8
AGEING IS A DISEASE
Ageing and disease are inextricably linked. Partial causes of disease accumulate as we get older, until, as it were, our ‘bingo card’ is full, and illness strikes. Ageing is not ‘normal’, because it results from damage that occurs where there was originally none. If ageing were normal, it would not be necessary to investigate ways to prevent it. A common form of ageing-related damage to the brain is dementia, which covers much more than just Alzheimer’s disease. All indications are that fewer people in the future will develop dementia than is the case now. But older people will continue to become frail, and that is a key insight in geriatric medicine.
On 25 July 2000, an Air France Concorde crashed. Shortly after taking off for New York, the plane developed serious problems. A few minutes later, it came down on a hotel close to Charles de Gaulle airport in Paris. All 109 people on board, as well as four staff members at the hotel, were killed.
The crashing of that supersonic aircraft led to a highly detailed criminal investigation, which eventually resulted in a final verdict in 2012. The fact that there was still debate about the cause of the crash twelve years later says a lot about the origin of this kind of accident, which involves the failure of complex systems.
During initial inspections, pieces of rubber were found on the runway. Could a tyre blowout have caused the disaster? Research into the Concorde’s flight history revealed that there had often been blowouts, but they had never caused any serious problems. Initially, that did not seem to the investigators to be a likely explanation.
Eventually, they reconstructed the following concatenation of events. It began when a Continental Airlines plane took off from the runway before the Concorde, and lost a titanium-alloy strip measuring about 50 by 3 centimetres. That metal strip caused the blowout while the Concorde was racing along the runway prior to taking off a few minutes later. What had never taken place before now happened: a piece of the blown-out tyre hit the fuel tank above it and caused it to rupture. An electric spark then ignited the fuel that came gushing out of the tank. In response to the fire warning in engine 2, the crew shut it down. The explosion had caused so much damage to the electronic and hydraulic systems that the landing gear could not be retracted, and the plane failed to gain enough speed to climb further. With just three of its engines working, the aircraft banked sharply to the left, so the crew throttled back power to engines 3 and 4, causing the Concorde to lose even more speed. Then the plane fell out of the air.
So what was the cause of the disaster, and whose fault was it? Was it caused by the titanium strip, the tyre blowout, or a design fault? On 4 July 2008, the families of the victims brought a case against two technicians from Continental, the airline that owned the plane that left the titanium strip on the runway. The charge was manslaughter. The head of Aérospatiale, the company that built the Concorde, was also charged, since he was revealed to have known of more than seventy previous incidents involving Concorde’s tyres. The prosecutors accused the aviation authority of failing to take appropriate steps to ensure the plane’s safety. Finally, an engineer who had been involved in the design of the supersonic aircraft was also in the dock. It was claimed he knew that the design was not entirely safe. In 2012, an appeals court ruled that charges of manslaughter could not be proven against the accused.
Not surprisingly, the entire fleet of Concordes was grounded immediately after the Paris disaster. After the initial investigation had established the most likely chain of events, it was decided to develop burst-resistant tyres, and to line the interior of the wheel arches with shock-absorbent material so that the fuel tanks would no longer be susceptible to rupture. A reconstruction of the relevant part of the plane was built, and the scenario was tested experimentally, with encouraging results. The chain of events that gave rise to the disaster was effectively broken, and, after the necessary adjustments were made, the aircraft was once again given a certificate of airworthiness.
WHAT CAUSES CANCER?
Pathogenesis — that is, how disease develops — has much in common with the Concorde disaster. Especially disease that occurs in old age. There is never one single cause; it always has a series of partial causes, which together are enough to explain the onset of disease.
One example: smoking is seen as the cause of lung cancer. But if that is the case, why does only one smoker in every five develop the disease? Perhaps the other four died of something else before lung cancer had a chance to arise. Some people reason that if those four smokers had lived long enough, they, too, would have developed lung cancer. Others believe that some people are simply lucky and others are not. But medical science does not deal in random chance. There is always a biological mechanism behind the appearance of disease, even if we sometimes do not know what that mechanism is. As already mentioned, there is never just one cause, but rather a combination of various partial causes.
Lung cancer occurs when cells multiply uncontrollably at the expense of the surrounding tissue, and then spread. Those malignant cells are able to avoid the stimuli from their environment that normally keep rampant cell-growth in check. Malignancy can only raise its ugly head if there are faults in various parts of the cell’s DNA that are essential for normal cell division. One single mutation in the DNA is usually not enough to cause cancer. It is the combination of specific types of damage in various genes that makes the rampant growth of malignant cells possible. This proposed mechanism of pathogenesis is called the ‘multiple-hit hypothesis’. The accumulation of ‘multiple hits’ to the cells’ DNA causes cancer to develop. In the pathogenesis of cancer, smoking alone is sufficient to damage the DNA, the genes, of a cell. Smoking is like a man with a gun trying to hit a target — the DNA — with a random hail of bullets. But that alone is not enough to explain how lung cancer occurs.
Damage to our DNA — or, more precisely, damage to the genes that contain the code for life — is just one side of the matter; the other is the ability to repair that damage. The molecules of DNA in every cell are constantly checked for errors, and, once identified, mistakes are corrected. The repair of faulty DNA molecules is therefore essential for the maintenance of our genes, which, in turn, is necessary for keeping our cells, tissues, and organs in good order.
Human evolution has selected in favour of this ability, but we are not all equally good at it. Sexual reproduction creates constant variations among our offspring. Too little DNA repair can cause problems — for example, cells lose their ability to function. But investing a lot in the maintenance of our own DNA, so that no damage at all occurs, brings no evolutionary advantage, since we are not built to last forever, and our children already carry good copies of our DNA. Furthermore, DNA repair is an intensive process that must be made at the expense of investing in other processes, such as reproduction. Thus, DNA repair illustrates the disposable soma theory translated to the molecular level. The genetically determined variation in DNA repairability can offer a good explanation of why cancers appears more often or earlier in life among members of certain families. Others may smoke like chimneys and still never develop lung cancer.
The vast majority of lung cancer patients are smokers or ex-smokers. However, there are also patients who get lung cancer although they have never smoked in their lives. There are countless other processes that can damage DNA and allow cells to grow out of control. For example, much damage is caused by free oxygen radicals, which arise when glucose is metabolised to provide cells with energy. DNA is a large, complex molecule, and damage can occur in various places and in various ways within one individual. This means that all patients have their ‘own’ tumour. Patients can develop several tumours in their lungs, and they are not necessarily all exactly the same. Thus, lung cancer is not one single disease. Each tumour is the result of a unique set of partial causes, which together are ‘sufficient’ to cause cancer. And this is no different from the way every plane crash is the result of a unique chain of partial causes.
Damaged cells must be removed from the body, to prevent cancer and other mischief. The mechanism for this is called ‘apoptosis’, or programmed cell death. It has been selected for in our evolution, and dismantles cells from the inside, causing them to implode, as it were. This prevents a cell from bursting and leaking its contents into the surrounding tissue, where it could cause an inflammatory reaction. Apoptosis is also the mechanism that gets rid of excess cells as we develop in the womb. A classic example of this is the way our fingers develop: cells are removed from between the bones of the budding digits, like a sculptor chipping away bits of stone, and our fingers are formed, so that we don’t have to go through life with webbed hands.
When a cell has accumulated a lot of damage to its DNA, an apoptosis programme is activated inside it. A ‘counting machine’ also keeps track of whether the cell has already divided many times and might be worn out. The DNA in cells that have undergone many divisions may contain an accumulation of copying errors, and those cells are removed as a precaution. Every time a cell divides, the telomeres within it get a little bit shorter. Telomeres are the ends of the DNA molecule, and are, as it were, the end of the rails along which the DNA copying machine runs, like a train. When the rails become too short, no more copying can be done, and the cell stops dividing.
Because the ability of cells to divide is crucial for tissue repair, telomeres were originally thought to be a clue to cause of ageing when they were first discovered. However, this turned out not to be the case. Mice have longer telomeres than humans, but age more quickly. Also, average telomere length says nothing, or very little, about how long we will live. It is more probable that telomeres developed as a protection against cancer. Some cells that carry out special functions are ‘arrested’ when their telomeres have become shortened. They can then continue to exist without the risk of cancer developing. Other cells meet a much more drastic fate, and are removed from the tissue of the body.
NORMAL AGEING DOES NOT EXIST
There is no single cause that can explain the signs of human ageing. Ageing arises due to a unique combination and interaction of partial causes, which renders us increasingly infirm and eventually results in death. The combination of partial causes is different for everyone, and ageing takes a different course in each of us: sometimes it progresses quickly; sometimes slowly. An older person’s kidneys might still be functioning fantastically well, but he can still be hit suddenly by a stroke.
Failing organs can be compared to old beer glasses that have accumulated tiny breakages over time. Humans, too, acquire more and more different kinds of minuscule damage as they pass through life — for example, from smoking, oxygen free radicals, an injury, or an infection. One kind of minor damage is in itself insufficient to cause an illness or infirmity. That’s why you think you are healthy. But if a doctor were to examine your body extremely carefully, she would notice all the minute damage that has accumulated over time. A whole-body scan will always reveal a certain number of defects, and that number will be higher the older the patient is.
A whole-body scan that revealed no abnormalities would be really remarkable, but the fact that such scans are increasingly being used when there is no apparent need for them is a worrying development. Usually, there is no need to do anything about the defects they reveal. It is not always better for a person to undergo more and more diagnostic testing for damage that is only minor. Indeed, the side effects, both emotional and physical, of such a scan can leave a patient worse off.
This accumulation of minor damage is what makes people frail in old age. No one develops a disease ‘just like that’ or ‘suddenly’ falls ill. The missing link, the final partial cause that triggers a biological mechanism, is what leads to the sickness or disease. It is like a game of bingo: as the game progresses, players’ cards are increasingly full of marked-off numbers, then one more number is called and BINGO! — you have a full house. In the bingo game of illness and disease, the chance of getting a full house increases the older you get, since you acquire more and more partial causes. Your body becomes frail and vulnerable.
Many researchers, doctors, and patients try desperately to make out a difference between the ageing process and the onset of illness and disease in old age. Is a worn-out knee a result of ageing, or is it an ailment or disease? In principle, there is no difference. After all, ageing arises due to an accumulation of partial causes, just like sickness and disease in old age. Looking in the mirror, we can see the wrinkles advancing and our jowls beginning to sag. The elastin that keeps our face straight is damaged, just like an old pair of underpants with no more give in the elastic. A whole-body scan can also show us the traces left by the ageing process on our bodies. The whole idea of ‘normal ageing’, entertained by many patients and doctors, is nonsensical. The very definition of ageing is that damage has accumulated where once there was none.
I think that for most people, ‘normal’ ageing means that the damage they have accumulated feels ‘typical’ for their age. An example: if, at the age of 45, you are trying to find your way on a map in the dark and you realise that you can’t read it, it’s time to get a pair of reading glasses. That’s because the translucent proteins in the lens of your eyes are damaged and have lost their elasticity. Then you need a pair of glasses to correct the problem. People consider that ‘normal’. We have rendered this acquired defect ‘normal’ because it appears at the expected age. But the phrase ‘normal ageing’ can be misleading. If someone needs reading glasses at 38 — is that abnormal? After all, it’s only seven years earlier than expected … But the speed at which people age varies; some people can still read without glasses when they are 52, because their lenses have retained their elasticity for longer. This is just as unexpected as needing reading glasses at the age of 38.
Ailments and diseases are also labels used by doctors and researchers to recognise individuals with specific characteristics, so they can provide treatment and care. By diagnosing a condition or disease, doctors can try to make someone better or prevent infirmity from occurring.
It should not surprise us that ‘new’ conditions and diseases appear all the time. There will always be a good reason for recasting an existing biological phenomenon as a new condition or disease. Sometimes, this results from a better understanding of the causal mechanism; other times, defining a condition or disease is part of a new medical strategy to delay the onset of infirmity, or prevent it from occurring.
For example, the phenomenon of weakened bones in old age has been known for a very long time. This used to be considered a symptom of the ‘normal’ ageing process, and therefore unworthy of particular attention. But our view of ‘normal bone weakening’ was completely changed when medicines were developed that could slow down the decalcification that leads bones to become brittle. Suddenly, there was a need for a precise definition of this biological phenomenon, and the medical condition of ‘osteoporosis’ was born. Now there is a veritable fashion for identifying the condition early and treating it as a disease.
Conversely, some conditions and illnesses disappear from view: doctors no longer diagnose ‘hysteria’, for example. Others cease to exist because they are given a new name: ‘dropsy’ is now known as ‘heart failure’. But the underlying biological mechanism that causes these physical and mental problems has, of course, remained unchanged.
If we are to find ways of preventing physical deterioration in old age, it is essential that researchers and doctors realise that ageing is not normal. They must investigate the biological mechanism of ageing, and develop treatments to prevent lasting damage. Doctors and researchers will continue to label the signs of the ageing process as new conditions and diseases. This means that they will declare us to be ill earlier and earlier, which is only justifiable and desirable if it ultimately leaves us better off.
THE DEMENTIA EPIDEMIC
We find it completely ‘normal’ that our thinking slows down, and we notice ourselves easily forgetting trivial things as we get older. It also takes us longer to find our bearings in an unfamiliar city, and we get lost more easily. ‘What was that person’s name again?’ we ask our partner. We do worry about such signs: ‘What’s happening to me? Am I getting dementia?’ But they do not really affect our ability to function properly in daily life, and so a doctor would not declare you sick or diagnose dementia on the basis of such complaints. The definition of dementia is that the functioning of the brain is so impaired that day-to-day life is disrupted. And that is not the same as feeling anxious or irritated.
Does that mean, then, that minor disturbances in brain function are harmless and unimportant? To some extent, it does. Almost everyone has difficulty remembering things sometimes — even young people for whom a loss of brain function is not an issue. It seems we sometimes demand more of our brains than they can handle at that particular moment. There is nothing special in this. The same is true of all skills, whether it’s working, cooking, or running. We always want to perform better.
However, memory problems in old age are indeed often associated with a ‘substrate’, a small amount of damage to the brain, which can be identified on a scan. Much scientific research is done on people with and without memory problems, in order to find out which kinds of damage appearing on such a brain scan can be related to a reduction in memory performance. To put it another way, which kind of damage contributes to memory problems, and which does not?
Damage that shows up on a scan can result from high blood pressure over a protracted period, from atherosclerosis in the carotid arteries, from the remnants of a virus infection, from a lasting inflammation of the brain tissue, from clumped proteins, or from other biological processes we are still unaware of. Knowledge of the way this damage is caused can help make it possible to intervene early in disease processes. The best thing would be to prevent the damage from occurring in the first place, but that is not likely to be possible in the near future. What we can do is slow down the pace at which damage accumulates in the brain, to defer the moment when the doctor diagnoses dementia. Not smoking, not being overweight, and taking sufficient exercise keeps your heart and blood vessels healthy for longer, and all that is good for your brain, too. Your blood pressure should also not be too high in middle age, since high blood pressure can damage the tiny blood vessels in the brain, causing a rapid increase in memory problems.
Some people are mentally still as sharp as a razor in old age, and their doctors tell them, ‘Your brain scan looks like that of a youngster.’ In such cases, the accumulation of damage appears to progress extremely slowly. The person in question goes home reassured, and is pleased not to have been labelled a patient. No more thought is given to it, since, after all, there is nothing ‘wrong’.
This is a big mistake. People whose minds remain razor sharp in old age have a lot to tell us about ageing without accumulating damage in the brain. If researchers and doctors manage to find out their secret, that knowledge will be the first step towards helping others stay sharp of mind. It is for this very reason that we at the Leiden Longevity Study analyse families whose members show no signs of illness in old age. We hope to discover what protective factors make for their above-average healthy life expectancies. This strategy is the ‘reverse’ of the usual method of research that involves monitoring (older) people over an extended period to find out what causes them to get sick. We did the latter in the Leiden 85-plus study. Researchers identify the risk factors among sick people.
The brain scans of many older people, do, incidentally, display abnormalities even when they do not have dementia. Damage is there, but not so much that it inconveniences them in their everyday lives. It makes a big difference whether the person’s IQ was high or low earlier in life — that is, whether they had a ‘good’ or ‘not-so-good’ brain. The reason is easily understood: if you are blessed with a good set of brains, you can handle more damage before your mental capacity starts to deteriorate and you begin to have problems functioning in day-to-day life. This idea is called the ‘cognitive reserve theory’. A high IQ, or a ‘good brain’, is a sign that you have a lot of reserve capacity. It also explains why a solid education early in life offers ‘protection’ against the onset of dementia.
One view is that dementia occurs as the result of a gradual increase in various kinds of damage in the brain, caused by different biological mechanisms. This contrasts with a widely held view among researchers and the public that the cause of dementia is amyloids. When the proteins in the body become crumpled — that is, misfolded or clotted due to damage — they can be deposited in the tissue of the brain, and damage the surrounding brain cells. This leads to Alzheimer’s disease. Some families have a genetic predisposition for producing many such amyloids, or for making proteins that are quicker to misfold. The effect is the same. These people’s genetic makeup means amyloid proteins are deposited more quickly in their brains than others’. Members of such families have a higher-than-average risk of developing dementia, and more members than average are affected by early-onset dementia. Unfortunately, despite a great deal of research, we are still not able to control the deposition of amyloids in the brain. This particular disease process occurs in the majority of patients who develop dementia before the age of 70. However, they make up fewer than 10 per cent of dementia patients overall.
Unlike those with early-onset dementia, the majority of patients who develop the condition in old age have a complex disorder with several biological mechanisms at play. At the end of the twentieth century, the US-based researcher Dr David Snowdon reported his findings on the post-mortem examinations of nuns who had developed dementia in old age. Some of them showed widespread amyloid deposits in their brains, others showed only limited amyloid deposition, whereas a significant proportion of them showed no evidence of amyloids at all. All of their brains, however, displayed damage — after all, that is what causes someone to develop dementia — but that damage could be related to reduced blood supply due to impairment of the tiny blood vessels in the brain. Another possible cause of damage is a stroke, which kills off a small, or even large, part of the brain.
Examination of the brains of people who did not have dementia before they died confirms what a brain scan would have shown while they were still alive. Their brains also showed signs of damage, sometimes just as extensive as those of dementia patients, but their cognitive reserves were clearly greater and so they did not develop the condition. Remarkably, many people who did not have dementia did have amyloid deposits in their brains.
From this we can conclude that amyloid deposits are not sufficient to cause dementia in old age alone, but they are rather one of several partial causes. In old age, amyloids have limited impact, because other causes, such as damage to blood vessels in the brain, play a more important part. I myself prefer to speak of ‘dementia’ with my patients, rather than ‘Alzheimer’s disease’.
The worldwide attention afforded to Alzheimer’s disease did not appear out of the blue. In the early 1900s, the German doctor Alois Alzheimer described the symptoms of a middle-aged psychiatric patient suffering from dementia. After her death, he examined her brain, and became the first researcher to describe amyloid deposits. With this, he had discovered a plausible mechanism for the cause of dementia. At the time, Alzheimer’s work did not receive much attention. Psychiatrists and anatomists disputed the importance of his new discovery, preferring to emphasise the relation between blood vessels and damage in the brain. Dementia caused by damaged blood vessels is now called ‘vascular dementia’. Later, dementia disappeared entirely into the background as a recognised illness, and people who became confused in old age were declared to be ‘senile’. Senility was thought to be a result of the ‘normal’ ageing process. In the middle of the last century, many people died of senility, and little attention was paid to their problems.
The denial of the existence of dementia is a sign of the discrimination that old people faced at the time. This view did not help in the development of preventive measures to slow or completely stop the deterioration of the brain. Led by Dr Robert Butler, American researchers in the nineteen-eighties attempted to break down this fatalistic view of dementia and its inevitability in old age. Butler was a pioneer, and this enthusiastic director of the National Institute on Aging wanted to make a statement for both young and old. ‘Alzheimer’s disease’ was finally recognised by doctors and medical-research scientists.
The positive part of the ‘war on Alzheimer’s’ is that it put the issue of dementia back on the map. That led to much research activity. One ‘side effect’ of this is that many people, even doctors and research scientists, now only tend to think of amyloids when they consider dementia. Some patients get dementia solely because amyloids have been deposited in their brain tissue. Others get dementia because the blood vessels leading to their brains have become blocked. But by far the vast majority are affected by both. Now, some researchers have begun to look into the relation between amyloids and blood flow. They have found amyloid deposits not only in brain tissue, but also in the walls of the brain’s blood vessels. That can cause them to become blocked or burst, with lasting damage to the tissue of the brain as a result.
Many researchers believe that the complex pathogenesis of dementia makes the disease more difficult to combat effectively. If so many factors come together to cause the problem, how can we ever find a solution? Many are sobered by the fact that the war on amyloids has still not been won. Opinion formers and policymakers in many developed countries have predicted horror scenarios, with the numbers of dementia patients increasing drastically in the coming years. This is partly true for the Netherlands, because the post-war baby-boom generation will have reached a very old age by that time. After all, dementia is a disease that principally affects old people. But those prognoses are based on the assumption that the statistical risk of getting dementia will remain the same. However, that is very doubtful. Dutch researchers have shown that the risk of getting dementia in old age was significantly lower after the year 2000 than before. Brain scans carried out after 2000 showed far less damage due to atherosclerosis, which would appear to be a plausible explanation for the reduced risk. The epidemic of cardiovascular disease has long been on the decline, beginning with a fall in the numbers of heart attacks in middle age, and followed by a drop in the number of strokes suffered by old people. Now, bringing up the rear, we see dementia figures falling for the oldest in society.
A remarkable confirmation of this general improvement in the condition of body and mind was provided by colleagues in Denmark. They showed irrefutably that the physical and mental functions of people now in their 90s are simply better than those of nonagenarians born ten years earlier. They believe this is due, in part at least, to the fact that today’s old people generally enjoyed a much better education early in life. Their brains were better nurtured.
A similar decrease in the risk of getting dementia has now also been recorded in Sweden. And, finally, a large-scale population survey in the United Kingdom has prompted researchers to report a 30 per cent drop in the risk of getting dementia over the past twenty years. So dementia is not an inevitable fate that awaits us at the end of our lives. An end to the epidemic is in sight.
FRAILTY
Equating ageing with ‘collecting’ partial causes of disease helps us to understand the difference between chronological and biological age. When people have accumulated a lot of lasting damage, and so have ‘collected’ many partial causes of disease, they become frail. They are biologically old, and that is usually also reflected in their appearance. ‘He looks old for his age,’ people will say. Physical appearance is also the first thing doctors look at when a new patient comes into their surgery: how old do I judge him to be? Only then do they check the patient’s date of birth to see whether their estimate was right. Sometimes patients turn out to be older than thought — this usually has something to do with the reason they are visiting the doctor — but other people sometimes look amazingly good for their age. Perhaps they have been able to avoid damage during their lifetimes, or they may be blessed with a better capacity for repair.
This initial estimation of biological age helps a doctor get a feeling for whether a patient is generally ‘alright’ or ‘not alright’. If someone is biologically young, their chance of falling sick, becoming infirm, or dying in the near future is considerably reduced, because they have collected fewer partial causes. But judging whether someone is ‘alright’ or ‘not alright’ is difficult on the basis of appearance alone.
I recently met one of my neighbours on the street. He is in his late eighties, and has been married for more than sixty years. He and his wife live down the street, in the house they used to live in with his wife’s grandmother. When the grandmother died, the couple inherited the house. They are of the pre-war generation, amiable and doughty. When you meet this couple, you might almost think such mild manners and resolve are the secret to reaching old age. When my neighbour and I saw each other, and he beckoned me over for a word, I looked at him in surprise.
‘Are you using a walking stick?’ I asked him. I had never seen him with a stick before.
‘Yes, I get such a pain in my shoulders from using the rolling walker. So I put it to one side and started using a walking stick.’ He stabbed the air triumphantly with his walking aid. ‘That’s a colourful tie you’ve got on,’ he said, pointing to my bowtie.
‘Thank you,’ I replied. ‘Anyway, you’re looking well!’ Which really was the case. We exchanged a few more words, and went our separate ways.
As I walked towards my house, I glanced back at my neighbour. I thought about the fact that he had given up cycling a few months before. He just wasn’t up to it anymore. The doctor in me concluded that he had become frail. He had been living for a time with a heart condition that was difficult to treat: a leaky heart valve. There was a possibility he could die suddenly of cardiac arrest at night.
Frailty is a key concept in geriatric care. It’s a familiar story: ‘He was in such good shape. He lived alone and was able to fend for himself, hardly ever went to the doctor, but once he went into hospital, everything went downhill and he was dead within three weeks.’ These are cases where ‘one thing leads to another’, when a broken hip or a bout of pneumonia triggers a series of events leading to eventual loss of life. Doctors and scientists define frailty in old people as the occurrence of complications — including death — following an event that would hardly cause problems for a young patient. The very word ‘frail’ comes from the same Latin root as ‘fragile’, which describes the medical condition well.
Old people are literally and figuratively frail and fragile — some more than others, but certainly more than when they were young. For example, when people over 50 go jogging, and play tennis or other sports, they render themselves susceptible to injury. If they run a little too fast or train too often, their knees, backs, or shoulders refuse to play along. What seemed to be a normal amount of stress now leads to a torn tendon or muscle, which would never have happened when they were younger. Tendons, muscles — everything has aged.
Ageing leads to a greater likelihood of a negative outcome than before. It bothers us that we do not always notice when our bodies or brains begin to deteriorate, and that we can suddenly become sick and die. So we want to know how frail we are. When we know that, we can take action or adapt to the situation, so that sickness and death no longer come as a surprise. Perhaps more importantly, that knowledge lets doctors know when they need to be on their guard, when a treatment is likely to have side effects, and when an operation makes no sense. In cases of cancer, for example, doctors and patients need to weigh up the benefits of a course of chemotherapy against the expected side effects. A good way of measuring frailty would help doctors and patients enormously when deciding whether an operation or a course of chemotherapy is worth it or not.
The big problem is that we do not yet have an adequate way to quantify a patient’s level of frailty. We can only conclude in retrospect that someone was frail, and that surgery should not have been performed. Sometimes after an intervention, we consider it a ‘miracle’ that someone is still alive, and conclude that the patient must have had more reserves than we thought. And that we should be happy about the result.
Much scientific research is currently being done to find a way to quantify old people’s level of frailty by using tests and questionnaires. Doctors hope this will help their ‘clinical eye’ and help them adapt their medical actions properly: continue with treatment when possible; be cautious when necessary. Dozens of tests, questionnaires, or combinations of the two already exist, and still doctors and researchers are trying to get it right. They have often thought they have finally come up with the right tool, but, in fact, none of those instruments are any better than the ‘rule of four’.
This rule of thumb can be relied on to predict that doctors will estimate the correct level of frailty in two out of every four older patients they see, while the other two will be wrongly assessed. As a result, doctors sometimes do more than is necessary, and sometimes they do too little. This is how the rule works:
These tests and questionnaires are sometimes remarkably simplistic. ‘Have you lost weight recently?’, ‘Do you need help washing or doing housework?’, ‘Are you forgetful?’ When these questions are answered in the affirmative, the assumption is that this is a sign of large amounts of accumulated damage and few remaining reserves. It is striking that the predictive power of a list of five such questions is not significantly lower than that of a lengthy questionnaire with fifty detailed points. But that’s not all. If a doctor knows a patient’s age and sex, he already has the most important predictors in his hands, which are almost as accurate as all the other instruments together. All of us, both doctors and laypeople, believe we are better at predicting biological age than chronological age. But all too often we are proved wrong by the ‘rule of four’, and we still lose older patients unexpectedly.
For doctors and scientists, it is intolerable that they are so bad at estimating the biological age of patients, because this ability is so urgently needed in medical practice. For this reason, a whole new scientific tradition has arisen, aimed at identifying so-called ‘biomarkers’ — substances in the blood that give a better indication of the biological condition of the body than existing questionnaires. Despite many efforts, this research has so far yielded only scant results.
Other researchers take a completely different tack. They reason that frailty only comes to light when the body is exposed to stress, when the existing equilibrium is disturbed. That is correct, because when an older person is in equilibrium, little appears to be wrong with her. This has led some researchers to expose people to a ‘quasi-intervention’, or, to put it another way, to disturb their equilibrium and observe how they react. The predictive power of such a ‘stress test’ may well be higher. For example, the predictive power of a simple walking test — where subjects are asked to cover a distance of twelve metres as quickly as they can — appears to be just as high as that of all currently available questionnaires. Since this walking test has been carried out on people all over the world, after which the subjects were monitored to see whether and when they died, we now have detailed tables showing the risk of mortality as a function of age and walking speed — separately for men and women, of course.