Jacob J.E. Koopman

Risk of Cardiovascular Disease in a Traditional African Population with a High Infectious Load: A Population-Based Study

Background To test the inflammatory origin of cardiovascular disease, as opposed to its origin in western lifestyle. Population-based assessment of the prevalences of cardiovascular risk factors and cardiovascular disease in an inflammation-prone African population, including electrocardiography and ankle-arm index measurement. Comparison with known prevalences in American and European societies. Methodology/Principal Findings Traditional population in rural Ghana, characterised by adverse environmental conditions and a high infectious load. Population-based sample of 924 individuals aged 50 years and older. Median values for cardiovascular risk factors, including waist circumference, BMI, blood pressure, and markers of glucose and lipid metabolism and inflammation. Prevalence of myocardial infarction detected by electrocardiography and prevalence of peripheral arterial disease detected by ankle-arm index. When compared to western societies, we found the Ghanaians to have more proinflammatory profiles and less cardiovascular risk factors, including obesity, dysglycaemia, dyslipidaemia, and hypertension. Prevalences of cardiovascular disease were also lower. Definite myocardial infarction was present in 1.2% (95%CI: 0.6 to 2.4%). Peripheral arterial disease was present in 2.8% (95%CI: 1.9 to 4.1%). Conclusions/Significance Taken together, our data indicate that for the pathogenesis of cardiovascular disease inflammatory processes alone do not suffice and additional factors, probably lifestyle-related, are mandatory.

Handgrip strength, ageing and mortality in rural Africa

Background: muscle strength measured as handgrip strength declines with increasing age and predicts mortality. While handgrip strength is determined by lifestyle through nutrition and physical activity, it has almost exclusively been studied in western populations with a sedentary lifestyle. This study aims to investigate the relation between handgrip strength, ageing and mortality in a population characterised by a predominance of malnutrition and manual labour. Design: a population-based longitudinal study. Setting: a traditional African rural population in Ghana. Subjects: nine hundred and twenty-three community-dwelling individuals aged 50 and older. Methods: demographic characteristics were registered. At baseline, height, body mass index (BMI) and handgrip strength were measured and compared with those in a western reference population. Survival of the participants was documented during a period of up to 2 years. Results: handgrip strength was dependent on age, sex, height and BMI. Compared with the western reference population, handgrip strength was lower due to a lower height and BMI but declined over age similarly. Risk of mortality was lower in participants having higher handgrip strength, with a hazard ratio of 0.94 per kg increase (P = 0.002). After adjustment for age, sex, tribe, socio-economic status, drinking water source, height and BMI, only handgrip strength remained predictive of mortality. Conclusion: in a traditional rural African population characterised by malnutrition and manual labour, handgrip strength declines over age and independently predicts mortality similar to western populations. Handgrip strength can be used as a universal marker of ageing.

Senescence rates in patients with end‐stage renal disease: a critical appraisal of the Gompertz model

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end‐stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age‐specific mortality rates for European patients on dialysis (n = 274 221; follow‐up = 594 767 person‐years), for European patients with a functioning kidney transplant (n = 61 286; follow‐up = 345 024 person‐years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P < 0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.

Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling

Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species.

Longevity is impacted by growth hormone action during early postnatal period

Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life. Our data suggest that developmental programming of aging importantly contributes to (and perhaps explains) the well documented developmental origins of adult disease. DOI: http://dx.doi.org/10.7554/eLife.24059.001

Intrinsic and extrinsic mortality reunited.

Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic stressors in the causation of aging leads to the recognition that aging is not inevitable, but malleable through the environment.

Effect of APOE ε4 allele on survival and fertility in an adverse environment

Background The apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer’s disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility. Methods and findings This rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018). Conclusions Contrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.

Heart rate variability, but not heart rate, is associated with handgrip strength and mortality in older Africans at very low cardiovascular risk: A population-based study

A high heart rate and a low heart rate variability at rest are established predictors of various forms of functional impairment, morbidity, and mortality [1–6]. Two explanations can be given for these associations. On one hand, a high heart rate and a low heart rate variability are thought to reflect dysfunction of the flexible autonomic regulation of the heart rate in particular and of the bodys functioning in general that arises during ageing [3–5]. On the other hand, a high heart rate and a low heart rate variability are brought about by cardiovascular risk factors, such as obesity, hyperlipidaemia, diabetes, hypertension, and physical inactivity [2,3,7–9]. Since research on heart rate and heart rate variability has almost exclusively been conducted in western populations with an affluent sedentary lifestyle and high prevalences of these risk factors, it has been difficult to determine whether or not heart rate and heart rate variability are associated with functional impairment, morbidity, and mortality independently of cardiovascular risk factors.

Liver transplantation with geriatric liver allografts: The current situation in Eurotransplant

In light of the donor organ shortage and the high number of liver transplantation (LT) candidates on the waiting list, the number of extended criteria donors (ECD) increased over time. Among the criteria defining an ECD, donor age is stretched most, so that the use of septuagenarian, octogenarian and even nonagenarian donors increasingly became common practice (1,2). This article is protected by copyright. All rights reserved.

Turning Points in the Conception and Regulation of Physician-Assisted Dying in the Netherlands

The United States and Canada stand at a turning point, which manifests as spreading support and legalization of physician-assisted dying. The Netherlands, with its pioneering experiences of physician-assisted dying to which reference is often made, has gone through developments with more than one turning point. Here, we describe and clarify the origins as well as the current trends of these turning points and developments. A first turning point occurred after physicians, jurists, and ethicists had deliberated during the decades after the Second WorldWar about the definition and permissibility of physicianassisted dying, encompassing euthanasia and physician-assisted suicide. This deliberation gained public attention in 1973, when a physicianwas sentenced for administering lethalmedication to her terminally ill mother. Two days later, the Dutch Society for Voluntary Euthanasia (NVVE, later changed to Dutch Society for a Voluntary Death) was founded, aiming at “social acceptance and legalization of voluntary euthanasia.” Subsequent lawsuits against physicians who had assisted others in dying, various committees, and publications gradually outlined a compromise on the definition of physician-assisted dying and the conditions for its permission. As a second turning point, physician-assisted dying became defined, its legislation initiated, and its practice tolerated around 1985. The Royal Dutch Medical Association (RDMA) and a State Committee on Euthanasia defined physician-assisted dying as the intentional life-terminating act at the request of the patient performed by another, in case of euthanasia, or by the patient himself with the assistance of another, in case of physician-assisted suicide. A first bill was introduced in parliament and a report was published by the State Committee, both proposing conditions, built on those previously formulated, under which physician-assisted dying could be permitted. In the same year, RDMA and the Public Prosecutor agreed that physicians would not be prosecuted if these conditions were met.