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The rate of senescence can be inferred from the acceleration by which mortality rates increase over age. Such a senescence rate is generally estimated from parameters of a mathematical model fitted to these mortality rates. However, such models have limitations and underlying assumptions. Notably, they do not fit mortality rates at young and old ages. Therefore, we developed a method to calculate senescence rates from the acceleration of mortality directly without modeling the mortality rates. We applied the different methods to age group-specific mortality data from the European Renal Association-European Dialysis and Transplant Association Registry, including patients with end-stage renal disease on dialysis, who are known to suffer from increased senescence rates (n = 302,455), and patients with a functioning kidney transplant (n = 74,490). From age 20 to 70, senescence rates were comparable when calculated with or without a model. However, when using non-modeled mortality rates, senescence rates were yielded at young and old ages that remained concealed when using modeled mortality rates. At young ages senescence rates were negative, while senescence rates declined at old ages. In conclusion, the rate of senescence can be calculated directly from non-modeled mortality rates, overcoming the disadvantages of an indirect estimation based on modeled mortality rates. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the risks of coronary heart disease (CHD) and total mortality among adults with subclinical hypothyroidism. The study included 55,287 adults in the U.S., Europe, Australia, Brazil and Japan, who were followed up from 1972 to 2007. Of the total study participants, 3,450 developed subclinical hypothyroidism, while 51,837 had euthyroidism. Study authors found that increased thyroid-stimulating hormone (TSH) concentration increased the risk of CHD and CHD-related mortality. They concluded that patients with subclinical hypothyroidism have higher risk of CHD.

Background: Inflammation may play an important role in atherothrombosis and in promoting cerebral damage after stroke. We hypothesized that plasma adipocytokine concentrations would be associated with risk of stroke in older people.Methods: Nested case-control study from the Prospective Study of Pravastatin in the Elderly (PROSPER). Subjects were aged 70-82 years and followed up for a mean of 3.2 years: 266 incident stroke cases (179 confirmed as ischaemic) were compared with 532 controls matched for age, gender and treatment allocation (pravastatin or placebo). Adipocytokines [adiponectin, interleukin- (IL-)18 and tumour necrosis factor (TNF)alpha] were measured on stored baseline plasma samples.Results: Elevated plasma adiponectin was associated with lower risk of ischaemic stroke on univariate analysis: odds ratio (OR) 0.78 per 1 SD increase (95% CI 0.62-0.97). There were no associations of IL-18 or TNFalpha with risk for ischaemic or total strokes. In multivariate models the independent predictors of ischaemic stroke were prior cerebrovascular accident (OR 2.68, 95% CI 1.60-4.50), any alcohol use (1.98, 1.33-2.94), triglycerides (1.40, 1.11-1.77), Barthel score (0.75, 0.58-0.96) and known diabetes (1.72, 1.04-2.83); adiponectin, IL-18 and TNFalpha did not contribute. A similar pattern of risk was seen for total stroke.Conclusions: Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL-18 and TNFalpha are unlikely to play any important part. These adipocytokines do not have clinical predictive utility; history of prior cerebrovascular accident, known diabetes mellitus, prior disability and higher alcohol intake explain much of the stroke risk. [ABSTRACT FROM AUTHOR]

Background: The cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD)., Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH., Methods: Combined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age., Results: The median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age., Conclusion: Treatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+)., Competing Interests: SM reported receiving grants from ZonMW and nonfinancial support from Merck during the conduct of the study. RP reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. DS reported receiving grants from European Union FP7 and nonfinancial support from Merck Serono during the conduct of the study. NR reported receiving grants from the Swiss National Science Foundation and the Velux Foundation during the conduct of the study. KP reported receiving grants from Netherlands Organisation for Health Research and Development (ZonMw) and the European Union FP7-HEALTH-2011 programme during the conduct of the study. T-HC reported receiving grants from the Swiss National Science Foundation during the conduct of the study. JG reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zijlstra, Jukema, Westendorp, Du Puy, Poortvliet, Kearney, O’Keeffe, Dekkers, Blum, Rodondi, Collet, Quinn, Sattar, Stott, Trompet, den Elzen, Gussekloo and Mooijaart.)

Context: Many assume that having poor physical health in old age lowers life satisfaction, but in fact there are large differences in life satisfaction among older people who experience disability., Objective: To investigate whether psychosocial factors modify the negative association between disability and life satisfaction in older people and whether these differ across the life course., Design: Cross sectional study., Setting: 66,561 community-dwelling Survey of Health, Ageing, and Retirement in Europe (SHARE) participants aged 50-106 with a mean age of 67.8 ± 9.9 (SD) years from 17 European countries and Israel., Methods: Psychosocial factors included depression (EURO-D scale), perceived loneliness, having a spouse, having children, contact with children, and participation in social activities. Disability was assessed by limitations in (Instrumental) Activities of Daily Living ((I)ADL) and life satisfaction by Cantril's ladder. We also ran the analyses with the Control Autonomy Self-realization Pleasure (CASP-12) Index, a normative measure of quality of life. We used multiple linear regressions to estimate associations and proportion of variance explained., Results: The variance in life satisfaction that could be attributed uniquely to ADL and IADL disability was 0.17% and 0.33% respectively (both p < 0.001). The impact of (I)ADL disabilities on life satisfaction was strongest at age 50 and gradually decreased with increasing age (p trend < 0.001). Mental health explained more variance; 5.75% for depressive symptoms and 2.50% for loneliness and for social resources this ranged from 0.09% to 0.47% (all p < 0.001). While disability has a negative effect on life satisfaction, the effect was not stronger in older persons who were depressed, neither in those who felt lonely nor in those without social resources. Similar outcomes were found when using CASP-12 as the explained variable., Conclusion: The impact of (I)ADL disabilities on life satisfaction in community-dwelling older people decreases with age. These associations are not affected by psychosocial factors and these patterns cannot be explained by people changing their norms and values., Competing Interests: The authors have declared that no competing interests exist.

Background: Visit-to-visit variability in blood pressure is an independent predictor of cardiovascular disease. This study investigates biological correlates of intra-individual variability in blood pressure in older persons., Methods: Nested observational study within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) among 3,794 male and female participants (range 70-82 years) with a history of, or risk factors for cardiovascular disease. Individual visit-to-visit variability in systolic and diastolic blood pressure and pulse pressure (expressed as 1 SD in mm Hg) was assessed using nine measurements over 2 years. Correlates of higher visit-to-visit variability were examined at baseline, including markers of inflammation, endothelial function, renal function and glucose homeostasis., Results: Over the first 2 years, the mean intra-individual variability (1 SD) was 14.4mm Hg for systolic blood pressure, 7.7mm Hg for diastolic blood pressure, and 12.6mm Hg for pulse pressure. After multivariate adjustment a higher level of interleukin-6 at baseline was consistently associated with higher intra-individual variability of blood pressure, including systolic, diastolic, and pulse pressure. Markers of endothelial function (Von Willebrand factor, tissue plasminogen activator), renal function (glomerular filtration rate) and glucose homeostasis (blood glucose, homeostatic model assessment index) were not or to a minor extent associated with blood pressure variability., Conclusion: In an elderly population at risk of cardiovascular disease, inflammation (as evidenced by higher levels of interleukin-6) is associated with higher intra-individual variability in systolic, diastolic, and pulse pressure., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA., Approach and Results: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke., Conclusions: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity., (© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No SNP was related to vascular disease at baseline. Only the KIF6 SNP was related to LDL-C lowering with homozygous Arg 719 subjects being significantly less responsive than other groups (p=0.025, -34.2 vs. -36.1%). With regard to the primary CHD endpoint on trial (fatal or non-fatal myocardial infarction or stroke), we observed a significant relationship for KIF6 719Arg homozygotes (p=0.03, hazards ratio 0.47, 12.8% of the population) in women on pravastatin only, and for TAS2R50 for the AA genotype (p=0.03, hazards ratio 1.76, 8.9% of the population), also only in women on pravastatin. Our data indicate that the assessment of KIF6 rs20455 and TAS2R50 rs1376251 genotypes are not useful for predicting statin induced cardiovascular risk reduction in men, but do predict CHD risk reduction in women in this elderly population. However, these differences are no longer significant after correction for multiple comparisons, and we do not recommend the assessment of any of these SNPs in clinical practice., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

The systolic hypertension in Europe (Syst-Eur) trial has been the only trial that has suggested a protective effect of antihypertensive treatment on incidence of dementia. It is unclear whether this protective effect has been caused by the blood pressure lowering effect of the calcium antagonist nitrendipine or by the calcium channel inhibition. From the Leiden 85-plus study, a population-based cohort study of 599 subjects aged 85 years, we selected 204 subjects who used at least one antihypertensive at baseline. Associations between use of antihypertensives at baseline and change in cognitive functioning over time were assessed with linear mixed models. After adjusting for gender, education, and use of other antihypertensives, only use of calcium antagonists was associated with a significant decelerated annual cognitive decline during follow-up (0.40 MMSE-points per year, p=0.001). Use of other antihypertensives was not associated with a decelerated annual cognitive decline (all p values >0.3). Our data support the interpretation that the reported prevention of dementia by calcium antagonists is exerted through its calcium channel inhibition rather than its blood pressure lowering properties.