by Nick Lane
Insulin-resistance in people almost certainly has other effects that are similar to those noted in nematodes, especially increases in stress-resistance and long-term survival. In countries where poor nutrition is widespread, babies are often born with a low birth weight. As in all species, runts are more likely to die than bigger, stronger babies. When almost all babies are born with low birth weight, however, those most likely to survive are insulin-resistant. As in nematodes, insulin-resistance confers general stress-resistance. Children who are genetically insulin-resistant are thus more likely to survive into adulthood, and to pass on their genes for insulin-resistance. This only becomes a problem when a high-carbohydrate diet is imposed on a thrifty genotype.
Resistance to insulin persuades the body that food is scarce, that we are starving, even when we are obviously not — the equivalent of sensory deprivation in nematodes. The switch is the same, if grievously misguided, in both cases: towards longevity and away from reproduction.
When plentiful food is superimposed over a thrifty genotype, blood glucose levels can only be controlled by producing more and more insulin.
In the end, pushed past its limit for many years, the pancreas begins to fail. Less insulin is produced. Low insulin secretion, combined with insulin-resistance, means that blood glucose levels can no longer be controlled. Loss of glucose control marks the onset of type 2 diabetes. All the terrible afflictions of the disease are secondary to this failure to control blood levels of glucose and lipids.
Type 2 diabetes is less common in populations of European ancestry than in peoples whose immediate ancestors were hunter-gatherers.
Presumably the ancestors of Europeans somehow escaped the most severe
250 • EAT! OR YOU’LL LIVE FOREVER
selection pressure for the thrifty genotype. This seems to be so. The reasons are not entirely clear, but may be linked to the origins of farming, and especially of drinking milk. Milk is rich in lactose, a valuable source of glucose. Lactose is broken down to release glucose by an enzyme called lactase. Lactase is present in all breast-feeding babies, but is often lost later in life. Loss of the enzyme accounts for lactose intolerance — the reason many people cannot digest cheese or other milk products. Most European and Asian peoples adapted long ago to drinking milk throughout their lives — cattle, for example, were common throughout Europe and Asia —
but others, notably the native Americans and the Pacific Islanders, never herded milk cattle, and remained predominantly lactose intolerant. They were therefore denied the most plentiful source of sugar in a farming community. Whether lactose tolerance signalled the demise of the thrifty genotype in Europeans is unknown, but the fact is that all populations with lactose tolerance have a low susceptibility to diabetes. Conversely, all populations that are lactose intolerant are highly susceptible to diabetes.
There is nothing special about lactose. It is simply that when high blood sugar levels become the norm, natural selection penalizes the thrifty genotype. This is happening today on Nauru. The diet and lifestyle of the islanders have not changed since the 1980s when the incidence of diabetes was at a high point, yet even so the incidence of diabetes is falling. Underlying this fall, genetic insulin-resistance — the thrifty genotype — is today present in only 9 per cent of young adults, a fall of two thirds since the late 1980s. The decline in diabetes illustrates natural selection in operation. It happened because mortality exceeded fertility in people with diabetes.
In conclusion then, diabetes, rather than longevity, is the outcome of insulin-resistance in present-day conditions because we are not starving.
The underlying mechanism offsetting reproduction against longevity is conserved, however, in nematodes and humans. Insulin presses a genetic switch, which makes organisms gear up for reproduction. In this light, the fact that many people with diabetes have problems with fertility makes more sense — diabetes is a forlorn attempt to survive by postponing reproduction. Insulin-resistance causes the organism to store away food and prepare to survive the coming period of abstinence. The adaptations for survival include stress-resistance and the suppression of metabolism at the level of individual cells — in other words, a redistribution of energy towards dormancy and weight gain, as in nematode worms. Unlike nematode worms, which pass out in a dauer state, we just keep on eating.
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Nonetheless, both the studies of human diabetes and the genetic findings in nematodes point us to the central importance of metabolism and stress-resistance in ageing. Here we tie in with 70 years of empirical research from a completely different direction: oxygen and the rate of living. In the next chapter, we shall see why a fast metabolism, coupled with a low stress-resistance, shortens life, while a slow metabolism, coupled with a high stress-resistance, has the reverse effect. We will also look into the possibilities of combining a fast metabolism with a high stress-resistance.
C H A P T E R T H I R T E E N
Gender Bender
The Rate of Living and the Need for Sexes
The distinguished Johns Hopkins University biologist
Raymond Pearl cast a long shadow over biology from the early years of the twentieth century. An unusually tall, overbearingly arrogant and brilliant man, Pearl dominated his peers, publishing over 700
academic papers and 17 books, to say nothing of newspaper articles.
Although one of the founding fathers of biometry (the application of statistics to biology and medicine), he is now chiefly remembered for the theory of ageing that he named the ‘rate-of-living’ theory in a book published in 1928. The observations underpinning his ideas related to the effect of temperature on the fruit fly Drosophila. The higher the temperature, the shorter the flies’ lifetimes. The relationship between temperature and lifespan was similar to that between temperature and the rate of a chemical reaction, implying that the biochemical reactions sustaining life speed up at higher temperatures. Raising the temperature from 18°C to 23°C halved the lifespan of Drosophila, but doubled their metabolic rate, so that they consumed twice as much oxygen in an hour. Pearl also noted that the short lifespan of a mutant strain of Drosophila, the shaker mutant (which moves relentlessly), was related to its high metabolic rate. His conclusion was intuitively appealing: live fast, die young. He encapsulated his ideas in an article in 1927 for the Baltimore Sun, headlined “Why Lazy People Live the Longest”.
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Acceptance of Pearl’s theory gained momentum from the empirical notion that animals have a fixed quota of heartbeats. If we measure the heart rate of a mouse and multiply it by the lifespan, we get a number that is similar for most other mammals, whether horse, cow, cat, dog or guinea-pig. The same is true if we measure the total volume of blood pumped, the quantity of glucose burnt, or the weight of protein synthesized, over a lifetime. Each of these parameters relates to the metabolic rate, which is quantified as the oxygen consumption per hour. Smaller animals generally have faster metabolic rates, to maintain their body temperature. If we compare the metabolic rates and maximum lifespans of different animals, the relationship is striking. A horse has a maximum lifespan of about 35 years and a basal metabolic rate of about 0.2 litres of oxygen per kilogram per hour. Over a lifetime, it consumes around 60 000
litres of oxygen per kilogram. In contrast, a squirrel lives for a maximum of seven years, and its basal metabolic rate is five times faster: about 1 litre of oxygen per kilogram per hour. In its lifetime, it too consumes around 60 000 litres of oxygen per kilogram. The correlation holds surprisingly well for most mammals. The ‘constant’ is known as the lifetime energy potential.
At first, the lifetime energy potential was thought of in terms of the rate of chemical reactions. Later, a connection was made between the rate of metabolism and the rate of free-radical production. The reasoning is as follows. A small proportion of the oxygen consumed in cellular metabolism (a few per cent) leaks out of the mitochondria
in the form of superoxide radicals (see Chapter 6). Over a lifetime, such continuous leakage should account for a substantial production of superoxide radicals — perhaps as much as 2000 litres per kilogram. If a fixed proportion of respired oxygen escapes as free radicals, then the faster the oxygen consumption, the faster these radicals will be produced. In principle, therefore, a small animal that lives fast and dies young should have a high rate of free-radical production. This seems to be generally true. Across a spectrum of mammals, there is a strong inverse relationship between the rate of free radical production and the lifespan — the more free radicals, the shorter the life.1
1 I am including molecules such as hydrogen peroxide under the general umbrella of free radicals, even though, strictly speaking, they are not (see Chapter 6).
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The possibility that free radicals might play an important role in ageing was first suggested in 1956 by Denham Harman, then a young chemist at Berkeley. Harman had spent seven years at Shell Oil, working on the chemical properties of free radicals, before taking a course in biology at Stanford. He soon realized that the same reactions might underlie the process of ageing. The terms in which he summarized his argument in 1956 were a model of clarity, and can still be used today: Ageing and the degenerative diseases associated with it are attributed basic-ally to the deleterious side attacks of free radicals on cell constituents and on the connective tissues. The free radicals probably arise largely through reactions involving molecular oxygen catalysed in the cell by oxidative enzymes and in the connective tissues by traces of metals such as iron, cobalt, and manganese.
The damage caused by free radicals to cell membranes, proteins and DNA has been measured with growing refinement over half a century. There is no question that free radicals are produced, or that they cause damage proportional to their rate of production. The problem with the free-radical theory, from the very beginning, was that correlations say nothing about causality. More free radicals are produced in species that age rapidly, but this could mean that free radicals cause ageing, or that they are a product of ageing, or even that they are a co-variable with no direct link to ageing. The best way of proving a causal relationship is to modulate it, for example by extending lifespan using antioxidants. Early experiments by Harman suggested that antioxidants could slow down ageing in mice, but these findings were not supported by later work.2 As we saw in Chapter 9, there is still no evidence that antioxidant supplements increase maximum lifespan. Instead, a balanced diet probably corrects for vitamin deficiencies that might otherwise cut short our lives. Such failures have led many to dismiss the importance of free radicals.
There is a more general difficulty with the rate-of-living theory: it does not apply universally, even among warm-blooded vertebrates. That is why I had to limit my remarks ‘to most mammals’. Birds and bats are at low risk of predation, as they can fly away; and they have evolved life-2 The mice in Harman’s control group (which did not receive extra antioxidants) did not live as long as they should have done. One possible explanation is that the control mice died early because their standard diet was deficient in antioxidants, and Harman simply corrected for this. In fact this is quite likely because we are still uncertain about the optimal diet for most animals, either in the wild or in captivity.
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spans out of all proportion to their metabolic rate. Bats live as long as 20 years, despite a basal metabolic rate equivalent to that of mice, which live for three or four years at most. Pigeons have a basal metabolic rate similar to rats, but live for 35 years, nearly ten times longer than the poor rat. The most extreme examples are the hummingbirds, which have heart rates of 300 to 1000 beats per minute and must visit thousands of flowers a day just to stave off coma. They ‘should’ survive for no more than a year or two, but can actually live for ten years or more, consuming 500 000
litres of oxygen per kilogram in this time. In general, if we multiply the oxygen consumption of birds by their longevity, we can calculate that their exposure to oxygen free radicals ought to be ten times that of short-lived mammals such as rats, and more than double that of humans. The fact that birds have evolved long lifespans, despite such high metabolic rates, is often cited as the death-knell of the rate-of-living theory.
However, this is to interpret the theory rather rigidly, as if all living things really were granted a fixed number of heartbeats. In fact, the exceptions only go to prove the rule — or at least a slightly modified version of it.
Birds are an ideal test case for the hypothesis that it is the rate of free-radical production, rather than some other facet of metabolism, that is linked to longevity. If lifespan is linked to metabolism in a general sense, then we would expect free-radical production to vary with metabolic rate in all cases, as indeed it does in most mammals. On the other hand, if free radicals are responsible for ageing, the fact that birds consume so much oxygen can only mean that they have a very efficient mechanism for cutting down free-radical production. Put another way, if the free-radical theory is correct, birds must produce fewer free radicals than mammals, even though they consume far more oxygen.
Gustavo Barja, a biologist at the Complutense University in Madrid, spent most of the 1990s examining this question, steadily refining his measurements of hydrogen peroxide released from the mitochondria of birds and mammals, and the amount of damage done to mitochondrial and nuclear DNA. He found that isolated pigeon mitochondria consumed three times as much oxygen as rat mitochondria isolated from the equivalent tissues. Despite such high oxygen consumption, pigeon mitochondria produced only one third as much hydrogen peroxide under the same conditions. Barja concluded that the proportion of oxygen converted into free radicals in pigeons is nearly 10 per cent that of rats, corresponding to
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the nearly tenfold longer lifespan of pigeons. He went on to obtain analogous data from mice, canaries and parakeets; not yet formal proof, perhaps, but if not, an uncanny coincidence (Figure 11).
Why are bird mitochondria so efficient? Presumably, flight must have imposed a powerful selection pressure for energetic efficiency, regardless of lifespan — the power-to-weight ratio required for flight demands an efficient energy metabolism. The mammals have lagged far behind. Barja found that bird mitochondria are more oxygen-tight: relatively few free radicals leak from the mitochondria, and a correspondingly greater proportion of respired oxygen is converted into water. As a result, birds actually need fewer antioxidants to mop up the few escaping radicals.
This explains one long-standing puzzle: the poor relationship between the antioxidant content and the lifespan of birds and mammals. The assumption that birds should need more antioxidants to live longer is falsified because they leak fewer free radicals in the first place. From an anthropocentric point of view, this is a blow: it is a much tougher proposition to redesign our genetically leaky mitochondria than it is to add more of the right antioxidant. Nonetheless, there are grounds for hope.
Even if the example of the birds does not apply to us, Barja’s findings do 2
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Figure 11: Hydrogen peroxide leakage from heart mitochondria in (a) mice (maximum lifespan 3.5 years), (b) parakeets (maximum lifespan 21 years) and (c) canaries (maximum lifespan 24 years). The rate of leakage is much lower in birds than in comparably sized mammals; the asterisks denote statistically significant differences between the groups (p<0.05 and p<0.01, respectively). All three animals are similarly sized, and have similar resting metabolic rates. Analogous relationships are found in pigeons and rats. The mitochondrial theory of ageing predicts that free-radical leakage should be lower from the mitochondria of bats than from mice (which have similar metabolic rates but live only a fifth as long), but this is as yet unknown.
Adapted with permission from Gustavo Barja and the New York Academy of Sciences.
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e Need for Sexes • 257
corroborate the theory that free radicals limit lifespan. If we cannot emulate the birds, what can we do about free radicals?
We have seen that it is possible to extend the lifespan of nematode worms. We do not need to select for mitochondrial efficiency over generations: only a handful of master genes, such as daf-16, need to be activated. daf-16 almost certainly controls the expression of a large number of subsidiary genes. Most of these have yet to be identified, but stress-resistance is a good pointer. Unable to wait for the systematic identification of all the genes controlled by daf-16, a few researchers have leapt in to measure changes in the expression of known stress proteins —
like the police checking up on the whereabouts of known criminals before investigating the scene of the crime. We might predict, for example, that more SOD (superoxide dismutase) would be made in stress-resistant nematodes. True enough: in 1999, a Japanese team reported that long-lived mutant nematodes have dramatically more mitochondrial SOD (see Chapter 10) than normal adults. Mutations in daf-16 blocked this rise, implying that the gene for mitochondrial SOD is indeed among those regulated by daf-16. Similarly, in 2001, a team at Manchester University reported that in stress-resistant nematodes metallothionein (another stress protein, also discussed in Chapter 10) reached seven times the normal levels.