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More Evidence for the Genetic Contribution to Longevity to be Smaller than Suspected

How much of the natural human variation in longevity and pace of aging has its roots in genetics, and how much is determined by lifestyle and environment? Some gene variants result in beneficial metabolic alterations such as lower cholesterol or a greater resilience in the face of the molecular damage of late old age. Lifestyle choices such as calorie intake and exercise clearly influence long term health and mortality. Similarly, exposure to pathogens and pollutants can accelerate the pace of aging via their interaction with the immune system. The consensus of the past few decades had come to be that the split is around 25% due to gene variants versus 75% due to choice and environmental factors.

Large vaults of familial history data have been created since the advent of the internet, one of the many consequences of ubiquitous, low-cost channels of communication. Data of all varieties is more easily collected, stored, and analyzed. More rigorous analysis of this historical data of human lineages is now suggesting that the genetic contribution to longevity is much smaller than thought. The study here can be compared with a similar effort published last month. That both came to roughly the same conclusions, via quite different methods of analysis, is worth bearing in mind when balancing this against earlier, higher estimates of the degree to which genes determine life expectancy.

Our goal for the next few decades is, of course, to make all of this analysis a quaint curio that is only of interest only as part of a vanished past - a consideration of how the human system worked in the absence of rejuvenation therapies, to be placed next to work on the spread of smallpox and tuberculosis through populations lacking any effective treatment. When aging can be controlled through medical technology, and when those therapies are universally available, there will be only academic interest in how aging functions in people who have no access to rejuvenation therapies. Even the first, crude rejuvenation therapies that are now available, the pharmaceutical senolytics that selectively destroy a fraction of senescent cells in old tissues, will have a greater effect on human life span than near all genetic variants found in the wild.

Family tree of 400 million people shows genetics has limited influence on longevity

Calico Life Sciences and Ancestry teamed up to use publicly available pedigree data to approach the problem of figuring out the genetic contributions to human longevity. The heritability of life span has been well investigated in the literature, with previous estimates ranging around 15-30%. But some of these studies found that it wasn't just blood relatives who shared similar life spans - so did spouses. This suggested that the heritability estimates might have been confounded by shared environments or assortative mating (the tendency to choose mates who have similar traits to ourselves). Starting from 54 million subscriber-generated public family trees representing six billion ancestors, Ancestry removed redundant entries and those from people who were still living, stitching the remaining pedigrees together.

The data set, called the SAP for "set of aggregated and anonymized pedigrees," included almost 500 million individuals (with a single pedigree accounting for over 400 million people), largely Americans of European descent, each connected to another by either a parent-child or a spouse-spouse relationship. The scale of the data allowed the researchers to get accurate heritability estimates across different contexts; they could stratify the data by birth cohort or by sex or by other variables without losing the power needed for their analyses.

Running the numbers, the team initially found heritability estimates to be between 15-30% - similar to the reported literature. But genetics aren't the only thing that can be passed down between generations: sociocultural factors can also influence certain traits, and these too can be inherited. The combination of genetic heritability and sociocultural heritability is the total transferred variance, that is, the total amount of variability in a trait that can be explained by inheritance. Researchers looked not only at siblings-in-law and first cousins-in-law but also examined correlation in both types of co-siblings-in-law. None of these relationship types generally share household environments, and yet their life spans showed correlation.

If they don't share genetic information and they don't share household environment, what accounts for the similarity in life span between individuals within these relationship types? Going back to their impressive dataset, the researchers were able to perform analyses that detected assortative mating. In other words, people tend to select partners with traits like their own - in this case, how long they live. Of course, you can't easily guess the longevity of a potential mate, but the basis of this mate choice could be genetic or sociocultural - or both. For a non-genetic example, if income influences life span, and wealthy people tend to marry other wealthy people, that would lead to correlated longevity. By correcting for these effects of assortative mating, the new analysis found life span heritability is likely no more than seven percent, perhaps even lower.

Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating

Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long life runs in families for genetic reasons, estimates of life span "heritability" are consistently low (∼15-30%). Here, we used pedigree data from Ancestry public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity.

Although "nominal heritability" estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating.

Comments

So I guess Methuselah's Children was wrong.

Posted by: gwood at November 13th, 2018 6:48 PM

Well, RAH was right about young blood. :)

Posted by: Gary at November 13th, 2018 9:56 PM

@Antonio

Indeed very interesting. And it is a very promising approach for anti cancer drugs delivery which reduces the off-site toxicity.
In a way it is comparable in the effects what OISIN is trying to achieve. The implications well go well beyond senolitics... I will have to read the article more carefully, though

Posted by: Cuberat at November 14th, 2018 8:14 AM

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