Postmenopausal hormone therapy and cognition in twins.

OBJECTIVE: Mild cognitive impairment may be caused by pathophysiological changes occurring decades prior to symptom development. It has been hypothesised that oestrogen can prevent such changes. We aimed to investigate the association between postmenopausal hormone therapy and cognition in Danish female twins and to examine differences in this association before and after publication of the findings from the Women's Health Initiative study in 2002. STUDY DESIGN: This study includes cognitive assessment of 4510 twins aged 50+ years. Information on hormone therapy was obtained through Danish health registries. The association between current hormone therapy use and cognition was analysed in twins aged 50+ using both cross-sectional, intrapair and longitudinal analysis, adjusting for age, education, social class, and unobserved familial confounding. RESULTS: Cross-sectionally, systemic HT users aged 70+ had a significantly lower cognitive function than non-users, whereas systemic HT users aged 50-69 did not differ from non-users before 2002. Longitudinal data in younger twins aged 50-69 showed a significantly lower cognitive function in systemic HT users after 2002 compared to non-users. Systemic HT users aged 70+ showed that the lower cognitive function was most explicit before 2002, whereas after 2002 the cognitive function was closer to non-users. Twins aged 50-69 who changed from systemic HT to local HT after 2002, or dropped it altogether, performed cognitively better. CONCLUSIONS: Our findings cautiously indicate a change in the association between cognition and hormone therapy use after 2002, which suggests an alteration in the hormone therapy user profile in the wake of the 2002 WHI publication.

Cognitively high-performing oldest old individuals are physically active and have strong motor skills-A study of the Danish 1905 and 1915 birth cohorts.

Preserving cognitive function with age or super-aging greatly contributes to successful aging. Super-aging nonagenarians born in Denmark in either year 1905 or 1915 were classified as Cognitively High-Performing Oldest Old individuals with a five item cognitive composite score, equivalent to or better than mean middle-aged subjects. Cognitively high-performers were more physically active and had a better physical performance on e.g., Activity of Daily Living (p-value < 0.01), gait speed (p-value < 0.01) and grip strength (p-value < 0.05) compared with age-matched peers. Cognitive high-performing was also linked to lower depression symptomatology. When comparing super-agers with semi super-agers classified by Mini Mental State Examination > 27, super-agers were still more physically active and had a better physical performance (p-value < 0.05). Results suggests that physical activity is a lifestyle factor strongly associated with both semi and full cognitive super-aging.

Postmenopausal hormone therapy and mortality before and after the Women's Health Initiative study.

Weighing risks and benefits of postmenopausal hormone therapy (HT) has proven a balancing act. We aimed to investigate the association between HT and mortality before and after the 2002 publication from the Women's Health Initiative (WHI) study. This publication found that the risk of using HT outweighted the benefits, and thus it caused a marked reduction in systemic HT user prevalence. The 2002 WHI publication may also have caused a change in the subsequent HT user profile, as HT is no longer recommended in the prevention of chronic diseases. This cohort study included two populations followed from 1995: A 5% random sample of female singletons from the Danish general population (n = 52,388) and a sample of Danish female twins (n = 15,261). HT use was evaluated in 1995, 2000, 2005, and 2010. The association between HT, education, and mortality was investigated and controlled for potential unobserved familial confounding in a within-pair analysis. Singletons aged 56-75 using systemic HT in 2000 had a lower mortality compared to non-users (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.78-0.89). In 2005, the mortality was like that of the background population for this age group (HR 1.02, 95% CI 0.94-1.11). Recently postmenopausal twins showed a similar tendency. Systemic HT users, who had switched to local HT by 2005, had a substantially lower mortality than non-users (HR ranging from 0.42 to 0.67 depending on age group). In conclusion, we found that the prevalence of systemic HT use declined after 2002, and systemic HT users' mortality changed from lower before 2002 to similar to that of the background population after 2002. This indicates that the healthiest users decided to either drop systemic HT or switcted to local HT, as recommendations changed following the WHI publication.

Systemic hormone therapy and dementia: A nested case-control and co-twin control study.

OBJECTIVE: The effect of systemic hormone therapy (HT) on dementia risk is unclear. Our aim was to investigate the association between HT and dementia. STUDY DESIGN: This register-based study consists of a nested case-control study and a co-twin control design, which controls for familial confounding, including shared genetics. MAIN OUTCOME MEASURES: Through Danish national registries from 1995 to 2011, we identified: a) 2700 female singletons with incident dementia and 13,492 matched controls; b) 288 female twins with incident dementia and co-twins without dementia. Data on HT and education were retrieved, and analyses were performed using conditional logistic regression and McNemar's χ2-test. HT use decreased dramatically after the Women's Health Initiative study results were published in 2002, and the analyses were stratified accordingly to account for potentially different HT user characteristics. RESULTS: The odds ratio (OR) for the association between systemic HT and dementia was 1.05, 95% CI = [0.93-1.19] in singletons and 2.10, 95% CI = [0.99-4.46] in twins. A statistically significant association was found for systemic HT before 2003 in both populations, with an OR of 1.14, 95% CI = [1.01-1.28] in singletons and an OR of 2.20, 95% CI = [1.04-4.65] in twins. CONCLUSION: Using Danish nationwide registries and controlling for education and for familial factors in a subsample, systemic HT was found to be associated with increased dementia risk if used before 2003, when HT was more commonly prescribed.

Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study.

BACKGROUND: Previous research has suggested that individuals with Type 2 diabetes and initiated on metformin monotherapy present with a survival advantage compared with the general population without diabetes. This finding has generated considerable interest in the prophylactic use of metformin against age-related morbidity. METHODS: Utilizing Danish National Health Registers, we assessed differences in survival associated with metformin monotherapy for Type 2 diabetes compared with no diagnosis of diabetes in both singleton and discordant twin populations between 1996 and 2012. Data were analysed in both nested case-control and matched cohort study designs, with incidence rate ratios (IRRs) and hazard ratios estimated using conditional logistic regression and Cox proportional hazards regression, respectively. RESULTS: In case-control pairs matched on birth year and sex or co-twin (sex, birth year and familial factors), incident Type 2 diabetes with treatment by metformin monotherapy initiation compared with no diagnosis of diabetes was associated with increased mortality in both singletons (IRR = 1.52, 95% CI: 1.37, 1.68) and discordant twin pairs (IRR = 1.90, 95% CI: 1.35, 2.67). After adjusting for co-morbidities and social indicators, these associations were attenuated to 1.32 (95% CI: 1.16, 1.50) and 1.64 (95% CI: 1.10, 2.46), respectively. Increased mortality was observed across all levels of cumulative use and invariant to a range of study designs and sensitivity analyses. CONCLUSIONS: Treatment initiation by metformin monotherapy in Type 2 diabetes was not associated with survival equal or superior to that of the general population without diabetes. Our contrasting findings compared with previous research are unlikely to be the result of differences in epidemiological or methodological parameters.

Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians.

Oxidative stress is an important factor in age-associated neurodegeneration. Accordingly, mitochondrial dysfunction and genomic instability have been considered as key hallmarks of aging and have important roles in age-associated cognitive decline and neurodegenerative disorders. In order to evaluate whether maintenance of cognitive abilities at very old age is associated with key hallmarks of aging, we measured mitochondrial bioenergetics, mitochondrial DNA copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians in a Danish 1915 birth cohort (n = 120). Also, the circulating levels of brain-derived neurotrophic factor, NAD+ /NADH and carbonylated proteins were measured in plasma of the centenarians and correlated to cognitive capacity. Mitochondrial respiration was well preserved in the centenarian cohort when compared to young individuals (21-35 years of age, n = 33). When correlating cognitive performance of the centenarians with mitochondrial function such as basal respiration, ATP production, reserve capacity and maximal respiration, no overall correlations were observed, but when stratifying by sex, inverse associations were observed in the males (p < 0.05). Centenarians with the most severe cognitive impairment displayed the lowest activity of the central DNA repair enzyme, APE1 (p < 0.05). A positive correlation between cognitive capacity and levels of NAD+ /NADH was observed (p < 0.05), which may be because NAD+ /NADH consuming enzyme activities strive to reduce the oxidative DNA damage load. Also, circulating protein carbonylation was lowest in centenarians with highest cognitive capacity (p < 0.05). An opposite trend was observed for levels of brain-derived neurotrophic factor (p = 0.17). Our results suggest that maintenance of cognitive capacity at very old age may be associated with cellular mechanisms related to oxidative stress and DNA metabolism.

Stratification in health and survival after age 100: evidence from Danish centenarians.

BACKGROUND: The existence of a super-select group of centenarians that demonstrates increased survivorship has been hypothesized. However, it is unknown if this super-select group possesses similar characteristics apart from extreme longevity. METHODS: In this study, we analyse high-quality health and survival data of Danish centenarians born in 1895, 1905 and 1910. We use Latent Class Analysis to identify unobserved health classes and to test whether these super-select lives share similar health characteristics. RESULTS: We find that, even after age 100, a clear and distinct gradient in health exists and that this gradient is remarkably similar across different birth cohorts of centenarians. Based on the level of health, we identify three clusters of centenarians - robust, frail and intermediate - and show that these groups have different survival prospects. The most distinctive characteristic of the robust centenarians is the outperformance in different health dimensions (physical, functional and cognitive). Finally, we show that our health class categorizations are good predictors of the survival prospects of centenarians. CONCLUSIONS: There is a clear stratification in health and functioning among those over 100 years of age and these differences are associated with survival beyond age 100.

A neuronal blood marker is associated with mortality in old age.

Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21-107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2-30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

Apolipoprotein E ε4 and cognitive function after surgery in middle-aged and elderly Danish twins.

BACKGROUND: Transient cognitive impairment is common in adult patients of all ages following anaesthesia and surgery. Apolipoprotein E (APOE) ε4 carriers may have a larger deterioration in short-term cognitive function after major surgery compared with APOE ε4 noncarriers. OBJECTIVES: The aim was to examine the effect of APOE ε4 on the association between exposure to surgery and anaesthesia, and subsequent cognitive functioning. A more pronounced deterioration in cognitive function in APOE ε4 carriers was hypothesised. DESIGN: An observational cross-sectional and a 6 to 10 years longitudinal twin cohort design. SETTING: Survey and register study of 2936 Danish twins aged 45 to 92 years. MAIN OUTCOME MEASURES: Cognitive function was assessed using five age-sensitive cognitive tests. In the cross-sectional study, we compared twins exposed to surgery with a reference group (unexposed). Linear regression models were used adjusting for sex and age and stratified by APOE ε4 carrier status. In the longitudinal cognitive follow-up study 1671 twins participated. Intrapair analyses were also performed using 70 same-sexed twin pairs concordant for APOE ε4 carrier status, but discordant for major surgery. RESULTS: APOE ε4 carriers had lower cognitive scores compared with noncarriers, and this was statistically significant in elderly twins 70+ years of age (mean difference, -0.67; 95% CI, -1.14 to -0.17). There was no significant impact on cognitive function after surgery according to APOE ε4 carrier status in the cross-sectional study. Similarly, there was no APOE ε4 modification in the longitudinal study. Also, in the intrapair analyses no evidence was found of lower cognitive score after major surgery compared with the nonexposed cotwins among APOE ε4 carriers. CONCLUSION: No evidence was found of more pronounced long-term deterioration in cognitive function after surgery among APOE ε4 carriers, but elderly APOE ε4 carriers in general performed worse on the cognitive tests than noncarriers.

Are Advances in Survival Among the Oldest Old Seen Across the Spectrum of Health and Functioning?

BACKGROUND: Mortality rates have been reduced by half over the last 60 years for nonagenarians, and the progress is continuing. The greater survival might be due to overtreatment of severely physically and cognitively disabled individuals, which is a big concern for societies and individuals. METHODS: The study population comprised two Danish birth cohorts: the 1905 Cohort and the 1915 Cohort. At age 95, all from the two cohorts who were still alive and living in Denmark were invited to participate in a health survey that used the same assessment instrument. A total of 2,670 (56.8%) persons participated in the two surveys and survival was assessed through a 7.3-year follow-up period during which 2,497 (93.5%) had died, and with virtually no loss to follow-up. RESULTS: Despite the increasing chance of surviving to age 95, the 1915 Cohort had significantly better health and functioning than the 1905 Cohort. The survival advantage in the 1915 Cohort continued in the follow-up period after age 95: Median survival length was 2.4 months longer, p = .011. This advantage was not statistically associated with different levels of activities of daily living, physical performance, cognitive functioning, self-rated health and life satisfaction. However, the advantage tended to be more pronounced among people with better health. CONCLUSIONS: Life span and health increases among the oldest old. The improvement in survival for 95-year olds born in 1915 compared with 1905 was seen across the whole spectrum of health and functioning, with a tendency towards bigger improvement among those in good health.

Sex differences in health and mortality by income and income changes.

BACKGROUND: The adverse association between income, health and survival is well documented, but little is known about how income trajectories influence health and survival for men and women. We aim to investigate sex differences in mortality and hospitalisations by income and income changes. METHODS: We performed a population-based, nationwide study including 1 063 787 Danes born 1935-1955 and residing in Denmark during 1980-2015. Income was calculated during two age intervals: 45-49 and 55-59 years. The average income was divided into quartiles for men and women separately, which formed the basis for the income trajectories. Individuals were followed up from age 60 until 2014/2015 for hospital admission and mortality, respectively. RESULTS: Men had higher mortality and were more hospitalised than women. Sex differences in mortality were most pronounced for people with stable low income (relative difference in hazard=1.93; 95% CI 1.89 to 1.98) and a downward income trajectory (1.91; 95% CI 1.85 to 1.98) with smaller sex differences for people with an upward trajectory (1.59; 95% CI 1.56 to 1.62) and stable high income (1.37; 95% CI 1.33 to 1.41). A similar pattern was found for family income. Regarding hospitalisations, similar results were found, though less pronounced. Investigation of mortality and hospitalisations by all possible trajectories demonstrated that income at ages 55-59 was an important predictor of mortality, with increasing mortality for decreasing income quartile. CONCLUSION: Income trajectories as a proxy for change in social position have a larger influence on men's than women's health and mortality. Income in the late 50s is an important predictor of mortality, particularly for men.

Sex Differences in Comorbidity and Frailty in Europe.

OBJECTIVES: To examine sex differences in prevalent comorbidity and frailty across age and European regions. METHODS: This is a cross-sectional study based on 113,299 Europeans aged 50+ participating in the Survey of Health, Ageing and Retirement in Europe from 2004-2005 to 2015. Sex differences in the Comorbidity Index and the Frailty Phenotype were investigated using ordinal logistic regressions. RESULTS: European women had generally higher odds of prevalent comorbidity (OR 1.11, 95% CI 1.07-1.15) and frailty (OR 1.56, 95% CI 1.51-1.62). Sex differences increased with advancing age. No overall sex difference in comorbidity was found in Western Europe, but women had more comorbidity than men in Eastern (OR 1.30, 95% CI 1.18-1.44), Southern (OR 1.23, 95% CI 1.15-1.30), and Northern (OR 1.08, 95% CI 1.01-1.16) Europe. Women were frailer than men in all regions, with the largest sex difference in Southern Europe (OR 1.84, 95% CI 1.72-1.96). CONCLUSIONS: European women are frailer and have slightly more comorbidity than European men lending support for the male-female health survival paradox.

How to estimate mortality trends from grouped vital statistics.

BACKGROUND: Mortality data at the population level are often aggregated in age classes, for example 5-year age groups with an open-ended interval for the elderly aged 85+. Capturing detailed age-specific mortality patterns and mortality time trends from such coarsely grouped data can be problematic at older ages, especially where open-ended intervals are used. METHODS: We illustrate the penalized composite link model (PCLM) for ungrouping to model cancer mortality surfaces. Smooth age-specific distributions from data grouped in age classes of adjacent calendar years were estimated by constructing a two-dimensional regression, based on B-splines, and maximizing a penalized likelihood. We show the applicability of the proposed model, analysing age-at-death distributions from cancers of all sites in Denmark from 1980 to 2014. Data were retrieved from the Danish Cancer Society and the Human Mortality Database. RESULTS: The main trends captured by PCLM are: (i) a decrease in cancer mortality rates after the 1990s for ages 50-75; (ii) a decrease in cancer mortality in later cohorts for young ages, especially, and very advanced ages. Comparing the raw data by single year of age, with the PCLM-ungrouped distributions, we clearly illustrate that the model fits the data with a high level of accuracy. CONCLUSIONS: The PCLM produces detailed smooth mortality surfaces from death counts observed in coarse age groups with modest assumptions, that is Poisson distributed counts and smoothness of the estimated distribution. Hence, the method has great potential for use within epidemiological research when information is to be gained from aggregated data, because it avoids strict assumptions about the actual distributional shape.

Comparison of cognitive and physical functioning of Europeans in 2004-05 and 2013.

Background: Adult mortality has been postponed over time to increasingly high ages. However, evidence on past and current health trends has been mixed, and little is known about European disability trends. Methods: In a cross-sectional setting, we compared cognitive and physical functioning in same-aged Europeans aged 50+ between 2004-05 (wave 1; n = 18 757) and 2013 (wave 5 refresher respondents; n = 16 696), sourced from the Survey of Health, Ageing and Retirement in Europe (SHARE). Results: People in 2013 had better cognitive function compared with same-aged persons in 2004-05, with an average difference of approximately one-third standard deviation. The same level of cognitive function in 2004-05 at age 50 was found in 2013 for people who were 8 years older. There was an improvement in cognitive function in all European regions. Mean grip strength showed an improvement in Northern Europe of 1.00 kg [95% confidence interval (CI) 0.65; 1.35] and in Southern Europe of 1.68 kg (95% CI 1.14; 2.22), whereas a decrease was found in Central Europe (-0.80 kg; 95% CI -1.16; -0.44). We found no overall differences in activities of daily living (ADL), but small improvements in instrumental activities of daily living (IADL) in Northern and Southern Europe, with an improvement in both ADL and IADL from age 70 in Northern Europe. Conclusions: Our results indicate that later-born Europeans have substantially better cognitive functioning than earlier-born cohorts. For physical functioning, improvements were less clear, but for Northern Europe there was an improvement in ADL and IADL in the oldest age groups.

No impact of surgery on cognitive function: a longitudinal study of middle-aged Danish twins.

PURPOSE: To examine the association between exposure to surgery and 10-year change in cognitive functioning. METHODS: Among 2351 middle-aged twins, a 10-year change in composite cognitive scores derived from five cognitive tests was compared between 903 (38%) twins exposed to surgery classified as major, minor, knee and hip replacement, and other, and a reference group of 1448 (62%) twins without surgery, using linear regression models adjusted for socioeconomic factors. Genetic and shared environmental confounding was addressed in intrapair analyses of 48 monozygotic and 74 dizygotic same-sexed twin pairs. RESULTS: In individual-level analyses, twins with major surgery (mean difference, -0.37; 95% CI, -0.76 to 0.02) or knee and hip replacement surgery (mean difference, -0.54; 95% CI, -1.30 to 0.22) had a tendency of a negligibly higher rate of decline in cognitive score than the reference group. In the intrapair analyses, the surgery-exposed twin had a higher rate of cognitive decline than the co-twin in 55% (95% CI, 45% to 63%) of the pairs. The mean difference in cognitive decline within pairs was -0.21 (95% CI, -0.81 to 0.39). CONCLUSIONS: No significant associations were found between exposure to surgery and change in cognitive score either in individual-level or in intrapair analyses.

Improvement in Activities of Daily Living Among Danish Centenarians?-A Comparative Study of Two Centenarian Cohorts Born 20 Years Apart.

Background: With the continued rise in the proportion of the oldest-old in high-income countries, it is of interest to know whether the functional health of today's oldest-olds is better or worse than in previous cohorts. Using two Danish centenarian birth cohorts born 20 years apart we aimed at investigating if the later born cohort had better functioning in terms of activities of daily living (ADL). Methods: Identification, methodology, and assessment instruments were identical in the 1895-West and 1915-West Birth Cohort Studies: All persons living in the western part of Denmark and turning 100 years old in 1995 and 2015, respectively. Data were collected through structured in-home interviews. Participation rates were 74% (n = 106) and 79% (n = 238), respectively. Results: The proportion of nondisabled women of the 1915-West cohort was more than twice as high compared to the 1895-West cohort and with corresponding lower proportions of moderately and severely disabled persons (17% vs 7%, 33% vs 40% and 50% vs 53% in the 1915-West and 1895-West cohorts, respectively, p = .047). Only nonsignificant improvements were seen among men in the 1915-West cohort. In both sexes, considerably higher proportions of the latest cohort used assistive devices than the former (statistically significant for the majority of assistive devices). Conclusion: This comparative study shows improvements in reported ADL in the later born cohort of centenarians, even though only significant among women. As women constitute the majority of the oldest-olds, our findings are encouraging from a public health care view.

Handgrip strength and its prognostic value for mortality in Moscow, Denmark, and England.

BACKGROUND: This study compares handgrip strength and its association with mortality across studies conducted in Moscow, Denmark, and England. MATERIALS: The data collected by the Study of Stress, Aging, and Health in Russia, the Study of Middle-Aged Danish Twins and the Longitudinal Study of Aging Danish Twins, and the English Longitudinal Study of Ageing was utilized. RESULTS: Among the male participants, the age-standardized grip strength was 2 kg and 1 kg lower in Russia than in Denmark and in England, respectively. The age-standardized grip strength among the female participants was 1.9 kg and 1.6 kg lower in Russia than in Denmark and in England, respectively. In Moscow, a one-kilogram increase in grip strength was associated with a 4% (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.94, 0.99) reduction in mortality among men and a 10% (HR = 0.90, 95%CI: 0.86, 0.94) among women. Meanwhile, a one-kilogram increase in grip strength was associated with a 6% (HR = 0.94, 95%CI: 0.93, 0.95) and an 8% (HR = 0.92, 95%CI: 0.90, 0.94) decrease in mortality among Danish men and women, respectively, and with a 2% (HR = 0.98, 95%CI: 0.97, 0.99) and a 3% (HR = 0.97, 95%CI: 0.95, 0.98) reduction in mortality among the English men and women, respectively. CONCLUSION: The study suggests that, although absolute grip strength values appear to vary across the Muscovite, Danish, and English samples, the degree to which grip strength is predictive of mortality is comparable across national populations with diverse socioeconomic and health profiles and life expectancy levels.

Telomeres and the natural lifespan limit in humans.

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

Investigation of the 5q33.3 longevity locus and age-related phenotypes.

A large meta-analysis recently found the 5q33.3 locus to be associated with survival to ≥ 90 years and lower all-cause mortality, thus suggesting it as a third human longevity locus alongside APOE and FOXO3A. The 5q33.3 locus has previously been associated with blood pressure regulation and cardiovascular diseases in middle-aged individuals. However, part of the influence on mortality appears to be independent of cardiovascular phenotypes, and the role of the 5q33.3 locus in longevity and survival is therefore still partly unknown. We investigated the association between the longevity-associated variant rs2149954 on chromosome 5q33.3 and age-related phenotypes in two cohorts of 1,588 and 1,271 long-lived individuals (mean ages 93.1 and 95.9 years, respectively) as well as in 700 middle-aged and 677 elderly individuals (mean ages 52.5 and 78.7 years). Altogether, nominally significant associations between the rs2149954 minor allele and a decreased risk of heart attack and heart failure as well as increased physical functioning were found in the long-lived individuals. In the middle-aged and elderly individuals, rs2149954 minor allele carriers had a lower risk of hypertension. Our results thereby confirm a role of the 5q33.3 locus in cardiovascular health and, interestingly, they also suggest a role in physical functioning.