Title: Against ageing
Key words: biochemical processes, the ageing process, free radicals, DNA, mitochondria, antioxidants, superoxide dismutase, catalase, low calorie diets, protein restriction,
Date: April 2001
Category: Life changes
No one wants to end up sans teeth, sans eyes, sans taste, sans everything. The good news is that we may be able to turn back the tide.
Statistics on ageing make dismal reading. After the first two decades, life appears to be all downhill: brain, muscle, heart and the immune system begin their slow decline. And as skin wrinkles, hearing dulls and memory fades, the death rate - the chance that this year will be your last - rises relentlessly, doubling every eight or nine years.
Can science bring any hope into this gloomy picture? All the signs are that it can. In laboratories around the world, the fundamental mechanisms of ageing are under unprecedented scrutiny, and the first clues to what causes living creatures to grow old are beginning to emerge. This research has a different aim from that of the cosmetic industry, which is more concerned to hide the prominent signs of ageing. Scientists want to understand the biochemical processes that underlie the multiple symptoms of ageing, and to ask if they can be slowed or even reversed.
The first small successes have already been registered. At the University of Kentucky, researchers have found that elderly gerbils can find their way around mazes just as expertly as their juniors, thanks to a free-radical trapping chemical called PBN, a variety of which may soon be tested in humans. Special diets, under study in a number of laboratories, have extended the lives of rats by up to half. And biologists have bred fruit flies and roundworms that live far longer than normal.
Nature itself offers some comfort, for ageing is apparently not inevitable for all creatures. Caleb Finch, a geron-tologist at the University of Southern California, has assembled an impressive catalogue of living things that grow old without obvious deterioration, including 20-kilogram lobsters, centenarian fish and veteran sea anemones.
The large natural variation in how long people live gives hope that life span can be artificially lengthened. Natural selection seems not to have pushed our life spans to the limit, perhaps because from an evolutionary point of view, passing on genes to the next generation is what matters, not a long and biologically useless old age. Faced with limited resources, reproduction is more important than maintaining the perfection of youth by means of complex repair processes. But if nature has never tried, all the more reason that there could be scope for improving our lot by our own efforts.
Researchers are currently testing a number of theories that link ageing to biochemical defects, in particular damage to important molecules such as DNA. These studies show that the DNA found inside mitochondria, the cellular structures whose job is to provide cells with energy, is particularly vulnerable, most probably because they handle oxidative chemical reactions. Any damage to mitochondria could compromise the smooth running of the cell.
Damage to proteins, which are essential for all the chemical reactions within the cell, could also have dire consequences. Cells routinely dismantle and recycle their proteins, but the rate of turnover slows with age, allowing defective proteins to hang around in cells for longer periods.
What causes the damage to DNA and proteins? A group of molecules called free radicals are the prime suspects helping biochemists with their inquiries. Free radicals are highly damaging by-products of normal cell chemistry. They behave like a cadre of easily provoked and well-armed molecular terrorists, rapidly oxidising other molecules they run into. Cells contain an array of defences against them, notably special enzymes such as superoxide dismutase and catalase that render them harmless. But some free radicals inevitably escape the net and live long enough to damage DNA, proteins and fats within cells.
Many researchers now think that damage caused by free radicals could be an underlying cause of ageing, and that it plays a part in a number of age-related diseases, including cancer and circulatory disease. 'It's almost the decade of the radical,' says John Carney, who studies ageing at the University of Kentucky. Some scientists are already so convinced of the importance of free radicals that they recommend people eat high daily doses of vitamins C and E, both of which act as antioxidants. But there is as yet no consensus that free radicals are the main cause of ageing in humans and other theories still enjoy support.
Some of the clearest evidence for the free radical theory comes from studies of laboratory gerbils. Like people, gerbils tend to grow a little forgetful with age. When set the task of exploring a special maze without retracing their steps, they make about twice as many mistakes as their younger relatives. Carney's team has forged a link between free radicals and deterioration in memory. They found that elderly gerbils could perform with all the flair of their juniors after receiving injections of PBN for 14 days, which protects against the effects of free radicals.
Carney and his colleagues also discovered that the brains of older gerbils tend to contain higher levels of proteins that have been damaged by free radicals than those of younger gerbils, again suggesting their importance in ageing. Autopsies on humans reveal a similar trend: brains from older people have a higher content of oxidised proteins than those from younger people. In the gerbils' case, injections of PBN reduced the amount of oxidised protein, as well as improving performance in the maze. So at least some age-related change can be reversed. 'What we think PBN is doing is possibly replenishing or replacing a system that is normally there when we are young but is progressively declining as we get older,' explains Carney. Could humans eventually benefit from this line of research? 'We anticipate that there will be some kind of clinical trial in the next two-and-a-half to three years with an analogue of PBN,' Carney says.
Research on lowly creatures such as fruit flies and roundworms is also playing an important part in exposing the mechanisms behind ageing and, once again, it is free radicals that are implicated as prime suspects. Thomas Johnson of the University of Colorado, for example, has bred a strain of the roundworm Caenorhabditis elegans which enjoys a 65 per cent increase in life span. Researchers in other laboratories have found that the long-lived worms have higher than normal amounts of superoxide dismutase and catalase. 'That's very exciting to a lot of people in the ageing field because it fits in with the most popular model,' says Johnson.
These discoveries dovetail neatly with findings from another strand of research. It has been known for years that rats and other rodents live up to 50 per cent longer if they are kept on low-calorie diets from an early age. As yet there is no consensus about how this works. One idea is that rats on a spartan diet keep their proteins turning over at higher rates than normal, says Brian Merry, who is studying ageing and diet at the Institute of Human Ageing in the University of Liverpool. This higher rate of turnover would presumably help them cope better with protein damage, however that damage arose.
Enter, once again, the ubiquitous free radical. Rats on meagre rations, it seems, suffer less protein damage at the hands of free radicals than their better-fed cousins. This could be because they make greater quantities of those all-important enzymes that protect cells from free radicals, according to Linda Youngman, who studies links between diet, ageing and cancer at the University of California at Berkeley and the University of Oxford.
Youngman's research shows that the biochemical benefits of a spartan diet in rats can come either from eating fewer calories, or from eating less protein. Does that mean our own species might also benefit from a restricted diet? 'For humans, caloric restriction is really not a feasible option, whereas protein restriction is - and deserves more study in my opinion,' says Youngman.
Other researchers agree on the need for caution. 'I'd like to know how it works before we make the great leap forward,' says Merry. He stresses that scientists are studying dietary restriction to find out what controls the rate of ageing, and this work is still at an early stage. They are not saying that because rats can be made to live 40 or 50 per cent longer, the same can be done for humans.
No limit to life?
That may change when scientists learn more about the mechanism of action of free radicals and the effects of special diets on ageing. But one fundamental question will still remain: is there a final limit to life span, even if it is considerably longer than we are accustomed to? Or will we be able to go on putting off ageing for ever?
This century has already witnessed some quite outstanding gains. Life expectancy at birth in Britain at the turn of the century was 46 for males and 49 for females; now the figures are 73 and 79, thanks largely to reductions in infant and maternal deaths. Official predictions are that citizens born in 2001 will on average live to 75 if they are male and 80 if they are female.
Whether or not these gains could continue indefinitely is a subject of intense debate. James Carey, a demographer at the University of California in Davis, sums up the issue this way: 'In 1940 in the US a 65-year-old had a one out of fourteen chance to attain age 90; in 1980 it was one out of four, and in 1990 it's almost one out of three. The question is whether we are eventually going to bump up against a limit where you can't improve mortality any more at advanced ages.' In other words, is there a fixed upper limit to age in our species?
In collaboration with researchers in Mexico and Denmark, Carey turned to Mediterranean fruit flies in the search for clues. The team ran a huge experiment involving over a million flies kept at a special agricultural breeding laboratory near Tapachula in southern Mexico. Such large numbers were necessary to obtain reliable figures at very old ages, after most of the original flies have died. The researchers reasoned that if the flies had a fixed life span, the death rate would increase relentlessly with age - and go on increasing until the bitter end. But this was not the case. Sure enough, the death rate rose at first: the older a fly became, the more likely it was to die within a given time. But then the death rate levelled off, and the risk of death remained the same from one day to the next.
Of course the flies did die in the end - the last two veterans finally croaked at the age of nearly six months - but not in the way one would expect if their life span were preordained by some sort of molecular time bomb.
Does this discovery have any relevance for the problem of the human life span? 'It has been argued that we are bumping up against a limit,' says Carey. 'What our research has done is challenge the concept of a limit.'
Antioxidants and ageing
GIVING worms antioxidants can make them live up to twice as long as normal. The finding adds to the evidence that the damage wreaked by free radicals-which are mopped up by antioxidants-is a major cause of ageing.
An international team of researchers added two powerful antioxidants, superoxide dismutase and catalase, to the liquid in which adult nematode worms were living. They found that, on average, the worms lived 50 per cent longer (Science, vol 289, p 1567).
"We predicted the lifespan extension but I was still surprised," says Gordon Lithgow of the University of Manchester.
"I started seeing these things that should be dead swimming around. We've seen that with mutants before. But it's just amazing to see it with a drug," says Lithgow. However, it's not clear whether these antioxidants would have the same effect on humans.
© New Scientist 2000