Genetic differences are definitively the cause of differences in life span between species, self-evidently so. But within our own species, a few decades of earnest investigation has failed to turn up much evidence for genetic variants to be all that important in determining natural variation in human life span. If anything, the development of large genetic databases, such as the UK Biobank, has led to a reduction in the estimated contribution of genetic variation to life span variation. Near all associations between gene variants and longevity have tiny effect sizes, and also fail to replicate in other study populations, suggesting that there is little here to find, or at best a landscape of thousands of variants with small, interacting effects.
Thus for the vast majority of people, life span appears to be near entirely the result of lifestyle choices, such as weight and fitness, and environmental factors, such as exposure to persistent pathogens. Even the few known longevity-associated genes have very small effects on survival to late life. This means that even were everyone equipped with such variants, or drugs that mimicked the effects of these variants, then survival odds would still be very low. If we want more than this when it comes to ways to extend healthy life span, then it must come from medical technologies that repair the damage of aging, not ways to emulate specific genetic variants.
Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite the efforts made by the international scientific community and the use of high-throughput genotyping methodologies, satisfactory results have not been obtained. The most significant associations have been obtained with the two genes, APOE and FOXO3A, which had already been identified for some time with simple case-control studies. From the evolutionary point of view, longevity depends on the residual maintenance functions after the end of the reproduction period. Aging depends on stochastic events and the aging phenotype is the result of the accumulation of cellular damage that cannot be repaired by the cellular maintenance systems that are running out. Therefore, longevity depends on the possibility of survival after the end of the reproductive period and the genes that lead to longevity are "survival genes" rather than "longevity genes".
Several studies of formal genetics strongly suggest the role of genes in achieving longevity. The comparison between the survival of the siblings of centenarians and that of their brothers-in-law, who likely shared the same lifestyle for most of their lives, showed that "the survival advantage" of siblings of long-lived subjects was not fully shared from their brothers-in-law. This suggested that beyond the family environment, there are genetic factors that influence survival and, consequently, longevity. This was not true comparing the survival of sisters with that of sisters-in-law. Interestingly, in this study, the survival curve of the sisters of long-lived subjects did not differ from the one of sisters-in-law, suggesting that the genetic component explains longevity in men more than in women. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed to estimate that about 25% of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females.
It is thought that for the first eight decades of life, a correct lifestyle is a stronger determinant of health and life span than genetics. Genetics then appears to play a progressively important role in keeping individuals healthy and live as they age into their eighties and beyond. For centenarians, it reaches up to 33% for women and 48% for men. However, in general, the effect sizes were not large, suggesting that many genes of small effect play a role, as indeed in all multifactorial traits; however, it needs to be considered that there is a dynamic interplay between genetic and environmental variations in the development of individual differences in health, and hence, longevity. Therefore, it is not surprising that GWAS-replicated associations of common variants with longevity have been few since they pool different populations losing the "ecological" dimension of longevity.
Overall, the findings discussed in this paper strongly suggest that longevity genetics are closely associated with protection against age-related diseases, particularly cardiovascular diseases (CVDs). The association with longevity is not surprising because CVDs are the leading cause of death globally, with an estimated 17.9 million deaths annually.