Death is the one certainty in life – a pioneering analysis of blood from one of the world's oldest and healthiest women has given clues to why it happens.
Born in 1890, Hendrikje van Andel-Schipper was at one point the oldest woman in the world. She was also remarkable for her health, with crystal-clear cognition until she was close to death, and a blood circulatory system free of disease. When she died in 2005, she bequeathed her body to science, with the full support of her living relatives that any outcomes of scientific analysis – as well as her name – be made public.
Researchers have now examined her blood and other tissues to see how they were affected by age.
What they found suggests, as we could perhaps expect, that our lifespan might ultimately be limited by the capacity for stem cells to keep replenishing tissues day in day out. Once the stem cells reach a state of exhaustion that imposes a limit on their own lifespan, they themselves gradually die out and steadily diminish the body's capacity to keep regenerating vital tissues and cells, such as blood.
Two little cells
In van Andel-Schipper's case, it seemed that in the twilight of her life, about two-thirds of the white blood cells remaining in her body at death originated from just two stem cells, implying that most or all of the blood stem cells she started life with had already burned out and died.
"Is there a limit to the number of stem cell divisions, and does that imply that there's a limit to human life?" asks Henne Holstege of the VU University Medical Center in Amsterdam, the Netherlands, who headed the research team. "Or can you get round that by replenishment with cells saved from earlier in your life?" she says.
The other evidence for the stem cell fatigue came from observations that van Andel-Schipper's white blood cells had drastically worn-down telomeres – the protective tips on chromosomes that burn down like wicks each time a cell divides. On average, the telomeres on the white blood cells were 17 times shorter than those on brain cells, which hardly replicate at all throughout life.
The team could establish the number of white blood cell-generating stem cells by studying the pattern of mutations found within the blood cells. The pattern was so similar in all cells that the researchers could conclude that they all came from one of two closely related "mother" stem cells.
Point of exhaustion
"It's estimated that we're born with around 20,000 blood stem cells, and at any one time, around 1000 are simultaneously active to replenish blood," says Holstege. During life, the number of active stem cells shrinks, she says, and their telomeres shorten to the point at which they die – a point called stem-cell exhaustion.
Holstege says the other remarkable finding was that the mutations within the blood cells were harmless – all resulted from mistaken replication of DNA during van Andel-Schipper's life as the "mother" blood stem cells multiplied to provide clones from which blood was repeatedly replenished.
She says this is the first time patterns of lifetime "somatic" mutations have been studied in such an old and such a healthy person. The absence of mutations posing dangers of disease and cancer suggest that van Andel-Schipper had a superior system for repairing or aborting cells with dangerous mutations.
Opportunity in mutation
The study is novel because it is the first to investigate the accumulation of somatic mutations within the tissues of an old individual, says Chris Tyler-Smith of the Wellcome Trust Sanger Institute in Hinxton, UK. "This contrasts to the germ-line mutations [present at birth] measured in previous studies," he says.
"When there is mutation, there's an opportunity for selection and some somatic mutations lead to cancer," says Tyler-Smith. "Now we see the range of somatic mutations in normal, non-cancerous tissues like blood, so we can start to think about the health consequences."
Tantalisingly, Holstege says the results raise the possibility of rejuvenating ageing bodies with injections of stem cells saved from birth or early life. These stem cells would be substantially free of mutations and have full-length telomeres. "If I took a sample now and gave it back to myself when I'm older, I would have long telomeres again – although it might only be possible with blood, not other tissues," she says.
Next, Holstege hopes to hunt for clues to genes that protect against Alzheimer's disease by comparing van Andel-Schipper's genome to that of people who succumb abnormally early to the disease.
Journal reference: Genome Research, DOI: 10.1101/gr.162131.113
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