ANNUAL SYMPOSIUM

Australia's science future 3-4 May 2000
Full listing of papers

Dr Roger Reddel received a medical degree and a PhD from the University of Sydney. He initially trained as a cancer specialist before commencing full-time laboratory-based cancer research. After postdoctoral work at the US National Cancer Institute in Bethesda, Maryland, he returned to Sydney in 1988 as the NSW Cancer Council's Bicentennial Research Fellow, and joined the Children's Medical Research Institute to set up a cancer research unit. His work focuses on how molecular changes permit cancer cells to become immortalised and why normal cells have a limited proliferative life span. Although this research aims to develop effective cancer treatments, it may also have major implications for understanding ageing.

Symposium themes - Ageing
Cellular ageing: Can we reverse it?
by Roger Reddel
rreddel@cmri.usyd.edu.au

Abstract
Most normal cells appear to have an in-built biological clock that imposes a limit on the number of times that they can reproduce themselves. This cellular ageing may contribute to the overall ageing process. We have recently started to understand the biological clock mechanism, and have learnt how to counteract it in cells cultured in the laboratory. This may eventually permit us to repair some of the effects of ageing by replacing old cells with rejuvenated ones. In addition, recent developments in stem cell research may make it possible to replace a diseased organ with a new organ grown from the individual's own cells.

Biological systems are self-repairing, self-maintaining systems. Cell division allows cells to proliferate to repair damage. Eventually, the maintenance processes fail, resulting in ageing. There is a limit on proliferation that appears to be determined by a biological clock.

What is this biological clock? In each cell's nucleus, DNA is packaged into chromosomes. At each end of the chromosome is a structure called a telomere. These contain repetitive DNA and specific binding proteins, which together form a protective cap for the chromosomes. The telomeres shorten slightly each time a cell divides. This shortening may eventually signal when a cell’s time is up, stopping it from further division. So telomere shortening may be an important biological clock. Clearly, there has to be some mechanism to avoid passing on chromosomes with short telomeres to the next generation. So cells of the germ line (which produce ova in females, or sperm in males) contain an enzyme called telomerase that replaces the telomeric DNA that is lost during cell division. There are very low or undetectable quantities of this enzyme in other normal cells. Telomerase is a complex enzyme with several subunits. Some of the subunits have recently been identified and cloned. Putting a switched-on copy of the gene encoding the telomerase catalytic subunit into normal cells turns on telomerase activity. This prevents telomere shortening and, for some types of normal cells, allows an apparently unlimited number of cell divisions (often referred to as 'immortalisation'). What can we do with these cells? Tissues such as the cornea have been reconstructed using immortalised cell lines. Skin cells immortalised by telomerase have been used to reconstruct epidermal tissue. There are many other types of specialised cells – examples include blood, muscle, and brain cells – which are all derived from a single cell, a fertilised embryo. Cells of the embryo's inner cell mass are stem cells that have the potential to differentiate into any type of cell. Later, more specialised stem cells appear that are much more limited in the types of specialised cells they can produce. It is likely that we will be able to reconstruct tissues from human stem cells. The use of embryonic stem cells for this purpose is controversial because obtaining them currently requires destruction of an embryo. Stem cells from adults are already used for bone marrow transplants and may be able to be used elsewhere. The finding that non-embryonic stem cells are more versatile than previously believed was regarded as one of the major discoveries of 1999. For example, muscle stem cells could give rise to blood cells. It is now possible to clone animals from 'old' specialised cells. An adult cell nucleus can be placed into an egg cell from which the nucleus has been removed, then the egg is placed into a surrogate mother who produces a new animal. There would be ethical and practical problems doing this in humans. The cloning process somehow reprograms the nuclei of highly specialised cells so that they obtain the ability to form large numbers of any type of cell. When this re-programming process is understood, it may be possible to take a few cells from an individual and use them to reconstruct whole organs for transplantation into that individual. This would avoid problems with transplant rejection. Although there do not appear to be any theoretical barriers to achieving this goal, there are formidable technical problems still to be overcome. The telomeres of the cloned sheep, Dolly, are quite short. In contrast, it was recently found that cloned cattle had lengthened telomeres. It is not yet clear what implications this may have for the longevity of cloned animals. Can we reverse cellular ageing? Yes, to a limited extent, at least in the lab. Some old cells in which telomerase is switched on can divide an unlimited number of times. We could use this to rejuvenate or replace cells and tissues. In future, it is possible that stem cells, including re-programmed specialised cells, will be used for the replacement of organs that have been damaged by disease or ageing.

Session discussion

Productive activity increases vitality. Does depression lead to less productive feelings and suicide?

Julie Byles. Reactive depression is more common among older people. We are still coming to grips with the impact of war-related events on late-life depression.

Rob Helme. Pain and depression particularly affect older age groups.

Stroke is one of the most common causes of disability and yet doctors don’t treat hypertension in older people. That is extremely undesirable.

Julie Byles. One of the problems in treating hypertension in older people is the lag between research results and changes in the prescribing behaviour of doctors. We need a change of view.

Mice with their telomerase template knocked out still aged normally. How do you explain this?

Roger Reddel. They aged normally until the telomeres became short. After six generations the telomeres had become very short, the males were sterile, and there were some signs of premature ageing. However, the role of telomere shortening in the ageing of normal animals needs a lot more study.

How long are the telomeres in cancers?

Roger Reddel. The telomeres of cancer cells can be long or short. But the important point is that the cancer cells are able to keep their telomeres at a fairly constant length. In other words, they avoid the inexorable telomere shortening that occurs during the proliferation of normal cells. In most cases, cancer cells use telomerase to maintain their telomeres, but there is also another process that they can use. So one of the concerns about switching on telomerase in normal cells would be that it increases the risk that they will later become cancer cells. But we could switch on telomerase in normal cells, use them to reconstruct an organ, and then get rid of the telomerase gene. We already have ways to do this.

Burnet started eating zinc sulphate in his seventies. Is it prophylactic for ageing?

Zeinab Khalil. I am not aware of any studies. There is a link between zinc and Alzheimer’s disease.

There has been a study of ageing in women. Is there a study of men’s health in Australia?

Julie Byles. The study was a result of the women’s health movement. A men’s study would require a political decision, with government funding. Men may be quite different, for example, in their need for social interactions.

Rob Helme. Other studies have small numbers and variable outcomes. We need to do some genetic epidemiology in this country.

Studies at the Australian National University have been testing people at intervals of 4 and 5 years.

How long do you delay using antioxidants after injury?

Zeinab Khalil. One week.

Does a decrease in calorie intake slow ageing?

Zeinab Khalil. A decrease in calorie intake increases lifespan and decreases oxygen free radicals. It is one anti-ageing strategy. But how many of us could cope with it? Hungry rats lived four years instead of the normal two years.

What happens if you transplant organs from a short-lived species to a longer-lived species?

Roger Reddel. It is hard to predict. The tissue’s proliferative capacity may not be the limiting factor. Immunity may be more important.

Social contact appears to improve old people’s lives. Is there a difference between contacts with young or with old?

Julie Byles. The survey did not show the age of contact. But it is an important point; there is a need for intergenerational contact.

In bees, the workers die young and the queens live a long time. We could try transplants on them.

How does bereavement status affect quality of life?

Julie Byles. For women, quality of life decreases with widowhood but recovers after a couple of years. They manage to reinvent their lives.

Should we take antioxidants before injury?

Zeinab Khalil. There are no studies examining the relationship between long-term intake of antioxidants and tissue repair. Long-term intake of exogenous antioxidants could depress our endogenous antioxidant defence system. It could alter the balance of the internal system.

Are the gender differences in life expectancy due to biological or environmental factors?

Julie Byles. I don’t know. The cliché is women get sick, men die. Women are the greatest users of the health care system. Women’s life expectancy may change as their lifestyles become more like men’s.

What is productive activity?

Julie Byles. Gardening, volunteer work, paid work. No one activity is linked to survival.

Is there telomerase in trees that live hundreds or thousands of years?

Roger Reddel. Those parts of plants that can be propagated long-term have telomerase activity, those parts that can’t be propagated don’t have telomerase.

Rob Helme. Jogging can extend your life by 2 years, but you’ll spend 2 years doing it. You have to
enjoy running.