Thyroid axis challenges in Leiden Longevity Study

The thesis describes the study design and primary outcomes of two challenge studies: one with recombinant human thyroid-stimulating hormone, and the other with triiodothyronine, in members of the Leiden Longevity Study.LUMC / Geneeskund

Familial longevity is associated with an attenuated thyroidal response to recombinant human thyroid stimulating hormone

Context: Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived families (F2-LLS) and their partners (F2-Con). The mechanism underlying this observed difference remains unknown.Objective: We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels.Methods: We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 F2-LLS and 15 similarly aged F2-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations.Results: The AUC free T4/AUC TSH ratio was significantly lower in F2-LLS than in F2-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUCTSH ratio was also lower in F2-LLS than in F2-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07).Conclusions: The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners.Diabetes mellitus: pathophysiological changes and therap

Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH

Context: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear. Objective: Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH). Methods: Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days. Results: At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time p = 0.01, P1NP time p < 0.01); the response was similar between offspring and controls. Conclusions: Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge.Pathophysiology, epidemiology and therapy of agein

Association Between CNDP1 Genotype and Diabetic Nephropathy Is Sex Specific

OBJECTIVE-The 5-5 homozygous CNDP1 (carnosinase) genotype is associated with a reduced risk of diabetic nephropathy. We investigated whether this association is sex specific and independent of susceptibility for type 2 diabetes. RESEARCH DESIGN AND METHODS-Three separate groups of 114, 90, and 66 patients with type 2 diabetes and diabetic nephropathy were included in this study and compared with 93 patients with type 2 diabetes for >15 years without diabetic nephropathy and 472 population control subjects. The diabetes control group was used to determine an association in the three patient groups separately, and the population control group was used to estimate the genotype risk [odds ratio (CI)] for the population in a pooled analysis. The population control subjects were also compared with 562 patients with type 2 diabetes without diabetic nephropathy to determine whether the association was independent of type 2 diabetes. The CNDP1 genotype was determined by fragment analysis after PCR amplification. RESULTS-The frequency of the 5-5 homozygous genotype was 28, 36, and 41% in the three diabetic nephropathy patient groups and 43 and 42% in the diabetic and population control subjects, respectively. The 5-5 homozygous genotype occurred significantly less frequently in women in all three patient groups compared with diabetic control subjects. The genotype risk for the population was estimated to be 0.5 (0.30-0.68) in women and 1.2 (0.77-1.69) in men. The 562 patients with type 2 diabetes without diabetic nephropathy did not differ from the general population (P = 0.23). CONCLUSIONS-This study suggests that the association between the CNDP1 gene and diabetic nephropathy is sex specific and independent of susceptibility for type 2 diabetes. Diabetes 59:1555-1559, 201

Algal assemblages in springs of different lithologies (ophiolites vs. limestone) of the Konjuh Mountain (Bosnia and Herzegovina)

The biodiversity of algal communities and environmental conditions were investigated in the springs of Mt. Konjuh. The assemblages of 20 springs emerging from different lithologies (limestones and ophiolites, respectively) comprised 234 algal taxa. Diatoms and cyanobacteria were the most species-rich groups. The most common alkaliphilic, circumneutral, and eutraphentic diatoms were represented by the genera Gomphonema, Nitzschia, Navicula, Cymbella, and Achnanthidium, and by the cyanobacterial genus Phormidium. Hierarchical clustering and SIMPROF analysis based on relative algal abundance clustered springs into six groups, separating them mainly according to spring type and lithology. Indicator species for groups and springs on different lithological substrata were singled out, revealing 33 taxa with preferences for ophiolites, and 20 taxa with preferences for carbonates. The values of the Shannon-Wiener diversity index were moderately high per spring location, and similar for the two groups of springs on different lithologies. A higher similarity in species composition was noted between springs on ophiolites and limestones than between springs on ophiolites and other types of siliceous substrata. The present study suggests that algal assemblages in springs emerging from ophiolites, even those made up by a preponderance of silicates, should be analyzed separately from those related to springs on other siliceous substrata. The results obtained showed that most of the springs studied are affected by anthropogenic impacts and morphological alterations leading to the dominance of highly competitive meso- and eutraphentic algal species, thus emphasizing the importance of further investigation and conservation of these habitats

Circulating thyroid hormone profile in response to a triiodothyronine challenge in familial longevity

Context: Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown.Objective: We hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls.Methods: In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 mu g 3,5,3'-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration.Results: Circulating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events.T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P= .11, fT3 GLM P= .46).TSH levels decreased in a biphasic manner and started returning to baseline by day 5. TheTSH concentration profile over 5 days was similar between offspring and controls (GLM P= .08), as was the relativeTSH decline (%).Conclusions: Members of long-lived families have neither higherT3 turnover nor diminished negative feedback of T3 on TSH secretion.The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated

Intrinsic carnosine metabolism in the human kidney

Pathophysiology, epidemiology and therapy of agein