The Genetics of Human Longevity in a Nutshell: Only a Few Identified Variants, and Everything Else a Mystery

The human genetics of longevity are exceedingly complex, that much is possible to say from the research to date. Nearly every study of associations between gene variants and longevity in a human population identifies some correlations, and, barring just a few genes, none of those associations are found in any other study. So the genetics of longevity involves myriad tiny conditional contributions, each such contribution very dependent on a web of environmental factors and a network of other gene variants. This is one of the reasons why I see efforts to map the genetics of centenarians and long-lived families to be of only scientific interest. Given what we know of the genetics of longevity, research programs of that nature are very unlikely to deliver the basis for therapies that can make any meaningful difference to the pace of aging.

Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise in multi-morbidity and frailty among older individuals. Nevertheless, some individuals appear someway resistant to causes of death, such as cancer and heart disease, compared with the rest of the population, and are able to reach very old ages in good clinical conditions, while others are not. Thus, during the last two decades we have witnessed an increase in the number of studies on biological and molecular factors associated with the variation in healthy aging and longevity.

Several lines of evidence support the genetic basis of longevity: from the species-specific maximum lifespan to the genetically determined premature aging syndromes. Studies in human twins, that aimed to distinguish the genetic from the environmental component, highlighted a heritability of life span close to 25%. In centenarians' families, the offspring of long-lived individuals not only exhibit a survival advantage compared to their peers, but also have a lower incidence of age-related diseases. On the other hand, population studies found that genetic factors influence longevity in age- and sex-specific ways, with a most pronounced effect at advanced age and possibly in men compared to women. All this evidence indicates that a genetic influence on longevity exists, laying the foundation for the search for the genetic components of extreme long life.

Consequently, over the past three decades, there has been a surge in genetic research, due in part to advances in molecular technologies, starting as studies of single genetic variants in candidate genes and pathways, moving on to array-based genome-wide association studies (GWAS) and subsequently to next generation sequencing (NGS). However, despite a plethora of studies, only few variants (in the APOE, FOXO3A, and 5q33.3 loci) have been successfully replicated in different ethnic groups and the emerging picture is complex.

For instance, it is an understatement to think that long-lived people harbor only favorable variants, completely avoiding risk alleles for major age-related diseases; indeed, there is evidence that many disease alleles are present in long-lived people. It is more probable that the longevity phenotype is the result of a particular combination of pro-longevity variants and risk alleles for pathologies, likely interacting in networks in a sex- and age-specific way. Finally, characteristics of aging are extremely heterogeneous, even among long-lived individuals, due to the complex interaction among genetic factors, environment, lifestyle, culture and resiliency. Population and study specificity, lack of statistical power for such a rather rare phenotype and missing heritability represent further hard obstacles to overcome in genotype-phenotype association studies. Thus, many challenges remain to be addressed in the search for the genetic components of human longevity.

Link: https://doi.org/10.3390/genes10080585

Comments

So, basically, we are still not even close? I think we are closer than we think. And I do believe once A.I. (artificial intelligence) comes about, it will be able to identify it faster or help tremendously.

Posted by: Person1234 at August 19th, 2019 9:44 AM

Sigh...

Again, this more of the same "metabolism is too complicated" nonsense (in this case "genomics is too complicated") so let's say it's "very unlikely to deliver the basis for therapies that can make any meaningful difference to the pace of aging."

If you can't control this genomic complexity, you can never control aging

Posted by: Fred Zobrisk at August 19th, 2019 11:00 AM

@Fred Zobrisk

What about CRISPR or Gene Splicing? In the movie rampage (I know its a movie) but they use advanced CRISPR techniques to create hybrid animals with super powers. I don't see how this cannot be possible with humans and animals alike.

Posted by: Person1234 at August 19th, 2019 12:05 PM

Person1234: Please read the introductory material on the right hand side, under "The Root Causes of Aging".

Posted by: Antonio at August 19th, 2019 3:23 PM

Longevity is the low hanging fruit. I want to not get old looking.

Posted by: NY2LA at August 20th, 2019 9:19 PM

@NY2LA
Longevity is not given and by no means it is a low hanging fruit. By having priority of looking younger it means your [perceived] health is good enough for you to worry about the looks. However, the moment you face the specter of disability or imminent death the looks become a distant second concern. Besides, there are whole industries that fix the looks with a varying degree of success. On the other hand, the going assumption within SENS is that if you can fix the underlying issues the looks will be [much] better too. For example, removing collagene cross links should improve the skin and cardio vascular health.

Posted by: Cuberat at August 21st, 2019 12:35 PM

You can't study semelparity without concluding that aging is one of several genetic default programs of limited evolutionary selection strategies. Evolutionary strategy goals of species maintenance - logically preclude immortality as a natural selection choice - in non-sentient species.

Consequently, extended longevity and or immortality genetic clues will not be found in the super aged. In reality, extended longevity and or immortality has to be the consequence of uninterrupted maintenance - both cellular and genetic - to achieve a state of perpetual rejuvenation.

We would be far better off conceptually of looping or replacing the cellular metabolism program of early adulthood in our adult genetic default programs - than trying to prevent the accumulation of cascading genetic maintenance shut-down and its resulting aging symptoms - which is currently the unfortunate focus of vast majority of longevity research and the wasted funds going into it.

Posted by: Dug at August 25th, 2019 10:35 AM

This article just makes me sad to think of just how complex these issues truly are! The biggest question about all this that comes to my mind, is:

How much of the REAL ANSWERS to these much needed genetic therapies are being hidden from us by the Elites? It is my deeply held suspicion, that much is being purposefully withheld and hidden. Truly sad.

Posted by: ejc110 at August 27th, 2019 8:06 AM

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