Ageing caused by unstable DNA

old manWerner syndrome is a genetic disease that causes premature ageing. Many Werner patients start developing age-related problems like osteoporosis, cataracts and grey and thinning hair in their twenties and thirties. This happens due to a mutation in the WRN gene. 

The protein made from the WRN gene is essential to keeping the DNA inside cells stable, and ensuring that DNA can be repaired when it is damaged and replicated properly when a cell divides. The WRN protein also keeps telomeres, the protective caps at the end of chromosomes, working properly. DNA repair problems and telomere shortening are both known to happen during normal ageing and can also cause accelerated ageing.

A new study shows how the WRN protein keeps DNA functioning properly – it keeps heterochromatin stable. Every cell in our body carries a full copy of all our DNA which would be two metres long if stretched out. To fit inside our cell nuclei, the DNA is packaged. When it is tightly wound, it is called heterochromatin, when it is more loosely packaged, it is called euchromatin.

Scientists recently found that older people have less WRN protein in their stem cells than young people. So the scientists removed the WRN gene from human stem cells grown in the lab to see what would happen to the DNA inside those cells. They found that stem cells without WRN aged much faster than normal stem cells. The cells without WRN lost their ability to divide earlier than normal cells (a process called senescence).  They also had more DNA damage and shorter, less active telomeres than normal cells. And WRN-deficient cells had less heterochromatin. When scientists re-activated WRN in the stem cells, all these signs of premature ageing were partially reversed. This shows that gene therapy, which aims to replace a mutated gene with a normal gene, may not effectively treat all genetic diseases. As I’ve mentioned before, the timing of gene therapy is very important – the earlier, the better.

So the scientists investigated further and found that the WRN protein binds to other proteins that keep heterochromatin stable. These results show that WRN is required to keep heterochromatin stable. When this process doesn’t work properly cells age more quickly than normal.

The Scientific Paper:

Zhang et al. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015.

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