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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:B3-B9 (2004)
© 2004 The Gerontological Society of America

Sex Differences in the Effect of Dietary Restriction on Life Span and Mortality Rates in Female and Male Drosophila Melanogaster

Tapiwanashe Magwere, Tracey Chapman and Linda Partridge

Department of Biology, University College London, United Kingdom.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Dietary restriction (DR) has been shown to increase life span in taxonomically diverse animal species. In this study we tested for sex differences in the response of life span to graded severity of DR in Drosophila melanogaster. In both sexes, life span peaked at an intermediate food concentration and declined on either side. However, the magnitude of the response and the food concentration that minimized adult mortality differed significantly between the sexes. Female life span peaked at a food concentration 60% of the standard laboratory diet compared to a concentration of 40% for males. Moreover, female flies subject to DR lived up to 60% longer than did starved or fully fed females, whereas males subjected to DR lived only up to 30% longer. Analysis of age-specific mortality rates showed that DR extended life span by decreasing baseline mortality rates in both sexes, and to a greater extent in females. The differences in the response to DR in female and male Drosophila may be due to previously documented sex differences in sensitivity of life span to insulin/insulin-like growth factor-1 signalling or in nutrient/energy demand and allocation/utilization.

BIOLOGICAL ageing may be an inescapable fate (1), but experimental research has revealed that genetic and environmental interventions can increase life span (2–4). Because the invertebrate model organisms are relatively short lived and easy to maintain and manipulate under laboratory conditions, they have become an important resource for analyzing the mechanisms by which interventions such as dietary restriction (DR) increase longevity. At least some mechanisms of ageing show a remarkable degree of evolutionary conservation (2,4–7), and an understanding of ageing mechanisms in these invertebrate model organisms is therefore likely to be useful in identifying homologous mechanisms in mammals. For instance, the insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) pathway controls growth, development, reproduction, and ageing in Drosophila (8,9), Caenorhabditis elegans (10–12), and mice (7,13).

Dietary restriction is one of several interventions that has been shown to increase longevity in invertebrate and vertebrate organisms (14–17). Dietary restriction extends life span in the invertebrate model organisms such as the budding yeast Saccharomyces cerevisiae (18–20), the nematode worm C. elegans (21,22), the fruit fly Drosophila (23), as well as in laboratory rodents, where its effects were first discovered (14). During DR, life span reaches a peak as nutrition is lowered. With further reduction in nutrients, starvation causes life span to decline from the peak under DR (23,24). DR does not simply rescue the animal from the deleterious effects of over-nutrition, because DR reduces both age-specific and lifetime fecundity compared with those seen at higher levels of nutrition (23).

Although the effects of IIS on ageing show evolutionary conservation, there are also some striking differences in the effects on the sexes. In Drosophila, some mutations in the insulin receptor (Inr) have been shown to produce dwarf flies with increased female life span of up to 85% and shorter-lived males with reduced late age-specific mortality (25,26). Loss of chico (an insulin receptor substrate) in Drosophila also produces dwarf flies with increased median life span of about 48% in females (27), yet chico homozygous males are shorter-lived than controls (25,27). In the nematode C. elegans, mutations that cause reduction of function of daf-2 (an insulin/IGF-1 receptor that is homologous to the Drosophila Inr) confer greater life extension to male worms compared to hermaphrodites (28). In mice, deletion of the insulin receptor in adipose tissue led to an increase of 18% in life span in both males and females (7). By contrast, the extension of life span due to heterozygosity for a null mutation in the Igf1R receptor gene was seen only in females (7). Such sex differences may reveal important differences in the mechanisms by which the sexes age.

Although a lot is known about the effects of DR in several species of animals, sex-specific effects of DR on mortality rates and life span have so far rarely been investigated. In Drosophila, an effective DR regimen is exerted by means of food dilution as described by Chapman and Partridge (23). In this study, we used this method to test for sex differences in the responses of life span to graded severity of DR, to determine if the magnitude of the response and the level of DR that minimized adult mortality differed between the sexes, and to characterize the effects of sex on the mortality trajectories in populations subjected to DR.


   METHODS
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 Abstract
 Methods
Results
 Discussion
 References
 
Flies
Wild-type Drosophila melanogaster of the Dahomey base stock, obtained as previously described (23), were cultured in 189 ml bottles for two generations on normal strength 1.0 sucrose-yeast (SY) medium (Table 1) at standard density as previously described (29). Experimental flies were collected from the third generation and, of these, only flies that hatched within a 6-hour period were used for the experiment to ensure that the experimental cohort was of uniform age. Newly hatched flies were transferred to fresh bottles of 1.0 SY medium for a period of 24 hours to allow mating. The sexes were then sorted into female and male groups using CO2 anesthesia. Five hundred female or male flies were randomly allocated to each of 8 different food treatments. There were 5 bottles of 100 flies for each treatment, and the total number of flies of each sex was 4000. Flies were maintained throughout the experiment at 25°C and 60% humidity on a 12:12 hour light:dark cycle in controlled-temperature rooms, and were taken out briefly once every 2 days for transfer to fresh food and for the scoring of deaths.


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  		Table 1. Composition of the Different Sucrose-Yeast Fly Food Media.

 
Dietary Restriction
Eight types of food media were prepared, in which the concentrations of yeast and sugar varied from 20% to 160% of that in the standard SY food (Table 1). The standard SY food was used as a reference for the other food media and designated as "1.0 SY." Accordingly, the other food media concentrations were named in terms of their sugar and yeast content, relative to 1.0 SY. The treatments were 0.2 SY, 0.4 SY, 0.6 SY, 0.8 SY, 1.0 SY, 1.2 SY, 1.4 SY, and 1.6 SY. Nipagin (33 g/L) and propionic acid (3 ml/L) were added as antifungal and antibacterial agents. Agar content was varied between 12.5 g/L and 20 g/L to ensure that the consistency and availability of moisture was similar in all food media. Daily and lifetime fecundity of females increases over this range of food concentration (23). The DR method that we used corresponds to that used in rodents, in that it takes down total calories in a coordinate fashion.

Cumulative Survival Statistics and Mortality Trajectory Analyses
Log rank tests (30) and estimations of mean/median life spans were performed using JMP statistical software version 5.0 (SAS Institute, Inc., Cary, NC). Analysis of mortality trajectories was done by using the Gompertz model available in WinModest (31) statistical software. The mortality rate (µx) at age x can be expressed mathematically as: µx = -ln(px), where px is the probability of an individual alive at age x surviving to age x + 1 (32). In the Gompertz model, the increase of mortality (µx) with age (x) is expressed as: µx = aebx, where the constant a is the intrinsic baseline mortality rate, and b is the rate at which mortality rates accelerate with age (33). Taking natural logarithms of the Gompertz equation gives a linear function: ln(µx) = lna + bx, which is analogous to a straight-line with slope b and intercept a on the vertical axis. A comparison of the intercepts and slopes of the mortality trajectories was used to assess the impact of each food medium concentration on female and male mortality rates and to compare mortality rates between the two sexes at each food level.


   RESULTS
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 Abstract
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 Results
Discussion
 References
 
Effect of Food Concentration on Cumulative Survival
The cumulative survival curves for female (Figure 1A) and male (Figure 1B) flies maintained on the different food media show that, for both sexes, survival peaked at an intermediate food concentration and declined on either side. However, the food concentration at which life span peaked differed between the sexes and was higher for females. In females, life span was maximized at a food concentration of 0.6 SY. Comparisons of survival using the nonparametric log rank tests (30) showed that female survival was significantly greater on 0.6 SY food than on either 0.8 SY (Chi-squared [{chi}2] = 4.258, p =.039) or 0.4 SY ({chi}2 = 6.792, p =.009). In contrast, in males, life span was maximized by a food concentration of 0.4 SY, with life span significantly lower on 0.6 SY ({chi}2 = 6.901, p =.009) and 0.2 SY ({chi}2 = 39.436, p <.0001).



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  		Figure 1. Cumulative survival curves for (A) female and (B) male Drosophila melanogaster kept on different food media ranging in concentration from 20% sucrose-yeast (0.2 SY) medium to 160% sucrose-yeast (1.6 SY). Each curve represents the average profile of 500 flies per food type divided into 5 groups of 100 (100 flies per 189 ml bottle). Rearing of the flies was done from eggs under standard density conditions and the flies were allowed to mate before being separated into the different treatment groups. Flies were transferred to bottles of fresh food of the appropriate concentration once every 2 days, and deaths were scored simultaneously

 
The response of life span to DR was also greater in females than in males (Figure 2). In females, median life span was maximal at 51 days on 0.6 SY, and was reduced by 39% to 31 days on 1.6 SY and by 31% to 35 days on 0.2 SY. In males, median life span was maximal at 41 days on 0.4 SY, and was reduced by 24% to 31 days on 1.6 SY and by 10% to 37 days on 0.2 SY. Female flies were more sensitive to the effects of DR and starvation because they exhibited a larger drop in median life span on either side of the peak than did males (Figure 2).



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  		Figure 2. Effect of different food concentrations on median life span in female and male Drosophila

 
Effect of Food Concentration on Mortality Trajectories
Mortality trajectories are a useful method for studying the age-specificity of the effects of interventions that affect survival. Because survival curves are cumulative, age-specific effects cannot be easily analyzed. In contrast, in a mortality trajectory, the mortality rate (the proportion of individuals that enter a time interval who die during it) is calculated independently for each age. The mortality trajectories for female and male flies exposed to the different food concentrations showed a different pattern for females and males (Figure 3). DR resulted in an apparent delay in the onset of ageing-related mortality compared with the trajectories for starved or fully fed female (Figure 3A) or male (Figure 3B) flies. The effect of DR on mortality trajectories in Drosophila is similar to that previously reported (34,35). Further analysis of the mortality rates using the Gompertz model in this study gave values for the parameters a and b as shown in Table 2. DR in female flies dramatically decreased the intrinsic baseline mortality rate for 0.6 SY [a = 0.00006 (lower, upper 95% confidence limits: 0.00004, 0.00010)] compared with starved 0.2 SY [a = 0.00301 (0.00235, 0.00387)] or fully fed 1.6 SY [a = 0.00800 (0.00649, 0.00987)] flies. The rate at which mortality rates accelerated with age in female flies was, however, greater in DR [b = 0.14533 (0.13574, 0.15560)] compared with either starved 0.2 SY [b = 0.08825 (0.08154, 0.09551)] or fully fed 1.6 SY [b = 0.06327 (0.05724, 0.06993)] groups. In male flies (Table 2), a similar picture emerged to that seen in female flies except that, as shown earlier (Figure 2), the magnitude of the effects were less than those obtained for female flies. DR in males decreased the initial risk of death for 0.4 SY [a = 0.00099 (0.00071, 0.00136)] compared with starved 0.2 SY [a = 0.00222 (0.00171, 0.00288)] and fully fed 1.6 SY [a = 0.00411 (0.00327, 0.00516)] flies; but the rate of increase of mortality with age was not altered significantly regardless of whether the flies were under DR [b = 0.09973 (0.09238, 0.107660], starved [b = 0.08760 (0.08124, 0.09445)], or fully fed [b = 0.08016 (0.07401, 0.08682)]. From these results it can be surmised that DR increases median life span in Drosophila by decreasing the initial intrinsic baseline mortality rate, and more so in females than in males. The rate at which mortality rate accelerates with age does not seem to play a significant role in the response of life span to DR or to starvation.



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  		Figure 3. Mortality trajectories for (A) female and (B) male Drosophila melanogaster maintained under the different feeding conditions shown in Methods. The female and male mortality trajectories were truncated for clarity, and only the portions ranging between 10 and 50 days of age are shown

 

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  		Table 2. Parameter Values for the Gompertz* Mortality Model Showing the 95% Confidence Intervals for Each.

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The principal finding from this study is that the response of life span and mortality rates to DR differs between female and male Drosophila. Female life span peaked at higher food concentration and was more responsive to DR. In addition, DR delayed the onset of the age-related mortality rate increase, and this delay was more marked in females than in males. Two possible explanations for the sex differences are: 1) there are differences in nutrient demand and energy allocation between the two sexes, and 2) there are differences in insulin/IGF-1 signalling between male and female Drosophila. This list is not exhaustive, and these two hypotheses are not mutually exclusive, due to the possible roles of the IIS pathway in regulating metabolic processes that involve nutrient demand and energy allocation and in mediating the response of life span to DR in Drosophila (24,36).

The greater response of female life span to DR and the peaking of female life span at a higher food concentration than for male life span may reflect a higher nutrient demand in females needed to maintain egg production. Daily fecundity declines under DR in female flies (23). A study of RNA transcript profiles showed that, in adult females under DR, genes involved in cell growth, metabolism, and reproduction exhibit relatively lowered transcript representation (34), reflecting the decline in processes related to fecundity. If the down-regulation of reproduction in females plays a causal role in life span extension, then the response of males to DR may differ. This is because the high throughput of nutrients into eggs that occurs in females is not mirrored in males, in which the main life-shortening aspect of reproduction is activity and courtship (37). Differences in energy intake and energy expenditure between female and male flies have been reported (38). It is known, for example, that increasing sucrose concentration in the food medium encourages feeding by female flies and results in increased egg production, whereas the food intake of males is not altered by sugar concentration (38). In mammalian species, it has also been shown that the availability of metabolic fuels seems to increase reproduction and that the energy demand is higher in females than in males (39,40). It is probable, therefore, that female animals generally have greater nutrient demands for reproduction than do their male counterparts, and the differences in the response to DR between the two sexes could result from differences in the basic physiological processes of determining how extra energy is allocated or utilized.

Alternatively, the reason why female flies show a more marked response to DR than male flies could reflect sex differences in IIS (27). IIS has been implicated in mediating the response of life span to DR in Drosophila. Female flies homozygous null for the chico1 mutation subjected to graded DR showed a response that was right-shifted relative to controls, with the life span peaking at a higher food concentration in the chico1 flies (24). This suggests that the effects of DR and reduced IIS may involve common mechanisms. Male flies show a lower increase in life span than do females in response to reduced IIS and their life span decreases with stronger reductions in IIS, while that of females continues to increase. Taken together, these results suggest the hypothesis that IIS is constitutively reduced in males relative to females. This would be consistent with the greater longevity of wild-type males compared to chico1 mutant homozygotes. However, if this were the case, it would predict that males' response to DR would be right-shifted relative to females. In fact, it is weakly left-shifted (Figure 2).

Males appear typically to be longer-lived than hermaphrodites in nematode species such as C. elegans (41,42). In C. elegans, increased male life span is dependent on the IIS-regulated transcription factor daf-16 (28). Yet, unlike Drosophila, daf-2 mutant males are longer-lived compared to hermaphrodites, and the basis for this sex difference is unclear. In mammals, despite the abundance of data on the effects of DR on life span, there is a paucity of information on how sex differences in IIS could influence life span. Some studies have shown a sexual dimorphism in factors that affect growth hormone signalling in rats and lambs (43,44), but still no data on the effect of this on life span. Nor are there reports of systematic studies of sex difference in the response to DR in mammals.

While, in rodents, it has been demonstrated that the effects of DR are due to reduced caloric intake (14,45), in fruit flies, the precise mechanisms by which food dilution affects life span remain to be fully characterized. Our dilution procedure takes down the caloric content of the food without changing the ratio of its ingredients. Several studies have shown that reduction in the availability of yeast can shorten life span through starvation (46–49). However, it remains to be determined whether yeast is the crucial ingredient for producing starvation when SY medium is diluted, or whether sugar also plays a role. The identity of the nutrient(s) responsible for the increase in life span in response to DR has not yet been investigated. Work with defined diets will be valuable in this context. Ingredients such as "yeast" vary greatly in chemical composition between batches from the same supplier and different suppliers, making direct comparison of the results from different laboratories impossible. There may also be differences between Drosophila strains in the response to DR.

Conclusion
Results in this study have shown that both male and female Drosophila show a positive response to DR, although the magnitude of the response and the level of DR that minimized adult mortality and increased life span differed between the sexes. Such sex differences in response to DR could be caused by differences in physiological processes of nutrient energy intake and expenditure/allocation, or sex differences in insulin/IGF-1 signalling. A paradox emanating from our results is that males and females of the same species may be as different from each other as are different species in terms of ageing patterns under DR. The large magnitude of the sex difference in response to DR point to the existence of major differences in the biological determinants of ageing in females and males. Further study of these differences promises to yield deeper insight into the physiological and evolutionary determinants of ageing.


   Acknowledgments
 
We thank the Experimental Research on Ageing initiative of the Biotechnology and Biological Sciences Research Council for the research grant to L. P. and T. C. and the Professorial Fellowship to L. P.; and the Royal Society (University Research Fellowship to T. C.) for funding. We also thank David Gems (University College London) for insightful discussions and comments on the manuscript, and Brian Merry (University of Liverpool) for providing useful information on the subject.

Address correspondence to Linda Partridge, DPhil, University College London, Department of Biology, Darwin Building, Gower Street, London WC1E 6BT, U.K. E-mail: l.partridge{at}ucl.ac.uk


   Footnotes
 
Decision Editor: James R. Smith, PhD

Received July 25, 2003

Accepted October 3, 2003


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