Video transcript: Human ageing gene found in flies

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May 2008

Cox: "Human ageing is a perfectly normal process. Everybody gets old."

Saunders: "We’re continually bombarded with adverts of products that are going to ameliorate the effects of ageing. However the fundamental biology of ageing remains something of a mystery."

Cox: "Getting old per se is not a problem. It’s the frailty, the disease that we’re concerned about in older people, so we want to find out why cells lose the ability to divide as they get old. To look at that, we can’t look at a whole swathe of the human population. We can’t look from birth to 80-years-old because we can’t do experiments that way. So we look at a premature human ageing syndrome. It’s called Werner Syndrome and the people with that syndrome get old very, very quickly. The interesting thing about Werner syndrome is that we know it is caused by the loss of a single gene. One gene not working means that you get old very, very quickly. So obviously we’re very interested in looking at what that gene does, to explain why people get old quickly, why so many characteristics, like grey hair, wrinkled skin, cataracts, are all caused by the loss of a single gene."

"Now the problem with working with human cells, even with premature ageing syndrome, is when we try and grow the patients’ cells in the lab, they don’t grow very well, they get old very quickly and we don’t have long to do the experiments. The other problem is, the gene that’s lost we know has many different functions in the cell and what we’re trying to do is tease apart what the different bits do."

"What we’ve done is started to look at fruit flies, called Drosophila melanogaster, and in the fruit fly we’ve discovered a version of the gene that’s very similar to the human gene, so we can study that in much more detail."

Saunders: "Having obtained a stock of fruit flies in which our gene of interest wasn’t functional, we wanted to see if there was any similarity in the appearance of these flies in comparison to the appearance of Werner syndrome patients. Now because flies in this regard have a bit of a limitation, that is to say that they don’t show signs of overt ageing, such as grey hair, wrinkles, cataracts and all the other things, we were really interested in looking at the evidence of molecular events, which were shared between Werner syndrome patients and our flies."

Cox: "Their DNA is very, very unstable. It gets cut and spliced much more frequently than you would expect."

Saunders: "We used for this experiment a different mutation, one that solely affects the appearance of the fly. This mutation is called multiple wing hairs, and this is because each cell of the wing blade normally has a single hair and in this mutation it has a tuft of hairs. We used multiple wing hairs in an experiment to look for chromosome instability. In our experiment, instances where inappropriate chromosome behaviour has occurred, we see this as a patch of cells on the wing blade, which have the multiple wing hairs instead of single wing hairs. When we looked at our mutant flies, we found that these events happened at a very, very high frequency – approximately 150 of these events per fly. The observation of high levels of genome instability in our flies lacking this gene function is reminiscent of the situation in human Werner syndrome patients, whose cells are known to show similarly high levels of genomic instability."

Cox: "So we know that the chromosomes are unstable. We also know that the flies are very, very sensitive to a drug that in human Werners patients, they are also very, very sensitive to. And that drug itself causes problems with the DNA. What we think is happening is that the role of the gene that would normally prevent you from ageing prematurely is to deal with problems in the DNA. We now have a model system where we can look at a gene very heavily implicated in ageing and find out what it does, if you like, from birth to death. What we can do with the fly is find exactly what the activity of the gene is cells, and look through development and how it impacts on the life cycle of the organism. What we can’t do is absolutely directly say that because the mutation in the gene in flies causes problems with DNA recombination, that is a direct cause for human ageing. We think that there’s a very strong link between DNA instability and ageing, but the research at this stage has not taken us that far."