Sci. Aging Knowl. Environ., 26 November 2003
Vol. 2003, Issue 47, p. pe32
[DOI: 10.1126/sageke.2003.47.pe32]

PERSPECTIVES

Linking Development and Aging

Bas J. Zwaan

The author is in the Evolutionary Biology Department, Institute of Biology, Leiden University, Kaiserstraat 63, 2311GP Leiden, The Netherlands. E-mail: Zwaan{at}rulsfb.leidenuniv.nl

http://sageke.sciencemag.org/cgi/content/full/2003/47/pe32

Key Words: insulin signaling • life history • calorie restriction • development

Genes and Aging

The life history of organisms reflects adaptations to the natural environment in which they live (1). Diverse traits such as growth rate, size, age-specific fecundity, and age-specific survival are coordinated to ensure maximum reproductive success, given the physical, historical, developmental, and genetic constraints. What matters in evolutionary terms is not to avoid aging but to achieve full potential reproduction given the prevailing environmental conditions. Thus, increased reproductive output is selected for even if it is accompanied by decreased late-life survival (see Williams Classic Paper). Aging, therefore, should be seen as a lethal side effect of this adaptive process (2). All organisms are subject to this process, and hence the genetic, developmental, and physiological mechanisms that result from this selection are expected to be conserved in diverse evolutionary lineages. These mechanisms are then "public" in the sense of being common to many species (Fig. 1A) (3). It is important to note that this realization yields a strong argument for studying several invertebrate organisms in different evolutionary lineages as models for mammalian and human aging. Clearly, late-acting deleterious mutations that accumulate over evolutionary time can contribute to increased mortality at late ages (that is, to aging), but because mutagenesis is a random process, these aging effects can be species-specific ("private") (Fig. 1A) (3).



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Fig. 1. The expression of different classes of genes relevant to reproduction, aging, and longevity throughout the life history of an insect. Here I use the seasonal tropical butterfly Bicyclus anynana as an example. The developmental stages of the butterfly are similar to those of the fruit fly. The gray shading represents the importance of the genes during a particular life stage (light-to-dark shading represents low-to-high importance). (A) A more classical view, in which the effects of developmental genes and pathways are restricted to development until sexual maturation. Also indicated are the public and private genes. Note that the effects of the private genes are restricted to late in life, where the efficacy of natural selection against these deleterious mutations is very low. (B) A more realistic view of how pathways that are active during development and in the adult affect an organism's entire life history. These pathways are mostly hypothetical at this stage, but given the ample evidence for developmental influences on adult traits, their discovery seems to be only a matter of time. Note that these pathways do not exclude the existence of separate pathways that regulate developmental or adult life, but not both.

 
Insulin/IGF Signaling: A Public Mechanism

The insulin/insulin-like growth factor (IGF) signaling pathway (INS pathway) has emerged as an evolutionarily conserved pathway that regulates life span and reproduction. Beginning with the identification of genes in the dauer pathway of the nematode Caenorhabditis elegans as members of the insulin signaling pathway (4) (see Johnson Review), the role of the INS pathway in longevity determination has since been confirmed in flies (Drosophila melanogaster) (5, 6) and mice (Mus musculus) (7, 8) (see "One for All"). In addition, the yeast Saccharomyces cerevisiae has an intracellular pathway that shows some similarities to the INS pathway (9) and has similar effects on longevity (see Kaeberlein Perspective).

These studies share a common denominator in that mutations spectacularly extend life span in these organisms by reducing INS signaling, but this pathway also affects growth, development to sexual maturity, and reproduction (10). Other mutations that extend life span have also been found in model organisms (see SAGE KE's Genes/Interventions database) (11-13). Establishing the relationships between these genes and the pathways in which they function and the INS pathway within and between species (that is, public or private mechanisms) is a major challenge for the future. However, I maintain that robust functional and evolutionary insights from such mutants can only be gained when the effects on aging and longevity are measured in the environments in which the genes and their pathways were shaped by natural selection. In other words, it is essential that the tools of environmental manipulation and of gene-by-environment (GxE; determining the dependence of the gene or genotype effect on the environment) interactions become much more widely used than they are now (14).

The Importance of Environmental Manipulation and GxE Interactions

In C. elegans and D. melanogaster, the importance of GxE interactions for interpreting the function of the INS pathway has been demonstrated by manipulating environmental conditions. Under experimental conditions designed to mimic the worm's natural environment, age-1 (phosphatidylinositol 3-OH kinase catalytic subunit) mutants suffer a 23% reduction in fitness relative to wild-type worms (15); this change in fitness had remained unnoticed under standard laboratory conditions. Furthermore, flies that carry mutations in the gene that encodes the Drosophila homolog of the insulin receptor substrate (chico) exhibited a longer life span than wild-type flies only when the adults were kept on concentrated food; chico flies had a shorter life span than wild-type flies when kept under diluted food conditions that are more likely to mimic their natural habitat (16). Moreover, altered expression of the Indy gene (I'm not dead yet), which encodes an aberrant membrane protein involved in the transport of Krebs cycle intermediates (see Rogina Science article), doubles the fly life span, but Indy mutant flies show decreased fecundity only when they are calorically restricted as adults (17).

There are at least two reasons to study environmental manipulations and GxE interactions. As mentioned above, the first is to fully understand the function of longevity-determining pathways. The second is to determine the critical stage of the animal's life history in which these pathways need to be (de)activated to affect aging and longevity. An experimental approach that addresses this second reason must include an analysis of the environment during the development of the organism and how this environment influences adult traits. In a recent paper in the journal Aging Cell, such an approach was taken by Tu and Tatar using D. melanogaster (18).

Does Larval Food Restriction Mimic Reduced Insulin Signaling?

The question that Tu and Tatar asked themselves was the following: At what stage(s) does INS need to be reduced to yield increased longevity in flies? Using an RNA interference (RNAi) approach, Kenyon and colleagues (see Dillon Science article) showed that, in worms, suppression of the insulin/IGF-like pathway from hatching until the last larval stage lengthened the reproductive period. In addition, suppression of INS only during larval development, but not during adulthood, did not increase life span. Finally, when suppression of INS was begun in young adults, life span was increased, but reproduction was not affected (see Sonntag Perspective).

As a first approach to the timing question in flies, Tu and Tatar manipulated the larval diet to examine whether this change was sufficient to slow aging. This reasoning makes sense, because like the INS mutations, reduced larval feeding delays development and reduces adult size. Larvae were reared under standard (sucrose-cornmeal-agar-yeast) food conditions up until the third larval instar (92 to 96 hours after egg laying). After this time, the fly larvae were transferred to vials that contained either the standard medium (yeast-fed) or medium without yeast (yeast-deprived). The characteristics of the resulting adults were compared across these groups.

The yeast-deprived adults indeed phenocopied many of the traits of the INS mutants, such as small body size, longer developmental time, and reduced ovariole number (a measure of potential fecundity) (18). Probably as a consequence, lifetime fecundity (the number of eggs laid during the life of females) was reduced by 65% in adults that resulted from yeast-deprived larvae. This reduction in reproduction was apparent at every age. Remarkably, though, age-specific mortality (a measure of aging) and mean life span did not differ for the yeast-fed and yeast-deprived females (it is mentioned in the text that the same applies to males, but no data are given for male flies). Life span was measured using groups of flies with both sexes mixed; because sex has been shown to affect life span (19), it would be interesting to measure mortality and life span in single-sex groups to avoid the potential confounding effects of sexual activities on aging and life span.

Because the yeast-deprived adults were much smaller than the yeast-fed adults, Tu and Tatar calculated the total reproductive investment in terms of egg volume per unit of female fly volume and found that, as a relative effort, reproduction was reduced by 48% in adults that resulted from yeast-deprived larvae. Although these figures are convincing, some caution is warranted, because the quality of the eggs (for example, water content) was not determined.

Previous research from the Tatar group showed that reduced INS results in a juvenile hormone (JH) deficiency. Treatment of INS pathway mutants with a JH analog restores normal life span, indicating that the decreased JH concentrations resulted in an extended life span (6) (see Tatar Science article). The lack of life span extension in the yeast-deprived adults indicates that synthesis of the insulin-like peptide, which activates INS, and of JH should be normal in these adults. Insulin activity was assessed by Tu and Tatar (18) by immunostaining of the insulin-like protein in the neurosecretory cells of the pars intercebralis in the adult brain. For this experiment, only female adults from yeast-deprived larvae were used. At eclosion, yeast-deprived females displayed small insulin peptide-containing vesicles. However, once these flies reached adulthood and were fed yeast, they attained a normal insulin-like protein staining pattern. These results indicate that the females that were yeast-deprived before adulthood displayed a normal insulin signaling response to yeast feeding as adults. The corresponding data were not shown for adults that were yeast-fed during development.

In addition, both the flies that were yeast-deprived and those that were yeast-fed during development showed qualitatively similar patterns of JH synthesis when either fed yeast or deprived of yeast as adults: JH synthesis increased upon yeast feeding but was suppressed under adult yeast-deprived conditions. This finding fits with the observation that neither life span nor the age-specific mortality pattern (aging) differed between the two groups of adults. However, the authors also note that the JH concentrations at eclosion differed between the two groups (they were higher in adults that were yeast-deprived during development). Moreover, the quantitative differences in JH synthesis between the two groups were large, but this is not discussed in the paper: The adults that resulted from yeast-fed larvae showed much higher JH synthesis over the first 3 days of life than did the adults from yeast-deprived larvae when both groups were fed yeast as adults. Under adult yeast-deprived conditions, the differences between the groups that were present at eclosion persisted throughout the 4 days during which JH synthesis was measured. At this stage, it is unclear what the significance of these differences is, but they warrant further investigation (see below).

From these observations, the authors conclude that caloric restriction during larval life influences many adult life history traits, but that only caloric restriction in adults prolongs adult life [for example, see (20)]. Moreover, they suggest that, similar to the observations made with worms, the suppression of INS must occur during adulthood to have an effect on aging. They also conclude that decreased fertility and increased life span don't always go hand in hand.

The Link Between Development and the Adult Stage of Life

The study of Tu and Tatar (18) is not the first to report on the effects of larval development on adult life span and aging. Most relevant to this study are the effects of larval crowding (that is, a high density of developing larvae in vials or bottles). Four studies have reported that adults resulting from high larval density conditions exhibit increased life span (21-24). One consequence of larval crowding is a reduction in the amount of food (including yeast) available per larva. Two other components are an increased level of competitive interactions among conspecifics and the influence of larval waste products. The Tu and Tatar study (18) neatly confirms the results of a previous one in which the components were analyzed separately (24). Dilution of the larval food throughout growth prolongs developmental time and decreases adult size in a way similar to larval crowding but does not affect adult life span [the food effect (24)]. However, increasing the number of larvae per vial while keeping the ratio of units of yeast per larva constant only marginally affects developmental time and adult size but, comparable to larval crowding, does increase adult life span [the density effect (24)]. Larval crowding appears to be a stress factor for developing larvae, because heat shock protein 70 (Hsp70) expression is induced in these larvae (23). Heat stress-related adult traits (such as time until heat coma at 37°C) are also increased in adults that emerged from the high-larval-density treatment, but adult Hsp70 expression is independent of larval developmental conditions (23). The cellular mechanisms that are activated because of the larval-density stress apparently carry over to adult life ("hardening memory") (23) and must have affected pathways in adults other than those that involve Hsp70 expression.

The Tu and Tatar study (18) and the observations summarized above indicate that future work needs to focus more on the relationship between development and aging. For example, is the density effect during development related to a change in the INS pathway? Moreover, Tu and Tatar (18) use the important tools of environmental manipulation, but they could have taken it one step further, namely, by measuring the adult traits not only under affluent conditions but also under deprived conditions. The adults resulting from yeast-deprived larvae may then be favored in terms of survival and egg laying, because of the "hardening" effect. The quantitative differences in JH synthesis patterns between the two experimental groups (see above) might be relevant in these respects. This idea is akin to what is known as the "thrifty genotype" in humans (25, 26). The original idea was that during human evolution, quick response by the INS pathway to food conditions was selected for to ensure maximum glucose intake and minimize renal glucose loss. However, as a result of this selection, affluent conditions, such as a continuously high food supply, result in obesity, insulin resistance, and diabetes mellitus. Unfortunately, the "thrifty phenotype" hypothesis of Barker (27) has also been applied in the context of the observation that poor nutrition early in life (mainly during the prenatal period) produces permanent changes in glucose-insulin metabolism, such as reduced capacity for insulin secretion and insulin resistance. Therefore, experiments must be designed that distinguish between these various concepts.

Some Recommendations

When applying different environmental conditions during development, it is essential to address whether the effects on adult life are (i) adaptive (that is, increase reproductive success) or (ii) the result of a general, nonadaptive, physiological response (for example, due to a general breakdown of homeostasis). Distinguishing between these possibilities can be achieved by using environmental manipulation not only during development but also during adult life. Moreover, the effects of such manipulations need to be studied in a variety of relevant genotypes (for example, in other selected lines with INS defects) or strains with different mutations. For example, if INS mutants respond similarly to the Tu and Tatar treatment, then this provides strong evidence that the larval food-deprivation treatment does not involve the INS pathway. This is because the INS mutations already lower INS, and any additional effect of food deprivation on adult INS is expected to be less than for wild-type flies. In other words, the involvement of INS in the food-deprivation treatment would show up in an analysis of variance as a significant "treatment by genotype" interaction.

On another level, illustrated by the INS pathway in Fig. 1B, researchers need to distinguish among three types of developmental influences on adult traits: (i) the aforementioned general effects on organismal homeostasis (see the Barker hypothesis above); (ii) the existence of genetic variation in developmental genes and genetic pathways that exert their effects on other traits (Fig. 1B); and (iii) developmental influences that reflect the flexibility of a given pathway in reacting to environmental conditions and the ability of that pathway to change the adult life history. For instance, the INS pathway tunes organismal energy expenditure to prevailing external food conditions. In Drosophila, the insulin-like peptides are coded for by several genes, but only some of these are regulated by nutrient availability (28).

To me, it is clear that research in the field of aging should expand to include the study of (early) developmental processes within the context of reproduction, longevity, and aging. I take this stance not only because there is ample evidence that developmental processes affect adult life but also because evolutionary theory predicts that natural selection has worked to integrate the whole of an organism's life history, which includes the development process. This approach will eventually lead to the identification of genes and pathways that are relevant for development alone, for adult life alone, and for both development and adult life (Fig. 1B). As a first task, the pathways that have already been implicated in aging and longevity should be investigated in this light. We should therefore applaud the approach of Tu and Tatar.


November 26, 2003
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Citation: B. J. Zwaan, Linking Development and Aging. Sci. Aging Knowl. Environ. 2003 (47), pe32 (2003).




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