Wednesday 22 August 2018

We cannot live for ever – we are programmed to die

The limitations of the duration of life

"We have a maximum lifespan set by our own evolutionary history, which ultimately depends on the complexity of synaptic connections in our brains, and the size of stem cell populations in other tissues."

Nick Lane - "The Vital Question"

(Stem cells are cells of embryonic origin. They are found in most organs and tissues of the body, and when necessary they can differentiate into mature functioning specialised cells. They can also divide to produce more of the same type of stem cells.)

Average life expectancy has increased during the past thirty years and this has led to extravagant claims as to how long the human being might live in the future. 

Japan has been viewed as having many very old people but it appears that there is fraud. Investigation has demonstrated that most of these very old people are in fact dead.Their deaths had not been officially declared, so that their relatives have been able to continue to receive their financial benefits.

The longest documented human life was that of Jean Calment whose death in France was certified in 1997 at the age of 122 years. 

Jean Calment
Italy is known to have a relatively large number of very elderly persons and research there has shown that life expectancy tends to plateau at about 105 years. Life beyond 105 is very exceptional.

We read in the Book of Genesis that many of the patriarchs lived exceptionally long lives, but we have no way of knowing whether a year then was the same as a year now.

My recent Post indicted that among UK doctors, 50% lived beyond the age of 87 years. This is remarkable. It is the median measure, which is more useful than the arithmetic mean as this is influenced by the exceptional extreme. 

It can be seen clearly in Figure 1, which displays the ages at death of a sample of 568 UK doctors dying in 2016 and 2017. Each vertical column represents one person dying, and the height of the column indicates the age at death. Obviously as we are dealing with doctors only, childhood deaths are not shown, but we know that today childhood deaths are fortunately rare in the UK. 

Figure 1. Ages at death of UK doctors, 2016–17

We can see the vertical 50% line, the middle of the range, and this is the median of age at death, 87 years. What is happening at present is that this median age at death is increasing, more people surviving beyond their 87th birthday. In a short time the median age at death might be 90 years. 

Increasing average life expectancy

Remember that someone dying now at the age of 87 years was born in 1931, a time of much greater austerity than now, an era before modern medicine and before antibiotics. The next generation would have been born in about 1961, a very different and more prosperous era. They are now about 57 years of age, and when they die in the middle of the present century, the median age at death might be 97 years. Imagine the social impact of 50% of adults living beyond their 97th birthday. But this is not far-fetched. 

So more and more people will live to see their 105th birthday, but not beyond. This is a much more likely scenario than the maximum possible age at death increasing. It is shown in Figure 2. The blue columns illustrate the ages at death today of  hypothetical individuals, and the green columns illustrate the likely ages at death in thirty years time, the deaths of the next generation. People are living longer and more will achieve the maximum age of 105 years. It will be exceptional to live beyond this and maximum length of life will not be significantly exceeded.

Figure 2. Hypothetical age at death of two generations
If overall survival of the population is increasing, it is because deaths from something have come to an end, and we have previously seen the main reason for so many people now surviving into very old age. It is the end of the epidemic (pandemic) of coronary heart disease (CHD). This killed millions of people in middle age or early old age during the second half of the 20th century. Now that the epidemic is at an end, many more people are living into very old age. We can see in Figure 3 the rapid and continuing increase in the number of those reaching their 100th birthdays.

The peak of deaths from CHD was in about 1970, and the rapid decline of these deaths is responsible for the rapid increase in very old people that we see in Figure 3. This mirrors the decline of deaths from CHD.

Figure 3. Number of centenarians in the UK
The slow-down of life expectancy

There has been recent publicity in the UK to the effect that there is a slow-down of the increase in average life expectancy that we have witnessed since 1970. 

".... from 2006 to 2011 life expectancy at birth for females in the UK rose by 12.9 weeks per year, but between 2011 and 2016 the increase dropped to 1.2 weeks per year." (Guardian 08-08-2018).  In males the corresponding figures are 17.3 weeks and 4.2 weeks. "[This] has been observed in all countries in Europe, North America, and Australia". [Data from the UK National Office of Statistics]

This is not a "bad thing", and it is nothing to do with claims that it is the result of government policy or austerity. We are not now living for a shorter time, but a longer time. The increase in life expectancy during since 1970 has been the result of the end of the epidemic of CHD, but the dramatic effect of this can last for only a few decades. We are now entering the end of that effect with an inevitable slowing down of the increase of average life expectancy. As people will continue to die before the age of 105 because of disease, it is likely that we will move into a new steady state – until the next pandemic arrives.

We must think about the major diseases that in the early 21st century cause premature death, and the most obvious are cancers. When the survival from cancers improves dramatically (or the incidence drops dramatically) we will see another increase in overall survival. As will be described below, there is at present nothing that can be done about strictly age-related causes of death.

Programmed death

Each animal species appears to have a specific limit of duration of life, that is programmed death. This is specific to a species and obviously indicates a genetic control over the duration of life. We will look at this shortly. There is however an important variation among individuals.

Another factor to consider is that death in old age does not come suddenly. There is a progressive deterioration during most of our lives, a deterioration of physical performance and also a deterioration of what is called "physiological reserve". This means that recovery from a given illness is prolonged, and in old age a minor illness can lead rapidly to the end of life.

We can appreciate the development of frailty, a reduction of exercise capacity and the visible appearance of ageing in the skin in particular. With increasing age there is a greater susceptibility to infections and of more importance a greater mortality or a longer recovery time.

A simple way of envisaging life and death is as follows. Let us accept that about 105 is the age beyond which human life will not normally  exist. It is as though at birth we have 105 units of "life force". We lose one unit each year and when they are all gone, we die, we "conk out" like a car that has run out of fuel.
Figure 4. Simple view of programmed death
This is perhaps not strictly true as at birth our body systems have not developed their full power. This would occur at about the age of 20 years, when we have maximum strength and fitness, unless of course disease occurs. In Figure 5 we can see the increase in physiological capacity to the age of about 20 years. This maximum is that of the 20 year-old fully grown individual, but it is possible that physiological capacity per kilogram of body weight is greater at a younger age.

By the age of 70 years there will be significant frailty with physiological capacity, "life force" at about only 30% of maximum.

Figure 5. Adjusted life-long pattern of "life force".

Illness modifies this profile, and there is wide individual variation, especially later in life. Figure 6 illustrates an individual who maintains greater physiological activity into later life (60 units remaining at age 70) compared to Figure 5 (30 units remaining at age 70).
Figure 6. Good vitality in old age.

Disease diminishes our natural life force, sometimes permanently, shown in Figure 7. In this case chronic illness develops early in life. There would be a maximum life force of only 80 units, with considerable disability and early death at or before the age of 60 years.
Figure 7. Life profile of life-long chronic illness.
There can be complete recovery from serious illness early in life, when there is considerable physiological reserve. This is clear from Figure 8.
Figure 8. Serious illness early in life, with full recovery.

In Figure 8 there is complete recovery from what has been a life-threatening illness (temporarily reducing "life force" to only 30 units), but ultimately there is full life expectancy.

Figure 9. Serious acute illness later in life with incomplete recovery.
An acute illness later in life (Figure 9) mightl result in a very close encounter with death, but with incomplete recovery and reduced life expectancy.

Towards the end of life a relatively minor illness can be and often is fatal, whereas in earlier life there would be recovery. This is shown in Figure10.

Figure 10. End of life acute event in the elderly.
This is seen frequently. An elderly person appears to be "perfectly healthy" and active. But then something happens – an illness such as influenza or other infection, a fall, a bone fracture followed by surgery. The family cannot understand the rapid deterioration, but they will be unaware of the presence of a considerable reduction of physiological reserve. For the doctor the dilemma arises in certifying the cause of death. Is it really a fall? Or is it "old age", which means the exhaustion of physiological reserve. In the absence of illness or injury, death will inevitably result from "old age", and that is arguably one of the main purposes of medicine and public health.

The compression and decompression of morbidity

The late 20th century saw what has been called "the compression of morbidity". 

The compression of morbidity was characterised by the life pattern changing from that shown in Figure 7 (which could represent tuberculosis or a chronic respiratory disease such as bronchiectasis) to Figure 6.  

Rather than death being preceded by several years of frailty, it came to pass that life came to an abrupt end without any frailty. This is shown in Figure 11.

Figure 11. Sudden death and the compression of morbidity.
During the 20th century sudden death in adults became common and it could occur at any age. Death in mainly men between the ages of 18 and 30 years became common during the two world wars. Sudden death related to childbirth had a similar effect (Figure 12) but fortunately became less common during the 20th century and is now very rare.

Figure 12. Sudden premature death in an individual due to war or childbirth 

Such young men and women did not have the good fortune to live long enough to experience the frailty of old age. 

The compression of morbidity that was characteristic of the second half of the 20th century was the result of the pandemic of coronary heart disease / myocardial infarction. Figure 11 illustrates in particular the sudden death in healthy middle age that was so common  particularly around 1970, the peak of the pandemic. 

We can easily see that the "compression" of morbidity was brought about by sudden death in middle age. It was hardly a success of medicine but the result of events outside medical control. It is illustrated in Figure 13.

Figure 13. The compression of morbidity due to early sudden death.
The blue graph line shows the life pattern of a typical individual who at the age of 60 years was superficially healthy with a maximum life expectancy of a further 55 years. However sudden death occurred as the result of myocardial infarction, a common occurrence during the pandemic of CHD, by far the most common cause of death in 1970 and up to the turn of the century. 

This was robbery of expected life, but although robbed of living, the individual was also deprived of, or perhaps saved from, the progressive deterioration that would give rise to the typical frailty and morbidity of old age. This is illustrated by the green graph line, and the shaded area indicates the compression of morbidity.

Today, with a major reduction of deaths from CHD resulting from the end of the pandemic, life is expected to follow the green graph line, and morbidity will be decompressed. Many more people are now experiencing the morbidity of old age.

Now, in the early 21st century we see major health, social, and political pressures resulting from the rapid increase in the number of very elderly people. The green shaded area shown in Figure 13 is now coming to life. 

We now experiencing the "decompression of morbidity" and the serious public health pressure resulting from it.

Mitochondria and programmed death

The frailty of old age is difficult to measure and there are efforts to find a simple surrogate measurement, such as grip strength, walking, or balance. Generally these attempts measure muscle strength as this most obviously reduces with age, even in the absence of disease.

Then there is "physiological reserve", the innate ability to heal quickly, to repair tissues, and to restore function. Observation leads us to understand that children recover after an acute illness or injury much faster than would their parents and grandparents.

The basis of this is energy, energy to power muscles, to enable healing, and energy to drive metabolism and brain function. Energy is derived from the controlled breakdown of glucose, and to a lesser extent of fatty acids (especially in heart muscle). I do not wish to describe the biochemistry of energy production, but it is important to understand where the process takes place.

The proposal made in 1970 by Dr Lynn Margulis is that one of the major steps in evolution (more than 2 billion years ago) was the chance incorporation by endosymbiosis of a specific bacterium into the cell of different bacteria or archaea. This previously free-living  bacterium multiplied within the new host cell and ultimately became intracellular mitochondria. This might have happened only once in evolution, but it gave the cell a huge boost in energy production, allowing an enormous evolutionary advantage. The potential for reproduction was enhanced and also that for metabolic development.

The mitochondria are the site of biochemical energy production, the breakdown of glucose in the Kreb's cycle. Carbon dioxide and water are the metabolic results and energy is released. It is captured as adenosine triphosphate (ATP)  and used for metabolic purposes.

Each cell contains 20,000–40,000 mitochondria, and each time the cell divides the mitochondria must replicate. This is where the process of ageing is thought to lie, and with it programmed death. 

Mitochondria have a very small genome, as during evolution most of the controlling mitochondrial DNA (1500 genes) migrated to the cell nucleus. When the cell is dividing the mitochondria are instructed to replicate. But replication is not always complete, and very gradually the number of mitochondria in each cells diminishes. 

In addition, during cell division mitochondrial mutations can occur, more with increasing age. Mutations will result in reduced mitochondrial function. Serous mutations result in a non-functioning cell, which in many (but not all) tissues will be replaced from stem cells.

In all cells mitochondria need constant replacement, and this is achieved by mitochondrial replication within the cell even when it is not dividing. Once again with ageing this process deteriorates, with reduction of mitochondrial numbers and function. In tissues without stem cells. the deteriorating cells cannot be replaced. 

As a result of these mitochondrial changes, energy levels reduce, and this is the mechanism behind the gradual reduction of what above I have called "life force". The full "life force" during early life is a full complement of fully functioning mitochondria, inherited from the cytoplasm of the ovum, and derived entirely from the mother.

The rate of decline of mitochondrial function will therefore occur in different organs at different rates, leading to variation in age-related organ failure. It is particularly important in cells with a high energy requirement, those with the highest metabolic activity. 

Skeletal muscle, heart muscle, brain and retina (including optic nerve) have the highest metabolic activity, the retina the highest of all. It is in these cells that the reduction in mitochondrial performance will have the most serious consequences in the form of age-related disabilities. Recovery by cell replacement is not possible because of the absence of stem cells in these tissues.

Some organs such as the liver in particular, have many stem cells to replace failing cells. The power of recovery of the liver after serious damage is remarkable, and age-related liver failure does not occur. Other organs do not have this advantage.

The brain is most obvious: each neuron ("brain cell") develops about 10,000 connections. If the neuron dies (by apoptosis, the removal of metabolically failing cells), these connections are lost for ever, together with life experiences and personality that are written into them.

And so in the absence of disease (including Alzheimer's disease) we ultimately experience age-related muscle weakness, heart failure, brain failure including memory loss, and macular degeneration with visual failure and blindness.

The point will ultimately be reached when mitochondrial replication and function will fall to a level that will be incompatible with life. Programmed death will then be reached.

We will not live for ever. We are programmed to die.

For further reading on the subject of the role of mitochondria in programmed death I would suggest:

Nick Lane - "The Vital Question"

This book is outstandingly good, but inevitably technical and far from an easy read. I have referred to it in a previous Post:

The origins of life - rock and water

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