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Looking for Clues to Longevity, Disease Resistance in Super-Centenarian Genome

By Andrea Anderson

NEW YORK (GenomeWeb News) – A research team from the Netherlands and the US has sequenced the genome of a woman who lived to be 115 years old and remained exceptionally healthy for most of her life.

The researchers, from VU University Amsterdam, Life Technologies, Scripps Translational Science Institute, and elsewhere, used the SOLiD platform to sequence DNA from the super-centenarian's blood and brain samples. They are now working on a de novo assembly of the genome, which they say might serve as a reference in other studies related to longevity and late-onset disease.

For their part, the team intends to catalog the single nucleotide variants, copy number changes, small insertions and deletions, and larger structural variants in the genome to look for insights into the woman's long life and apparent ability to resist most age-related disease — including heart disease, Alzheimer's disease, and Parkinson's — while maintaining her mental agility.

"This genome, I think, has a lot of interesting elements in it, because you can be 115 with it and you can become 115 without Alzheimer's and heart diseases," VU University Amsterdam clinical geneticist Henne Holstege told GenomeWeb Daily News.

Holstege presented some preliminary findings from the project at the International Congress for Human Genetics/American Society for Human Genetics meeting in Montreal earlier this month.

The super-centenarian, known as W115 for the study, initially requested to have her body donated to science when she was in her 80s, Holstege explained.

Decades later, after surviving a bout of breast cancer at the age of 100 years old, she called a Dutch hospital to inquire about whether her body might still be of interest to scientists. Tests done at the time suggested the woman, then around 112 years old, had the mental dexterity of someone closer to 60 years old.

Moreover, when she died of stomach cancer a few years later, post-mortem tests showed that the woman had dodged brain and vasculature problems normally associated with aging: her blood vessels were free from atherosclerotic plaques and her brain did not show signs of vascular brain pathology, beta-amyloid plaque formation, or any significant degeneration.

While researchers cannot rule out environmental factors in her extraordinary health and longevity, analysis of the woman's pedigree showed that individuals on both sides of her family had longer life spans than the mean of their respective generations. This was especially true of her maternal lineage, Holstege explained, noting that the woman's mother lived to be 101 years old.

Together, such patterns suggest W115 came from a line of individuals who were predisposed to longevity, likely due to some inherited genetic factor(s).

To begin exploring this in more detail, the researchers used the SOLiD 4 to do paired-end and mate pair sequencing on genomic DNA isolated from W115's blood and brain tissue, generating sequence to cover 92 percent of her genome to an average depth of around 120 times. Researchers at Life Technologies performed the SOLiD sequencing for the study.

"We had this interesting genome and we wanted to sequence it very well," Holstege said, "so we decided to give them a call and see if they were interested in helping us out. And they were."

Collaborators at Scripps are currently leading the effort to do de novo assembly of the genome using the SOLiD short read data. The team plans to make the W115 genome data available to other members of the research community when the sequencing, assembly, and quality control stages of the study are done.

The study is the latest in a line of recent projects focused on healthy aging and/or longevity.

A Duke University-led team has already sequenced the genomes of more than a dozen centenarians and has plans to sequence another 50 or so individuals who have reached their 100th birthdays in the near future. And earlier this month, investigators from Complete Genomics and Scripps Health announced that they intend to sequence the genomes of about 1,000 elderly individuals who have remained free of chronic disease throughout their lives.

The goal is to not only learn more about healthy aging but also to establish a Wellderly Genomic Reference Resource that can be used as a universal control set for age-related disease studies involving individuals of European descent.

"For all the late-onset diseases, most studies in the past have not had suitable controls," Eric Topol, director of the Scripps Translational Science Institute and chief academic officer for Scripps Health, told GWDN, explaining that most genome-wide association studies have relied on age-matched controls who may or may not be at risk of developing the disease being investigated.

Topol said the Wellderly team has enrolled 1,200 healthy individuals between 80 and 108 years old and have already done exome sequencing on a few hundred individuals with the Illumina HiSeq platform. As part of their collaboration with Complete Genomics, the Scripps group hopes to get whole-genome sequence data for around 1,000 Wellderly individuals by the end of the year.

For his part, Topol said he is pleased to see more studies tackling the genetics of longevity and healthy aging rather than disease alone.

"These are very complementary and, I think, vital projects," he said, "whether they are addressing lifespan or health span."