Source: The Times
Date: 20 November 2004

Just blame it on Granny

by Jerome Burne
What your forebears ate — and how healthy
they were — reverberates down the generations

So you take care of your health. You eat well, exercise and quite reasonably you assume that such prudence will raise significantly your chances of a disease-free old age. After all, it’s what all the experts advise. This may be, however, wishful thinking. Not just your parents but also your grandparents may already have had a lot more input into your risk of disease than is dreamed of in our personal responsibility philosophy. And this is not about bad genes. Want to know your risk of diabetes? How much your granddad got to eat just before puberty could have a major effect. What’s your risk of an autoimmune disease? Cells that came originally from your grandmother could be a major factor. Ever wondered how long you are likely to live? If you are a girl, the age that your father was when you were conceived plays a part. It’s irrelevant for boys.

These intergenerational effects on health are a fascinating new area of research. There are, as yet, still plenty of unknowns but the broad outline of a fresh understanding of the roots of our health is beginning to emerge. Although some of it flies in the face of what most of us understand about genetics, it now seems that the way our forebears lived — what they ate and how healthy they were — can reverberate down the generations.

For instance, two years ago a group of Swedish researchers reported (European Journal of Human Genetics) that the grandchildren of men who had been on the edge of puberty when there was a serious famine in their area had a significantly reduced risk of heart disease. On the other hand, those who had plenty of food at that time had grandchildren with a fourfold increased risk of diabetes.

How on earth could grandfather’s eating patterns possibly have these effects? A clue comes from the timing of the feast or famine. It made a difference only if it was around puberty, when the sperm-producing cells were developing. The suggestion is that something in the nutrition that grandfather was getting was able to change the genetic information contained in the sperm.

Now this is heresy in terms of conventional genetics; biology text books say that the genetic blueprint takes generations to alter. But there is a way to change, not the genes themselves, but the way they behave. It involves one of the hottest areas of genetic research, known as “methylation”, which is how chemicals in a cell affect the packing around DNA to make genes harder or easier to read.

Only a proportion of the DNA in any one cell of the body is active at any one time and some is turned off all the time — you don’t want genes that build bone active in kidney cells. Methylation is one of the ways a cell can instantly raise or lower the activity of a gene. “It’s a rapid mechanism by which an organism can respond to the environment without having to change its hardware,” says Randy Jirtle of Duke University in North Carolina.

Last year Jirtle published a key study showing that various health-store supplements such as folic acid, vitamin B12 and choline added to the diet of pregnant mice could have a methlylating effect on their genes. The pups from the supplemented mothers not only developed coloured coats quite different from an identical non-supplemented group, but also had a lower risk of obesity, diabetes and cancer. “It doesn't mean these supplements necessarily confer the same benefits on humans,” says Jirtle, “but it shows that supplements can have a dramatic effect on inheritance.”

The Swedish grandfathers wouldn’t have been taking supplements but getting either a starvation diet or a reasonable one could well have had a big effect on methylation in the sperm cells. “A similar intergenerational effect has been seen in rats,” says Professor Mark Hanson, the director of the Centre for Developmental Origins of Health and Disease, at Southampton University. “If you give female pregnant rats a very low protein diet, their pups will be rather low weight. If you then feed the sons normally and mate them with normal females, their pups are likely to have cardiovascular problems.”

Father’s sperm also features in another study which showed that a man’s age when a girl is conceived — but not a boy — affects how long she is likely to live. Researchers at the Centre on Ageing at Chicago University looked at records of European aristocratic families and found that daughters born to fathers aged between 35 and 39 were generally more long lived than those either older or younger. This had a bigger effect even than the age of the mother.

In general, though, as might be expected, it is the mother and her physical and mental state during pregnancy that can have the greatest effect on your future risk of a variety of chronic diseases. This in turn is strongly linked with your birth weight and the best way to predict that is by knowing your mother’s birth weight — the second best predictor is your grandmother’s.

Research by Professor Hanson and his team at Southampton suggests that the way a foetus develops has considerably more impact on its later health than the advocates of life-style changes allow for. “The foetus growing in the womb isn’t passively following the genetic blueprint,” he explains. Instead the actions of some genes are modified by changes in methylation as a result of the chemical information about the outside world that constantly flows across the placenta from the mother. How much food is around? Is it good quality? How stressful is it out there?

“The problems arise when there is a mismatch between the world the newborn baby encounters and the one the womb had prepared him for,” says Hanson. “The worst scenario is if nutrition in the womb was poor, so the foetus emerges designed for life in a world of scarcity, only to find food in abundance.” Hanson, who last month published a major review of this research in the journal Science, estimates that womb environment mismatches contribute about as much to chronic health problems as smoking.

The way a foetus tries to prepare for the outside world is known as PAR (predictive adaptive response) and research in animals shows that small deficiencies can have long-term results. In sheep, for instance, slightly reducing the nutritional value of food for the first 30 days of pregnancy makes no difference to the lambs’ birth weights but they are at increased risk of cardiovascular problems later. Just four days of low protein fed to pregnant rats has been linked with adult high blood pressure in the pups. Variations in diet can also affect the risk of developing osteoporosis and kidney problems.

“This suggests that it is possible that even becoming pregnant while you are on a diet could have a long-term effect,” says Hanson, who is also the British Heart Foundation professor of Cardiovascular Science. But there is yet another mechanism at work in the developing foetus, known as “microchimerism”, that is even more mysterious. There is a constant two-way traffic across the placenta of cells from both mother and child and a number of them stay in the other body after birth. A report in the Journal of the American Medical Association in September describes how sometimes these cells have been linked with autoimmune diseases. Once again the grandmother is present because some of her cells can show up in the grandchildren.

There are still plenty of unanswered questions about the way life in the womb and the even more distant lives of our ancestors continue to shape our health today, but this research suggests that we need more than a gym subscription and deliveries of organic vegetables to stay fit. More attention to all women’s health in pregnancy would seem vital. And it also raises questions about what is in store for the grandchildren of today’s overweight 10-year-olds?

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