Abstract
Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer’s disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.
Highlights
The study of apolipoprotein E (APOE) and its isoforms has spread in all the studies about the genetics of human longevity and this is one of the first genes that emerged in candidate-gene studies and in genome-wide analysis in different human populations
Isoform ε3 helps in maintaining the structural integrity of cholesterol-rich lipoproteins and enhances their solubilization in blood plasma, regulates lipid homeostasis of both hepatic and non-hepatic tissues, It is important to remember that no definitive mechanism for how APOE binds to lipids has been elucidated even though different hypotheses have emerged over the years, especially in relation to the implication of its isoforms in pathological traits
Many studies have attempted to grasp the complexity of the genetics of human longevity [128,129,130,131,132,133]: recent findings suggest that alleles associated with this phenotype are population-specific and, at the same time, that the achievement of extreme longevity is modulated by mechanisms shared among populations [134,135,136]
Summary
The study of APOE and its isoforms has spread in all the studies about the genetics of human longevity and this is one of the first genes that emerged in candidate-gene studies and in genome-wide analysis in different human populations. The pleiotropic roles of this gene as well as the pattern of variability across different human groups provide an interesting perspective on the analysis of the evolutionary relationship between human genetics, environmental variables, and the attainment of extreme longevity as a healthy phenotype. The role of APOE in human longevity, its physiological functions, and the involvement in pathological traits in modern populations. APOE evolution and variability among human populations, including a novel analysis of modern and ancient data. The evolutionary mechanisms that maintained APOE deleterious variants in modern human populations
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