by Nick Lane
His achievements are celebrated by his people, and when he dies, like a hooked fish stretched on the bed, the people of the city, great and small, are not silent; they lift up the lament. All men of flesh and blood lift up the lament.
The Epic of Gilgamesh, the oldest surviving masterpiece of the Sumerian dynasty of ancient Mesopotamia, is at least 1500 years older than Homer. From the dawn of recorded history, its tale of friendship and heroism resonates with the eternal concerns of mankind: bereavement, ageing, death, the dream of immortality. These themes recur throughout
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history, and not just in a vague sense — we cling to the idea that everlasting youth is attainable through the possession of some kind of magical artefact, be it a plant, the nectar of the gods, the Holy Grail, the grated horn of a unicorn, the Elixir of Life, the philosopher’s stone, or growth hormone.
Biologists fall victim to the same yearning for an antidote to ageing.
The history of biology affords a succession of bizarre claims. In 1904, for example, the Russian immunologist and Nobel laureate Elie Metchnikoff claimed that ageing was caused by toxins released from bacteria in the intestinal tract. He regarded the large intestine as a necessary evil, a reser-voir of waste material that relieved the need for constant defecation stops while on the run from predators (or after them). He was fascinated by Bulgarian fables of centenarians, and ascribed their longevity to yoghurt, which was unknown in western Europe at the time. Metchnikoff championed the idea that we would all live to 200 if only we ate more yoghurt, full of “the most useful of microbes, which can be acclimatised in the digestive tube for the purpose of arresting putrefactions and pernicious fermentations.” He did have a point — gut bacteria do influence health, if not maximum human lifespan.1
Other theories linked ageing in men with diminishing testicular secretions. In 1889, Charles Edouard Brown-Sequard, a prominent French physiologist, announced to the Société de Biologie in Paris that he had rejuvenated his mind and body by injecting himself with a liquid extracted from the testicles of dogs and guinea-pigs. Apparently the injections not only increased his physical strength and intellectual energy, but also relieved his constipation and lengthened the arc of his urine. Later, a number of surgeons tried implanting whole or sliced testicles into the scrotums of recipients. Leo L. Stanley was resident physician in San Quentin prison in California. He began transplanting testicles (removed from recently executed prisoners) into inmates in 1918. Some of the recipients reported full recovery of their sexual potency. By 1920, the scarcity of human gonads induced Stanley to substitute ram, goat, deer and boar testes, which he said worked equally well. He went on to perform hundreds of 1 We must distinguish between average life expectancy and maximum lifespan. In the West, average life expectancy has risen dramatically over the last century: fewer people die of infectious disease, in childhood or in childbirth, and far more people live into old age.
Despite these massive demographic changes, maximum lifespan has changed little, if at all.
A few people have always survived past 100; today many more do, but we are hardly more likely now than we were in biblical times to live beyond 115–120. Short of a major breakthrough, this can be considered the maximum human lifespan.
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operations, treating patients with ailments as diverse as senility, asthma, epilepsy, tuberculosis, diabetes and gangrene.
The high demand for gonadal implants made the fortunes of at least two surgeons during the 1920s and 1930s. In France, the Russian émigré Serge Voronoff transplanted monkey glands to extend the life of his wealthy and famous clients. A respected biologist, Voronoff experimented on eunuchs in the courts of Egypt, and even tried grafting monkey ovaries into women, with dire consequences. In America, the notorious quack,
‘Doctor’ John R. Brinkley, transplanted hundreds of sliced goat testicles into his ageing customers in Milford, Kansas, where he became so popular that he was nearly voted governor in 1930. Each patient had the privilege of selecting his own goat from the doctor’s herd. The financial success of this venture enabled him to build and operate the first radio station in Kansas — KFKB, or Kansas’ First, Kansas’ Best — through which he brazenly promoted his own secret remedies, including goat gland transplants. After a series of court cases, and opposition from both the American Medical Association and the Federal Radio Commission, Brinkley fled to the Mexican borderlands, where he set up a new, even more powerful, radio station, and continued his shady medical operations, amassing an estimated $12-million fortune. He is said to have kept penguins and giant Galapagos turtles on his estates in Texas. It was not to last. Endless lawsuits and punitive taxes eventually obliged him to file for bankruptcy in 1941. His health collapsed, and after suffering a heart attack, kidney failure and the amputation of a leg, he died penniless later that year, at the age of 57, the most famous charlatan in American history.
The craving for renewed youth is not just a historical curiosity. In more recent times, vitamin C, oestrogen, melatonin, telomerase and growth hormone have all been touted as miracle cures. Each retains a faith-ful band of adherents but, whatever their merits, their failure to extend maximum lifespan is plain to most. Medicine has distanced itself from this kind of wishful thinking, but the effect has not been altogether positive. Rather, the traditional attitude of mainstream medicine, that ageing is in some sense necessary or inevitable, and thus beyond the domain of medical science, has perpetuated the mystique. Even today, ageing is rarely considered a proper field of study within the discipline of medicine
— it is still contaminated by the legacy of quacks like Brinkley. In most countries, medical school curricula devote no classes to ageing. Yet while turning a blind eye to the study of ageing, medicine has accumulated a tremendous wealth of information on the infirmities of old age. This mass
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of information is all part of gerontology, even though most specialists do not think of themselves as gerontologists: they are cardiologists, neurolo-gists, oncologists or endocrinologists. Few refer to each other’s journals, so there is little sense of overall perspective.
Examining diseases in isolation, medical researchers have historically paid little attention to evolutionary theories, and tend to consider illness from a mechanistic point of view. In the case of heart disease, for example, we know in minute detail how oxidized cholesterol builds up in coronary arteries, producing atherosclerotic plaques, how these plaques rupture, and how thrombosis causes myocardial infarction. As a corollary, we know how to deflect the impending calamity, for a period at least: how to lower blood cholesterol or dilate the coronary arteries using drugs, how to salvage heart muscle after an infarction. What we are far less certain about is how heart disease relates to other diseases of old age, such as cancer, and whether it is possible to prevent both diseases by targeting a common underlying cause. As we saw in the last two chapters, the closest we have come, in the face of all the advances of modern medicine, is to say ‘Eat your greens!’; and even then we are not quite sure why. This bleak situation is gradually changing. With so much at stake in a greying world, many more researchers are applying themselves squarely to the problem of ageing. The field of gerontology is now one of the most fertile in biology, and generates more interest than at any time since the alchemists.
At last the dismal mountains of biological and medical evidence are being remodelled into broader, testable theories.
Half a century ago, in a celebrated inaugural lecture as professor of zoology at University College London, Peter Medawar described ageing as a great unsolved problem in biology. For many people outside the field, his assertion still holds true today. This is not the case. The two main theories of ageing — which we might loosely call the programmed and the stochastic theories — are daily growing closer together. Theories of programmed ageing hold that ageing is programmed in th
e genes, and is equivalent to other developmental processes such as the growth of the embryo, puberty or the menopause. Stochastic theories hold, in contrast, that ageing is essentially an accumulation of wear and tear over a lifetime and is not programmed in the genes. As is so often the case in science, the reality lies somewhere in between, drawing on elements from each theory.
We do not know all the answers, and many details are perplexing, but in broad terms I think it is true to say that we do now understand why and how we age. As the eminent British gerontologist Tom Kirkwood has
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argued, ageing is not biologically inevitable, and does not follow a fixed genetic programme — although it is most certainly written in the genes.
We shall see in future chapters that oxygen is central not just to ageing and death, but also, through the deepest of connections, to sex and the emergence of gender. There remain a number of outstanding questions.
To what extent is ageing distinct from age-related diseases? Most important of all, how tractable is the ageing process, given the evolved architec-ture of the human body? We will explore these issues in later chapters.
First, though, we must consider a few basic principles of biology.
Ageing, or rather senescence — the loss of function over the years — is not inevitable. We saw in Chapter 8 that we are all connected to LUCA, the Last Universal Common Ancestor, through an unbroken chain of ancestors. We know this because we, in common with our most distant cousins, the archaea and the bacteria, have inherited a few of LUCA’s genes almost intact. At the most basic level, life shares a unity that would be baffling if we were not all related. In the sense that life has not remained static — that we have evolved — life itself has aged; but in no sense are we the senescent products of primordial DNA. Wines, cheeses and some human beings improve with age; nothing improves with senescence. We need only look around us to see that life is flourishing at the grand old age of 4 billion. If we accept that all life is descended from a common ancestor, then clearly senescence is avoidable.
The mechanism that has prevented the senescence of life — indeed, propelled life’s evolution — is natural selection. Darwin’s idea is most commonly expressed in the phrase coined by the English philosopher Herbert Spencer: the ‘survival of the fittest’. This phrase is often criticized by evolutionary biologists as misleading, as natural selection is concerned not with survival as such, but with reproduction. The individuals that reproduce themselves most successfully are most likely to pass on their genes to the next generation. Those that fail to reproduce perish (unless, of course, they live for ever). But if we step back for a moment, we can see that there is something to be said for Spencer’s misrepresentation. Why on earth do individuals want to reproduce themselves at all? Where does the reproductive imperative come from? The way in which even simple viruses seem compelled to replicate themselves is uncanny. It is hard not to succumb to the idea of a mysterious life force, an urge to reproduce. If
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we shun the idea of a life force, we need an explanation: why do living things want so desperately to reproduce?
The answer is that only reproduction can ensure survival. All complex matter is eventually destroyed by something. Even mountains are eroded over the aeons. The more complex the structure, the more likely it is to be broken down. Organic matter is fragile and will be shredded by ultraviolet rays or chemical attack sooner or later. Its atoms will be recycled in simpler combinations. Carbon dioxide, being a simple molecule, is more stable than DNA. On the other hand, if a piece of matter happens to have a propensity to replicate itself, for a little while its chances of persisting intact are doubled. It is still only a matter of time before the daughters are destroyed; but if one of the daughter molecules succeeds in replicating itself in the meantime, then the process can continue indefinitely.
The ability to replicate is not a magical property. As the Glasgow chemist Graham Cairns-Smith argues in his thought-provoking book Seven Clues to the Origin of Life, clay crystals replicate themselves in stream beds through a purely physical process. It is hard (unless you are Cairns-Smith) to see a life force here. Even so, the reason that life appears to have such a powerful urge to reproduce is simply because it would not exist if it did not. Only replicators can survive, so all survivors must replicate.
Given the tendency to destruction, the rate of replication is profoundly important. If we assume a steady rate of destruction, then to ensure survival, the rate of replication must surpass the rate of destruction. The importance of this relationship was addressed by the chemist Leslie Orgel, at the Salk Institute in San Diego, in 1973. Orgel theorized about the likely behaviour of populations of ‘immortal’ cells in culture, if subjected to different levels of irradiation. In this sense, immortal refers to a population of cells that has the potential to continue dividing indefinitely without becoming senescent; it does not mean that individual cells cannot die by accident or old age. Two cell types that behave in this way are bacteria and cancer cells. Both can be grown in cell culture without any appearance of senescence, but at any one time a proportion (perhaps 10 to 30 per cent) are unable to divide. They are doomed to die. Their place is taken by the progeny of cells that do continue to divide. Orgel made the point that if these ‘immortal’ cell populations are irradiated, so that the probability of any daughter cells surviving is less than 50 per cent (in other words, the rate of replication fails to surpass the rate of destruction), then the overall population will gradually decline and die out, at
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least in theory. At a lower radiation dose, the population might continue to grow, albeit at a lower rate than the unirradiated one.
We have already seen that the effects of radiation on biological molecules are mediated largely by the splitting of water (by the radiation) to produce oxygen free radicals such as hydroxyl radicals. The hydroxyl radical is not discriminating in its targets: almost all organic molecules are damaged by its attack. Such attacks take place continuously, in a more-or-less random manner. Unless the damage inflicted undermines the integrity of the cell at one fell swoop, the destruction of proteins and lipids is not necessarily a calamity. Given a suitable supply of energy, they can be replaced, new for old, following instructions in the DNA.2 The problem comes when the code itself, the DNA, is damaged. If the damage to DNA results in the production of a faulty protein, which is incapable of carrying out a critical function such as the manufacture of other proteins, then the cell will almost certainly die. The central question in biology is therefore how to maintain the integrity of DNA from generation to generation.
Let us think again about the ‘immortal’ cells in culture. Imagine that they are being irradiated at an intensity calculated to kill more than 50
per cent of them. For a while, the population dwindles, as predicted by Orgel; but then it shows signs of recovery, even though it is still being irradiated at the same intensity. After a little longer, we may have a thriv-ing population once more, which seems to be immune to radiation. This is not at all what the theory projects. What is going on?
This is natural selection at work. Several changes take place in the cells. First of all, some of the cells divide faster. These faster replicators are disproportionately represented among the survivors, because they are more likely to have replicated themselves before their DNA was destroyed.
For the population as a whole, each population doubling now takes place in a shorter period. The survivors produce a new set of genes in a shorter time than that required for radiation to dismember a single set. The progeny now have a greater than 50 per cent probability of surviving intact to the next generation.
As long as the cells have sufficient space and nutrients, this adaptation alone might suffice. However, many cells have probably made a second, closely related, adaptation. As the population growth steadies, we 2 DNA of course code
s for RNA and proteins, which in turn provide the cellular infrastructure that enables the replication of more DNA. The origins of this system are beyond the scope of this book; if you are interested I recommend the writings of Leslie Orgel himself, in Further Reading.
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see that these cells have extra copies of their own DNA. They now have multiple identical chromosomes. The effect is similar to increasing the speed of replication, but is much more profound. The reason is as follows.
If each cell has only one copy of each gene, then a single unfortunate hit to any gene has the power to knock out a critical protein and kill the entire cell. On the other hand, if the cell has multiple copies of all its genes, it can take an equivalent number of hits with a good chance that the same gene will not be destroyed on all the chromosomes. As a back-up plan, this is much less costly than producing a whole extra cell, with its proteins, mitochondria, vesicles and membranes, which then faces exactly the same problem as its parent.
We are also likely to see two other adaptations: the first is an increased rate of bacterial conjugation, in which two bacterial cells become temporarily connected and one passes additional copies of its genes to the other; the second is a stress response. Bacterial conjugation is, in principle, similar to sex. Accumulating genes that have come from different places, with different histories, reduces the likelihood of having two copies of a gene with the same error in the same place, which would be the case if you simply replicated the chromosome containing the aberrant gene. If you own a suit with torn trousers, and are given an identical suit by an equally careless friend, there’s a fair chance that the rip in your friend’s suit would be in the jacket. Wear your jacket with your friend’s trousers, and you have a fully functional suit. Such mixing and matching is the basis of both bacterial conjugation and sex in higher organisms.