Caloric Restriction, Hormesis and Life-History Plasticity

Thomas B.L. Kirkwood Ph.D.

Daryl P. Shanley Ph.D.

Biological Gerontology Group, Department of Geriatric Medicine,

University of Manchester, 3.239 Stopford Building, Oxford Road,

Manchester M13 9PT , U.K.

Tel: 0161-275-5655, Fax: 0161-275-5654

E-mail: Tom.Kirkwood@man.ac.uk

Turturro et al (1999) provide an illuminating discussion of the relationship between caloric restriction (CR) and hormesis. We believe that both of these phenomena need to be understood in terms of how natural selection has shaped the organism's life history, particularly its range of adaptive response to stress. Recently, we analyzed the question of whether the rodent response to CR may be an evolutionary adaptation to cope with temporary intervals of food shortage in the wild (Shanley & Kirkwood 1999).

The essence of this hypothesis, proposed independently by Holliday (1989) and Harrison & Archer (1989), is as follows. During periods of food shortage, animals may lack sufficient resources both to carry out essential somatic maintenance and to reproduce. In these circumstances, fertility might at best waste scarce resources on doomed attempts at reproduction, and at worst prove lethal. Hence, the animal is suggested to shut down reproduction and to direct the available metabolic resources to maintenance, i.e. survival. The logic is similar to that which underlies the disposable soma theory of ageing (see Kirkwood & Rose 1991; Kirkwood 1996), namely, that organisms are under constant pressure to optimise their allocation of metabolic resources between activities of reproduction and somatic maintenance. The hypothesis explains the life-extending effects of CR if an animal that has its caloric intake reduced through CR, but which is not actually starved, temporarily puts more effort into maintenance than it would under ad libitum feeding. The strategy might have an evolutionary basis if it allows the animal to emerge from a period of food shortage without having used up too much of its relatively short reproductive span.

The plausibility of this adaptive explanation for the life-extending effects of CR depends critically upon the quantitative trade-offs that are involved. These require careful consideration of the effects of CR on life history parameters. Such an analysis might, in principle, identify whether a similar strategy could also be beneficial for longer-lived species with lower levels of extrinsic mortality in the wild, and whether there are limitations to the types of environment in which such an adaptive response would be expected.

We developed a model for dynamic resource allocation that allowed us to predict the optimal resource allocations when the organism is exposed to periodic bouts of food shortage (Shanley 1999; Shanley & Kirkwood 1999). Using the methodology of dynamic programming, we described the age of the organism as a state variable that changes through time, depending on the allocation of resources to maintenance. This state variable can be envisaged as an irreversible accumulation of intrinsic damage. Within the model, individuals are followed in time and Darwinian fitness, defined as the number of descendants that are produced far into the future, is maximized. Our model was based on the mouse, Mus musculus, whose life history has been extensively studied in the wild as well as in the laboratory (Berry & Bronson 1992).

We showed that a temporary reduction in food intake could indeed evoke an increase in the level of investment in somatic maintenance and repair. In other words, the model supports the idea that the life-extending effects of CR are an evolutionary adaptation. The model also helped to clarify certain physiological prerequisites for this conclusion to be valid. One of these is that there is a "reproductive overhead"; in other words, a fixed investment in reproduction must be made before resources can be applied to producing progeny. This seems reasonable and corresponds to activating the endocrine and cellular mechanisms required for fertility. A second constraint is a decrease in juvenile survival in periods of food shortage. Again, this seems reasonable.

A criticism of the evolutionary interpretation of CR is that, in the wild, animals short of food may have limited survival. However, food-restricted animals are generally healthier and more active than ad libitum animals, suggesting that this concern is not critical. Long-term food deprivation in the wild would, of course, severely limit an individual's fitness. But animals maintained on long-term CR in the laboratory undoubtedly represent an unnatural situation. In responding to CR in these circumstances, the physiological systems of the mouse do not know that the restriction will persist.

Masoro (1998) addressed the relationship between CR and hormesis along somewhat similar lines to the above evolutionary hypothesis. During periods of food restriction in nature, animals are likely to engage in riskier behaviours and to sample novel foods that may be toxic. There may be adaptive value in these circumstances in up-regulating cell maintenance and stress response mechanisms. This may have effects similar to hormetic induction of cell maintenance and stress response systems, such as are seen when damaging agents like radiation and elevated temperature applied at young ages cause long-term induction of protective mechanisms that again retard ageing rate (Van Wijngaarden & Pauwels 1995; Lithgow 1996).

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