Aging is associated with changes in heart rate (HR), heart rate variability (HRV), and 24-h rhythms in HR. Longevity has been linked to lower resting HR, while a higher resting HR and a decreased... Show moreAging is associated with changes in heart rate (HR), heart rate variability (HRV), and 24-h rhythms in HR. Longevity has been linked to lower resting HR, while a higher resting HR and a decreased HRV were linked to cardiovascular events and increased mortality risk. HR and HRV are often investigated during a short electrocardiogram (ECG) measurement at a hospital. In this study, we aim to investigate the relationship between HR parameters with familial longevity and chronological age derived from continuous ambulatory ECG measurements collected over a period of 24 to 90 hours. We included 73 middle-aged participants (mean (SD) age: 67.0 (6.16) years), comprising 37 offspring of long-lived families, 36 of their partners, and 35 young participants (22.8 (3.96) years). We found no association with familial longevity, but middle-aged participants had lower 24-h HR (average and maximum HR, not minimum HR), lower amplitudes, and earlier trough and peak times than young participants. Associations in HR with chronological age could be caused by the aging process or by differences in environmental factors. Interestingly, middle-aged participants had a less optimal HRV during long-term recordings in both the sleep and awake periods, which might indicate that their heart is less adaptable than that of young participants. This could be a first indication of deteriorated cardiovascular health in middle-aged individuals. Show less
Zutinic, A.; Roelfsema, F.; Pijl, H.; Ballieux, B.E.; Westendorp, R.G.J.; Blauw, G.J.; Heemst, D. van 2021
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... Show moreContext: 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. Show less
Zutinic, A.; Blauw, G.J.; Pijl, H.; Ballieux, B.E.; Westendorp, R.G.J.; Roelfsema, F.; Heemst, D. van 2020
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... Show moreContext: 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. Show less
Zutinic, A.; Pijl, H.; Ballieux, B.E.; Roelfsema, F.; Westendorp, R.G.J.; Blauw, G.J.; Heemst, D. van 2020
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... Show moreContext: 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. Show less
Berg, N. van den; Rodriguez-Girondo, M.; Mandemakers, K.; Janssens, A.A.P.O.; Beekman, M.; Slagboom, P.E. 2020
Loci associated with longevity are likely to harbor genes coding for key players of molecular pathways involved in a lifelong decreased mortality and decreased/compressed morbidity. However,... Show moreLoci associated with longevity are likely to harbor genes coding for key players of molecular pathways involved in a lifelong decreased mortality and decreased/compressed morbidity. However, identifying such loci is challenging. One of the most plausible reasons is the uncertainty in defining long-lived cases with the heritable longevity trait among long-living phenocopies. To avoid phenocopies, family selection scores have been constructed, but these have not yet been adopted as state of the art in longevity research. Here, we aim to identify individuals with the heritable longevity trait by using current insights and a novel family score based on these insights. We use a unique dataset connecting living study participants to their deceased ancestors covering 37,825 persons from 1,326 five-generational families, living between 1788 and 2019. Our main finding suggests that longevity is transmitted for at least two subsequent generations only when at least 20% of all relatives are long-lived. This proves the importance of family data to avoid phenocopies in genetic studies. Show less
Alu hypomethylation promotes genomic instability and is associated with aging and age-related diseases. Dietary factors affect global DNA methylation, leading to changes in genomic stability and... Show moreAlu hypomethylation promotes genomic instability and is associated with aging and age-related diseases. Dietary factors affect global DNA methylation, leading to changes in genomic stability and gene expression with an impact on longevity and the risk of disease. This preliminary study aims to investigate the relationship between nutritional factors, such as circulating trace elements, lipids and antioxidants, and Alu methylation in elderly subjects and offspring of healthy nonagenarians. Alu DNA methylation was analyzed in sixty RASIG (randomly recruited age-stratified individuals from the general population) and thirty-two GO (GeHA offspring) enrolled in Italy in the framework of the MARK-AGE project. Factor analysis revealed a different clustering between Alu CpG1 and the other CpG sites. RASIG over 65 years showed lower Alu CpG1 methylation than those of GO subjects in the same age class. Moreover, Alu CpG1 methylation was associated with fruit and whole-grain bread consumption, LDL2-Cholesterol and plasma copper. The preserved Alu methylation status in GO, suggests Alu epigenetic changes as a potential marker of aging. Our preliminary investigation shows that Alu methylation may be affected by food rich in fibers and antioxidants, or circulating LDL subfractions and plasma copper. Show less
Vliet, N.A. van; Spoel, E. van der; Beekman, M.; Slagboom, P.E.; Blauw, G.J.; Gussekloo, J.; ... ; Heemst, D. van 2017
