Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

Abstract

Genetics of human longevity within an eco-evolutionary nature-nurture framework. -Circulation Research 2018 ; 123(7) : 745-772.The final published version is available online at: https://www.ahajournals.org/ ABSTRACTHuman longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequence for biomedicine. The genetics of human longevity is still poorly understood, despite a number of investigations that used different strategies and protocols. Here we argue that such rather disappointing harvest is largely due to the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan appears to be the result of an intriguing mixture of geneenvironment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as GWAS and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as APOE, FOXO3, IL-6, IGF-1, chromosome 9p21, 5q33.3 and somatic mutations among others. The major results of this approach suggest that: i) the genetics of longevity is highly population-specific; ii) small-effect alleles, pleiotropy and the "complex allele timing" likely play a major role; iii) genetic risk factors are age-specific and need to be integrated in the light of the geroscience perspective; iv) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the three genetics of human body, i.e. nuclear, mitochondrial and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.

Shotgun Metagenomics of Gut Microbiota in Humans with up to Extreme Longevity and the Increasing Role of Xenobiotic Degradation

“…L ongevity has been described as the result of a complex combination of variables, deriving from genetics, lifestyle, and environment (1,2). In this context, the intestinal microbiome has been proposed as a possible mediator of healthy aging that preserves host-environment homeostasis by counteracting inflammaging (3,4), intestinal permeability (5), and deterioration of cognitive and bone health (5,6).…”

Literature review in support of adjuvanticity/immunogenicity assessment of proteins

“…During the entire lifespan, new G×E interactions emerge as a consequence of the continuous remodeling process that the body set up to adapt to the changes occurring over time, which on the other hand occur concomitantly with the changes of the environment 293 . Humans are characterized by a higher level of complexity because of their biological and cultural capabilities of adapting to all areas of the planet and changing their environments, by developing an extraordinary variety of cultural adaptive strategies including different food habits.…”

The Microbiome Mediates Environmental Effects on Aging

“…[3,4] The major environmental contribution includes lifestyle components such as diet, exercise, and stress. It has been estimated that an organism's genetics accounts for 25% of the factors, while the environment contributes to about 75%.…”

“…It has been estimated that an organism's genetics accounts for 25% of the factors, while the environment contributes to about 75%. [3,4] The major environmental contribution includes lifestyle components such as diet, exercise, and stress. The remarkable environmental contribution suggests that humans should be able to further increase their life span by modulating environmental factors.…”