Power, Sex, Suicide: Mitochondria and the Meaning of Life (33 page)

The fact that bones necessarily take up a greater proportion of body mass as body size increases, coupled with their metabolic inertia, means that a greater proportion of a giant’s body is metabolically inert. This lowers the total metabolic rate, and so contributes to the scaling of metabolic rate with size (the scaling exponent is 0.92). However, the difference in bone mass alone is not sufficient to account for the reduction in metabolic rate with size. But might other organs scale in a similar fashion? Might there be a threshold of liver or kidney function, beyond which there is little need to continue amassing ever more hepatic or renal cells? There are two reasons to think that there may indeed be a threshold of function in these organs. First, the relative size of many organs falls as body size rises. For example, the liver accounts for about 5.5 percent
of the body mass of a 20 gram mouse, about 4 per cent that of a rat, and just 0.5 per cent that of a 200 kg pony. Even if the metabolic rate of each liver cell remains the same, the proportionately lower mass of the liver would contribute to the lower metabolic rate of the pony. And second, the metabolic rate of each liver cell is
not
constant: oxygen consumption per cell falls about ninefold from the mouse to the horse. Presumably there is a limit to just how small an organ can be within the body cavity—it is better to maintain the size of the liver, so that it does not swing loose in the peritoneum, and instead restrict the metabolic rate of its component cells. The combination of both factors (a relatively small liver, along with a lower metabolic rate per cell) means that the contribution of the liver to metabolic rate falls quite dramatically with size.

By now we can begin to see that the resting metabolic rate of an animal is composed of many facets. To calculate the overall metabolic rate we need to know the contribution of each tissue, of each cell within that tissue and even of particular biochemical processes within cells. Such an approach can also explain how and why the metabolic rate changes from rest to aerobic exercise. This was the tack taken by Charles-Antoine Darveau and his colleagues at the University of British Columbia, Vancouver, in the lab of the Canadian guru of comparative biochemistry, Peter Hochachka, in work published in
Nature
in 2002. Darveau and colleagues attempted to sum up the contribution of each facet, and the influence of critical hormones (such as thyroid hormones and catecholamines) to derive an equation that could explain the scaling of metabolic rate with size, giving a flexible overall exponent of about 0.75 for the resting metabolic rate and 0.86 for maximal metabolic rate. Both West and colleagues, and Banavar and colleagues refuted their paper on mathematical grounds in the letters pages—and plainly Darveau’s equations did need some refinement. Hochachka’s group defended the soundness of their conceptual approach and did modify their equations, publishing a more detailed exposition in the journal
Comparative Biochemistry and Physiology
in 2003. Sadly, this was among the last works of Peter Hochachka, who died of prostate cancer at the age of sixty-five in September 2002. It is a measure of his unquenchable thirst for knowledge that his final paper was a study of the wayward metabolism of malignant prostate cells, published with his doctors as co-authors.

The strident mathematical dismissal of Hochachka’s argument, and the concession of errors in its defence, may have caused some dispassionate observers (including me, initially) to suspect that if the maths was wrong, then so too, perhaps, was the whole approach. Not so: this might have been a flawed first approximation, but it was robustly grounded in biology, and I’m looking forward to more sophisticated revisions. But it already offers a quantitative demonstration that metabolic demand
does
fall with size, and that this controls the supply network, rather than the other way around. Even more importantly,
it gives an insight into the evolution of complexity, and especially into a problem that has long eluded biologists—the evolution of warm-bloodedness in mammals and birds. There is no better illustration of the link between size and metabolic efficiency, and the way in which these attributes pave the way to greater complexity. For warm-bloodedness is about far more than just keeping warm in the cold: it adds a whole new energetic dimension to life.

Warm-bloodedness is a misleading term. It means that the temperature of the blood, and with it the body, is maintained at a stable temperature above that of the surroundings. But many so-called ‘cold-blooded’ creatures, such as lizards, are really warm-blooded in this sense, for they maintain a higher temperature than their surroundings through behaviour. They bask in the sun. While this sounds inherently inefficient, at least in England, many reptiles succeed in regulating their body temperature within tightly specified limits at a similar level to mammals—around 35 to 37°C (although it usually falls at night). The distinction between reptiles, such as lizards, and birds and mammals lies not in their ability to regulate temperature, but to generate heat internally. Reptiles are said to be ‘ectothermic’, in that they gain their body heat from the surroundings, whereas birds and mammals are ‘endothermic’—they generate their heat internally.

Even the word endothermic needs some clarification. Many creatures, including some insects, snakes, crocodiles, sharks, tuna fish, even some plants, are endothermic: they generate heat internally, and can use this heat to regulate their body temperature above that of their surroundings. All of these groups evolved endothermy independently. Such animals generally use their muscles to generate heat during activity. The advantage of this is related directly to the temperature in the muscle. All biochemical reactions, including the metabolic rate, are dependent on temperature. The rate of metabolism doubles for each 10°C rise in temperature. Along with this, the aerobic capabilities of all species improve with higher body temperature (at least up to the point that the reactions become destructive). Speed and endurance are therefore enhanced at higher body temperature, and this clearly offers many advantages, whether in the competition for mates or in the battle for survival between predators and prey.
¹

Birds and mammals stand apart in that their endothermy is not dependent on muscle activity, but on the activity of their organs, such as liver and heart. In mammals, muscles contribute to heat generation only during shivering in intense cold, or during vigorous exercise. When at rest, the body temperature of all other groups falls (unless they maintain it by basking in the sun) whereas the mammals and birds maintain a constant and high temperature even at rest. The difference in resource use is profligate and shocking. If an equally sized reptile and mammal maintain the same temperature, through behavioural and metabolic means, respectively, the mammal needs to burn six to ten times as much fuel to maintain this temperature. If the surrounding temperature falls, the distinction becomes even greater, because the temperature of the reptile will fall, whereas the mammal strives to maintain a constant temperature of 37°C, by increasing its metabolic rate. At 20°C, a reptile uses only about 2 or 3 per cent of the energy needed by a mammal, and at 10°C barely 1 per cent. On ‘average’, in the wild, a mammal uses about thirty times more energy to stay alive than an equivalent reptile. In practical terms, this means that a mammal must eat
in one day
the amount of food that would sustain a reptile for a whole month.

The evolutionary costs of such a profligate lifestyle are profound. Instead of merely keeping warm, a mammal could divert thirty times more energy towards growth and reproduction. I shudder to think of the consequences on teenage angst; but given that natural selection is all about surviving to maturity and reproducing, the costs are grave indeed. The benefits must at least equal these costs, or natural selection would favour the reptilian lifestyle, and the evolution of mammals and birds would have been snuffed out at the beginning. Most attempts to explain the evolution of warm-bloodedness for its own sake fall prey to this difficulty.

For example, the benefits of endothermy include the ability to operate at night, and to expand ecological niches into temperate and even polar climates. A high body temperature, as we have seen, also speeds up the metabolic rate, with potential benefits on speed, stamina, and reaction time. The drawback is the cost-to-benefit ratio, and in particular the large amount of energy needed to raise the body temperature by a trifling degree. Revealingly, digesting a very large meal can raise the resting metabolic rate of lizards by as much as fourfold for a period of several days, but only raises the body temperature by 0.5°C. To sustain such a rise in body temperature would require the reptile to eat on average four times as much food—and this is no easy matter, as it inevitably
demands extra hours of foraging, with a concurrent exposure to danger. The advantage in speed and endurance is also trivial: a 0.5°C rise in temperature speeds the rate of chemical reactions by about 4 per cent—well within the inter-individual variability of athleticism for most species. The problem is not merely one of heat loss, which could be offset by a fur coat or feathers. One amusing experiment, in which a lizard was dressed in a specially tailored fur coat, showed that far from warming the body by improving heat retention, the fur had the opposite effect: it interfered with the lizard’s ability to absorb heat from its surroundings. Insulation, of course, keeps the heat out as well as in. In short, there are serious and immediate costs to raising body temperature, which more than offset the trifling advantages. How, then, do we explain the rise of endothermy in mammals and birds?

Much the most coherent and plausible (albeit still unproven) explanation for the evolution of endothermy was put forward in an illuminating and unsurpassed paper in
Science
in 1979 by Albert Bennett and John Ruben, then (and indeed still) at UC Irvine and Oregon State University, respectively. Their theory, known as the ‘aerobic capacity’ hypothesis, makes two assumptions. First, it postulates that the initial advantage was not related to temperature at all, but to the aerobic capacity of animals. In other words, selection was primarily directed at speed and endurance—at the maximum metabolic rate and muscular performance, not at the resting metabolic rate and body temperature. Second, the hypothesis postulates that there is a direct connection between the resting and the maximal metabolic rate, such that it is not possible (evolutionarily) to raise one without raising the other. Thus, selection for a faster maximal metabolic rate (a higher aerobic capacity) necessarily entails raising the resting metabolic rate. This is plausible: we’ve already noted that there
is
a link between the resting and the maximal metabolic rate, and that the aerobic scope (the factorial difference between the two) rises with body size. So there certainly is a link; but is it causal? If one rises or falls,
must
the other?

Bennett and Ruben argued that the resting metabolic rate was eventually elevated to the point that internal heat production could raise body temperature permanently. At this point, the advantages of endothermy—niche expansion, and so on—were selected for their own benefit. Selection was now directed at maintaining internally generated heat, favouring the evolution of insulatory layers such as subcutaneous fat, fur, down, and feathers.

For the aerobic capacity hypothesis to work, both the maximal and the resting metabolic rate of mammals and birds need to be substantially higher than
those of lizards. This is well known to be the case.
²
Lizards become exhausted quickly and have a low capacity for aerobic exercise. While they can move very fleetly (when warmed up) their muscles are mostly powered by anaerobic respiration to produce lactate (see
Part 2
). They can sustain a burst of speed for little more than 30 seconds, enabling them to dart for the nearest hole and hide, whereupon they often need several hours to recover. In contrast, the aerobic performance of similarly sized mammals and birds is at least six to tenfold greater. While not quicker off the mark or fleeter of foot, they can sustain the pace for far longer. As Bennett and Ruben put it in their original
Science
paper: ‘The selective advantages of increased activity are not subtle but rather are central to survival and reproduction. An animal with greater stamina has an advantage that is readily comprehensible in selective terms. It can sustain greater levels of pursuit or flight in gathering food or avoiding becoming food. It will be superior in territorial defense or invasion. It will be more successful in courtship or mating.’

What must an animal do to improve its stamina and speed? Above all else, it has to augment the aerobic power of its skeletal muscles. To do so requires more mitochondria, more capillaries and more muscle fibres. We immediately run into a difficulty with space allocation. If the entire tissue is taken up with muscle fibres, there is no room left over for mitochondria to power muscle contraction, or for capillaries to deliver oxygen. There must be an optimal tissue distribution. To a point, aerobic power can be improved by a tighter packing of these components, but beyond that improvements can only be made by greater efficiency. This is indeed what happens. According to Australian researchers Tony Hulbert and Paul Else, at the University of Wollongong, New South Wales, mammalian skeletal muscles have twice as many mitochondria as the equivalent lizard muscles, and these are in turn more densely packed with membranes and respiratory complexes. The activity of respiratory enzymes in rat skeletal muscle is also about twice that of the lizard. In total, the aerobic performance of rat muscle is nearly eight times that of the lizard—a difference that wholly accounts for its greater maximum metabolic rate and aerobic capacity.

This deals with the first part of the aerobic capacity hypothesis: selection for
endurance raises the mitochondrial power of muscle cells, leading to a faster maximum metabolic rate; but what about the second part? Why is there a link between maximal and resting metabolic rate? The reason is not clear, insofar as none of the possible explanations has been proved. Even so, there is a good intuitive reason to expect a connection. I mentioned that lizards may often take several hours to recover from exhaustion, even after a few minutes of vigorous exertion. Such a slow recovery is less dependent on muscles than on organs, such as the liver and kidneys, which process the metabolic waste and other breakdown products of vigorous exercise. The rate at which these organs operate depends on their own metabolic power, which in turn depends on their mitochondrial power—the more mitochondria, the faster the recovery. Presumably the advantages of endurance also apply to recovery time: given the eightfold rise in aerobic power of mammalian muscles, if there were no compensating changes in organ function it would take a whole day, rather than a few hours to recover from exercise.