In 1909, when the old age pension for those over 65 was introduced in Australia, life expectancy was about 55. It is now about 80.
For most of the 20th century, people in their 60s and 70s were expected to be seen with walking sticks. Now, many of them are working out regularly in the gym. And, as populations age, the developed world’s biggest health problems are now degenerative diseases rather than infections.
So perhaps it’s not surprising there has been an upsurge in interest in research into ageing—and the Centenary Institute is taking a major interest in applying its unique skill sets and clinical know-how to the problem. Leading the way will be the Institute’s newest research group leader, Dr Masaomi Kato, who moved to Australia from Yale University earlier this year to establish a Laboratory of Ageing.
“To understand the ageing process and ensure that we live well longer, one has to understand what goes wrong with the body as it ages,” says Centenary Executive Director, Prof Mathew Vadas AO. “To attack this problem, two things have to happen. The first is to think of ageing as a molecular—as well as a social—process, and find molecular cures for the abnormalities. So, treat ageing as we do cancer.”
“The second is to be able to test hypotheses quickly. For this we need a model organism that ages rapidly. Luckily a lowly roundworm, Caenorhabditis elegans, shares many issues of ageing with humans. And it only lives two weeks.”
Using this millimetre-long, transparent roundworm—the first multicellular organism to have its genome sequenced— geneticists have led the way. They have found that the ageing process is under genetic control. And it can be manipulated, quickened or slowed.
And the more we know about the ageing process, says Dr Kato, the better able we will be to improve the quality of elderly people’s lives. “So rather than just life span, I want to understand more about health span.”
At Yale, as a postdoctoral fellow in the laboratory of Prof Frank Slack, Dr Kato used C. elegans to study the small snippets of RNA, called microRNAs, which bind to and adjust the output of genes. He was especially interested in their role in the regulation of lifespan and in the response to DNA damage.
First, he discovered that one microRNA, miR-34—which is very similar in roundworms and humans—is an essential component in the response to radiation damage of DNA. If you increase the level of miR-34, cells become more resistant to radiation, and if you remove miR-34, they become more sensitive. This has a potentially useful clinical spin-off. Given that controlled doses of radiation are used to destroy tumours, a means of making tumour cells more sensitive to radiation and normal cells more resistant could be very handy.
At Yale, Dr Kato also found that the production of certain microRNAs varies with age and that some of these microRNAs contribute to lifespan regulation in the roundworm via the insulin-signalling pathway.
In the late 1980s, molecular biologists showed that mutations in the genes for proteins in this pathway—which regulates the glucose uptake of cells—can affect the rate of ageing. In other words, that ageing can be controlled by the body’s gene regulatory machinery.
Initially discovered in roundworms, the same phenomenon has now been demonstrated in several other species, including yeasts and fruit flies. And because the insulin-signalling pathway is almost the same in humans, it is likely to be true of us as well. That ageing is linked to the regulation of glucose uptake would seem to explain another well-known experimental result: individuals with a lower food intake, particularly of carbohydrates, tend to live longer. This has been dubbed caloric restriction.
Dr Kato is now introducing his model organism, C. elegans, into the Centenary Institute so that he can extend his ageing research. His group has already identified some of the genes which enhance longevity in response to caloric restriction. “Although I am not yet thinking specifically about direct clinical applications, hopefully our studies will provide target compounds which can improve metabolic disorders.”
He is already planning a collaborative project with Professor Jennifer Gamble and her Vascular Biology laboratory. She has been studying the gene SENEX and its protein products, and has found that they are important in signalling ageing and decline in the endothelial cells that line blood vessels. A very similar gene to the human SENEX is also found in C. elegans. “If we can understand in which genetic pathway SENEX is involved, it will be very useful, I think. We can expect many more contributions to the biology of human ageing in the future from ageing research in C. elegans,” Dr Kato says.