MONDAY, 4 JANUARY 2010
In this regard, Tom Kirkwood, Cambridge alumnus and the director of the Newcastle Institute for Ageing and Health, can be considered a pioneer. Kirkwood has been at the forefront of educating the public about our current understanding of ageing, promoting his ideas during his 2001 Reith Lectures and in the House of Lords Science and Technology Select Committee report on scientific aspects of ageing. Kirkwood is trying to counter the view that most people hold of ageing, that it is an inevitable process and it is somehow programmed into our genes.
“We’re used to thinking in terms of a program of development for everything,” says Kirkwood. “Naturally we accept a program of ageing. Rather, the body is programmed for survival and the reason we age is that, due to the intense biological competition for resources, there was never a need to invest in good cellular programs to ensure longevity. At the end of the day, how ageing actually plays out tends to be governed, to a very large extent, by chance.”
Kirkwood sees two principal lines of evidence against ageing being programmed – the first, evolutionary: “It’s almost impossible to find a plausible way for a program for ageing to evolve,” says Kirkwood. “The idea that there is a program in hypothetically old creatures just does not make sense.” We can find no biological evidence for it either. “You would expect there to be an organisational self-destruct program. What we in fact see is that in the last moments of someone’s life their vital organs are doing their utmost to keep them alive.”
This radical change in how we perceive ageing has been made clear by the recent recipients of the Nobel Prize for medicine and their research into the role of telomeres in ageing, as well as the burgeoning development of age-research institutes in the last decade, such as the Cambridge Interdisciplinary Research Centre on Ageing, the Oxford Institute of Ageing, and the Newcastle Institute for Ageing and Health. All investigate fundamental questions on how ageing can be defined scientifically and how it can be prevented. In addition, fringe groups like Aubrey de Grey’s Methuselah foundation have predicted that the first person to live to 1,000 may already be in our midst.
“In theory,” says Kirkwood, “it is possible to imagine that we can enhance the functioning of maintenance and repair processes [to prevent ageing]. Where I would part company with someone like Aubrey de Grey is the ease with which we can modify that to extend human life capacity. What we are seeing in our own research is exciting data to show how complex these mechanisms actually are. The idea that we can modulate these complex mechanisms is running way beyond current science capabilities – it is moving from science to almost a fantasy.”
If ageing is not genetically determined, then why do we age? Correlations between body mass, metabolic rate and life span observed in the early 20th century led to the ‘rate of living’ theory of ageing, which proposes that a faster metabolism speeds up ageing. The mechanism behind this is suggested to be the cellular damage caused by free radicals, a by-product of metabolism.
Free radicals are molecules that contain unpaired electrons. Many are highly unstable and can easily rip electrons from other molecules. Free radicals produced in a cell will bump into biologically important molecules like DNA, proteins and lipids, modify their structures and alter their properties. This damage can be repaired, but if there is more damage than the repair pathways can cope with, it accumulates over time. Such accumulation corresponds to what is seen in ageing; little change for most of an organism’s life, but fairly rapid decline towards the end.
In our bodies, free radicals are primarily formed as a by-product of respiration. Unwanted transfer of electrons to oxygen forms members of the reactive oxygen species (superoxide, hydroxyl and peroxide), some of the most aggressive reactive species that can form. All these species can cause significant damage in the mitochondria where they are produced but only hydrogen peroxide can cross the mitochondrial inner membrane and cause damage throughout the cell.
Antioxidants have been championed as miracle cures for ageing. They are the first line of defence against these reactive oxygen species and act by neutralising the free radicals to prevent damage. Whilst their benefits may be exaggerated in adverts for anti-ageing cosmetics, there is some evidence that a diet containing more antioxidants can increase life expectancy. Consumption of foods that are high in antioxidants has so far produced mixed results in increasing longevity.
Another way to increase life expectancy is by restricting calorie intake. Studies in nematode worms, mice, fruit flies and primates have shown that caloric restriction reduces the likelihood of diabetes, cancer and cardiovascular disease and extends life. To date, this is the only lifestyle regimen that has been shown to delay the symptoms of ageing in a wide range of species.
Early studies suggest that similar benefits may be seen in humans. The ongoing CALERIE (Comprehensive Assessment of Long-term Effects of Reduced Intake of Energy) study in America has been running since 2007 and is constantly recruiting patients to participate in a long-term diet restriction experiment. A six month preliminary study indicated that a 25 per cent reduction in calorie intake has similar benefits to those seen in other animals.
The obvious way that caloric restriction may help is by altering rates of metabolism and free radical production. However, it appears that the mechanism may not be so passive. Caloric restriction causes huge changes in gene expression, increased levels of several proteins – including antioxidant enzymes and proteins involved in metabolism – and increased mitochondrial biogenesis. The net result is a reduction in free radical cellular damage.
By its very nature, free radical damage is random. But as our understanding of specific ageing mechanisms increases, we will be able to exhibit some control. One of the most exciting mechanisms to have recently emerged is the role of telomeres.
The nobel prize in physiology or medicine was shared last year between Elizabeth Blackburn, Carol Greider and Jack Szotak, the founders of telomere research. Telomeres are long repeated sequences of non-coding DNA at the ends of linear chromosomes that prevent loss of the coding DNA during replication.
During DNA replication the telomeres are shortened. Telomere lengths are reduced with each cell division, leading to the eventual loss of genetic information that causes cell dysfunction and death. If we can enhance the protective power of telomeres we may be able to extend lifespan.
The body already has an enzyme that does just that. Telomerase rebuilds telomeres to prevent the cell from dying and make them ‘immortal’. However, it is only expressed highly in stem cells and cells that divide frequently, such as in the immune system; expression in most somatic cells is low. It is also expressed highly in cancer cells. This suggests that telomere shortening is a protective mechanism against cancer, stopping damaged DNA from replicating, but the side effect is that cells die and we age.
Telomeres are prone to damage from free radicals, resulting in double strand breaks or simply removal of large sections. The reactive oxygen species cause rapid telomere shortening and therefore premature ageing. Repairing telomeres and preventing free radical damage could allow cells to divide indefinitely, ultimately increasing our longevity.
Increasing telomerase activity has indeed been achieved at the cellular level. This has been shown to induce a 50 per cent increase in the lifespan of cancer-resistant mice. This not only provides hope for anti-ageing therapy, but could be important in new treatments for cancer. High levels of telomerase in tumour cells allow them to divide indefinitely. If telomerase activity could be reduced in these cells specifically, tumour growth could be slowed or stopped altogether.
Telomere length is just one of the many contributing factors to ageing. Damage to mitochondrial DNA has also been implicated. Mitochondria contain their own DNA, which codes for several of the core respiratory chain enzyme subunits. Since mitochondrial DNA is in close proximity to the major sites of free radical production, it mutates up to ten times faster than nuclear DNA. The mitochondrial mutator mouse is unable to replicate mitochondrial DNA correctly and mutations accumulate with each replication. These mice show the signs of premature ageing.
There are still many unknowns, but what is clear is that the ageing process is a highly complex interconnected network of mechanisms that probably all contribute to cell death and the functional decline of an organism.
Extended life expectancy does not come without major consequences for society as well as some difficult questions that need answers. The impact on society has as many unknowns and complexities as the scientific research. Some are straightforward: Will the average lifespan continue to rise as it has done for the past century? Is there an upper limit to the current trend? Answering these will depend on finding cures to the big killers – cancers, neurodegenerative disorders, heart disease – and the challenges are immense.
Perhaps a more potent question is not how long we will live, but how high our quality of life will be. Currently, ‘dying of old age’ is preceded by approximately ten years of ill health. What’s more, 30 per cent of deaths in the UK are preceded by dementia, and that number has been predicted by Cambridge researchers to increase to 50 per cent by 2050.
Our increased life expectancy has largely been brought about by medical advances that have removed many acute causes of death. Morbidity and prolonged ill health have become more common with this increased life extension, threatening to create a disparity between long life and good life. In medical terms, this transition from short, young life to long, degenerative death is referred to as the epidemiological transition.
This is, to a certain extent, why groups like the Methuselah Foundation, which aims to extend healthy human lifespan, have such a strong appeal. However, the science tells us that this kind of research is still in its infancy. From the study of telomeres we have a better idea of what ageing actually entails on a fundamental level, yet there’s little to say how this can be applied to developing treatments. Those treatments that have been suggested remain speculative and have yet to be demonstrated in practice. Despite this, just as we have to consider what an ageing population means for society today, the question begs to be asked: what if populations ceased to age?
The most obvious effect of a significantly longer lifespan is the population increase and the subsequent strain on our natural resources. Ethical issues also emerge. Advances in ageing technology could cause further disparity between the developed and developing worlds, divided between those for whom mortality is a fact of life and those for whom death is a rare event. Would our perception of death change? It was Robert Winston who said that humanity’s last taboo is in fact death rather than sex. Would a society in which death is even less common see death as a greater tragedy?
What kind of family relationships could we expect to see were it feasible for siblings to be born generations apart? And if the age range of female fertility is not extended to the same extent as lifespan, what effect would this have on people’s choice between career and family? With a longer lifespan it would seem reasonable and feasible for some to seek professional success after having raised a family.
Concerns about life extension and its effects on the workplace were raised in a 2003 paper from the US President’s Council of Bioethics, whose chair at the time, Leon Kass wrote: “The succession of generations would be obstructed by a glut of the able. The old would think less of preparing their replacements, and the young would see before them only layers of their elders blocking the path.”
There is also the question of how elderly people would be treated. In a work environment where older and younger people have the same physical and mental capabilities, would ageism disappear? And when people were to retire, would they suddenly be subject to ageism? A 2008 review in the journal Age and Ageing indicated that more than six per cent of the older general population reported receiving significant abuse. Given our current poor record of benevolence towards those over 70, could we be trusted with vulnerable members of society whose age can be measured in centuries rather than decades?
As science evolves, the question is clearly becoming less about tackling the causes of death and more about preventing the causes of ageing. As much as we would prefer things to be otherwise, there is still a long way to go and the likely outcome is that the steady increase in average lifespan may reach a plateau, at least in the short term. Biogerontologists like Kirkwood are optimistic, but the foreseeable future presents undeniable challenges.
“I’m very positive about the scope for understanding the mechanisms,” says Kirkwood, “and I think the ageing program is malleable, but this is really hard science.”
“To take an analogy, if one were to apply the same simplistic thinking to cancer – we know absolutely what happens in cancer, cells divide when they shouldn’t. With that kind of logic it’s really very simple to say how we should cure cancer, but we just need to find ways to activate these mechanisms. That’s what 50 years of cancer research has been about. We’ve made progress, but we haven’t cracked it.”
“My knowledge of the science of ageing urges caution. Ageing is going to be here with us in basically its present form for some years to come.”
The consequences of any major advances in life extension and their effect on society may seem profound. However, it is clear that most scientists do not expect these kinds of advances any time soon. All things considered, perhaps this isn’t a bad thing.
Anders Aufderhorst is a PhD student in the Department of Physics
James Birrell is a PhD student at the MRC Mitochondrial Biology Unit
Taylor Burns is a Natural Sciences Tripos Part IIA student in Experimental Psychology
Alex Jenkin is a Natural Sciences Tripos Part II student in Plant Sciences The quest to prevent ageing is beginning to move slowly from science fiction to science fact. Perhaps the most profound consequence of this revolution in longevity is the notion, now widely agreed upon within the biological gerontology community, that ageing is unnatural, unnecessary and certainly not inevitable.