It is a reasonable explanation, but it appears to be quite wrong. The reason that SOD1 mutations kill motor neurons has nothing to do with free radicals or hydrogen peroxide poisoning. Rather, their deleterious effects seem to be related to some other, slightly mysterious, role that superoxide dismutase has in the brain. Neurons are strange cells. They are large, have long protrusions called axons, and a whole special cellular architecture that goes with this. Besides scavenging free radicals, superoxide dismutase appears to have some role in this architecture. Biologists have adopted a lovely phrase to describe such multitasking proteins – they call them ‘moonlighters’. Moonlighting SOD1 may also contribute to another neurological disorder, Down’s syndrome. Children with Down’s syndrome have three copies of chromosome 21 – the chromosome on which the SOD1 gene resides – instead of the usual two. Hundreds of different genes reside on this chromosome, and any or all of them might contribute to the distinctive features of Down’s (mental retardation, the facial abnormalities, heart problems to name but a few), but the extra copy of SOD1 has long been fingered as one of the more destructive.
If superoxide dismutase moonlights, then the argument proposed above is predicated on a false premise. And with it goes one of the few good reasons for believing the whole free radical theory of ageing. The proponents of this theory (and among scientists they surely number in the thousands) may well feel that this is a harsh assessment of the only mechanistic account of the origin of ageing that has any pretensions to generality. It is certainly still possible that superoxide dismutase’s seemingly beneficial effects on ageing are mostly due to free radical scavenging, but this remains to be shown. For the time being, however, few would disagree that superoxide dismutase can be struck from the list of elixirs that might one day stave off the decline of our later years.
A WRINKLE
Even if free radicals are not the sole, or even major, source of mutations, mutations may still cause at least some aspects of ageing. Mutations may be especially destructive in those tissues, such as skin, whose cells divide continually throughout life. Some of us keep relatively youthful complexions well into old age, while others wrinkle when young. This variety partly depends on the exposure to the elements, sun most obviously, that each of us has received; ultraviolet light is a powerful mutagen. But even sheltered skin ages. And for all the parasols, veils and sun-block in the world, no thirty-five-year-old’s skin has ever glowed as it glowed when she was fifteen.
Wrinkling is a manifestation of a deeper inability of epidermal cells to replace themselves and maintain the integrity of the connective tissue of our skins. It is a problem that pervades our bodies. This is evident from people whose skins and connective tissues age with unusual, indeed catastrophic, rapidity. An inherited disorder called Werner’s syndrome causes its victims to go grey and bald when still in their teens. In their twenties, the testicles atrophy in men as the ovarian follicles do in women – a kind of premature menopause. In their thirties sufferers need lens transplants to cure cataracts, and their arteries stiffen and become covered in fat deposits. In their forties they die, usually from heart attacks.
Werner’s syndrome is one of a group of inherited rapid-ageing disorders called ‘progerias’. The disorder is caused by mutations that disable a protein that maintains the integrity of DNA during replication. Cells that lack the protein have very high mutation rates. This barrage of mutations causes the cells to die instead of proliferating, or else to produce abnormal proteins. Tissues, such as skin, which rely on large numbers of dividing cells in order to maintain their integrity, fall apart. Perhaps something similar happens to us all, only at a much slower rate.
As we age, vitality slips away from our cells. This can be seen in the laboratory. It has long been possible to grow human cells in petri-dishes by means of elaborate and delicate protocols. No matter how salubrious their environment, however, freshly harvested cells will divide only a certain number of times and then divide no more. Their decline is gradual, and is caused by some intrinsic limit. Many have suggested that this cellular senescence is not merely a consequence of the ageing body but its direct cause.
Supporting this idea, cells taken from human foetuses can divide for about twice as many generations as can those from ninety-year-olds before sinking into decline. Perhaps, then, elderly people have many cells that are closer to the end of their replicative lifespans and which are, therefore, unable to contribute to repairing the wear and tear of everyday life as well as they might. When, therefore, in 1998, the molecular cause of the limit to cell division was discovered, and then broken, the thrill was tangible. If cellular senescence could be cured, perhaps so could ageing.
Each time a cell divides, its chromosomes must be replicated as well. But the enzymes that replicate chromosomal DNA are unable to replicate the ends of the chromosomes. These ends are, therefore, protected by sequences, thousands of base-pairs long, called telomeres that are gradually whittled away over the course of many cell divisions at a rate of about a hundred base-pairs per cell division. When the telomeres are gone, the cell can no longer divide and it dies. It is the rate of whittling that sets the fundamental clock of ageing. Or so the argument goes.
What is needed, then, is a way to prevent the attrition of telomeres. Not all cells lose their telomeres. The germ cells that give rise to eggs and sperm possess a complex enzyme called telomerase that maintains their telomeres and so confers upon them the immortality that they must necessarily have. The loss of telomeres that occurs in the rest of the body’s cells is precisely due to the fact that they do not contain this enzyme. If telomerase is engineered into cells that normally lack the enzyme, their telomeres are preserved division after division. The cells also became immortal.
If the route to cellular immortality is so easy, why have we not taken it? The reason is quite simple: immortality is a property of cancers. Nearly all tumor cells have, somewhere in their history, undergone mutations that cause them to have telomerase where other cells do not. The absence of telomerase in our cells is probably one of the first defences we have against the multiplication of rogue cells. Besides, there is still little to show that short telomeres do, in fact, cause ageing. Only one experiment has addressed the problem directly: an experiment in which telomerase-defective mice were engineered and then bred for six generations.
Mice, it seems, can get by without telomerase for at least a while. The first generation of telomerase-defective mice that was ever produced showed no signs of premature ageing. In a way this is not surprising. These mice had telomeres as long as those of any other mice, for mice, like us, inherit their telomeres from their parents, and their parents were normal. For want of telomerase in their germ cells, however, each successive generation of these mutant mice started life with ever shorter telomeres. The effects became apparent by the fourth generation when the male mice proved to have few viable sperm. By the sixth generation they had none at all. Females were not sterile, but they produced fewer eggs than normal, and those they did produce often gave rise to defective embryos. By the sixth generation, too, male and female mice alike began to age prematurely. Like humans, mice go bald and grey with age, and the sixth-generation mice did so while still young.