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Sequencing a supercentenarian’s genome to unlock the secrets of longevity

DNA_043014In an effort to determine the genetic underpinnings of longevity, scientists at Stanford and elsewhere are mapping the human genomes of supercentenarians, individuals that have lived beyond 110 years old.

A recent entry on the NIH Director's blog offers an in-depth overview of one such project involving a 115-year-old Dutch woman named Hendrikje "Hennie" van Andel-Schipper, who died in 2005 and donated her body to medical research. Scientists examined the genome of her blood and brain tissue and analyzed the number of somatic mutations, the type of DNA mutations that are acquired over the course of a lifetime rather than inherited. The results raised some interesting questions:

You might imagine that someone who reaches the extreme age of 115 may have a low number of somatic mutations because his or her cells have exceptional protection against DNA damage. [Scientists] rather expected this to be the case for Hennie, particularly because she’d never had leukemia, lymphoma, or any other type of blood cancer. To the researchers’ surprise, the DNA sequencing results showed that Hennie’s blood cells had accumulated about 450 mutations since she was born. That is consistent with a mutation rate of about four mutations per year of life, which is in line with previous work suggesting that laboratory-grown cells derived from younger, healthy people acquire about five mutations annually.

Recognizing that circulating blood cells are derived from a large pool of stem cells in the bone marrow, and that each stem cell may have acquired a different set of mutations during life, researchers thought it would be challenging to detect any mutations in a collection of millions of blood cells. After all, in healthy adults, bone marrow contains about 11,000 hematopoietic stem cells, of which about 1,300 are actively dividing and replenishing our blood cells. If just one of those stem cells had undergone a mutation of an A to a T, the sensitivity of current DNA sequencing technology would be very unlikely to discover it.

However, further study of Hennie’s blood genome revealed that most of her circulating white blood cells were derived from just two hematopoietic stem cells. Not only did that make the process of detecting Hennie’s somatic mutations much easier, it raised fascinating questions about how the aging process affects bone marrow. While the work still must be reproduced in other older people, the researchers speculate that as we age, the pool of hematopoietic stem cells may shrink, until all of our white blood cells are clones of just a few parent cells.

Previously: She’s so 19th century: Women pushing their hundred-and-teens and California’s oldest person helping geneticists uncover key to aging
Photo by Duncan Hull

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