Who wants to live forever?

Finding a genetic signature of extreme longevity and determining what exactly is the impact of the genetic background on human lifespan have been one of the most discussed topics in recent times. Everybody asking: to live over 100 is a matter of life-style or is written in your DNA?

We remember the excitement generated by the article published in Science in 2010 that describes a set of SNPs significantly associated with extreme longevity, and the delusion when these findings revealed to be inconsistent (the paper has been retracted in 2011). However the authors have reanalyzed the data, corrected the issues and were able to produce robust conclusions and a new publication, this time on PLOS One, in the early 2012.

Together with other clues already discussed in literature, such as high familiarity of extreme longevity, this is a strong evidence of the role of genetic background in influencing the human life expectation.

Taking advantage of the NGS technologies, several projects have been launched aiming to sequence a consistent group of people older than 100 to get clues on which variants and/or

genetic mechanisms are at work to give these subjects a long and surprisingly healthy life. Examples are the Medco 100 over 100 Prize or the New England Centenarian Study.

Sebastiani (the first author of the previously cited paper) has also recently published the results from the whole genome sequencing of two individuals, one male and one female, over 114 years old. The paper reports interesting findings on the distribution of genetic variants and tested the 4 main models proposed for extreme longevity genetics: presence of alterations in metabolic pathways, lack of disease-associated variants, presence of rare variants, enrichment in longevity associated variants. Even if two individuals are clearly not sufficient for inferring final conclusion, the data obtained supported a scenario in which disease-associated variants are not depleted, but are likely counter-balanced by the enrichment of longevity associated variants (the two subject tested resulted enriched in variants near the ones previously identified as longevity associated). Moreover, a detailed annotation of the identified variants showed that modifications in splicing events may be an important factor, calling for future RNA-Seq studies on ultracentenarians.

Overall this is the first reported WGS on subjects >100 years old and an interesting pilot project for future larger studies.