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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, the proband 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.

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An international committee of demographers has created a carefully documented list of worldwide living supercentenarians (> or =110 years old) that has been published by the Los Angeles Gerontology Research Group on its web site and updated on a weekly basis for the past 6 years [see "snapshot" for the year 2003 in the Appendix]. What can be learned by studying this distinguished group of individuals? Also, what are the implications for understanding the fundamental biological limits to human longevity and maximum life span? Our conclusion: Although everyone agrees that average life expectancy has systematically advanced linearly over the last century, it is not realistic to expect that this pace can continue indefinitely. Our data suggest that, without the invention of some new unknown form of medical breakthrough, the Guinness Book of World Records benchmark established by French woman Jeanne Calment of 122 years, set back in 1997, will be exceedingly difficult to break in our lifetime.

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