Evol_55_914.1902_1905.tp

Evolution, 55(9), 2001, pp. 1902–1905 CAN EXPERIMENTS ON CALORIC RESTRICTION BE RECONCILED WITH THE DISPOSABLE SOMA THEORY FOR THE EVOLUTION OF SENESCENCE? Deptartment of Biology, Leidy Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6018 A publication by Shanley and Kirkwood (2000) attempts to explain data on caloric restriction (CR) and life extension in the context of the Disposable Soma (DS) theory for the evolution of senescence. As the authorsconcede, this juxtaposition appears at first to offend intuition: According to the DS theory, senescence is the resultof a tight budget for caloric energy, such that repair and maintenance functions are shortchanged; yet, in CR exper-iments, it is found that longevity decreases smoothly as the total caloric budget is increased. In the Shanley-Kirkwoodmodel, an optimized allocation of resources causes energy to be diverted away from somatic maintenance at a greaterrate than caloric intake increases, with the net result that more total energy is associated with less energy availablefor maintenance. In the present critique, the limitations of this model are detailed and its special assumptions reviewed.
While the CR experiments find comparable life extension for males and females, measured relative to nonbreedingcontrols, the Shanley-Kirkwood model draws its energy budget from data on breeding females. In addition, the successin reproducing the observed relationship between feeding and longevity depends crucially on a mathematical rela-tionship between food availability and the probability of reproductive success which may be difficult to justify.
Aging, antagonistic pleiotropy, caloric restriction, dietary restriction, disposable soma, senescence.
prospects for successful reproduction and for survival ofyoung, vulnerable offspring is diminished; hence, it may be According to the Disposable Soma (DS) theory (Kirkwood advantageous to delay reproduction, devoting extra metabolic 1977), every living organism must budget its energy among resources to maintenance and survival functions (Holliday various priorities, including metabolism, growth, activity, 1989; Austad 1995; Masoro and Austad 1996). This theo- and reproduction. Repair of damaged proteins and error- retical framework creates a context for modeling the effect checking in DNA replication constitute demands on energyresources that must compete with these other functions, and with optimization of reproductive value; allocation of an un- so their allocation is subject to compromise. Failure to do a specified, scarce metabolic resource may be directed either perfect job in these and other repair and maintenance func- toward the immediate goal of reproduction or toward the tions leads to an accumulation of damage over the lifetime long-term benefit of forestalled senescence. In times when of the organism, the outward manifestation of which is the the food supply is stressed, the optimum balance may sensibly constellation of symptoms we identify as senescence.
The DS theory for the evolution of aging is elegant and In the DS theory, the scarce resource is specified to be economical, with strong common-sense appeal. Perhaps for caloric energy itself; this puts an added burden on the model, this reason, it has enjoyed success relative to other theories which must account for an increasing repair/maintenance of senescence, in a field where experimental evidence is sub- budget even as the overall caloric intake is declining steadily.
Perhaps for this reason, it was not until just last year that anattempt to reconcile DS with the CR data was first put for- Caloric Restriction and Life Extension ward. This is the model of Shanley and Kirkwood (2000).
One experimental area which is comparatively unequivocal is the data on caloric restriction (CR). Laboratory animalsmaintained on a diet restricted in calories live longer than The Shanley-Kirkwood (S-K) model is based in a detailed ad libitum fed animals, and many of the physiological mark- accounting of optimized energy rationing in times of famine ers of senescence appear on a delayed schedule. These data and times of plenty. Life history optimization is used to de- pose a particular dilemma for the DS theory, with its foun- termine the allocation of caloric resources, presumably under dation in the metabolic energy budget. If senescence is caused genetic control, between reproduction and maintenance of by a failure to allocate adequate caloric energy for mainte- the soma. Reproduction is energetically expensive for the nance of the soma, why is it that the availability of caloric females modeled exclusively in the paper, but it offers an energy in abundance actually leads to more rapid senescence immediate payoff; energy expended in maintenance affords than occurs when energy is in short supply? no payoff until much later, delaying the effects of accumu- Theorists have explained the evolutionary provenance of lated damage which manifest as reduced fertility and in- the CR effect in terms of a shifted balance between the rel- creased mortality. Under the model’s base assumptions, the ative value of immediate reproduction and long-term surviv- authors report that increasing food supply makes more energy al: in times of famine, signaled by a meager food supply, the available for reproduction, while the maintenance portion holds constant over a wide range of caloric intake; hence, Limitation of the Model to Breeding Females the essence of the CR response remains unexplained. To en- Half of one sentence justifies limitation of the S-K model gineer an agreement with reality, the model is varied with to females: ‘‘By common convention, the analysis is restrict- ed to females, female demographic dominance being assumed The first is a reproductive overhead, the cost of maintaining . . . ’’ (Charlesworth 1994, p. 4). The reference is to the fact fertility independent of whether a litter actually ensues. When that population genetic analysis may be confined to females reproductive overhead is introduced, Shanley and Kirkwood with little loss of generality, and predictions concerning find, after optimizing energy allocation, that reproduction growth and steady-state population levels for mixed popu- turns off abruptly at a threshold CR level. The implication lation levels are little affected by male life histories. But this for senescence is that there is a narrow range around this is no reason to bypass males in the application of theories threshold in which energy allocation for maintenance de- of senescence or of CR. Life histories of males are separately creases sharply with increasing food supply. This result has optimized for fitness in a process analogous to that for fe- the right sign to explain the data, but the curve is the wrong males (Charlesworth 1994, p. 231), though, of course, the shape. In experimental findings, longevity decreases smooth- parameters of the cost/benefit calculus are different. There is ly with increasing food availability over a wide range (Wein- no logical basis in the Shanley-Kirkwood model for restrict- The model is extended with a second parameter, which The level of caloric restriction in lab settings as conven- relates the probability of infant survival to ambient food sup- tionally reported is measured relative to the ad libitum intake ply. It is proposed that foraging results for the mouse in the of nonbreeding animals, male and female. However, the CR wild are a linear measure of the local availability of food; variable in the S-K analysis is calibrated with respect to in- thus restricted caloric intake is a proxy for ambient famine take for breeding females. Pregnant and lactating females conditions. The infant’s prospects for survival through the consume up to twice as much food under ad libitum condi- nursing period are assumed to increase linearly with ambient tions (Bronson 1989). Without this large reservoir to draw food availability; combined with the assumed linear rela- down in times of caloric restriction, no adjustment of param- tionship between caloric intake and fertility, this amounts to eters in the model can reconcile it with the basic finding of a quadratic dependence of the effective reproductive rate on life extension due to caloric restriction, and, in fact, the op- caloric intake. Under these assumptions, Shanley and Kirk- posite result is predicted. It is an unstated prediction of the wood report that optimization can reproduce a smooth re- S-K model that breeding females should have a lifespan much lationship between longevity and food intake which agrees shortened compared to either males or nonbreeding females, qualitatively with the experimental findings.
and this is not observed. It is only from this shortened base-line that their model is able to predict life extension.
Shortcomings of the Shanley-Kirkwood Model Fertility is reduced but not completely curtailed in male Weaknesses of the model fall in three classes: First, there mice, even under severe calorie restriction (De Paolo 1993).
is a mismatch in breeding status between animals in the model The male control, fed ad libitum, consumed only half as much and in the laboratory. The model assumes 50% of total met- energy as a pregnant female to begin with. This male mouse abolic energy allocated to reproduction in the ad libitum con- on 50% caloric restriction still had most of its fertility (Merry trols, and this figure is only credible for pregnant or lactating and Holehan 1981), and weighed 60% as much as the control; females. But the laboratory experiments in which the CR yet it was more active (McCarter 1993), supported a stronger effect is observed typically compare nonbreeding animals, immune system (Venkatraman and Fernandes 1993), and male and female, with their CR counterparts. The model ap- lived one-third longer than the control (Weindruch and Sohal plied to males and to nonbreeding females unequivocally 1997). Where did the energy come from to fuel its increased predicts declining life span with declining caloric intake— Second, there are questionable assumptions in the for- Questionable Model of the Relationship Between Food mulation of the model: Among several variations in the mod- el, the only one that generates the observed qualitative be- As described above, Shanley and Kirkwood report several havior in the curve of life extension versus feeding level relies versions of the model results, only one of which reproduces upon a quadratically increasing relationship between the am- an allocation of food energy to maintenance which gradually bient food availability and the number of offspring success- decreases with increasing food supply, supporting results in fully weaned. This is justified with a kind of double counting, agreement with observation. The key element in the model that determines this behavior is the assumed relationship be- Third, there are disparities between the model results and tween ambient food supply and the probability of weaning the CR data: The model can explain the inverse relationship between food intake and lifespan only over a limited range In this version of the model, food intake is taken as a proxy of feeding levels; in experimental results, the relationship variable, predicting the availability of food in the environ- continues a smooth, quasi-linear behavior over more than a ment ten weeks in the future, when offspring conceived as factor of two, from the threshold of starvation at the low end a result of present fertility impose their greatest caloric de- to obesity at the high end (Weindruch et. al. 1986; Ross and mand on the nursing mother. The infants’ prospects for sur- vival through the nursing period is modeled as increasing Life span of nonbreeding female mice increases smoothly over a broad range as calories are reduced. Note that the increase Results of the best-fitting version of the Shanley and Kirk- continues substantially below the restriction level (80 K-cal) at wood model. Energy that is not allocated to reproduction is con- which female fertility is zero. This is difficult to reconcile with any sidered available for somatic maintenance. Graph is for reproducing model in which life-span extension derives from an energy reservoir females. Note that the plot should not be directly compared to Figure which is freed up as the animal diverts resources that had been 1 for this reason, and because both axes here have been normalized devoted to reproduction. Graph adapted from Weindruch and Sohal to body mass, which also varies with food intake. Graph adapted 1997, based on data from Weindruch et al. 1986.
linearly with ambient food availability, even as the mother’s food supply support a successively larger increment in the milk output per offspring is held constant.
In the base model, before this extra parameter is incor- porated, there is already a linear per-offspring energy cost of Ends of the Model’s Parameter Range reproduction, based upon published laboratory measurements Even the most successful variant of the S-K model cor- (Millar 1987; Bronson 1989). But in the variant model, each responds only to a limited range of the data for life extension of these offspring is assigned a probability of survival which from CR. The ends of the parameter ranges explored in their is scaled by a second factor of caloric intake/ad libitum. Thus, paper pose a difficulty, because the model has been optimized in this variant, the relationship between surviving offspring to work within these limits, and it falls apart at the bound- and available calories becomes quadratic. Without this qua- aries. There is a threshold feeding level at which fertility falls dratic dependence, the model fails to reproduce the quali- to zero. Below that level, somatic maintenance is predicted tative characteristics of life extension via CR.
to drop sharply with further caloric restriction. But in CRexperiments, lifespan continues to increase smoothly even at How the Shanley-Kirkwood Model Arrives at a the lowest feeding levels (Weindruch et al. 1986) (see Figs.
Many of our intuitions about optimization depend on the ‘‘law of diminishing returns’’: the more of a resource ex- Three Questions about the Model’s Theoretical Foundations pended in a given effort, the less that each additional incre- ment of allocation is able to accomplish. Very generally,optimization procedures converge because of diminishing re- The S-K model focuses on differential allocation of energy turns; in exceptional cases when diminishing returns fails, between reproduction and somatic maintenance; however, as the extremum is often obtained for variables at one end of progressive caloric restriction is imposed, the mouse’s prin- cipal adaptation is in neither of these variables, but rather in Under conditions characterized by diminishing returns, a body size. As total caloric intake is varied over a factor of reduction in the total amount of any resource always results three, body weight responds very nearly in proportion, and in a reduction in each of its optimized apportionments. Spe- it is not just adipose tissue that is affected, but muscle mass cifically, we expect that an increasing food supply should and most major organs, with notable exceptions of the brain result in parallel increases in energy allocations for fertility and the gonads (Weindruch and Sohal 1997). The net result and for longevity. In two variants of the S-K model, an in- is that the range of specific energy consumption (calories per crease in total caloric budget results in a decrease of the day per gram of lean body mass) varies by only 20%.
optimized portion allocated to somatic maintenance. Hidden Life history analysis can tell us how longevity and fertility in their assumptions is a violation of diminishing returns, in are related to fitness; but the relevance of size is much less the form of an effective fertility that varies quadratically with clear and, presumably, much less direct. The challenge not available caloric energy. Since the success of the model de- addressed by the S-K model may be stated: if energy allo- pends so critically on this relationship, the point becomes cation is optimized under genetic control to maximize fitness, crucial: why should each incremental increase in ambient then why, as feeding makes more energy available, is such a large proportion invested neither in fertility nor longevity food intake corresponds to more calories available for repair and maintenance. Only in the context of the model’s leastcredible variant is the observed sign for the relationship be- Is the measure of fitness appropriate? tween food intake and longevity correctly reproduced; andeven so, the result applies only to lactating females and only Consistent with common usage in the field of life histories, within a narrow range of the caloric intake variable. The DS the authors have applied a definition of fitness equivalent to theory remains an appealing and intuitively reasonable hy- the Malthusian parameter r in the Euler-Lotka equation, as pothesis; however, it may not be easily reconciled with a developed by Fisher (1958). It is appropriate to apply r-se- broad body of experimental data on caloric restriction.
lection to exponentially expanding populations; it places apremium on early reproduction, because each offspring is weighted by a factor eϪrt in its contribution to fitness. Theopposite extreme is K-selection, appropriate to steady-state Austad, S. 1995. Aging and caloric restriction: human effects and mode of action. Neurobiol. Aging, 16:851–852.
Benton, T. G. and A. Grant. 2000. Evolutionary fitness in ecology: Despite the ubiquity of Euler-Lotka in the literature, the comparing measures of fitness in stochastic, density-dependent use of r in steady-state environments (where, by definition, environments. Evol. Ecol. Res. 2:769–789.
r is identically equal to zero) entails paradoxes that have Bronson, F. H. 1989. Mammalian reproductive biology. Univ. of never been resolved. In fact, K may be very generally a more Charlesworth, B. 1994. The evolution of life histories. Cambridge robust measure of fitness than r, both as a theoretical tool and a model of real-world selection (Benton and Grant 2000).
De Paolo, L. V. 1993. Dietary modulation of reproductive function.
K-selection makes any pleiotropic theory of senescence (in- Pp 221–246 in B. P. Yu. Modulation of aging processes by cluding DS) more difficult to support (Mitteldorf, unpubl.
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Else, P. L. and A. J. Hulbert. 1987. Evolution of mammalian en- dothermic metabolism—leaky membranes as a source of heat.
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Thermodynamics of temperature maintenance Fisher, R. A. 1958. The genetical theory of natural selection. 2nd One of the competing energy demands invoked by Shanley Holliday, R. 1989. Food, reproduction and longevity: is the ex- and Kirkwood is the generation of heat, protecting the animal tended lifespan of calorie-restricted animals an evolutionary ad-aptation? BioEssays 10:125–127.
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rebuilding, and free radical scavenging. That useless fuel Ross, M. H. and G. Bras. 1975. Food preference and length of life.
burning has evolved instead is a fact that commands expla- Shanley, D. P., and T. B. L. Kirkwood. 2000. Calorie restriction nation; and on its face, this squandering of free energy casts and aging: a life history analysis. Evolution 54:740–750.
a shadow on any hypothesis that the caloric metabolism has Venkatraman, J. and G. Fernandes. 1993. Modulation of immune function during aging by dietary restriction. Pp. 193–220 in B.
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The Shanley-Kirkwood model is a serious and careful ef- Weindruch, R., R. L. Walford, S. Fligiel, and D. Guthrie. 1986. The fort to explain the observed relationship between caloric in- retardation of aging in mice by dietary restriction—longevity, take and lifespan in the context of the Disposable Soma the- cancer, immunity and lifetime energy intake. J. Nutr. 116: ory. Nevertheless, most versions of the model stubbornly predict what our intuition tells us is reasonable: that more

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