 2 diabetes, have lower circulating triglycerides, and exhibit marked protection against atherosclerosis. Here, we demonstrate a functionally significant genetic variation at the aP2 locus in humans that results in decreased adipose tissue aP2 expression due to alteration of the CAAT box/enhancer-binding protein binding and reduced transcriptional activity of the aP2 promoter. In population genetic studies with 7,899 participants, individuals that carry this T-87C polymorphism had lower serum triglyceride levels and significantly reduced risk for coronary heart disease and type 2 diabetes compared with subjects homozygous for the WT allele. Taken together, our results indicate that reduction in aP2 activity in humans generate a metabolically favorable phenotype that is similar to aP2 deficiency in experimental models.

The mammalian target of rapamycin regulates C2C12 myogenesis via a kinase-independent mechanism.

Rapamycin inhibits differentiation of mouse C2C12 myoblasts, a tissue culture model for skeletal muscle differentiation. The mechanism by which a rapamycin-sensitive signaling pathway regulates myogenesis is largely unknown. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation, but its role in myogenesis has not been examined directly. Here we report the investigation of the function of mTOR and its downstream effectors in muscle differentiation. Rapamycin exerts an inhibitory effect on C2C12 myogenesis at different stages, implying that a rapamycin-sensitive pathway may be required for multiple processes during muscle differentiation. The mTOR protein level increases 10-fold during differentiation, via a post-transcriptional mechanism. As the first direct demonstration of the essential role of mTOR in muscle differentiation, we show that a rapamycin-resistant mTOR, but not S6 kinase 1, can rescue rapamycin-inhibited myogenesis. Remarkably, the myogenic function of mTOR does not require its kinase activity. Two downstream effectors of the rapamycin-sensitive pathway, S6 kinase 1 and eIF4E-binding protein 1, undergo differential regulation during myogenesis, but neither protein is the relevant effector for the myogenic signaling of mTOR. Taken together, our observations suggest a novel mTOR signaling mechanism essential for skeletal muscle differentiation.

A comparison of different treatment techniques for posterior crossbite in the mixed dentition.

In this retrospective investigation, the changes occurring during the treatment of patients with posterior crossbite in the mixed dentition with the use of expansion plate and quad-helix appliances were evaluated and compared with those resulting from growth and development occurring in a control group of patients of similar age and type of malocclusion. The expansion plate group consisted of 13 patients, the quad-helix group of 14 patients, and the control group consisted of 10 children with transverse posterior crossbites in the mixed dentition. The research material was formed from orthodontic models and lateral and frontal cephalometric radiographs from 37 children. It was observed in this investigation that transverse expansion is achieved by both the expansion plate and quad-helix appliances. However, the average period of treatment was 1.2 years for the expansion plate, and 0.6 years for the quad-helix appliance. Although posterior crossbite was corrected in a fairly short period of time, the quad helix appliance caused considerable buccal tipping of the maxillary first permanent molars.

The effects of Frankel's function regulator (FR-4) therapy on the treatment of Angle Class I skeletal anterior open bite malocclusion.

The present study attempts to evaluate cephalometrically the effects of Fränkel's function regulator (FR-4) appliance on the treatment of Angle Class I skeletal anterior open bite malocclusion. Forty Turkish children (26 girls and 14 boys), with Angle Class I skeletal anterior open bite, were randomly divided into two groups of 20 (13 girls and 7 boys). Patients who had not undergone treatment served as the control group, whereas a second group was treated with lip-seal training and the FR-4 appliance. Chronologic mean decimal age at initial period of the investigation was 8.7 years in the treated group, and 8.9 years in the control group. Treatment and observation periods were 2 years. Investigation was carried out on lateral cephalograms taken before and after the study period. The results indicate that a spontaneous downward and backward growth direction of the mandible observed in the control group could be changed to a upward and forward direction by FR-4 therapy. The skeletal anterior open bite was successfully corrected through upward and forward mandibular rotation.