'It's as if you're the doctor,' says Rudi Westendorp, Professor of Geriatric Medicine to evolutionary biologist Bas Zwaan. Zwaan, who is researching the complex relationship between genotypes and phenotypes of butterflies and fruit flies, had just been stressing how important it is for the medical world to become convinced that factors at the very start of life have an enormous influence on life expectancy. So that we can make an early start on taking appropriate, and preferably preventive, action. Don't wait until middle age!
Westendorp himself, a doctor born and bred, is no less enthusiastic about the importance of evolutionary biology in studying ageing: ‘The majority of doctors don't think in biological terms. But, if you want to research ageing mechanisms, you have to. If you have to wait until people are old to see whether your hypothesis is right, it will take too long. So you have to start constructing experiments, you have to use animal models. Doctors still all too often think that an illness is determined either by genetics or by environmental factors. Evolutionary biologists always explain the variation between individuals as the interaction between genes and environment.'
The discussion is a good demonstration of how each of the scientists thinks from the perspective of the other's field. They and other Leiden scientists, like molecular geneticist Prof. Dr Eline Slagboom (LUMC) and her research group, have been working together for some four years on ageing in humans and animals, in species and individuals. It's not common to find such a synergy between doctors and biologists, and colleagues in other countries are often jealous of Leiden in this respect.
‘Early influences late’
These colleagues will now be able to participate in the research. The European Union has this week awarded Westerndorp and Zwaan 10 million euro for the LifeSpan project, within the Sixth Framework Programme. They have the opportunity to set up a network of excellence which has five years to develop research into the influence of the early development of organisms on their eventual lifespan. In recent years there have been an increasing number of indications that early development has considerable influence, and may even be definitive. 'Early influences late,' according to Zwaan. 'But how does it work? We're all well aware by now that pregnant women shouldn't smoke. But there are many more things we are not aware of. These are the things we want to find out more about. And more importantly: we want to understand the biology behind them.'
Westendorp continues: ‘This is the opportunity to set out one consistent line with the best partners in Europe. At this early stage it's particularly important to avoid fragmentation and to make good use of the work which has already been done. In Scandinavia, for example, researchers started early with research on twins. Now we can all benefit from their work. Here in the LUMC we are carrying out research into longevity, and we are following a large group of 85-year-olds and older. And the Leiden biologists have already done a lot of work to get selection lines of fruit flies. In Norway they are working with honey bees. These are very interesting because larvae with the same genetic baggage can develop into long-lived queen bees as well as into short-lived worker bees. And in Austria there is great deal of expertise in cell biology in the area of ageing of the immune system.'
Whether a person will live to old age is not only a matter of their genes. Zwaan: 'From time to time somebody will claim to have found the gene for longevity. The rest of the field is then silenced. And it means so little. The fact that a mutated gene may lead to longer life, does not mean that the gene contributes to variation in natural populations, including that of man.'
One of the most important environmental factors is food. Westendorp: ‘Ten to fifteen thousand years ago the composition of the diet was dramatically different from today. Now there is a mismatch between our diet and our genes. A comparable mismatch seems to be very important at individual level. If you receive very little food during your early development, for example while you are still in the womb, and you then have a surfeit of food later, this has an enormous influence on your health. As well as on the health of your children. In India there has been a rapid change in the food situation in a very short space of time. A study there shows that relatively small mothers with overweight, obese children develop a disturbance in their blood sugar level.' Zwaan: ‘We do know that some genotypes react differently to this. If you know which genes are involved, you can advise those people accordingly. It is important to also stress the positive side. It's about growing old and staying healthy.'
Because food is so important, a lot of experimental biological research is conducted on the relationship between resistance to starvation and longevity, for example in fruit flies, and on insuline management in animals. Human groups which are ideally suited for research into the trio of food, development and ageing, are the so-called 'hunger winter' people: those people who were in their mother's womb during the winter of 1944-45, when food in the Netherlands was extremely scarce. Researchers at LUMC are also following a group of people of different ages in part of Ghana where there have been no changes to the traditional food pattern.
Research into the relationship between 'cradle and grave' can provide important guidelines for human health. But research into these early mechanisms is also important for fundamental science. The expectation is that it will provide important informatin about the role of epigenetics. This branch of research studies the expression of genes, the - in some cases hereditary - changes, and the mechanisms and proteins which are related to it. Epigenetics wants to explain the variation between individuals, and poses such questions as: why does one half of a single-egg twin have a cleft lip or palate and the other not? Zwaan: ‘We are also going to use it differently. We are, for example, going to examine how cells are 'regulated', how they use their energy.'
The newness of research into development and ageing is apparent from the way in which the first expression of interest by Westendorp and Zwaan for the Sixth Framework Programme was received. That was four years ago. One of the themes in which researchers could indicate their interest was Development and Ageing. At least, that's what they thought. Westendorp: ‘We had only just started, so we submitted something. But that was apparently not the intention. The development and ageing themes were only linked because they were each too small for their own section.' The Leiden researchers were able to demonstrate with their three position papers (see below) that this combination had the potential of becoming a very promising research field. They have been successful with their final proposal for LifeSpan.
But there is still some missionary work to do. Westendorp: ‘Critics say: “Life expectancy is still increasing, isn't it? So why are you making things so difficult?' It's true, we have managed to overcome most infectious illnesses, so that we no longer live to only 40, but to 90 in many cases. But I can then point to research which shows that the overall mortality rate may be decliinng, but that mortality among those suffering from obesity, for example,i s actually increasing.'
Hilje Papma | alfa
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