The potential benefit of statin prescription based on prediction of treatment responsiveness in older individuals: An application to the PROSPER randomised controlled trial.

BACKGROUND & AIMS: Clinical guidelines often recommend to treat individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment strategies: (i) overall prescription, i.e. treatment to all individuals sharing the eligibility criteria of a trial; (ii) risk-stratified prescription, i.e. treatment only to those at an elevated outcome risk; and (iii) prescription based on predicted treatment responsiveness. METHODS: We reanalysed the PROSPER randomised controlled trial, which included individuals aged 70-82 years with a history of, or risk factors for, vascular diseases. We conducted the derivation and internal-external validation of a model predicting treatment responsiveness. We compared to placebo (n= 2913): (i) pravastatin (n= 2891); (ii) pravastatin in the presence of previous vascular diseases and placebo in the absence thereof (n= 2925); and (iii) pravastatin in the presence of a favourable prediction of treatment response and placebo in the absence thereof (n= 2890). RESULTS: We found an absolute difference in primary outcome events composed of coronary death, non-fatal myocardial infarction, fatal or non-fatal stroke, per 10 000 person-years equal to: -78 events (95% CI, -144 to -12) when prescribing pravastatin to all participants; -66 events (95% CI, -114 to -18) when treating only individuals with an elevated vascular risk; and -103 events (95% CI, -162 to -44) when restricting pravastatin to individuals with a favourable prediction of treatment response. CONCLUSIONS: Pravastatin prescription based on predicted responsiveness may have an encouraging potential for cardiovascular prevention. Further external validation of our results and clinical experiments are needed.

This study invistigates whether an algorithm to predict how much old age individuals would benefit from a statin treatment could be useful to guide clinicians in their prescription decision-making; the key findings are: About one out of seven individuals included in the study has no predicted benefit of pravastatin; Compared to prescribing pravastatin to all old age individuals at risk of cardiovascular diseases, withholding pravastatin in those with no predicted benefit seems to lead to a better prevention of cardiovascular events.

Inflammation in older subjects with early- and late-onset depression in the NESDO study: a cross-sectional and longitudinal case-only design.

OBJECTIVE: Different biological mechanisms may underlie depression beginning in early life (early-onset) and depression beginning later in life (late-onset). Although the relation between inflammation and depression has been studied extensively, the distinct role of inflammation in early and late-onset depression in older patients has not been addressed before. In the cross-sectional part of this study, we explored differences in levels of circulating inflammatory markers and cytokine levels in lipopolysaccharide (LPS) stimulated whole blood between older subjects with a late-life onset depression (≥60 years) and older subjects with an early-onset depression (<60 years). Secondly, in a 2-year follow-up study, we examined if circulating and stimulated inflammatory markers influenced the change in Inventory of Depressive Symptomatology (IDS) scores, and if this relation was different for early- and late-onset depression. METHODS: The study was part of the Netherlands Study of Depression in Older Persons (NESDO). We included 350 patients, all aged 60 and older, with a depressive episode in the previous 6 months: 119 with a late-onset depression and 231 with an early-onset depression. Blood samples were collected and CRP, IL-6, NGAL, GDF15, and, LPS plasma levels were determined and whole blood was LPS stimulated and cytokine levels IL-1ß, IL-6, TNFα, IFNγ, IL-10, and IL-1 receptor antagonist (IL-1ra) were determined. RESULTS: After adjustment for demographics, health indicators, and medication use, increased plasma CRP levels were more strongly associated with late-onset depression than early-onset depression (OR [95% CI]: 1.43 [1.05-1.94]). In the longitudinal analyses, higher circulating IL-6 levels were associated with a significantly slower decline in IDS scores in the crude and the adjusted models (p ≤ 0.027). This relation was not different between late- and early-onset depression. Other circulating and stimulated inflammatory markers were not associated with late- and/or early-onset depression. CONCLUSIONS: This study provides preliminary evidence that low-grade inflammation is more strongly associated with late-onset than early-onset depression in older adults, suggesting a distinct inflammatory etiology for late-onset depression. Cytokine production capacity did not distinguish between early- and late-onset depression.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

Assessment of health status by molecular measures in adults ranging from middle-aged to old: Ready for clinical use?

In addition to measures already used in clinical practice, molecular measures have been proposed to assess health status, but these have not yet been introduced into clinical practice. We aimed to test the association of functional capacity measures used in current practice and molecular measures with age and health status. The cohort consisted of 178 middle-aged to old participants of the Leiden Longevity Study (range 42-82years). We tested associations between functional capacity measures (physical tests: grip strength, 4-meter walk, chair stand test; cognitive tests: Stroop test, digit symbol substitution test and 15-picture learning test) with age and with cardiovascular or metabolic disease as a measure of the health status. These associations with age and health status were also tested for molecular measures (C reactive protein (CRP), numbers of senescent p16INK4a positive cells in the epidermis and dermis and putative immunosenescence (presence of CD57+ T cells)). All functional capacity measures were associated with age. CRP and epidermal p16INK4a positivity were also associated with age, but with smaller estimates. Grip strength and the Stroop test were associated with cardiovascular or metabolic disease, as was epidermal p16INK4a positivity. All associations with cardiovascular or metabolic disease attenuated when adjusting for age. In conclusion, in middle-aged to old persons, the molecular measures tested here were more weakly associated with age and health status than functional capacity measures. Whether these molecular measures associate more closely with health status in the elderly or in specific groups of patients needs to be explored further.

Non-response to (statin) therapy: the importance of distinguishing non-responders from non-adherers in pharmacogenetic studies.

PURPOSE: In pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers. METHODS: Baseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis. RESULTS: Non-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased. CONCLUSION: Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Overcoming Old in Age-Friendliness.

In this article, we explore views on an age-friendly space in the Netherlands by analysing the responses of older individuals (N = 54) in focus groups and by examining the perspectives around an age-friendly zone in the Netherlands, Parkstad Limburg. We found that a central issue in the wishes for living at a later age are adjustments to envisioned physical limitations that come with the ageing process; this includes adjustments to ensure safety, accessibility and mobility, in order to facilitate older individuals' efforts to stay engaged with the world around them. In their wishes, the older participants constructed ideal dwelling places that closely resembled a senior home, but at the same time they rejected wishing to live in a place that was identified as a senior home. We explain this paradox by the representation of such a space as being for old people, i.e. needy older individuals, which was not how the older participants wished to be identified. We conclude that the conception of age-friendly environments will have to face the difficult challenge of overcoming the association with old age, while simultaneously taking into account adjustments that signify and relate to the ageing process and that seem inescapably tied to oldness.

Lifestyle and youthful looks.

BACKGROUND: Lifestyle has been proven to have a dramatic effect on the risk of age-related diseases. The association of lifestyle and facial ageing has been less well studied. OBJECTIVES: To identify lifestyle factors that associate with perceived facial age in white north European men and women. METHODS: Lifestyle, facial wrinkling and perceived facial age were studied in two cross-sectional studies consisting of 318 Dutch men and 329 women aged 45-75 years who were part of the Leiden Longevity Study, and 162 English women aged 45-75 years who were nonsmokers. RESULTS: In Dutch men, smoking, having skin that went red in the sun, being outside in the sun most of the summer, sunbed use, wearing false teeth and not flossing teeth were all significantly associated (P < 0·05) with a total 9·3-year higher perceived facial age in a multivariate model adjusting for chronological age. In Dutch women, smoking, sunbathing, sunbed use, few remaining teeth and a low body mass index (BMI) were associated with a total 10·9-year higher perceived facial age. In English women, cleaning teeth only once a day, wearing false teeth, irregular skin moisturization and having skin that went red in the sun were associated with a total 9·1-year higher perceived facial age. Smoking and sunbed use were associated more strongly with wrinkling in women than in men. BMI, sun exposure and skincare were associated predominantly with perceived facial age via wrinkling, whereas oral care was associated via other facial features. CONCLUSIONS: Although associative in nature, these results support the notion that lifestyle factors can have long-term beneficial effects on youthful looks.

NT-proBNP, blood pressure, and cognitive decline in the oldest old: The Leiden 85-plus Study.

OBJECTIVE: To study the relation between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, used as a marker of heart failure in clinical practice, blood pressure (BP), and cognitive decline in the oldest old. METHODS: In 560 participants of the Leiden 85-plus Study, we measured NT-proBNP levels and BP at age 85 years, at baseline, and global cognitive function (Mini-Mental State Examination [MMSE]) annually during the follow-up of 5 years. RESULTS: Subjects in the highest tertile of NT-proBNP levels scored 1.7 points lower on the MMSE at age 85 years than subjects in the lowest tertile (p = 0.004), and had a 0.24-point-steeper decline in MMSE score per year (p = 0.021). The longitudinal association disappeared after full adjustment for possible confounders (0.14-point-steeper decline, p = 0.187). Subjects in the category "highest tertile of NT-proBNP and the lowest tertile of systolic BP" had a 3.7-point-lower MMSE score at baseline (p < 0.001) and a 0.49-point-steeper decline in MMSE score per year (p < 0.001) compared with subjects in the other categories. CONCLUSIONS: In the oldest old, high NT-proBNP levels are associated with lower MMSE scores. The combination of high NT-proBNP levels and low systolic BP is associated with worst global cognitive function and the steepest cognitive decline. Possibly, a failing pump function of the heart results in lower BP and lower brain perfusion with resultant brain dysfunction.

Insulin-like growth factor-1 and risk of late-onset Alzheimer's disease: findings from a family study.

Insulin-like growth factor-1 (IGF-1), part of an evolutionary conserved signaling pathway in both mammalian and non-mammalian species, is inferred in neurodegenerative disorders including Alzheimer's disease (AD). A murine model for AD shows that reduced IGF-1 signaling prevents AD-like characteristics. However, variation in serum levels of IGF-1 and risk of AD in humans has yet to be determined. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. The offspring under study carry an increased risk of AD but do not yet experience cognitive impairment. A total of 206 offspring from 92 families with a parental history of AD were compared with 200 offspring from 97 families without a parental history of AD. Apolipoprotein-E (APOE) genotypes and serum IGF-1 levels were compared in subjects with and without a parental history of AD using linear regression, adjusted for APOE genotype and other possible demographic and clinical confounders. Offspring with a parental history of AD were more likely to be an APOE ε4 allele carrier (46.5% vs. 21%, p = 0.001) than were offspring without such a parental history. Offspring with a parental history of AD had higher IGF-1 levels than subjects without such a history, in both unadjusted and adjusted analyses (18.3 mmol/L vs. 16.7 mmol/L, p = 0.001). In conclusion, higher serum IGF-1 levels in middle age are associated with risk of AD disease in older age, independent of APOE genotype.

Diagnostic measures for sarcopenia and bone mineral density.

SUMMARY: Currently used diagnostic measures for sarcopenia utilize different measures of muscle mass, muscle strength, and physical performance. These diagnostic measures associate differently to bone mineral density (BMD), as an example of muscle-related clinical outcome. These differences should be taken into account when studying sarcopenia. INTRODUCTION: Diagnostic measures for sarcopenia utilize different measures of muscle mass, muscle strength, and physical performance. To understand differences between these measures, we determined the association with respect to whole body BMD, as an example of muscle-related clinical outcome. METHODS: In the European cross-sectional study MYOAGE, 178 young (18-30 years) and 274 healthy old participants (69-81 years) were recruited. Body composition and BMD were evaluated using dual-energy X-ray densitometry. Diagnostic measures for sarcopenia were composed of lean mass as percentage of body mass, appendicular lean mass (ALM) as percentage of body mass, ALM divided by height squared (ALM/height(2)), knee extension torque, grip strength, walking speed, and Timed Up and Go test (TUG). Linear regression models were stratified for sex and age and adjusted for age and country, and body composition in separate models. RESULTS: Lean mass and ALM/height(2) were positively associated with BMD (P < 0.001). Significance remained in all sex and age subgroups after further adjustment for fat mass, except in old women. Lean mass percentage and ALM percentage were inversely associated with BMD in old women (P < 0.001). These inverse associations disappeared after adjustment for body mass. Knee extension torque and handgrip strength were positively associated with BMD in all subgroups (P < 0.01), except in old women. Walking speed and TUG were not related to BMD. CONCLUSIONS: The associations between diagnostic measures of sarcopenia and BMD as an example of muscle-related outcome vary widely. Differences between diagnostic measures should be taken into account when studying sarcopenia.

Thyroid hormone signaling and homeostasis during aging.

Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels, notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely, caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological responses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are advantageous for optimal aging.

Serum insulin-like growth factor 1 and facial ageing: high levels associate with reduced skin wrinkling in a cross-sectional study.

BACKGROUND: Insulin-like growth factor (IGF)-1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression. OBJECTIVES: To assess whether serum IGF-1, IGF-binding protein (IGFBP)3 and the ratio between IGF-1 and IGFBP3, as a measure of IGF-1 bioavailability, are associated with facial ageing and skin wrinkling. METHODS: From a random sample comprising 617 subjects from the Leiden Longevity Study, perceived age and skin wrinkling were assessed from facial photographs, and IGF-1 and IGFBP3 were measured in serum. The associations were assessed using linear regression models, adjusted for chronological age, sex, body mass index, smoking and sun exposure. RESULTS: Across tertiles of the ratio of IGF-1 to IGFBP3, and after adjusting for all potential confounding factors, the mean perceived age decreased from 60·6 years in the lowest tertile to 59·5 years in the highest (P = 0·045). Similarly, the mean skin wrinkling grade decreased from 4·8 in the lowest tertile to 4·5 in the highest (P = 0·011). Adding skin wrinkling as a covariate in the analysis between IGF-1 and perceived age diminished this association. CONCLUSIONS: This study demonstrates that a higher ratio of IGF-1 to IGFBP3 associates with a lower perceived age, via its association with reduced skin wrinkling. Whether high IGF-1 levels actually delay the accumulation of skin wrinkling now needs investigating.

Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study.

BACKGROUND: Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age. METHODS: Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months). RESULTS: In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045). CONCLUSIONS: Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.

Diagnostic criteria for sarcopenia relate differently to insulin resistance.

Skeletal muscle is important in insulin-stimulated glucose uptake. Sarcopenia is, therefore, a possible risk factor for insulin resistance. Currently, different diagnostic criteria for sarcopenia include low muscle mass, muscle strength, and walking speed. We assessed these muscle characteristics in relation to insulin resistance in nondiabetics. This cross-sectional study included 301 nondiabetics, mean age 65.9 years. Area under curve (AUC) calculations of insulin and glucose from a 2-h oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used as measures of insulin resistance. Muscle characteristics were relative muscle mass (total or appendicular lean mass (ALM) as percentage of body mass), absolute muscle mass (ALM/height(2) and total lean mass), handgrip strength, and walking speed. All muscle characteristics were standardized and analyzed in linear regression models, stratified by gender. For both males and females, relative muscle mass was inversely associated with AUC insulin, AUC glucose, and HOMA-IR (ALM percentage all p ≤ 0.004). Absolute muscle mass was positively associated with AUC insulin and HOMA-IR (ALM/height(2) all p < 0.001) but not with AUC glucose. Adjustments for fat mass attenuated aforementioned associations. There were no associations between handgrip strength and insulin resistance. Walking speed was inversely associated with AUC insulin in males (p = 0.032). The association between muscle characteristics and insulin resistance was strongest for relative muscle mass. Diagnostic criteria for sarcopenia relate differently to insulin resistance. The role of muscle tissue as an internal glucose-regulating organ is better reflected by relative muscle mass than by absolute muscle mass, muscle strength, or walking speed.

Defining sarcopenia: the impact of different diagnostic criteria on the prevalence of sarcopenia in a large middle aged cohort.

Sarcopenia, low muscle mass, is an increasing problem in our ageing society. The prevalence of sarcopenia varies extremely between elderly cohorts ranging from 7% to over 50%. Without consensus on the definition of sarcopenia, a variety of diagnostic criteria are being used. We assessed the degree of agreement between seven different diagnostic criteria for sarcopenia based on muscle mass and handgrip strength, described in literature. In this cross-sectional study, we included men (n=0325) and women (n=0329) with complete measurements of handgrip strength and body composition values as measured by bioimpedance analysis within the Leiden Longevity Study. Prevalence of sarcopenia was stratified by gender and age. In men (mean age 64.5 years), the prevalence of sarcopenia with the different diagnostic criteria ranged from 0% to 20.8% in the lowest age category (below 60 years), from 0%to 31.2% in the middle (60 to 69 years) and from 0% to 45.2% in the highest age category (above 70 years). In women (mean age 61.8 years), the prevalence of sarcopenia ranged from 0% to 15.6%, 0% to 21.8% and 0% to 25.8% in the lowest, middle and highest age category, respectively. Only one participant (0.2%) was identified having sarcopenia according to all diagnostic criteria that marked prevalence above 0%. We conclude that the prevalence of sarcopenia is highly dependent on the applied diagnostic criteria. It is necessary to reach a consensus on the definition of sarcopenia in order to make studies comparable and for implementation in clinical care.

Mortality in former Olympic athletes: retrospective cohort analysis.

OBJECTIVE: To assess the mortality risk in subsequent years (adjusted for year of birth, nationality, and sex) of former Olympic athletes from disciplines with different levels of exercise intensity. DESIGN: Retrospective cohort study. SETTING: Former Olympic athletes. PARTICIPANTS: 9889 athletes (with a known age at death) who participated in the Olympic Games between 1896 and 1936, representing 43 types of disciplines with different levels of cardiovascular, static, and dynamic intensity exercise; high or low risk of bodily collision; and different levels of physical contact. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: Hazard ratios for mortality among athletes from disciplines with moderate cardiovascular intensity (1.01, 95% confidence interval 0.96 to 1.07) or high cardiovascular intensity (0.98, 0.92 to 1.04) were similar to those in athletes from disciplines with low cardiovascular intensity. The underlying static and dynamic components in exercise intensity showed similar non-significant results. Increased mortality was seen among athletes from disciplines with a high risk of bodily collision (hazard ratio 1.11, 1.06 to 1.15) and with high levels of physical contact (1.16, 1.11 to 1.22). In a multivariate analysis, the effect of high cardiovascular intensity remained similar (hazard ratio 1.05, 0.89 to 1.25); the increased mortality associated with high physical contact persisted (hazard ratio 1.13, 1.06 to 1.21), but that for bodily collision became non-significant (1.03, 0.98 to 1.09) as a consequence of its close relation with physical contact. CONCLUSIONS: Among former Olympic athletes, engagement in disciplines with high intensity exercise did not bring a survival benefit compared with disciplines with low intensity exercise. Those who engaged in disciplines with high levels of physical contact had higher mortality than other Olympians later in life.