ANNUAL SYMPOSIUM

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

Dr Zeinab Khalil graduated in medicine from Cairo University and received a PhD on neuronal control of stress-mediated events from the University of Melbourne. She has worked actively in the neuroscience field since 1984. Her work has covered the functional, physiological and biochemical aspects of the sensory neurovascular system that are involved in the control of inflammation, pain perception and tissue repair. In 1987 she joined the National Ageing Research Institute (NARI), where she has focused on bridging the gap between basic science and clinical medicine to understand the mechanisms underlying age-related diseases. Her major research interests are the neurovascular mechanisms underlying delayed tissue repair, Alzheimer’s disease and chronic pain in old age. She is an academic associate with the Department of Medicine, University of Melbourne, and the Director of the Biomedical Research Division at NARI.

Symposium themes - Ageing

Intrinsic and pathological processes of ageing: The role of stochastic mechanisms
by Zeinab Khalil
z.khalil@nari.unimelb.edu.au

Abstract
The free radical theory of ageing has received increasing attention in the last two decades. The theory postulates that the free radical reaction is a single common process that might be responsible for ageing and intimately involved in many age-associated disorders. The modern concept of this theory takes as its basis a shift in the antioxidant/prooxidant balance that leads to increased oxidative stress, dysregulation of cellular function and ageing.

The revival of the free radical theory of ageing has led to an increase in consumption of antioxidants by the general public and prescription by the medical community. While this might have some merit, it is important to acknowledge that free radical reactions play an essential role in life. We should consider the possibility that, as the amount of antioxidant supplements consumed increases, we may reach a point where the beneficial effects of inhibiting deleterious free radical reactions outweigh the adverse effects on essential reactions. Thus, the basic mechanisms involved in pathological disease processes should be taken into account when considering antioxidants as therapeutic agents. Dr Khalil will allude to the role of free radicals in the pathology of Alzheimer’s disease and delayed tissue repair with age, and clarify the beneficial and harmful effects of antioxidants, particularly in managing age-associated diseases.

There are two major theories of ageing:

1. Ageing is genetically programmed.

2. Ageing is due to wear and tear.

Our bodies have adequate repair mechanisms for errors that occur in protein synthesis. But, as we get older, the ability to repair is outweighed by the cumulative errors occurring. Systems eventually drift outside homeostatically controlled range.

These cumulative errors produce defects in information transfer from DNA to RNA, which in turn produce defective proteins. These proteins can feed back the errors.

Oxygen free radicals are by-products of oxygen metabolism. Oxygen is utilised by the mitochondria to release energy and many essential enzymes require oxygen for their function. Oxygen free radicals are produced at the metabolic sites. They are neutralised by the antioxidant defence system, which converts them into harmless products like water. It is important to have a balance between oxygen free radicals and antioxidants.

Oxygen free radicals have desirable effects like ability to fight infection, inhibit the growth of tumour cells and aid tissue repair. They also have undesirable effects related to ageing and age-related diseases As we get older the balance tilts towards more oxygen free radical formation and less antioxidant. This produces oxidative stress that contributes to physiological ageing of body systems, with symptoms such as decline of the neurovascular system, and to pathological ageing, with a role in Alzheimer’s disease and delayed tissue repair.

One sign of physiological ageing is that the microvascular blood flow deteriorates. Old animals that have been fed antioxidants show an increase in blood flow.

Similarly, microvascular blood flow is limited in transgenic mice expressing Ab proteins (one of the underlying pathological features of Alzheimer’s disease). However, blood flow was significantly improved in these mice after antioxidant treatment. This indicates that oxygen free radicals could play a role in the pathology of Alzheimer’s disease. The implications of these findings to patients with Alzheimer’s disease is yet to be determined.

These experiments have not been done in humans. But antioxidants substances such as vitamin C, vitamin E, SOD, catalase and CoQ10 are increasingly being consumed.

Are antioxidants always good for you? Probably not, since they will also block the desirable effects of oxygen free radicals.

Studies of the time required for full contraction of skin wounds show that repair is delayed with age. Wounds that take 2 weeks to heal in a young animal take 3 weeks in an older animal. The repair of nerve injuries is also delayed in older animals, more than 11 weeks instead of 8 weeks in younger animals.

Is tissue repair affected by antioxidant therapy? Early treatment with antioxidants can cause delayed recovery, a bad outcome. But late treatment showed a speedier recovery than no treatment, a good outcome. These different results suggest that antioxidants can exert either beneficial or harmful effects.

The role of oxygen free radicals in physiological and pathological processes of ageing suggests that there is some merit in the use of antioxidants to prevent ageing. But consider the possibility of the beneficial effects being outweighed by the adverse effects of increasing consumption on essential reactions. The basic mechanisms of pathological disease should be taken into account when considering antioxidants as therapeutic agents.

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 four and five 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.