The free-radical theory of ageing provides a potential mechanism that links metabolism to ageing phenomena, since oxygen free radicals are formed as a by-product of oxidative phosphorylation. Despite this potential synergy in these theoretical approaches, the free-radical theory has grown in stature while the rate of living theory has fallen into disrepute. This is primarily because comparisons made across classes (for example, between birds and mammals) do not conform to the expectations, and even within classes there is substantial interspecific variability in the mass-specific expenditure of energy per lifespan. Using interspecific data to test the rate of living hypothesis is, however, confused by several major problems. For example, appeals that the resultant lifetime expenditure of energy per gram of tissue is `too variable’ depend on the biological significance rather than the statistical significance of the variation observed. Moreover, maximum lifespan is not a good marker of ageing and RMR is not a good measure of total energy metabolism. Analysis of residual lifespan against residual RMR reveals no significant relationship. However, this is still based on RMR.

A novel comparison using daily energy expenditure (DEE), rather than BMR, suggests that lifetime expenditure of energy per gram of tissue is NOT independent of body mass, and that tissue in smaller animals expends more energy before expiring than tissue in larger animals. Some of the residual variation in this relationship in mammals is explained by ambient temperature. In addition there is a significant negative relationship between residual lifespan and residual daily energy expenditure in mammals. A potentially much better model to explore the links of body size, metabolism and ageing is to examine the intraspecific links. These studies have generated some data that support the original rate of living theory and other data that conflict. In particular several studies have shown that manipulating animals to expend more or less energy generate the expected effects on lifespan (particularly when the subjects are ectotherms). However, smaller individuals with higher rates of metabolism live longer than their slower, larger conspecifics.

An addition to these confused observations has been the recent suggestion that under some circumstances we might expect mitochondria to produce fewer free radicals when metabolism is higher – particularly when they are uncoupled. These new ideas concerning the manner in which mitochondria generate free radicals as a function of metabolism shed some light on the complexity of observations linking body size, metabolism and lifespan.
KEY WORDS

ageing
rate of living theory
free radical
oxidative stress

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Introduction
Historical perspective

The recognition that things wear out with use, and that the more we use them the faster they wear out, must be very old. The identification that this principle might also pertain to the phenomena of human ageing and death, however, appears to have first been made by Aristotle, who suggested that among other things our deaths are hastened by engagement in sexual activity: “salacious animals and those abounding in seed age quickly”. Aristotle also made a prescient comparison of life and fire with respect to age: “A lesser flame is consumed by a greater one, for the nutriment, to wit the smoke, which the former takes a long period to expend is used up by the big flame quickly”, and he observed that larger animals live longer than smaller ones (Aristotle, 350 BC), but his primary thesis was that ageing and death are linked to the process of dehydration. It was not, therefore, until the late 1800s that the general idea of ageing reflecting the body `wearing out’ gained widespread popularity. It is around this time that many popular idioms that capture the idea originate – such as “burning the candle at both ends” (reviewed in Speakman et al., 2002). It is probably not a coincidence that this was the time of the industrial revolution, and the origins of modern capitalism. When attempting to get complex industrial machinery to deliver greater productivity, the fact that things break down the harder you work them would have been widespread and obvious. The German biologist Auguste Weismann, who originated the idea of the germline, was among the first biologists to promote the idea that ageing and death of the soma is an analogous process to `wear and tear’. Humans and animals, however, engage in a wide variety of activities, although which activities, and by how much they contributed to the `wearing out’ process, was unclear. A degree of clarity was brought to the field in 1908, when, recapitulating the flame idea of Aristotle, it was suggested that the linkage between what we do now, and why we age and die, lies in our energy metabolism (Rubner, 1908).

Rubner (1908) compared the energy metabolism and lifespans of five domestic animals (guinea pig, cat, dog, cow and horse) and man. He noted that the rate of metabolism of these animals increased as a function of body size, and that the larger animals also lived longer. When he multiplied the mass-specific rate of energy expenditure by the maximum lifespan, the result was relatively independent of body size (if data for humans was excluded from the comparison). The range of variation in expenditure per gram per lifespan was only a factor of 1.5 compared with the 50 000-fold difference in body mass between the smallest and largest species. Even including the data for humans the range was only fivefold. In other words, a gram of body tissue expends about the same amount of energy, before the animal dies, whether the tissue is in a guinea pig, cat, dog, cow or horse.

If the total energy expenditure per lifespan is fixed, it follows logically that using energy up faster will hasten death. This has become known as the `rate of living’ (ROL) theory. In his book `The Biology of Death’, Pearl (1922) concluded that life duration is a function of only two variables – the genetic constitution and the rate of energy expenditure. The idea was perhaps most eloquently summarised by Murray (1926) in his statement `If aliveness is measured by the velocity of chemical activity (heat production) an organism may in this sense be said to dig its own grave. The more abundant its manifestations of life, the greater will be its rate of senescence’. This idea had been strongly supported two years earlier by observations that once occupational accidents were excluded from the statistics, the rates at which males died after the age of 45 were directly related to the levels of energy expenditure in their occupations (Pearl, 1924).

By a rigorous statistical analysis of mortality rates in Drosophila and cantaloupe seeds, in the absence of any external sustenance, Pearl (1928) suggested that animals are endowed with an `inherent vitality’ that is depleted in relation to the rate of growth. He suggested that this `inherent vitality’ was an inherited factor related to `organisation’. There are, however, some clear problems with the `inherent vitality’ idea as a factor governing lifespan – not least of which being that the idea was developed from studies of animals that were starving to death. In this circumstance it is hardly surprising that the duration of life was inversely linked to the rate of energy expenditure, since the animals have a roughly fixed energy storage at emergence from the pupae (and the same is true of germinating seeds), which will be exhausted in relation to its rate of use. The wider relevance of `inherent vitality’ to `total vitality’, when animals can derive external sustenance, is less clear.

A rather different idea was proposed in the 1950s that resonated with the ROL theory, and builds on much earlier suggestions by, for example, Metchnikoff (1908), that ageing and death are consequences of toxic by-products of metabolism. This idea is the free-radical damage theory of ageing (Gerschmann et al., 1954; Harman, 1956). Free radicals and oxidants (collectively called radical oxygen species: ROS) are highly reactive agents that react readily with macromoleules in the body causing damage. Some ROS originate from exogenous sources – typical examples include gamma and UV radiation. However, the largest source of free radicals is the process of oxidative phosphorylation. Estimates of the rate at which oxygen radicals are generated during oxidative phosphorylation are frequently quoted as being up to 3% of the inspired oxygen (Beckman and Ames, 1998; Castiella et al., 2001; Golden and Melov, 2001; Acuna-Castroviejo et al., 2001). More recently, however, these estimates have been questioned and it is likely that the actual productions are much lower – of the order of 0.1% (St Pierre et al., 2002). Whatever these estimates finally turn out to be, the implication of expressing the value as a percentage of the total oxygen consumption is that as oxygen consumption increases (per gram of tissue) then radical oxygen species generation will do so as well. The idea behind the free-radical damage theory is that macromolecular components of the cell are under perpetual attack from ROS. Animals have a battery of protective mechanisms that aim to protect them from this damage, as well as a number of repair mechanisms that aim to ameliorate its effects. However, despite these defence and repair processes some damage always evades these systems and the consequence is a progressive lifetime accumulation of oxidation (Sohal and Weindruch, 1996; Beckman and Ames, 1998) that leads to advancing physiological attrition and ultimately failure (death). Oxidative phosphorylation is also the molecular mechanism that underpins the generation of ATP, which powers energy metabolism. The free-radical theory therefore provides a mechanism by which the ROL theory might work. In fact measured rates of free-radical production by mitochondria correlate to the resting rate of metabolism, and in turn these are also related to longevity (Ku and Sohal, 1993).

The free-radical theory of ageing has gone from strength to strength and it is probably true that most modern gerontologists believe that free-radical damage is an important aspect of the ageing process (e.g. Huang and Manton, 2004; Fukagawa, 1999; Finkel and Holbrook, 2000; Golden et al., 2002; Dufour and Larsson, 2004). Surprisingly, despite their evident synergies, while the free-radical theory has blossomed, the rate of living theory by contrast has fallen into general disrepute. The main reason why the ROL theory has diverged from the free-radical theory reflects two vital pieces of information. The first relates to the comparison of lifespans and rates of energy metabolism when the database of mammal species is expanded (Austad and Fischer, 1991; Austad, 1997), beyond the species included in the original comparison by Rubner (1908). To illustrate this point I have plotted in Fig. 1 accumulated data on lifespans and RMR for both mammals and birds. (RMR is defined as the rate of metabolism for an animal at rest within the themoneutral zone). When this enlarged database is examined the generalities remain – bigger mammals expend more energy, but at a declining rate with increasing body mass (Fig. 1A), and they live longer (Fig. 1B) – but the specificities, that animals expend the same amounts of energy per gram of tissue per lifespan, are seriously challenged. The trend is still broadly independent of body mass (r2=0.026, b=-0.06, although this shallow gradient is significantly different from 0 because of the large sample size; P=0.03), but within the mammals there is a 17-fold range in the lifetime expenditures of energy (Fig. 1C). Probably the most persuasive evidence against the ROL theory, however, comes from the inter-class comparison of birds and mammals. Within birds the patterns are very similar to the mammals. Bigger birds expend more energy but at a declining rate with size (Fig. 1D), and they live longer (Fig. 1E). In combination, these trends mean that birds also have rates of energy metabolism per gram per lifespan that are highly variable and relatively independent of body size (Fig. 1F; r2=0.126, b=-0.109, although again the gradient of this relationship is significantly different from 0, P=0.001). However, when comparing birds with mammals (Fig. 2) some striking things emerge. On average birds of any particular mass have rates of metabolism that are higher than equivalent-sized mammals, but at any particular mass they combine these higher rates of metabolism with longer lives. In consequence, lifetime expenditures of energy per gram of bird tissue are on average substantially greater than the equivalent values in mammals (Fig. 2), as observed by Holmes and Austad (1995a,b) Ogburn et al., (1998, 2001) and Holmes et al. (2001). On this basis it is argued that the `rate of living’ theory cannot be correct.