Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: Insights on mechanisms from the long life family study

The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR](>75)=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR(>76)=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(−3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span

Pleiotropic Meta-Analysis of Age-Related Phenotypes Addressing Evolutionary Uncertainty in Their Molecular Mechanisms

Age-related phenotypes are characterized by genetic heterogeneity attributed to an uncertain role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic meta-analyses of 24 age-related phenotypes dealing with such evolutionary uncertainty and leveraging longitudinal information. Our analysis identified 237 novel single nucleotide polymorphisms (SNPs) in 199 loci with phenotype-specific (61 SNPs) and pleiotropic (176 SNPs) associations and replicated associations for 160 SNPs in 68 loci in a modest sample of 26,371 individuals from five longitudinal studies. Most pleiotropic associations (65.3%, 115 of 176 SNPs) were impacted by heterogeneity, with the natural-selection—free genetic heterogeneity as its inevitable component. This pleiotropic heterogeneity was dominated (93%, 107 of 115 SNPs) by antagonistic genetic heterogeneity, a phenomenon that is characterized by antagonistic directions of genetic effects for directly correlated phenotypes. Genetic association studies of age-related phenotypes addressing the evolutionary uncertainty in establishing their molecular mechanisms have power to substantially improve the efficiency of the analyses. A dominant form of heterogeneous pleiotropy, antagonistic genetic heterogeneity, provides unprecedented insight into the genetic origin of age-related phenotypes and side effects in medical care that is counter-intuitive in medical genetics but naturally expected when molecular mechanisms of age-related phenotypes are not due to direct evolutionary selection

Dynamic Determinants of Longevity and Exceptional Health

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity

Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6×10(−6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10(−7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10(−8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms

Genomics of human health and aging

 Mathematical model of the ergotic systems operator is offered. Mathematical dependence between operator’s psycho-physiological description and complication of input signal is found, that allows to make diagnostic process more objective and to make a decision about operator’s professional training in time. Исследована математическая модель оператора эргатических систем в течение времени. Выявлено математическую зависимость между психофизиологическими характеристиками оператора и сложностью входного информационного потока, что позволяет повысить объективность процесса диагностики знаний и своевременно принять решение о профессиональной подготовке операторов эргатических системы. Досліджено математичну модель оператора ергатичних систем протягом часу. Виявлено математичну залежність між психофізіологічними характеристиками оператора та складністю вхідного інформаційного потоку, що дозволяє підвищити об’єктивність процесу діагностики знань та своєчасно прийняти рішення про професійну підготовку операторів ергатичної системи

Exome-Wide Association Study Identified Clusters of Pleiotropic Genetic Associations with Alzheimer’s Disease and Thirteen Cardiovascular Traits

Alzheimer’s disease (AD) and cardiovascular traits might share underlying causes. We sought to identify clusters of cardiovascular traits that share genetic factors with AD. We conducted a univariate exome-wide association study and pair-wise pleiotropic analysis focused on AD and 16 cardiovascular traits—6 diseases and 10 cardio-metabolic risk factors—for 188,260 UK biobank participants. Our analysis pinpointed nine genetic markers in the APOE gene region and four loci mapped to the CDK11, OBP2B, TPM1, and SMARCA4 genes, which demonstrated associations with AD at p ≤ 5 × 10−4 and pleiotropic associations at p ≤ 5 × 10−8. Using hierarchical cluster analysis, we grouped the phenotypes from these pleiotropic associations into seven clusters. Lipids were divided into three clusters: low-density lipoprotein and total cholesterol, high-density lipoprotein cholesterol, and triglycerides. This split might differentiate the lipid-related mechanisms of AD. The clustering of body mass index (BMI) with weight but not height indicates that weight defines BMI-AD pleiotropy. The remaining two clusters included (i) coronary heart disease and myocardial infarction; and (ii) hypertension, diabetes mellitus (DM), systolic and diastolic blood pressure. We found that all AD protective alleles were associated with larger weight and higher DM risk. Three of the four (75%) clusters of traits, which were significantly correlated with AD, demonstrated antagonistic genetic heterogeneity, characterized by different directions of the genetic associations and trait correlations. Our findings suggest that shared genetic factors between AD and cardiovascular traits mostly affect them in an antagonistic manner

Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging

We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort). We found that long-lived carriers and noncarriers have different average age trajectories and long-lived individuals have consistently higher levels and less steep declines at old ages compared to short-lived individuals. We applied the stochastic process model of aging aimed at joint analyses of genetic and nongenetic subsamples of longitudinal data and estimated different aging-related characteristics for carriers and noncarriers which otherwise cannot be evaluated from data. We found that such characteristics differ in carriers and noncarriers: (1) carriers have better adaptive capacity than noncarriers in case of CH, whereas for DBP the opposite situation is observed; (2) mean allostatic trajectories are higher in carriers and they differ from “optimal” trajectories minimizing mortality risk; (3) noncarriers have lower baseline mortality rates at younger ages but they increase faster than those for carriers resulting in intersection at the oldest ages. Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates

Exploring Entrepreneurship (2nd edition)

We have written this book to help you to explore entrepreneurship in all its complexity and variety. Our approach is based on the view that some subjects, such as medicine, engineering, and entrepreneurship, are particularly well-suited to experience-based learning. The basic idea is that people can learn a lot more if they are able to connect the research evidence and the theory to some kind of direct personal experience. The nature of this ‘experience’ depends a great deal on what you are studying. For example, a medical student spends time working in different parts of a hospital, while an engineering student might design a new product or test some materials in a laboratory. Providing practical experience is more difficult for entrepreneurship students, but it is possible to re-create some aspects of a ‘real-life’ experience using new venture exercises, business plan competitions, and computer simulations. In this book, we provide support for all three types of activity. However, experience-based learning is about more than just having an experience. Some of the most important learning happens when practical activity is combined with well-structured reflection. With this in mind, we have designed the book around three related aims: 1. to help you gain essential practical skills and underpinning knowledge, and reflect on the challenges involved in creating an entrepreneurial venture, either individually or as part of a team; 2. to help you develop a deeper understanding of entrepreneurship, as you make connections between your experiences, relevant theoretical concepts, research findings, and the experiences of others; 3. to encourage you to take part in a broader debate about entrepreneurship in the twenty-first century, examining contrasting perspectives on entrepreneurship across a wide range of ventures. Exploring Entrepreneurship covers practical issues related to the creation of an entrepreneurial venture, together with reviews of related research evidence and more theoretical discussion about entrepreneurship. We also make considerable use of case-based examples, so that you can learn from the experiences of real entrepreneurs as they struggle to create and to develop their ventures. It is worth noting two distinctive features of this book. Firstly, it provides detailed coverage of many different types of entrepreneurship. You will find examples of commercial, primarily profit-oriented ventures and what are often termed ‘social’ enterprises, where the primary aim is to address a social or environmental challenge, rather than simply to secure a profit. In contrast to most other texts, it also addresses ‘anti-social’ forms of entrepreneurship, with examples that range from the unethical and environmentally destructive behaviour of legitimate firms to the shady world of organised crime. The argument behind these decisions is simple: entrepreneurial activity is clearly a very powerful force in the world. We think it is important for entrepreneurship students to consider seriously how that power is exercised. In summary, this book offers a fresh, wide-ranging, and up-to-date approach to entrepreneurship, combining practical relevance with critical reflection. We also hope that it will help you to experience something of the excitement, uncertainty, passion, and sheer hard work that is involved in creating a successful entrepreneurial venture

How lifespan associated genes modulate aging changes: lessons from analysis of longitudinal data

Background and Objective: The influence of genes on human lifespan is mediated by biological processes that characterize body's functioning. The age trajectories of these processes contain important information about mechanisms linking aging, health, and lifespan. The objective of this paper is to investigate regularities of aging changes in different groups of individuals, including individuals with different genetic background, as well as their connections with health and lifespan. Data and Method: To reach this objective we used longitudinal data on four physiological variables, information about health and lifespan collected in the Framingham Heart Study (FHS), data on longevity alleles detected in earlier study, as well as methods of statistical modeling. Results: We found that phenotypes of exceptional longevity and health are linked to distinct types of changes in physiological indices during aging. We also found that components of aging changes differ in groups of individuals with different genetic background. Conclusions: These results suggest that factors responsible for exceptional longevity and health are not necessary the same, and that postponing aging changes is associated with extreme longevity. The genetic factors which increase lifespan are associated with physiological changes typical of healthy and long-living individuals, smaller mortality risks from cancer and CVD and better estimates of adaptive capacity in statistical modeling. This indicates that extreme longevity and health related traits are likely to be less heterogeneous phenotypes than lifespan, and studying these phenotypes separately from lifespan may provide additional information about mechanisms of human aging and its relation to chronic diseases and lifespan