Steffy W. Jansen

Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis

Subclinical hypothyroidism (SCH), defined as elevated thyroid stimulating hormone (TSH) and normal thyroid hormone levels, and cognitive impairment are both common in older people. While the relation between overt hypothyroidism and cognitive impairment is well established, data on the association between SCH and cognitive impairment are conflicting. This systematic review and meta-analysis was performed to assess available evidence on the association of SCH with cognition in community dwelling, relatively healthy older adults. PubMed, EMBASE, Web of Science, COCHRANE, CINAHL, PsycINFO, and Academic Search Premier (January 1966 to April 1, 2015) were searched without language restrictions, as were references of key articles, for studies on the association between SCH and cognition in older adults (>60 years). These studies were reviewed by two independent reviewers according to predefined criteria for eligibility and methodological quality, and data were extracted using standardized forms. Of the 844 reports initially identified, 270 remained after exclusion of duplicates. Of the 270, 15 studies comprising 19,944 subjects, of whom 1,199 had subclinical hypothyroidism were included. Data from the 15 studies was pooled, and meta-analyzed cross-sectionally for global cognition [assessed by Mini-Mental State Examination (MMSE)], executive function, and memory, using random effects models. Pooled effect size (ES) for MMSE was −0.01 (95% CI −0.09, 0.08), with heterogeneity (I2) of 55.1%. Pooled ES was < 0.001 (95% CI −0.10, 0.09) for executive function (I2 = 13.5%), and 0.01 (95% CI −0.12, 0.14) for memory (I2 = 46.9%). In addition, prospective analysis including four studies showed pooled ES of 0.033 (95% CI −0.001 − 0.067) for MMSE (I2 < 0.001%), indicating that subclinical hypothyroidism was not significantly associated with accelerated cognitive decline. This systematic review and meta-analysis provides no evidence that supports an association between SCH and cognitive impairment in relatively healthy older adults.

Familial Longevity Is Marked by Lower Diurnal Salivary Cortisol Levels: The Leiden Longevity Study

Background Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity. Methods Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors. Results Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28). Conclusion Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed.

Familial Longevity Is Associated With Higher TSH Secretion and Strong TSH-fT3 Relationship

CONTEXT Longevity is associated with changes in circulating levels of thyroid hormone (TH) and/or TSH in animals and humans, but underlying mechanisms remain elusive. OBJECTIVE We explored in 38 offspring of nonagenarian participants from the Leiden Longevity Study, who are enriched for longevity and in their partners, ultradian and circadian rhythmicity of TSH, temporal relationship, and feedback and forward interplay between TSH and TH. METHODS We collected blood samples every 10 minutes for 24 hours for TSH and TH profiles. We used a deconvolution analysis to estimate basal (nonpulsatile), pulsatile, and other secretion parameters to characterize ultradian rhythmicity and locally weighted polynomial regression of TSH to assess circadian rhythmicity. A cross-correlation analysis was used to investigate the temporal relationship between TSH and TH and cross-approximate entropy to assess feedback and forward interplay between TSH and TH. RESULTS Compared with partners, offspring displayed higher mean (95% confidence interval [CI]) basal TSH secretion (34.3 [95% CI 27.2-43.1] mU/L per 24 hours vs 18.5 [95% CI 14.4-23.7] mU/L per 24 hours, P = .001) but no differences in ultradian or circadian properties of TSH. The temporal relationship between TSH and free T3 at zero delay was higher in offspring (0.48 ± 0.2) compared with partners (0.26 ± 0.4) (P = .05), but the feedback and forward interplay between TSH and TH did not differ. CONCLUSIONS Familial longevity is associated with increased basal TSH secretion and a strong temporal relationship between TSH and free T3 but not with differences in ultradian or circadian TSH rhythmicity or feedback and forward interplay between TSH and TH.

Accuracy of Continuous Glucose Monitoring Measurements in Normo-Glycemic Individuals

Background The validity of continuous glucose monitoring (CGM) is well established in diabetic patients. CGM is also increasingly used for research purposes in normo-glycemic individuals, but the CGM validity in such individuals is unknown. We studied the accuracy of CGM measurements in normo-glycemic individuals by comparing CGM-derived versus venous blood-derived glucose levels and measures of glycemia and glycemic variability. Methods In 34 healthy participants (mean age 65.7 years), glucose was simultaneously measured every 10 minutes, via both an Enlite® CGM sensor, and in venous blood sampled over a 24-hour period. Validity of CGM-derived individual glucose measurements, calculated measures of glycemia over daytime (09:00h-23:00h) and nighttime (23:00h-09:00h), and calculated measures of glycemic variability (e.g. 24h standard deviation [SD]) were assessed by Pearson correlation coefficients, mean absolute relative difference (MARD) and paired t-tests. Results The median correlation coefficient between CGM and venous glucose measurements per participant was 0.68 (interquartile range: 0.40–0.78), and the MARD was 17.6% (SD = 17%). Compared with venous sampling, the calculated measure of glycemia during daytime was 0.22 mmol/L higher when derived from CGM, but no difference was observed during nighttime. Most measures of glycemic variability were lower with CGM than with venous blood sampling (e.g., 24h SD: 1.07 with CGM and 1.26 with venous blood; p-value = 0.004). Conclusion In normo-glycemic individuals, CGM-derived glucose measurements had good agreement with venous glucose levels. However, the measure of glycemia was higher during the day and most measures of glycemic variability were lower when derived from CGM.

Familial longevity is characterized by high circadian rhythmicity of serum cholesterol in healthy elderly individuals

The biological clock, whose function deteriorates with increasing age, determines bodily circadian (i.e. 24h) rhythms, including that of cholesterol metabolism. Dampening of circadian rhythms has been associated with aging and disease. Therefore, we hypothesized that individuals with a familial predisposition for longevity have a higher amplitude circadian serum cholesterol concentration rhythm. The aim of this study was to investigate circadian rhythmicity of serum cholesterol concentrations in offspring of nonagenarian siblings and their partners. Offspring from nonagenarian siblings (n = 19), and their partners as controls (n = 18), were recruited from the Leiden Longevity Study. Participants (mean age 65 years) were studied in a controlled in‐hospital setting over a 24‐h period, receiving three isocaloric meals at 9:00 h, 12:00 h and 18:00 h. Lights were off between 23:00 h and 8:00 h. Serum total cholesterol (TC), HDL cholesterol (HDL‐C), non‐HDL‐C and triglycerides (TG) were determined every 30 min over a 24‐h period. Serum TC concentrations were higher during day than during night in offspring (5.2 vs. 4.7 mm, P < 0.001) and in controls (5.3 vs. 5.0 mm, P < 0.001). The difference in TC concentrations between day and night tended to be greater in offspring than in controls (0.5 vs. 0.3 mm, P = 0.109), reaching statistical significance in females (P = 0.045). Notably, the day–night serum differences in non‐HDL‐C were twofold greater in offspring than in controls (0.43 vs. 0.21 mm, P = 0.044) and most explicit in females (0.53 vs. 0.22, P = 0.078). We conclude that familial longevity is characterized by a high circadian rhythmicity of non‐HDL‐C in healthy elderly offspring from nonagenarian siblings.

Association between the rs7903146 Polymorphism in the TCF7L2 Gene and Parameters Derived with Continuous Glucose Monitoring in Individuals without Diabetes

Background The rs7903146-T allele in the transcription factor 7-like 2 (TCF7L2) gene has been associated with impaired pancreatic insulin secretion, enhanced liver glucose production, and an increased risk of type 2 diabetes. Nevertheless, the impact of rs7903146 on daily glucose trajectories remains unclear. Continuous glucose monitoring (CGM) can estimate glycemia and glycemic variability based on consecutive glucose measurements collected over several days. The purpose of the present study was to investigate the associations of rs7903146 with glycemia and glycemic variability in middle-aged participants without diabetes. Methods Complete data from 235 participants without diabetes from the Leiden Longevity Study were available. Participants were divided into two groups based on rs7903146 genotype; rs7903146-CC genotype carriers (N = 123) and rs7903146-CT/TT genotype carriers (N = 112). Validated parameters of glycemia (e.g., mean 24h glucose level) and glycemic variability (e.g., 24h standard deviation) were derived from data collected with a CGM system for a 72-hour period. Results The study population was on average 64.7 years old (standard deviation = 5.9) and composed of 49.8% of women. Compared with rs7903146-CC carriers, rs7903146-CT/TT carriers exhibited a trend towards a higher mean 24-hour glucose level (5.21 versus 5.32 mmol/L; p-value = 0.15) and a significantly higher mean nocturnal glucose (3:00am– 6:00am; 4.48 versus 4.67 mmol/L; p-value = 0.03) that was explained for 34.6% by body weight and percentage body fat. No differences in measures of glycemic variability between the genotype groups were observed. Conclusion Despite limited sample size, our study indicates that the rs7903146-T allele in TCF7L2 was associated with a higher mean nocturnal glucose dependent on body composition, which might suggest that rs7902146 affects liver-specific aspects of glucose metabolism.

Characterization of the Hypothalamic-Pituitary-Adrenal-Axis in Familial Longevity under Resting Conditions

Objective The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls. Design Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls). Methods During 24 h, venous blood was sampled every 10 minutes for determination of circulatory ACTH and cortisol concentrations. Deconvolution analysis, cross approximate entropy analysis and ACTH-cortisol-dose response modeling were used to assess, respectively, ACTH and cortisol secretion parameters, feedforward and feedback synchrony and adrenal gland ACTH responsivity. Results Mean (95% Confidence Interval) basal ACTH secretion was higher in male offspring compared to male controls (645 (324-1286) ngl/L/24 h versus 240 (120-477) ng/L/24 h, P = 0.05). Other ACTH and cortisol secretion parameters did not differ between offspring and controls. In addition, no significant differences in feedforward and feedback synchrony and adrenal gland ACTH responsivity were observed between groups. Conclusions These results suggest that familial longevity is not associated with major differences in HPA-axis activity under resting conditions, although modest, sex-specific differences may exist between groups that might be clinically relevant.

High Liver Enzyme Concentrations are Associated with Higher Glycemia, but not with Glycemic Variability, in Individuals without Diabetes Mellitus

Background Elevated concentrations of liver enzymes have been associated with an increased risk of developing type 2 diabetes mellitus. However, it remains unclear to which specific aspects of diurnal glucose metabolism these associate most. We aimed to investigate the associations between liver enzyme concentrations and 24 h-glucose trajectories in individuals without diabetes mellitus from three independent cohorts. Methods This cross-sectional study included 436 participants without diabetes mellitus from the Active and Healthy Aging Study, the Switchbox Study, and the Growing Old Together Study. Fasting blood samples were drawn to measure gamma-glutamyltransferase (GGT), alanine transaminase, and aspartate transaminase. Measures of glycemia (e.g., nocturnal and diurnal mean glucose levels) and glycemic variability (e.g., mean amplitude of glucose excursions) were derived from continuous glucose monitoring. Analyses were performed separately for the three cohorts; derived estimates were additionally meta-analyzed. Results After meta-analyses of the three cohorts, elevated liver enzyme concentrations, and specifically elevated GGT concentrations, were associated with higher glycemia. More specific, participants in the highest GGT tertile (GGT ≥37.9 U/L) had a 0.39 mmol/L (95% confidence interval: 0.23, 0.56) higher mean nocturnal glucose (3:00 to 6:00 a.m.) and a 0.23 mmol/L (0.10, 0.36) higher diurnal glucose (6:00 to 0:00 a.m.) than participants in the lowest GGT tertile (GGT <21.23 U/L). However, elevated liver enzyme concentrations were not associated with a higher glycemic variability. Conclusion Though elevated liver enzyme concentrations did not associate with higher glycemic variability in participants without diabetes mellitus, specifically, elevated GGT concentrations associated with higher glycemia.

High Adiposity Is Associated With Higher Nocturnal and Diurnal Glycaemia, but Not With Glycemic Variability in Older Individuals Without Diabetes

Background It is well known that adiposity is a risk factor for insulin resistance and type 2 diabetes mellitus. In the present study, we aimed to investigate the associations of measures of adiposity with indices of glycemia and of glycemic variability over a 72-h period in non-diabetic older adults. Methods This cross-sectional study was conducted in non-diabetic individuals from the Active and Healthy Aging Study (N = 228), Switchbox (N = 116), and the Growing Old Together Study (N = 94). Body mass index (BMI) and waist circumference were measured, and indices of glycemia and glycemic variability were derived from continuous glucose monitoring (CGM) using the Mini-Med® CGM system. Associations between adiposity and CGM were studied separately for the three cohorts, and derived estimates were subsequently meta-analyzed. Results After meta-analyzing the results from the separate cohorts, individuals with a higher BMI had higher levels of glycemia. Individuals with BMI between 30 and 35 kg/m2 had 0.28 mmol/L [95% confidence interval (CI): 0.12–0.44] higher 72 h-mean glucose concentration, 0.26 mmol/L (0.10–0.42) higher diurnal glucose (6:00 a.m. to 0:00 a.m.), and 0.39 mmol/L (0.19; 0.59) higher nocturnal glucose (3:00 a.m. to 6:00 a.m.) than participants with a normal weight (BMI 18.5–25 kg/m2). However, no associations were observed between higher BMI and glycemic variability. Results for glycemia and glycemic variability were similarly observed for a high waist circumference. Conclusion High adiposity associates with constant higher mean glucose levels over the day in non-diabetic older adults.

Stress evokes stronger medial posterior cingulate deactivations during emotional distraction in slower paced aging

INTRODUCTION Middle-aged offspring from long-lived families are thought to have a slower pace of aging, possibly related to HPA-axis function. Here, we investigated the neural and behavioral effects of social stress in offspring compared to their regular aging partners on emotional distraction during working memory (WM). METHODS 104 middle-aged participants (53 males) consisting of offspring and their partners underwent the Trier Social Stress Test or a control procedure. Hereafter, a WM task with emotional distracters was performed using fMRI. Saliva cortisol levels were obtained during the procedure. RESULTS Partners had higher overall cortisol levels than offspring. In addition, partners had decreased deactivations compared to offspring in the medial posterior cingulate cortex (mPCC) during emotional distraction, which were significantly correlated with lower accuracy during emotional distraction. DISCUSSION mPCC-deactivations are known to be modulated by chronological aging, with more deactivations in the young than in the old. Here we show the same pattern in familial longevity versus regular aging after mild stress, with more deactivations related to better accuracy during emotional distraction. Functional mPCC deactivations might thus be related to pace of aging, and can be revealed by inducing mild stress.