Genetic determinants of healthy longevity

Lifespan in under genetic control. In this thesis we translated genes regulating lifespan in model organisms to humans. First we identified DAF-12 as a critical gene for lifespan regulation in the nematode worm C. elegans. Then we found that the Liver X Receptors and the Vitamin D Receptor are the most similar human proteins. We tested these genetic variation in these human genes in the Leiden 85-plus Study and found them to associate with with lifespan and cognitive decline respectively. Apolipoprotein E is a target gene of the Liver X Receptor. We found that plasma levels of apolipoprotein E associated with increased risk of cardiovascular mortality, cognitive decline and stroke in a manner independent of classical cardiovascular risk factors. Finally we reviewed the evidence from human candidate gene studies. We conclude that the use of model organisms provides useful directions for research into the genetics of human longevity. However, as the human signalling systems are more complex and our environment is different from that of model organisms, it is unclear to what extent results obtained in model organisms can be extrapolated to humans.LEI Universiteit LeidenTHE WORK DESCRIBED IN THIS THESIS WAS FUNDED BY AN INNOVATIVE ORIENTED RESEARCH (IOP) GRANT FROM THE DUTCH MINISTRY OF ECONOMIC AFFAIRS (GRANT NUMBER IGE01014).Pathofysiologie, epidemiologie en therapie bij verouderin

Geriatric screeners 2.0: time for a paradigm shift in emergency department vulnerability research

Pathophysiology, epidemiology and therapy of agein

Should subclinical hypothyroidism in older persons be treated?

Subclinical hypothyroidism is a common finding in older persons. Clinical guidelines are inconsistent in providing recommendations for the treatment of subclinical hypothyroidism, especially in older persons. To date, there is no high-quality evidence from randomized controlled trials about the effects of treatment of subclinical hypothyroidism in older persons. Any definitive recommendations on treatment should be based on data from large randomized placebo-controlled trials.Geriatrics in primary car

Association of complement receptor 1 gene polymorphisms with cognitive function

Previous evidence suggest involvement of the complement receptor 1 (CR1) in development of Alzheimer’s disease. We investigated the association of CR1 gene polymorphisms with cognitive function in older subjects. Single nucleotide polymorphisms (SNPs) within the CR1 region on chromosome 1 (n = 73) were assessed in 5,244 participants in the PROspective Study of Pravastatin in the Elderly at Risk (51.9% female, mean age 75.3 yr). Linear regression, adjusted for age, sex, country, and use of pravastatin, was used to assess the association between the SNPs and cognitive function. All 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. Eighteen were independent, according to a relatively stringent R2 threshold of >0.8 with LDlink. Twelve of the 18 investigated CR1 SNPs were significantly associated with a decline in cognitive function (all P < 0.05). These data indicate that genetic variation within the CR1 gene is associated not only with Alzheimer’s disease, but also with general cognitive function during late life

The kidney, subclinical thyroid disease and cardiovascular outcomes in older patients

Objective: Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate whether kidney function modifies the association of subclinical thyroid dysfunction and the risk of cardiovascular outcomes. Methods: In total, 5804 patients were included in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). For the current analysis, 426 were excluded because of overt thyroid disease at baseline or 6 months, 266 because of inconsistent thyroid function at baseline and 6 months, 294 because of medication use that could influence thyroid function, and 16 because of missing kidney or thyroid values. Participants with normal fT4 were classified, based on TSH both at inclusion and 6 months, into three groups: subclinical hypothyroidism (TSH >4.5 mIU/L); euthyroidism (TSH = 0.45–4.5 mIU/L); and subclinical hyperthyroidism (TSH <0.45 mIU/L). Strata of kidney function were made based on estimated glomerular filtration rate into three clinically relevant groups: <45, 45–60, and >60 mL/min/1.73 m2. The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke. Results: Mean age was 75.3 years, and 49.0% patients were male. Mean follow-up was 3.2 years. Of all participants, 109 subjects (2.2%) had subclinical hypothyroidism, 4573 (94.0%) had euthyroidism, and 182 (3.7%) subclinical hyperthyroidism. For patients with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, primary outcome occurred in 9 (8.3%), 712 (15.6%), and 23 (12.6%) patients, respectively. No statistically significant relationship was found between subclinical thyroid dysfunction and primary endpoint with adjusted hazard ratios of 0.51 (0.24–1.07) comparing subclinical hyperthyroidism and 0.90 (0.58–1.39) comparing subclinical hypothyroidism with euthyroidism. Neither was this relationship present in any of the strata of kidney function, nor did kidney function interact with subclinical thyroid dysfunction in the association with primary endpoint (P interaction = 0.602 for subclinical hyperthyroidism and 0.388 for subclinical hypothyroidism). Conclusions: In this secondary analysis from PROSPER, we found no evidence that the potential association between thyroid hormones and cardiovascular disease is modified by kidney function in older patients with subclinical thyroid dysfunction

Experiences with and attitudes towards geriatric screening among older emergency department patients: a qualitative study

BackgroundThe patient perspective on the use of screening for high risks of adverse health outcomes in Emergency Department (ED) care is underexposed, although it is an important perspective influencing implementation in routine care. This study explores the experiences with, and attitudes towards geriatric screening in routine ED care among older people who visited the ED.MethodsThis was a qualitative study using individual face-to-face semi-structured interviews. Interviews were conducted in older patients (>= 70years) who completed the 'Acutely Presenting Older Patient' screener while visiting the ED of a Dutch academic hospital. Purposive convenience sampling was used to select a heterogeneous sample of participants regarding age, disease severity and the result from screening. Transcripts were analyzed inductively using thematic analysis.ResultsAfter 13 interviews (7 women, median age 82years), data saturation was reached. The participants had noticed little of the screening administration during triage and screening was considered as a normal part of ED care. Most participants believed that geriatric screening contributes to assessing older patients holistically, recognizing geriatric problems early and comforting patients with communication and attention. None of the participants had a negative attitude towards screening or thought that screening is discrimination on age. Care providers should communicate respectfully with frail older patients and involve them in decision-making.ConclusionsOlder patients experienced geriatric screening as a normal part of ED care and had predominantly positive attitudes towards its use in the ED. This qualitative study advocates for continuing the implementation of geriatric screening in routine ED practice.Clinical epidemiolog

Regression discontinuity was a valid design for dichotomous outcomes in three randomized trials

Pathophysiology, epidemiology and therapy of agein