Enzyme could aid longevity

April 6, 2001

A "guardian" protein that protects the genome against wear and tear is helping scientists to explore the biochemical roots of longevity.

Genetically modified hamster cells that produce high quantities of the enzyme and possess particularly resilient genetic code have been created.

Alexander Burkle, a gerontologist at Newcastle University, believes poly (ADP-ribose) polymerase-1, known as PARP-1, may ultimately prove to be a potential source of treatments for age-related diseases and cancers.

"I find it especially satisfying and surprising that if we manipulate this single molecule, we can get significant changes in genomic stability. I can see a huge potential for exploiting it," he said.

PARP-1 plays a central role in one of at least five ways in which multi-cellular animals protect the genetic information inside their cells.

It helps ensure that single letter errors, often made by highly reactive byproducts of metabolism interfering with DNA, are repaired before any harm is done to the cell. Without such protection, cells are more likely to die or become cancerous as the "genetic manuals" they carry accumulate errors.

In tests on cells taken from 13 different species of mammal, Dr Burkle found longer lived creatures had more PARP-1 activity in their cells: five times more in humans than in rats.

It seems that natural selection has refined the enzyme to provide greater genomic stability for those creatures that need to survive longer before reproducing.

Yet Dr Burkle could find no evidence that human cells contained five times as much PARP-1 as rats - in fact, the quantity was more or less the same. Instead, the difference seems to be in the enzyme's quality, hidden in the subtle chemical differences between each species' version of it.

The scientists then took copies of the gene that codes for the PARP-1 in both rats and humans, put them into insect cell cultures and made straight comparisons between their activity levels.

This time, the difference was only two-fold, indicating that interplay with other molecules might have a significant role in the protective process.

Dr Burkle and colleagues in Heidelberg, Germany, recently added extra copies of the PARP-1 gene to hamster cells in culture, boosting the enzyme's activity. The results, published recently in the International Journal of Cancer , showed the genetic code inside these cells was much more resilient than normal.

One possible way to harness this for medicine would be to boost levels of PARP-1 inside cancer cells - either through pharmaceuticals or gene therapy. This could stabilise their normally highly unstable genetic code and effectively rob tumours of their malignancy.

The enzyme could, perhaps, be used to treat ageing associated diseases such as Alzheimer's and Parkinson's, in which damage to cellular components, including DNA, is thought to play a role.

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