Whole-Genome Sequencing of Supercentenarians

The search for longevity-associated genes continues, and the evidence taken as a whole suggests that the situation is very complex. It looks to be the case that potentially hundreds or thousands of genes each provide a tiny, environment- and lineage- specific contribution, and associations between single genes and natural variations in longevity are almost all either statistically weak or fail to replicate in different study populations. So the genetics of longevity looks like one of the many presently popular areas of study in which there is little to gain but knowledge of the details of our metabolism. The cellular and molecular damage that distinguishes old tissues from young tissues is well known and is the same in everyone. The best path towards treating aging is to repair this damage, not spend all our time figuring out how differences in the reaction to this damage causes some few very damaged people to live longer:

Supercentenarians (110 years or older) are the world's oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes.

We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, [this supercentenarian] lived to over 110 years.

The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies.

Link: http://dx.doi.org/10.1371/journal.pone.0112430


This reminds me of people trying to look for genes that predispose or protect people from Parkinson's disease. Worth doing, but it is far more likely that a functional cure in the form of replacement cells derived from induced pluripotent stem cells will get there a long time beforehand. the bulk of the research dollars should be concentrated on the most likely to succeed solution.

Posted by: Jim at November 13th, 2014 8:28 AM

Isn't this bad news? Its saying that aging is far more intricate than we imagined. Isn't this a huge set-back? I sincerely hope not.

Posted by: APersonOnline at November 13th, 2014 10:32 PM

I think this is a great approach, but I think a lot of the signal is currently getting lost due to genome sequencing noise (shotgun vs. long-read).

See, for example, http://www.eurekalert.org/pub_releases/2014-11/uowh-ton110714.php

In a few years, I think there will be much better results coming from this sort of study.

Posted by: John at November 13th, 2014 10:51 PM

@aperson - It is weak evidence against the idea that certain people live longer than others due to single longevity genes. It is also weak evidence against programed theories of aging. The sample size was pretty small. This has nothing to say about aging as accumulated damage theories of aging, other than that there is now some evidence against rival theories.

Posted by: jim at November 14th, 2014 1:06 AM
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