David van Bodegom

Selection for Genetic Variation Inducing Pro- Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population

Background Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions. Methodology/Principal Findings In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-α levels (p = 1.39×10−3), was enriched among Ghanaian elders (p = 2.46×10−6). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09–1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (pinteraction = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped. Conclusions/Significance Altogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments.

Regulation of human life histories : The role of the inflammatory host response

Abstract:  Most species with a long life span have few offspring while species with a short life span have many offspring. This evolutionary trade‐off between fertility and body maintenance, based on the theory of r/K‐selection, is a central theme in the theory of life history regulation. This trade‐off is not only found between various species but also between individuals within one species. There is accumulating evidence for this trade‐off in humans. We hypothesize that the innate immune system is a critical factor skewing an individual into the direction of either a high fertility or better maintenance strategy. As over thousands of years human survival has been highly dependent on resistance to infectious diseases, genetic adaptations resulting in inflammatory responses were favored. An inflammatory host response is critical to fight infection necessary to survive up to reproductive age. An inflammatory host response is also negatively associated with fertility and can explain for the trade‐off between fertility and body maintenance. After human reproductive age, these inflammatory responses contribute also to development of chronic degenerative diseases. These will especially become apparent in affluent societies where the majority of individuals reach old age. Identifying the inflammatory host response as a critical factor both in the regulation of human life histories and in the occurrence of chronic diseases at old age implies means for intervention allowing individuals to live healthier for longer.

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.

Socio-economic status by rapid appraisal is highly correlated with mortality risks in rural Africa.

Socio-economic status is an important determinant of health and survival in rural Africa and necessitates a practical and valid instrument to implement in health studies. Our objective was to investigate the validity of the rapid appraisal method to assess socio-economic status and its ability to identify individuals at risk. Among 1573 households in rural northern Ghana, we calculated the Demographic Health Survey (DHS) wealth index and conducted two rapid appraisal methods: self-reported wealth and interviewer-reported wealth. In addition we followed the 25,184 participants from these households for survival with a mean follow-up of 3.9 years, during which 885 participants died. The DHS wealth index was moderately correlated to self-reported wealth (Spearmans rho 0.59, P<0.001) and interviewer-reported wealth (Spearmans rho 0.75, P<0.001). Mortality risks were significantly higher for people with lower than average self-reported wealth [hazard ratio (HR) 1.30 (95% CI 1.11-1.51)] and lower interviewer-reported wealth [HR 1.40 (95% CI 1.21-1.62)]. Mortality risks were lower for people with higher self-reported wealth [HR 0.81 (95% CI 0.32-2.03)] and higher interviewer-reported wealth [HR 0.84 (95% CI 0.58-1.21)]. Similar discriminative mortality risks were assessed when using tertiles of the DHS wealth index (Ptrend<0.001).

Genetic Variation in Pentraxin (PTX) 3 Gene Associates with PTX3 Production and Fertility in Women

Pentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we report on a population-based study from a rural area of Upper East Ghana (n = 4346). We studied the association between the number of children given birth by women during their lifetime and ex vivo, lipopolysaccharide (LPS)-induced PTX3 production (n = 362). In addition, we studied the association of genetic variation in the PTX3 gene with PTX3 production (n = 617) and with female fertility (n = 1999). We found that ex vivo LPS-induced PTX3 production was associated with fertility (P = 0.040). Furthermore, we identified genetic variants in the PTX3 gene that influence PTX3 production, and also fertility. The strongest associations were observed for the rs6788044 single-nucleotide polymorphism (SNP). We found that carriers of this SNP had higher PTX3 production capacity (P = 0.003) and higher fertility (P = 0.043). The results reported here provide the first evidence, based on protein production and analysis of polymorphisms, that the long pentraxin PTX3 plays a role in female fertility in humans.

Adverse environmental conditions influence age-related innate immune responsiveness

Background-The innate immune system plays an important role in the recognition and induction of protective responses against infectious pathogens, whilst there is increasing evidence for a role in mediating chronic inflammatory diseases at older age. Despite indications that environmental conditions can influence the senescence process of the adaptive immune system, it is not known whether the same holds true for the innate immune system. Therefore we studied whether age-related innate immune responses are similar or differ between populations living under very diverse environmental conditions.Methods-We compared cross-sectional age-related changes in ex vivo innate cytokine responses in a population living under affluent conditions in the Netherlands (age 20–68 years old, n = 304) and a population living under adverse environmental conditions in Ghana (age 23–95 years old, n = 562).Results-We found a significant decrease in LPS-induced Interleukin (IL)-10 and Tumor Necrosis Factor (TNF) production with age in the Dutch population. In Ghana a similar age-related decline in IL-10 responses to LPS, as well as to zymosan, or LPS plus zymosan, was observed. TNF production, however, did not show an age-associated decline, but increased significantly with age in response to co-stimulation with LPS and zymosan.Conclusion-We conclude that the decline in innate cytokine responses is an intrinsic ageing phenomenon, while pathogen exposure and/or selective survival drive pro-inflammatory responses under adverse living conditions.

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.

Old age mortality and macroeconomic cycles

Background As mortality is more and more concentrated at old age, it becomes critical to identify the determinants of old age mortality. It has counter-intuitively been found that mortality rates at all ages are higher during short-term increases in economic growth. Work-stress is found to be a contributing factor to this association, but cannot explain the association for the older, retired population. Methods Historical figures of gross domestic product (Angus Maddison) were compared with mortality rates (Human Mortality Database) of middle aged (40–44 years) and older people (70–74 years) in 19 developed countries for the period 1950–2008. Regressions were performed on the de-trended data, accounting for autocorrelation and aggregated using random effects models. Results Most countries show pro-cyclical associations between the economy and mortality, especially with regard to male mortality rates. On average, for every 1% increase in gross domestic product, mortality increases with 0.36% for 70-year-old to 74-year-old men (p<0.001) and 0.38% for 40-year-old to 44-year-old men (p<0.001). The effect for women is 0.18% for 70-year-olds to 74-year-olds (p=0.012) and 0.15% for 40-year-olds to 44-year-olds (p=0.118). Conclusions In developed countries, mortality rates increase during upward cycles in the economy, and decrease during downward cycles. This effect is similar for the older and middle-aged population. Traditional explanations as work-stress and traffic accidents cannot explain our findings. Lower levels of social support and informal care by the working population during good economic times can play an important role, but this remains to be formally investigated.

Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis

Subclinical hypothyroidism (SCH), defined as elevated thyroid stimulating hormone (TSH) and normal thyroid hormone levels, and cognitive impairment are both common in older people. While the relation between overt hypothyroidism and cognitive impairment is well established, data on the association between SCH and cognitive impairment are conflicting. This systematic review and meta-analysis was performed to assess available evidence on the association of SCH with cognition in community dwelling, relatively healthy older adults. PubMed, EMBASE, Web of Science, COCHRANE, CINAHL, PsycINFO, and Academic Search Premier (January 1966 to April 1, 2015) were searched without language restrictions, as were references of key articles, for studies on the association between SCH and cognition in older adults (>60 years). These studies were reviewed by two independent reviewers according to predefined criteria for eligibility and methodological quality, and data were extracted using standardized forms. Of the 844 reports initially identified, 270 remained after exclusion of duplicates. Of the 270, 15 studies comprising 19,944 subjects, of whom 1,199 had subclinical hypothyroidism were included. Data from the 15 studies was pooled, and meta-analyzed cross-sectionally for global cognition [assessed by Mini-Mental State Examination (MMSE)], executive function, and memory, using random effects models. Pooled effect size (ES) for MMSE was −0.01 (95% CI −0.09, 0.08), with heterogeneity (I2) of 55.1%. Pooled ES was < 0.001 (95% CI −0.10, 0.09) for executive function (I2 = 13.5%), and 0.01 (95% CI −0.12, 0.14) for memory (I2 = 46.9%). In addition, prospective analysis including four studies showed pooled ES of 0.033 (95% CI −0.001 − 0.067) for MMSE (I2 < 0.001%), indicating that subclinical hypothyroidism was not significantly associated with accelerated cognitive decline. This systematic review and meta-analysis provides no evidence that supports an association between SCH and cognitive impairment in relatively healthy older adults.

When Grandmothers Matter

In a recent issue of this journal, Herndon [1] discussed the grandmother hypothesis and its implications for studies on cognitive ageing. According to this hypothesis, the long post-reproductive life span in human females is an adaptive mechanism that evolved to maximize female fitness by investing resources in the care of their grandchildren rather than by continuing to reproduce themselves. From this, Herndon deduces that special cognitive robustness to be maintained until after the age of menopause must have co-evolved because grandmothers can only exert the beneficial effect if their cognitive abilities remain intact. He therefore pleas to compare cognitive ageing in humans with other primates, especially chimpanzees, because they lack a long post-reproductive life span and would therefore not have evolved this cognitive robustness. Here, we question the important role of grandmothers in our evolutionary past, first because of the different family structures during this time and second because of the low number of females that actually lived to experience a post-reproductive lifespan. We also show that in a population that reflects our evolutionary past, grandmothers do not have an important role for child survival. Finally, we react on the implications for the study of cognitive ageing as put forward by Herndon.