The BBC broadcast the following "Discovery" program on the 31 meter shortwave band, October 10th, 1989.DISCOVERY, EDITION 785
STEPHEN HEDGES: Hello and welcome to Discovery. Today we discuss some ideas about the causes of ageing. I hope you're not enjoying a sticky bun or drinking a cup of sugary hot chocolate as you listen. If it's a between-meals snack, you could be in for a shock. Writing in a recent issue of the New Scientist, researchers based at the University of Oxford and at the Open University, report that taking sugary snacks between meals may damage vital body proteins and cause premature ageing. Their experiments suggest that high levels of sugars in the blood cause proteins to stick together. Normally special enzymes unstick the glycated proteins, but if sugar levels are raised between meals the enzymes can't cope, and the proteins become permanently damaged. Being partial to the occasional Chelsea bun myself, I took the train to Oxford and found Dr Anna Furth in her laboratory at the Open University's research unit. She explained why they think high levels of sugar damage proteins.
DR ANNA FURTH: Well the damage to the protein takes place in 2 stages because the first product that's formed by glucose attacking the protein is called a Schiffs base and that, within a matter of days, will slowly convert to the next product which is called an Amadory product and these 2 modified forms of the protein are known as the early glycation products and there's a lot of discussion as to how debilitating they are. But, as any protein chemist will tell you, you've only got to modify the surface of a protein very slightly and you are likely to alter its reactions with other molecules in the body because protein reactions are in essence controlled by their surface shape. So what it could well add up to is a series of minor disabilities rather than a specific illness. And with short-lived proteins you do get replacement molecules within a matter of weeks so you can get fresh molecules that are not glycated. Albumin, once it's glycated - and 1 in 3 molecules of albumin are glycated, even in normal people - is much less efficient at carrying long chain fatty acids, and this you'd expect to have some effect on fat metabolism, however minor. And there's another protein in the serum, a lipo- protein which is used to carry cholesterol and if you glycate that in a test tube to the same extent as you can find it in the body, then it's not picked up by cells and that is bound to have some effect on the metabolism and the transport of cholesterol.
HEDGES: Now I believe from what you were saying that diabetics have more of these glycated proteins. Is there any indication of the sort of long-term damage that high levels might cause?
FURTH: Most of the interest in long-term damage has been directed at the long-lived proteins which are there long enough for the final stages of glycation to take place and that's collagen and crystallin in the eye lens. It's well known that diabetics are more likely to have cataracts than non-diabetics. Even short-term damage may be caused by glycation of basement membrane components. Now, the basement membrane is a lining underneath capillaries and it's also part of the kidney filtration mechanism and its function seems to be to filter out large molecules from the nutrient fluid that comes out of capillaries and nourishes tissues like the retina and muscles and lots of other tissues. An unfortunate characteristic of diabetic tissue is that the basement membrane does get very thick, and that obviously upsets its filtration properties, and several of the components, notably a specialised collagen which is used to make a filtration network, and fibronectin, both of these proteins are more heavily glycated in diabetics and if you glycate them to the same amount in a test tube, you can impair their filtration mechanisms and they certainly don't form a nice network as they would otherwise do.
HEDGES: Are there any ways of preventing this damage? I'm thinking perhaps of drugs that you might use.
FURTH: The only drug that's been, as it were, designed to prevent glycation has been developed by Professor Cerami's group at the Rockefeller Institute in the States, and this is called amino- guanidin, and it was aimed to block the most reactive glucose modified protein called the Amadory product and it is said that if you feed it to diabetic rats, it does stop their basement membranes from thickening but that takes 5 months of feeding and it stops their aortic collagen from getting cross-linked. It has been tried on humans for 2 weeks with apparently no ill effects but there has been no large-scale clinical trial and at the moment they have taken out a patent to use it for preventing ageing in food proteins and in animals. So that's amino-guanidin. Surprisingly, the most effective drug seems to be aspirin - I say surprisingly because it wasn't intended as an anti-glycation drug, but studies by John Harding in Oxford, and his collaborators, have shown that if you take a group of people who have got cataracts and another group of comparable age, and ask them if they have taken any drug for more than 4 months continuously at any time in their life, you find that if they've taken aspirin or Paracetamol or Neurofen, there's a distinct so-called protective effect against cataracts. In other words, statistically they are less likely to develop cataracts than if they haven't taken these drugs over this period. And there's not been a deliberate clinical trial but it seems that if you take even just 1 aspirin a day for 18 months, you might protect against cataract. But cataract is largely due to glycation of the eye lens protein which is unusual in that it's never replaced, or virtually never - it's a very long-lived protein. And the big question is, of course, whether aspirin will have a similar protective effect against other proteins, particularly, say, the basement membrane proteins.
HEDGES: Is it known how these anti-inflamatory drugs like aspirin and Neurofen might be having this effect?
FURTH: Well it's originally thought with aspirin that it reacted itself with the protein at the same site that would otherwise be attacked by glucose. But then it was realised that some of these other anti-inflamatory drugs don't have quite the same structure as aspirin so they couldn't affect the proteins in the same way. So I think the answer is that no-one is very clear how the drugs work and maybe it is simply an effect through a rather complex series of reactions that actually lower the blood glucose.
HEDGES: Does the body itself have any way of preventing the cross- linking of these glucose modified proteins?
FURTH: Well it used to be thought not, but fairly recently a group in South Carolina, led by John Baines, have found a derivative of proteins called carboxylmethyl lysine which is much more pronounced in diabetics and has come from the breakdown of products that have been modified glucose, but have then oxidised to convert the glucose, add-up to something which is comparatively harmless because it can't cross-link. And the nice thing would be, of course, if you could encourage this oxidation reaction but at the moment naturally it only breaks down about 10% of the glucose modified proteins so on its own it doesn't help you very much.
HEDGES: Are all researchers agreed about the way that sugar damages proteins, or are there some scientists who have rather different ideas?
FURTH: I think most people agree that the route for the damage is that a glucose molecule attaches to a protein and then becomes irreversibly attached through an internal re-arrangement and may then go on to cross-linking. But there is a group at University College in London, led by Simon Wolff, who feel that it is not so much the glucose itself that attacks the protein but the oxidation products of glucose and that this can actually fragment proteins and therefore conditions which enhance oxidation are the ones to be avoided.
HEDGES: Now if Dr Wolff is right, what can you actually do about it? Is there some other way of preventing the damage?
FURTH: Well, there's a lot of interest in taking anti-oxidants like vitamin C and vitamin E, and if he's right that this oxidative fragmentation is the major route by which glucose damages proteins then possibly vitamin C or vitamin E would help but I have to point out that the body's own mechanism for getting rid of glucose- damaged protein seems to be the route discovered by John Baines which is an oxidation in itself. So if you go around taking a lot of vitamin C you would be tending to depress that reaction maybe. It's far more complicated than that. I would also point out that vitamin C in the test tube, if you leave it sitting with a protein, it will cross- link it and form the same sort of undesirable products very nicely.
HEDGES: Finally, what would your advice to people be to avoid this long-term protein damage? Do we have to take drugs or are there other things that we might do?
FURTH: Well there is a much simpler method which is to avoid taking glucose in the first place and obviously one can't be too glib about this because we rely on glucose for food and energy. I think it's important to point out that the body has no means of controlling this particular reaction unlike all the other reactions that go on, and are controlled by enzymes, and the only controls are the concentration of glucose that the protein is exposed to, and the length of time it's exposed. And obviously both those things tend to be greater in diabetics but I think that what people have not emphasised is that as you get older, every time you take a carbohydrate-containing meal, your blood glucose does go up and it's a perfectly normal phenomenon, but the older you get, the higher it goes and the longer it takes to come down. And if you're looking for small cumulative changes in your proteins, which is exactly what we think happens in ageing, this glycation after a meal could contribute and so if you wanted to reduce the likelihood of glycation, you clearly can't stop eating, but I think you can minimise the exposure by perhaps cutting down on snacks that contain carbohydrate.
HEDGES: Dr Anna Furth of the Open University. And the message would clearly seem to be, cut out those sugary between-meals snacks, even when you're list- ening to Discovery in the World Service of the BBC.
STILL LIKE SUGAR? WELL HERE'S A PARAGRAPH OF WHOLESALE NUTRITION'S MAY '84 NEWSLETTER #18:
VITAMIN C AND SUGAR: Ascorbic Acid (AA) and Dehydroascorbic Acid (DHA) are on opposite sides of a chemical equation that expresses an important reaction that's continually going on in our body. Depending on conditions, the reaction can go from left to right or from right to left, that is, AA and DHA are two forms of the same chemical that are constantly being transformed back and forth. Now we all know that AA (vitamin C) is extremely important to our health, but few of us know that DHA can be deadly. DHA, for instance, is thought to be involved in deterioration of the circulatory system, heart attacks, cancer, and birth defects. Also, and what may be most important, DHA has a lympholytic effect which reversibly atrophies the thymus and thus suppresses the immune system. It's known that stress will cause AA to convert into DHA and may be the reason why stress is implicated in all of the above conditions. It's very important, therefore, to maintain a high AA/DHA ratio (of at least 10/1). It's thought that the body may have developed a method of doing this for us by taking a certain amino acid precursor (found in high levels in raw or lightly cooked broccoli, cauliflower, Brussels sprouts and cabbage) and using it to make a tri-peptide amino acid, called glutathione, which then, inside every cell of our body, and as soon as the DHA enters the cell, converts the DHA back to AA. Unfortunately, when you eat sugar, you interfere with this whole delicate process by inhibiting the transport of DHA through the cell wall. Whatever type or form of sugar (including honey and fructose) or rapidly hydrolyzable starches (such as white rice, bread and potatoes) we eat, it's all converted by our body into glucose, and, since it's our only source of energy, is given 1st priority by the cells. The glucose then proceeds to occupy all of a cell's receptor sites and prevents the entrance into the cell of DHA, and, as a result, the DHA doesn't get converted back to AA by the glutathione in the cell. The best method of determining whether your average sugar intake is excessive is to test (for about $20) your blood for glycosylated hemoglobin A1C ("A-one-C"). Although the "normal" range is said to be from 5 to 9, Dr John Ely, of the Univ. of Washington in Seattle, strongly suggests your A1C must be less than 7. For instance, in a study of 114 pregnant women, those having an A1C greater than 8.5 during early pregnancy showed a 22% chance of giving birth to a markedly abnormal baby (malformed body, undeveloped brain). But it dropped to 0% for those whose A1C was less than 7.
So, the bottom line is, in addition to taking your normal vitamin C, to eat plenty of those vegetables mentioned above, avoid stress, and above all, TO AVOID SUGAR!! I want to thank Dr Ely for all of the above, since much of it is proprietary pre-publication information that he's allowing me to break to you first.
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