by Nick Lane
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— barely 1 per cent — emphasizes the stark conclusion that tiny benefits in youth can outweigh dreadful afflictions later in life, but only if the net result is to leave behind more children.
For many years, the theory of antagonistic pleiotropy dominated the field of ageing, and it is still one of the most prominent theories. There is certainly some truth in it. The theory is not at odds with the disposable soma theory — both are trade-offs, in which an individual’s genetic resources are concentrated on reproductive prowess in youth at the expense of health later in life. However, the similarities between the two theories have often led one to be seen as a special case of the other. This is far from the truth.
The disposable soma theory argues that there is a trade-off between reproductive success and bodily maintenance. To live for longer, we must invest more in maintenance and less in fertility. This is essentially a life choice, a resetting of our resource allocation, over which the individual can, in principle, have an influence. In contrast, the theory of antagonistic pleiotropy argues that the trade-off is between the effects of early and late-acting genes, which, on balance, favour early vigour against later decline. The trade-off probably involves hundreds, possibly even thousands of genes. This is a critical difference. If senescence is the rubbish bin of hundreds or thousands of deleterious late effects, then there is very little we can do about it. To change our maximum lifespan would require altering our entire genetic make-up, at an unknown cost to our health in youth. For this reason, the theory of antagonistic pleiotropy has had a baleful effect on biology. Essentially, it argues that everything that can go wrong will go wrong. Bad genes cause disease, so we will inevitably become mired in disease in old age.
Is this really true? Is it not possible to die of old age, free from disease?
Most people would think so, even if it only happens rarely. The ‘oldest old’, the centenarians, often die of muscle wastage rather than any particular disease. The implication is that there is indeed a distinction between ageing and age-related disease caused by late-acting genes. Perhaps the disposable soma theory can account for ageing in general, whereas the theory of antagonistic pleiotropy explains our susceptibility to age-related disease with a genetic basis? Perhaps. We will return to this possibility in Chapter 14.
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The idea that ageing is more tractable than implied by the theory of antagonistic pleiotropy is supported by the flexibility of longevity in the wild. If a change in longevity requires the coordinated mutation of hundreds or even thousands of genes with late-acting effects, then any change should take place over prolonged periods. We have seen that opossums can double their lifespan in less than 5000 years — a blink of an eye in evolutionary time. Humans have doubled the lifespan of higher primates in a few million years, while the primates themselves quickly evolved long lifespans by the standards of other mammals. In the laboratory, we can double the lifespan of Drosophila in ten generations. The rapidity of such changes suggests that lifespan can be modulated by selecting only a handful of genes.
This hope has been confirmed by recent research. A number of genes, so-called gerontogenes, have now been discovered, whose effects can double or even triple the lifespan of simple animals like nematode worms. At first sight, these genes have bemusingly diverse effects, but as we have learned more we have come to see that they are linked by a common factor — oxygen.
The first life-extending mutation was reported in 1988 by David Friedman and Tom Johnson, then at the University of California, Irvine. The mutated gene, known as age-1, doubled the maximum lifespan of the tiny (1 mm) nematode worm Caenorhabditis elegans, from 22 to 46 days. The mutant nematodes seemed normal in every other respect, except that their fertility was reduced by 75 per cent. In 1993, a mutation in a related nematode gene called daf-2, was discovered by Cynthia Kenyon and her team at the University of California, San Francisco, which nearly tripled the maximum lifespan of C. elegans, to 60 days — the equivalent of humans living for nearly 300 years. It transpired that both genes had the power to arrest the development of C. elegans, diverting it into a long-lived, stress-resistant form known as a ‘dauer’ larva (from the German dauern, meaning enduring).
In all, more than 30 genes are known to influence dauer formation.1
1 Other genes influence longevity in C. elegans, such as the clock genes, but do not affect dauer formation. They tend to have relatively small effects, in the order of 30 to 60 per cent extensions of lifespan. The clock gene products are thought to lower the metabolic rate, suppressing mitochondrial function, and may contribute to the effects of restriction of the intake of calories in nematodes.
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Dauer larvae normally form in response to extreme environmental conditions: in particular, food shortage and overcrowding. The larvae wait out the hard times in a state of dormancy. They store nutrients, freeing them from the need to eat, and develop a thick cuticle, which helps to protect them against environmental insults. When conditions improve, the worms emerge from the dauer state and resume life where they left off. The time spent as a dauer larva has no effect on their subsequent lifespan as an adult. If a worm had ten days left to live before its dauer interlude, it will survive for ten days afterwards. In this sense, dauer larvae are non-ageing, though in fact they rarely revive after about 70 days of slumber. The larvae have two characteristics that might account for their longevity: low metabolism and increased stress-resistance. In particular, dauer larvae are resistant to oxidative stress induced by hydrogen peroxide or high oxygen levels.
Mutations in the genes that control the formation of dauer larvae sometimes cause the larvae to form inappropriately, despite perfect environmental conditions. In other cases, the worms are unable to enter the dauer state, even in extreme conditions. But the most exciting and significant finding is that the effect on longevity can be dissociated from dauer formation. Given appropriate conditions, mutations in age-1 and daf-2 can double the lifespan of normal adult worms, without any requirement to enter the dauer state. Curiously, one of the conditions required is the correct function of a third gene, called daf-16. If daf-16 is mutated so that it does not work properly, lifespan cannot be increased by mutations in age-1 and daf-2. The implication is that age-1 and daf-2 normally reduce longevity by inhibiting daf-16.
Regardless of the exact mechanism, one point is clear: all these genes interact in a regulated manner, designed to be modulated according to circumstances. As Cynthia Kenyon put it in Nature, “longevity of the dauer results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf- 2 and daf-16 provide entry points into understanding how lifespan can be extended.”
What do these genes actually do? The answer to this question begins to make sense of many of the results discussed in this chapter and the last. In the late 1990s, Heidi Tissenbaum, Gary Ruvkun and their team at Harvard cloned the genes for age-1, daf-2 and daf-16 successively, in an impressive blaze of productivity. The genes code for proteins that control the response of cells to hormones. Each of the genes encodes a link in a
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chain of signals. The sequence is as follows. A hormone binds to its receptor on the cell membrane, which is coded by daf-2. This receptor activates an adjoining enzyme, coded by age-1. When activated by the receptor, the enzyme amplifies the message by catalysing the production of a large number of ‘second’ messengers, as if it were setting free a host of molecular gossips. The second messengers migrate to the nucleus, where their whispering can either activate or deactivate transcription factors (proteins that bind to DNA, controlling the activity of genes). One of the most important of these transcription factors is coded by daf-16. By binding to DNA, the daf-16 transcription factor coordinates the cell’s response to the hormonal message, selecting a particular set of genes for
transcription.
Such a relay is known as signal transduction. The details of these relays are learnt, somewhat resentfully, by all students of biochemistry and cell biology. Signal transduction pathways are the standard cellular communication system, allowing amplification of the original message and elimination of ‘noise’. Describing one of these relays is a little like explaining how a telegraph network operates. The really interesting question, in both cases, is not how the message is transmitted, but rather what the content is.
The answer lies hidden in the detailed sequences of the genes themselves. Even though these genes are from the lowly nematode worm, they share sequence similarities with the equivalent genes in other species. As we saw in Chapter 8, sequence similarities normally imply not only inheritance from a common ancestor, but also a conservation of purpose. In the case of the age and daf genes, the gene sequences betray a deep evolutionary kinship that links nematode worms to flies, mice and men. All these species have genes with strikingly similar sequences to those in the nematode worm. In each case, the genes code for the components of a signalling pathway. The signal comes from a small group of hormones — the insulin family.
Insulin belongs to a group of related hormones, all of which have profound effects on cellular metabolism. The exact function of each hormone varies from species to species, but in broad terms insulin and its cousins control the triangle of nutrition, reproduction and longevity.
Insulin induces a shift in metabolism towards growth. When insulin is
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present, glucose is taken up rapidly by all cells in the body and stored as the carbohydrate glycogen. Protein and fat synthesis is stimulated, leading to a gain in weight. Breakdown of glycogen and proteins for energy is inhibited. As glucose is used up, blood glucose levels fall. The actions of insulin are countered by the hormone glucagon, which restores blood glucose levels to normal. In a developmental sense, insulin is a signal of plenty. Glucose means that food is abundant. Insulin passes on the message: now is a good moment to grow, complete development, reproduce!
Seize the day!
If this message is repeated insistently enough, because glucose is plentiful in the diet, for example, the clarion call is taken up by other hormones of the insulin family, which act over longer periods. High blood glucose stimulates the production of growth hormone, which in turn elicits the production of insulin-like growth factors (IGFs). These are structurally and functionally similar to insulin, but with even more potent effects.
The IGFs stimulate the synthesis of new proteins, promoting cell growth, multiplication and differentiation. Critically, the IGFs also modulate the actions of sex hormones, influencing puberty, menstrual cycles, ovulation, implantation and foetal growth. Mutation of the gene for IGF-I leads to retarded development of the primary sex organs.
Here, if anywhere, is the switch between reproduction and longevity, which underpins the disposable soma theory of ageing. In the presence of plentiful food, insulin and the IGFs are produced. The organism gears up for sexual maturation and reproduction, throwing longevity to the wind.
There is a moment of choice, controlled by a genetic switch: sex or long life. In nematodes, this switch looks very much like the transcription factor encoded by daf-16.
If the switch is indeed the daf-16 protein, then long life works like this. Persistently low blood glucose keeps insulin and IGF levels low. The receptors in the cell membrane that would normally pass on the message stand idle. The gossiping second messengers fall silent. These messengers would normally block the action of daf-16, but in their absence daf-16
springs to life and coordinates the transcription of a number of specific genes. The products of these genes confer longevity on nematode worms, enabling them to wait out the lean times. Daf-16 is also activated when the daf-2 gene — coding for the insulin receptor in the membrane — is mutated. In this case, the insulin signals are not passed on. Daf-16 again springs to life and the organism behaves as if there was no insulin: it becomes resistant to the presence of insulin.
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Mutation of daf-2 thus confers insulin-resistance on worms. Interestingly, the same effect can be achieved by sensory deprivation.2 If a nematode thinks there is no food available, it produces less insulin and survives for longer, even if food is in reality abundant — and even if the nematode actually eats it. In the worm, then, longevity can be decoupled from metabolism through the power of thought (or at least the power of delu-sion).
These effects of insulin and IGFs on longevity are consistent in both Drosophila and mice, so it seems that similar signals control ageing in worms, insects and mammals. In 2001, David Clancy, David Gems, Linda Partridge and their team at University College, London, described in the journal Nature a mutant strain of Drosophila which had the same defects in the insulin signalling system as the daf-2 mutant nematodes. The result was a 50 per cent increase in maximum lifespan and, again, enhanced resistance to stress. Curiously, the long-lived mutant flies were dwarfs.
Gems drew comparison with dwarf mice, which are also long-lived and stress resistant, and almost certainly deficient in IGF-I. There is some evidence that stature influences longevity in people too. Population studies show that small, wiry men — the human equivalent of dwarf mice — live on average five to ten years longer than taller, heavier men. The Napoleon complex, it seems, goes beyond abrasiveness into hardiness and longevity. All the more reason not to pick a fight.
Insulin-resistance confers longevity! This is an irony that typifies the swings and roundabouts of science. In people, resistance to insulin and the IGFs is not at all beneficial. The outcome is type 2 diabetes and metabolic disarray. In the Western world, this form of diabetes is approaching epidemic status, and is probably the biggest health problem associated with the Western lifestyle. Far from living longer, people with type 2
diabetes are at high risk of heart attacks, stroke, blindness, renal failure, gangrene and limb amputation. Average lifespan is at least ten years shorter than the general population.
Such a disappointing reversal has led many researchers to dismiss the relevance of nematode research to human ageing. I think they are wrong.
2 C. elegans senses its surroundings through cilia located in sensory organs in the head and tail. Work from Cynthia Kenyon’s lab shows that mutants with defective cilia have impaired sensory perception — and live longer.
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A question mark must inevitably hang over the relevance of animal data to human conditions. Of course people are more complicated than nematodes: we should expect layers of complexity to be superimposed over the relative simplicity of tiny worms. Yet there are good grounds for thinking that similar processes are at work, even though the effects are very different.
To see the parallels between worms and men, we must step back from the small print and look at the terms of the contract in a general sense.
Insulin-resistance is clearly important in humans and affects both lifespan and fertility. Susceptibility to type 2 diabetes has a genetic basis. The sheer number of people who are susceptible to the disease implies that the susceptibility genes were positively selected for in our recent evolutionary past. This idea is sustained by the startlingly high incidence of diabetes among certain races, notably the Micronesian islanders of Nauru in the Pacific and the native American Pima. The case of Nauru is vivid and well known. A remote Pacific atoll, with a population of about 5000 Micronesians, its rich phosphate reserves attracted American mining companies during the 1940s. As the islanders grew wealthy, their diet and lifestyle was Coca Colonized: nearly all their food was imported and they now live on a typically high-energy, Westernized diet. The frequency of obesity and type 2 diabetes, which had been virtually nonexistent, started to reach epidemic proportions in the 1950s. By the late 1980s, half the adult population had diabetes. The problem was not simply one of overeating: the inc
idence of diabetes is far higher among Micronesians, Polynesians, native Americans and Australian aboriginals than it is among Caucasians, given a similar diet and lifestyle. The Indians are said to have a ‘thrifty’
genotype. They are genetically geared to hoard energy during times of plenty, and they use these big energy reserves to help them survive extended bouts of starvation or hardship (this is true for all of us to some extent, but is far less marked in agricultural societies, where food has been relatively plentiful for thousands of years). In the case of the Micronesians and Polynesians, the thrifty genotype might have helped them survive their long ocean voyages. Unfortunately, the thrifty genetic make-up is utterly counterproductive when the times of plenty are sustained continuously.
Resistance to insulin is one of the central features of the thrifty genotype. Insulin normally stimulates the uptake of glucose from the blood-stream, and its conversion into glycogen, proteins and fats in readiness for mighty reproductive endeavours. In times of hardship, however, the
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body strives to maintain blood glucose at normal levels, lest the brain —
which relies on glucose for all its energy — shut down and we lose consciousness. If hardship is the norm, with only occasional punctuations of plenty, then insulin-resistance helps to maintain blood glucose at normal levels by blocking its uptake in organs that can subsist on other fuels. As glucose availability inside individual cells falls, the metabolic rate is suppressed, preventing unnecessary energy expenditure. Insulin-resistance is not total. There are some aspects of insulin function that are unaffected or even strengthened. In particular, fats are still stored away. The process is not pathological: it is a carefully orchestrated response to likely circumstances. Taken together, the changes prepare the body for times of scarcity and are similar to those that take place in nematodes before they enter the dauer larva stage of their life cycle.