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Of old age and all that
EXTREME old age, at least viewed from the perspective of young or vigorous middle age, is not an attractive prospect. The successes of twentieth century medicine have created a paradoxical situation, with prophets of biotechnology predicting the death of ageing, but most of the elderly still suffering from distressing and largely incurable chronic diseases.
It seems that a few people have, since time immemorial, lived to a grand old age, managing to survive well into their nineties. But lately, what has changed is that more people in the West and Asia now live longer, just as their most fortunate ancestors.
In 1990, just one per cent of the world’s population was over 65. This figure is projected to rise to 20 per cent by the middle of this century. Furthermore, many people are staying healthy and productive during most of their extra years. However, the “old old” are having a tough time at it.
That grand old Frenchwoman, Jeanne Calment, may have been able to continue cycling well into her eleventh decade, but the lives of too many over-85s are burdened with dependence, disability and dementia.
The question, however, remains: Why do we age at all? It is highly probable that we are programmed to survive long enough to reproduce and care for our young. “When survival is uncertain… it is better not to squander effort on a greater level of bodily maintenance than is needed. If, to a rough approximation, the average lifespan of our ancestors was around 35 years…then a body which held itself together for three score years and ten would do just fine.”
We age, in crude terms, because our cells accumulate damage. One of the mechanisms that causes this damage is oxidative stress. Oxidation reactions in mitochondria, which release the energy we need, also generate charged molecules known as free radicals. Reactions between free radicals and other molecules, including DNA, can cause significant damage.
It has been estimated that the DNA in each of our cells suffer thousands of “hits” each day. In genetically normal humans, almost all these hits are immediately fixed by several DNA repair mechanisms. Occasional hits that are not repaired cause permanent changes in the DNA sequence.
As these changes accumulate during an average lifespan, the individual becomes more vulnerable to degenerative diseases and to cancer. A few unfortunate souls have defective DNA repair mechanisms. Accelerated ageing is one of the symptoms of Cockayne’s Syndrome and trichothiodystrophy — rare genetic disorders in which the nuclear excision repair mechanism is damaged.
The converse — that is, improving the effectiveness of DNA repair mechanisms can decelerate ageing — has also been observed, at least among laboratory animals. Transgenic mice that lack a protein known as p66shc are better able to withstand oxidative stress than their genetically normal mates, and they also have extended lifespans.
Could we alter our genes in a similar way, or develop a drug to inhibit the human equivalent of p66shc? If so, should we?
However, it is not clear that this will ever be possible. Gene therapy has not yet produced a cure for cystic fibrosis, a well understood single-gene defect. Any alteration to the complex DNA repair process is almost certain to have unforeseen consequences.
The double-edged nature of the damage control mechanisms in cells is exemplified by another system for protecting DNA. Each time a cell divides, a few bases at each end of each chromosome strand are not replicated. The non-coding segments of DNA at the ends of the strands, called telomeres, protect the coding sequence from degradation caused by this shortening.
These act as “molecular clocks.” Once they are reduced to a certain length, the cell can no longer divide. There is some evidence that long-living individuals start with longer telomeres.
Researchers at Geron, a California biotechnology company, are trying to develop ways to insert parts of telomeres into the chromosomes of senescent cells, to reset their clocks.
Yet, there are some types of cells that have self-repairing telomeres — cancer cells. Most tumour cells contain the enzyme telomerase, which systematically repairs the chromosome ends.
Scientists in other companies are investigating into whether telomerase inhibitors might be useful as anti-cancer drugs.
The way in which research into ageing is carried out will determine the kind of society that we will have. A society of super-centenarians with the health problems of today’s 80- and 90-year olds would not be a comfortable proposition for anyone, young or old.
Let those of us who work at the frontiers of medical science try to study in detail those diseases that blight the lives of the elderly. Where possible, this should add life to years, rather than merely adding years to life.
“For, as nature has marked the bounds of everything else, so she has marked the bounds of life. Moreover, old age is the final scene, as it were, in life’s drama, from which we ought to escape when it grows wearisome and, certainly, when we have had our fill.”
The writer, an HEC-designated national professor, works for the Dr Panjwani Centre for Molecular Medicine and Drug Research, University of Karachi. He can be contacted at
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