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redundant machines for passing genes from one generation to the next.2
The body protects the sex cells from injury, starvation and mutation, or from being eaten or infected, and advertises the quality of its genes by parading the protein products in public: a survival machine and display counter. How much the genes invest in bodily maintenance depends on their own likelihood of transmission — and this in turn depends on two main factors: fecundity (the number of offspring produced per unit time) and the time available.
The balance between sex and survival, between passing genes on to the next generation and surviving long enough to do so, underlies the evolution of an optimal lifespan. Reproduction must fit into the time window available before death becomes a statistical likelihood. It may pay to reproduce slowly and raise our children if we have 70 years at our disposal, but if we are guaranteed fodder for a sabre-toothed tiger within ten years of birth, we will not survive as a species unless we compress our reproductive cycle into the ten years available. For opossums, death by predation is likely within three years, and so this is how long they live. If the threat of predation is lifted, opossums can evolve to live longer. They commit more resources to survival — to keeping the body going for longer — and divert resources away from sex. Litter sizes and fecundity fall. Even so, the new-age opossums continue to produce litters for longer
— their fecundity falls on a unit-time basis, not over a lifetime (they commit fewer resources at any one moment but have more moments).
In all animals studied, senescence is postponed by shifting resources away from sex, towards the prevention and repair of damage at a molecular level. This shift may take place over generations (in which case the changes are inherited as fixed differences in lifespan) or within a single lifetime (in which case the expression of existing genes is altered). Either way, the genes that prolong lifespan are similar: their effect is always to restrict molecular damage. The extent to which they do so depends on their mobilization and efficiency rather than their nature, just as a standing army and a conscript army differ in training and discipline rather than in methods.
The allocation of resources within a lifetime is controlled by a hormonal switch — insulin and the insulin-like growth factors — which 2 This is a restatement of Richard Dawkins’ ‘selfish gene’ theory. Most biologists do not see the concept as a radical idea but as a helpful way of viewing natural selection. Of course our bodies are more than gene machines, as Dawkins is the first to admit; but many harsh facts of life, such as illness, ageing and death, can best be understood rationally in these terms.
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responds to the availability of food and the possibility of sex. The choice is simple: sex now, or defer and survive in the meantime. Calorie restriction simulates the physiological response to famine — survive now, sex later — and extends maximum lifespan in species as diverse as nematode worms and rats. Calorie restriction works at the genetic level, by changing the expression of genes responsible for maintaining the integrity of the body. The overall effect of these genetic changes is to reduce metabolic stress (the threat to the health of the cell caused by leakage of free radicals from mitochondria) for the duration of the famine.
Long-lived species can restrict metabolic stress throughout their lives, not just in periods of environmental hardship. The importance of metabolic stress to lifespan is borne out by comparisons between species. In many cases, lifespan varies simply with metabolic rate — the slower the metabolic rate, the longer the life. This idea is often criticized for being riddled with exceptions, but in fact the exceptions prove the rule. The metabolic rate is a proxy for free-radical production by mitochondria.
The more free radicals that escape to react with cellular components, the sooner we will die. Lifespan therefore varies according to the rate of free-radical production and the degree of protection against their effects.3
Birds have high metabolic rates, but live a long time because they leak relatively few free radicals from their mitochondria (good primary prevention) and have good repair systems. We also live a long time, despite leaking more free radicals than birds, because we have invested more in antioxidant defences (good secondary prevention) and, like birds, have good repair systems. Rats live a short time because they have a high metabolic rate, leaky mitochondria, poor antioxidant defences, and rudimentary repair systems.
Secondary defences are less effective than primary defences because the defences themselves can be damaged by free radicals. In the same way, in society, it is better to prevent an outbreak of violence before it happens than have to forcibly restrain a riot already in full swing. Even so, our secondary defences should be sufficient to help us live out our maximal lifespan of about 120 years. The fact that most of us do not, and 3 Think of this in terms of radiation poisoning. The greater the intensity of radiation, the more likely we are to die. If we are shielded from the full intensity of radiation by a screen, then we are less likely to die, even though the radiation intensity is not altered. Our chances of death vary with the intensity of ‘external’ radiation (which equates to the metabolic rate) and the thickness of the screen (which equates to antioxidant protection); or more simply, with the intensity of penetrating radiation.
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die of age-related diseases rather than old age, betrays a fundamental tension at the heart of life itself, a tension between the two cardinal properties of living things — reproduction and metabolism. If we want to rid ourselves of ageing and diseases, we must come to terms with this most ancient of tensions.
Imagine you are LUCA, floating in shallow seas under the boiling Sun.
You need energy and you need to reproduce. If you don’t reproduce, you will be torn to pieces one day — no physical matter can survive indefinitely without replication. But if you do replicate, if you succeed in cloning yourself, then you will survive in one sense or another. To clone yourself you need energy and you need a template. The best source of energy is the Sun. Even in the beginning, in the shallow seas, sunlight is splitting water and you are catching oxygen. In just a few hundred million years, your descendants will mimic this trick in photosynthesis, and release masses of oxygen into the air. Other descendants will become living machines that suck up this oxygen to fuel a spectacular leap in the potential of life: size, movement, strength, predation, consciousness, and mind.
The important point is this. From the very beginning, LUCA was using sunlight as an energy source. This had a downside: solar radiation produces a flux of free radicals, and the more energy, the more free radicals. Free radicals can destroy the all-important DNA template. Somehow, LUCA had to venture as close as she could to the sunlight for energy, without getting so close that her DNA template was jeopardized by free-radical attack. The health of the first cells must have depended on getting this balance just right. This, in turn, must have meant detecting free radicals and responding somehow if too many (or too few) were present. How could this have been done? Detection and response might have been coordinated by means of proteins that change their function when oxidized by free radicals. Certainly, representatives of all three domains of life have proteins that respond to oxidation. In Chapter 10 we met haemoglobin, SoxRS, OxyR, NFB, Nrf-2, AP-1 and P53, and more are being recognized all the time. Today, when these proteins become oxidized, the cell responds by correcting the free-radical balance, either by swimming away from the source of danger, or by stepping up the antioxidant defences and repair mechanisms.
Free radicals are therefore dynamic indicators of the energy levels
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and general ‘health’ of the cell. They should have been among the earliest and most important indicators of cellular health, as they are a unique chemical bridge between the most basic traits of life — metabolism and reproduction. The ‘right’ number of free radicals i
ndicates the ‘right’ balance between energy and replication (Figure 13). This is a critical point.
Evolution works by building on existing systems in the same way that the Spanish conquistadors built baroque cathedrals on the solid Inca walls of Cuzco. In biology, older foundations are rarely obliterated completely.
If it is true that the earliest ‘health-sensor’ of living cells operated by detecting free radicals, we would expect this system to underpin more recent innovations, such as the immune system. I think that it does. I have often wondered why oxidative stress should be a common denominator of stressful physiological states, from radiation and heavy-metal poisoning to infection and ageing, but from this perspective the parallels O2
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Figure 13: The primordial connection between metabolism and reproduction. LUCA (the Last Universal Common Ancestor) could generate energy using, indirectly, the energy of ultraviolet radiation, which splits water to produce oxygen (via free-radical intermediates). LUCA could trap the oxygen with haemoglobin and generate energy from its reduction using cytochrome oxidase. The greater the intensity of ultraviolet radiation, the greater the production of oxygen, hence the more energy available for successful reproduction. However, free-radical intermediates damage DNA and lower the chances of successful reproduction. The viability of primordial cells therefore depended on sensing the number of free radicals produced, and responding accordingly (optimal trade-off). This original ‘health-sensor’ system still underpins more sophisticated defences, such as our own immune system.
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begin to make sense. While our responses to different kinds of threat have become more sophisticated and autonomous as they evolved, all depend on oxidative stress in the same way that the emergency services depend on a 999 operator to verify that it is an emergency, and route the caller to the appropriate service. To see how this works in the body, think of the immune system, a bafflingly complex system, capable of recognizing and destroying a billion different antigens, most of which represent hypothetical microbes that our immune system will never meet. Yet simple drugs can suppress this entire network, making operations like organ transplantation feasible. They do so by interfering with the free-radical
‘health-sensors’ — the 999 operators — that still underpin the immune system. Blocking the activity of one sensor, NFB, with glucocorticoids or cyclosporin hinders the rejection of transplanted organs — a profound stress for the body — for months or years.4
These ideas underlie what I called the ‘double-agent’ theory of ageing in the last chapter. Far from being simply a pathological state, oxidative stress is a vital signalling mechanism that underpins the cell’s genetic response to all kinds of injury. In particular, oxidative stress marshals our resistance to infection. This takes the form of an aggressive inflammatory attack (which eliminates the invader) combined with a stress response (which bolsters our own cells against the attack). The importance of this mechanism to our chances of sexual success — we have a good chance of recovery when young — outweighs the downside, which is postponed until old age and so has little impact on our reproductive success. In old age, oxidative stress rises as our mitochondria leak free radicals into the cell. The body perceives this as a threat and responds accordingly. Unlike infections, however, the new threat cannot be eliminated: there is no cure for broken mitochondria. Instead, the chronic inflammatory response is perpetuated indefinitely and contributes to our physical and mental demise.
Guided by this evolutionary perspective, we can conclude that oxygen free radicals are an underlying cause of both ageing and age-related diseases. The ‘double-agent’ theory may explain why antioxidant supple-4 Glucocorticoids, such as prednisolone, block NFB by stimulating the synthesis of its natural inhibitor, IB. At high doses, prednisolone has such a potent and general immunosuppressive effect that many early transplant recipients died from infections and cancers.
Cyclosporin, the drug that led to a breakthrough in transplant medicine in the 1980s, is more selective for T lymphocytes, and so has a less catastrophic effect on overall health. It inhibits the enzyme calcineurin, which among other things blocks the activity of NFB in T
lymphocytes, but not in most other immune cells.
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ments have had so little effect on lifespan: they cannot halt mitochondrial leakage, and cells are refractory to overloading with antioxidants, lest they smother the powerful genetic response to injury. Thus, oxidative stress rises to cause age-related diseases, and antioxidants cannot reverse this rise, although they may slow it to some extent.
Is there anything we can do to prevent the diseases of old age?
Targeting ‘susceptibility’ genes is misguided, as there is nothing wrong with them: their negative effects are unveiled by oxidative stress, and in principle the best way of restoring their positive function is to alleviate oxidative stress. Despite the problems with antioxidants, this ought to be possible. Lifespan is flexible in nature. In Carboniferous times, life gave every sign of coping with higher oxygen levels (which must have increased oxidative stress). Healthy centenarians show that disease is not an inevitable feature of human ageing. How do they escape from age-related disease? If the double-agent theory is correct, there are two places we might look for help: infectious diseases, and the mitochondria themselves.
Malaria illustrates both the possibilities and the drawbacks of infectious disease as a solution to the problems of old age. To our shame, given the lack of real political will to eradicate it, malaria still affects half a billion people every year. The most feared complication, cerebral malaria, is caused by inflammation of the tiny blood vessels in the brain, which leads to fever, convulsions, coma and death in more than a million people each year. As we have seen, inflammation and fever are part of the reaction of the host to infection. If someone dies of cerebral malaria, they die more through the violence of their own immune system’s counter-attack than through the virulence of the parasite.
The selection pressure exerted by malaria is strong enough to maintain sickle-cell anaemia and the thalassaemias at a high frequency in populations across Africa and Asia. These conditions are not isolated curiosities, but part of a spectrum of adaptations that enable people to survive in areas where malaria is endemic. Among the most important of these adaptations is malarial tolerance. Tolerance develops after infections in early childhood and lasts a lifetime. It is not the result of a heightened ability to kill parasites (as in vaccination) but the triumph of realpolitik —
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a live-and-let-live policy in which the immune system is suppressed so that its attacks on the parasite do not damage the body. People who are tolerant to malaria sometimes harbour massive numbers of parasites in their blood — enough to kill ordinary people — yet show few or no symptoms of illness.
We know from the experience of transplantation and AIDS that immunosuppression has very serious side-effects: if the immune system is crippled we are far more susceptible to other infections, which may kill us, and are at high risk of some (but not all) cancers. Even today, transplant recipients have nearly 5 per cent chance of developing cancer within a few years of their operation, a 100-fold increase in risk over the general population. On the other hand, transplant immunosuppression has improved over the past 20 years and will no doubt continue to do so, while in AIDS, HIV infects the immune cells themselves, and so induces a purely pathological change in the immune system. In contrast, in malarial tolerance the immune system is regulated in a physiologi
cal manner, which has a lasting effect on susceptibility to malaria and presumably other aspects of health.
In 1968, Brian Greenwood, now at the School of Hygiene and Tropical Medicine in London, drew attention to the rarity of autoimmune diseases (such as multiple sclerosis, rheumatoid arthritis and lupus) in tropical Africa, but not in Africans living in North America. He suggested that the difference might relate to the frequency of parasitic infections in childhood, notably malaria. Over the following three decades, mounting evidence has confirmed that the low incidence of autoimmune diseases in Africa is indeed related to malarial tolerance.
I wonder how far we can take Greenwood’s ideas. Where should we draw the line between an autoimmune disease and other forms of illness?
An autoimmune disease is a condition in which our own immune system mistakenly attacks components of our own body. If ageing is essentially a chronic inflammatory response to oxidative stress, in which immune cells attack components of our own body, should we define the diseases of old age as autoimmune diseases? Not in a conventional sense, perhaps, but it is constructive to think of Alzheimer’s disease as an autoimmune disease.
If so, for example, we would expect the incidence of Alzheimer’s disease to be low in tropical Africa; and dementia is rare in Africa. This is not just because more Africans die from infections before they reach old age, or because social pressures lead to the real incidence being concealed by rela-
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tives. In 2001, Hugh Hendrie and his colleagues at Indiana University in the United States and the University of Ibadan in Nigeria, reported the results of a five-year study of dementia in Nigeria and the United States.
They tracked the fortunes of nearly 5000 Nigerian Africans and African Americans, living in the towns of Ibadan (an area where malaria is endemic) and Indianapolis. All were 65 or over, and none had overt dementia at the start of the study. After five years, the proportion of the study population diagnosed with dementia was significantly lower in Ibadan than in Indianapolis: 1.35 per cent compared with 3.24 per cent, or somewhat less than half the risk.