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BackgroundLittle is known about the impact of timing as opposed to frequency and intensity of daily physical activity on metabolic health. Therefore, we assessed the association between accelerometery-based daily timing of physical activity and measures of metabolic health in sedentary older people.MethodsHourly mean physical activity derived from wrist-worn accelerometers over a 6-day period was collected at baseline and after 3 months in sedentary participants from the Active and Healthy Ageing study. A principal component analysis (PCA) was performed to reduce the number of dimensions (e.g. define periods instead of separate hours) of hourly physical activity at baseline and change during follow-up. Cross-sectionally, a multivariable-adjusted linear regression analysis was used to associate the principal components, particularly correlated with increased physical activity in data-driven periods during the day, with body mass index (BMI), fasting glucose and insulin, HbA1c and the homeostatic model assessment for insulin resistance (HOMA-IR). For the longitudinal analyses, we calculated the hourly changes in physical activity and change in metabolic health after follow-up.ResultsWe included 207 individuals (61.4% male, mean age: 64.8 [SD 2.9], mean BMI: 28.9 [4.7]). Higher physical activity in the early morning was associated with lower fasting glucose (−2.22%, 95% CI: −4.19, −0.40), fasting insulin (−13.54%, 95%CI: −23.49, −4.39), and HOMA-IR (−16.07%, 95%CI: −27.63, −5.65). Higher physical activity in the late afternoon to evening was associated with lower BMI (−2.84%, 95% CI: −4.92, −0.70). Higher physical activity at night was associated with higher BMI (2.86%, 95% CI: 0.90, 4.78), fasting glucose (2.57%, 95% CI: 0.70, 4.30), and HbA1c (2.37%, 95% CI: 1.00, 3.82). Similar results were present in the prospective analysis.ConclusionSpecific physical activity timing patterns were associated with more beneficial metabolic health, suggesting particular time-dependent physical activity interventions might maximise health benefits.

With advancing age, many organs exhibit functional deterioration. The age‐associated accumulation of senescent cells is believed to represent one factor contributing to this phenomenon. While senescent cells are found in several different organ systems, it is not known whether they arise independently in each organ system or whether their prevalence within an individual reflects that individual's intrinsic aging process. To address this question, we studied senescence in two different organ systems in humans, namely skin and T cells in 80 middle‐aged and older individuals from the Leiden Longevity Study. Epidermal p16INK4a positivity was associated with neither CD4+ nor CD8+ T‐cell immunosenescence phenotype composites (i.e., end‐stage differentiated/senescent T cells, including CD45RA+CCR7‐CD28‐CD27‐CD57+KLRG1+ T cells). Dermal p16INK4a positivity was significantly associated with the CD4+, but not with the CD8+ immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals. Senescent cells are found in several organs, but it is unknown whether they arise independently in each organ or whether their prevalence within an individual reflects that individual's intrinsic aging process. Senescent cells in (epi)dermal skin cells and in CD 4+/CD8+ T cells do not co‐occur within 80 middle‐aged and older individuals. This suggests that the accumulation of senescent cells differs between different organs within individuals.

Abstract Context With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown. Objective To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism. Design Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial). Setting Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom. Participants The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included. Main Outcome Measures Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization. Results In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization. Conclusion Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. Trial registration ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851.

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18–109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex ( C -statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality ( C -statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation. Biomarkers that predict mortality are of interest for clinical as well as research applications. Here, the authors analyze metabolomics data from 44,168 individuals and identify key metabolites independently associated with all-cause mortality risk.

Lack of physical activity leads to detrimental changes in body composition and metabolism, functional decline, and increased risk of disease in old age. The potential of Web-assisted interventions for increasing physical activity and improving metabolism in older individuals holds great promise but to our knowledge it has not been studied. The goal of our study was to assess whether a Web-based intervention increases physical activity and improves metabolic health in inactive older adults. We conducted a 3-month randomized, waitlist-controlled trial in a volunteer sample of 235 inactive adults aged 60-70 years without diabetes. The intervention group received the Internet program Philips DirectLife, which was directed at increasing physical activity using monitoring and feedback by accelerometer and digital coaching. The primary outcome was relative increase in physical activity measured objectively using ankle- and wrist-worn accelerometers. Secondary outcomes of metabolic health included anthropometric measures and parameters of glucose metabolism. In total, 226 participants (97%) completed the study. At the ankle, activity counts increased by 46% (standard error [SE] 7%) in the intervention group, compared to 12% (SE 3%) in the control group (P(difference)<.001). Measured at the wrist, activity counts increased by 11% (SE 3%) in the intervention group and 5% (SE 2%) in the control group (P(difference)=.11). After processing of the data, this corresponded to a daily increase of 11 minutes in moderate-to-vigorous activity in the intervention group versus 0 minutes in the control group (P(difference)=.001). Weight decreased significantly more in the intervention group compared to controls (-1.5 kg vs -0.8 kg respectively, P=.046), as did waist circumference (-2.3 cm vs -1.3 cm respectively, P=.036) and fat mass (-0.6% vs 0.07% respectively, P=.025). Furthermore, insulin and HbA1c levels were significantly more reduced in the intervention group compared to controls (both P<.05). This was the first study to show that in inactive older adults, a 3-month Web-based physical activity intervention was effective in increasing objectively measured daily physical activity and improving metabolic health. Such Web-based interventions provide novel opportunities for large scale prevention of metabolic deregulation in our rapidly aging population.

Thyroid hormones have vital roles in development, growth and energy metabolism. Within the past two decades, disturbances in thyroid hormone action have been implicated in ageing and the development of age-related diseases. This Review will consider results from biomedical studies that have identified the importance of precise temporospatial regulation of thyroid hormone action for local tissue maintenance and repair. Age-related disturbances in the maintenance of tissue homeostasis are thought to be important drivers of age-related disease. In most iodine-proficient human populations without thyroid disease, the mean, median and 97.5 centile for circulating concentrations of thyroid-stimulating hormone are progressively higher in adults over 80 years of age compared with middle-aged (50–59 years) and younger (20–29 years) adults. This trend has been shown to extend into advanced ages (over 100 years). Here, potential causes and consequences of the altered thyroid status observed in old age and its association with longevity will be discussed. In about 5–20% of adults at least 65 years of age, thyroid-stimulating hormone concentrations are elevated but circulating concentrations of thyroid hormone are within the population reference range, a condition referred to as subclinical hypothyroidism. Results from randomized clinical trials that have tested the clinical benefit of thyroid hormone replacement therapy in older adults with mild subclinical hypothyroidism will be discussed, as well as the implications of these findings for screening and treatment of subclinical hypothyroidism in older adults. Thyroid hormones have key functions throughout the body. However, thyroid function declines with age and thyroid diseases increase in prevalence. This Review outlines our current knowledge about how thyroid function changes with age and the implications for patient care. Key points In line with the emerging role of thyroid hormone action in tissue maintenance and repair, studying local control of thyroid hormone in ageing is an area urgently in need of research. The mechanisms contributing to altered thyroid status in old age are probably heterogeneous and comprise selective survival, transient age-related changes and persistent age-related changes. Increased circulating levels of thyroid-stimulating hormone and/or reduced circulating levels of thyroid hormone is a heritable phenotype associated with exceptional longevity. Subclinical hypothyroidism is a frequent diagnosis among older adults; in randomized clinical trials, levothyroxine therapy provided no apparent clinical benefits in older adults with mild subclinical hypothyroidism. Older adults form a heterogeneous group, so future research should explore strategies for safe screening, initiation, continuation and/or discontinuation of treatment of subclinical hypothyroidism in specific subgroups of older adults.

Cytomegalovirus (CMV) latent infection and aging contribute to alterations in the function and phenotype of the T-cell pool. We have demonstrated that CMV-seropositivity is associated with the expansion of polyfunctional CD57+ T-cells in young and middle-aged individuals in response to different stimuli. Here, we expand our results on the effects of age and CMV infection on T-cell functionality in a cohort of healthy middle-aged and older individuals stratified by CMV serostatus. Specifically, we studied the polyfunctional responses (degranulation, IFN-γ and TNF-α production) of CD4+, CD8+, CD8+CD56+ (NKT-like), and CD4-CD8- (DN) T-cells according to CD57 expression in response to Staphylococcal Enterotoxin B (SEB). Our results show that CD57 expression by T-cells is not only a hallmark of CMV infection in young individuals but also at older ages. CD57+ T-cells are more polyfunctional than CD57− T-cells regardless of age. CMV-seronegative individuals have no or a very low percentages of cytotoxic CD4+ T-cells (CD1017a+) and CD4+CD57+ T-cells, supporting the notion that the expansion of these T-cells only occurs in the context of CMV infection. There was a functional shift in T-cells associated with CMV seropositivity, except in the NKT-like subset. Here, we show that the effect of CMV infection and age differ among T-cell subsets and that CMV is the major driving force for the expansion of highly polyfunctional CD57+ T-cells, emphasizing the necessity of considering CMV serology in any study of immunosenescence.

Summary Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128-216) mU L-1] compared with controls [238 (193-284) mU L-1]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39-0.53)] compared with controls [0.66 (0.56-0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.

Observational studies have implied associations between multiple cytokines and cognitive decline, anti-inflammatory drugs however did not yield any protective effects on cognitive decline. We aimed to assess the associations of systemic inflammation, as measured by multiple cytokine and growth factor, with cognitive performance and brain atrophy using two-sample Mendelian randomization (MR). Independent genetic instruments ( p  < 5e − 8 and p  < 5e − 6) for 41 systemic inflammatory markers were retrieved from a genome-wide association study conducted in 8293 Finnish participants. Summary statistics for gene-outcome associations were obtained for cognitive performance ( N  = 257,841) and for brain atrophy measures of cerebral cortical surface area and thickness ( N  = 51,665) and hippocampal volume ( N  = 33,536). To rule out the heterogeneity in the cognitive performance, we additionally included three domains: the fluid intelligence score ( N  = 108,818), prospective memory result ( N  = 111,099), and reaction time ( N  = 330,069). Main results were computed by inverse-variance weighting; sensitivity analyses taking pleiotropy and invalid instruments into account were performed by using weighted-median estimator, MR-Egger, and MR PRESSO. After correcting for multiple testing using false discovery rate, only genetically predicted (with p  < 5e − 6 threshold) per-SD (standard deviation) higher IL-8 was associated with − 0.103 (− 0.155, − 0.051, p adjusted  = 0.004) mm 3 smaller hippocampal volume and higher intelligence fluid score [ β : 0.103 SD (95% CI: 0.042, 0.165), p adjusted  = 0.041]. Sensitivity analyses generally showed similar results, and no pleiotropic effect, heterogeneity, or possible reverse causation was detected. Our results suggested a possible causal association of high IL-8 levels with better cognitive performance but smaller hippocampal volume among the general healthy population, highlighting the complex role of inflammation in dementia-related phenotypes. Further research is needed to elucidate mechanisms underlying these associations.

Oxidative stress has been proposed as a key contributor to lifestyle- and age-related diseases. Because free radicals play an important role in various processes such as immune responses and cellular signaling, the body possesses an arsenal of different enzymatic and non-enzymatic antioxidant defense mechanisms. Oxidative stress is, among others, the result of an imbalance between the production of various reactive oxygen species (ROS) and antioxidant defense mechanisms including vitamin E (α-tocopherol) as a non-enzymatic antioxidant. Dietary vitamins, such as vitamin C and E, can also be taken in as supplements. It has been postulated that increasing antioxidant levels through supplementation may delay and/or ameliorate outcomes of lifestyle- and age-related diseases that have been linked to oxidative stress. Although supported by many animal experiments and observational studies, randomized clinical trials in humans have failed to demonstrate any clinical benefit from antioxidant supplementation. Nevertheless, possible explanations for this discrepancy remain underreported. This review aims to provide an overview of recent developments and novel research techniques used to clarify the existing controversy on the benefits of antioxidant supplementation in health and disease, focusing on α-tocopherol as antioxidant. Based on the currently available literature, we propose that examining the difference between antioxidant activity and capacity, by considering the catabolism of antioxidants, will provide crucial knowledge on the preventative and therapeutical use of antioxidant supplementation in oxidative stress-related diseases.