Sci. Aging Knowl. Environ., 14 July 2004
Vol. 2004, Issue 28, p. pe30
[DOI: 10.1126/sageke.2004.28.pe30]


Sex-Specific Effects of Interventions That Extend Fly Life Span

Joep M. S. Burger, and Daniel E. L. Promislow

The authors are in the Department of Genetics, University of Georgia, Athens, GA 30602-7223, USA. E-mail: jmburger{at} (J.M.S.B)

Key Words: gender • sex-specific mortality • longevity assurance genes


In 1934, Señora Belmar was captured in Mexico, imprisoned in a basement, and fed a diet of grasshoppers and beetles; she died nearly 16 years later (1). The Señora, a female tarantula, exemplifies the high life expectancy of mature female spiders. Tarantulas reach maturity between 8 and 13 years (1). Mature males usually live for 2 to 3 months, whereas mature females often live from several years to more than 10 years (1-3). Even among mammals we see some equally striking examples, as in the brown marsupial mouse Antechinus stuartii. Antechinus males and females mate during a brief period when they are 11 months old, after which the males, and only the males, experience a catastrophic die-off over the course of a week (4, 5). Life expectancy can be female-biased, as in most mammals (6); male-biased, as in most birds (7) and nematodes (8); or unbiased, as in some dioecious plants (9, 10). But until now, most of our research efforts investigating life span differences have focused not so much on differences between the sexes, but rather on differences among genotypes (11) and species [for example, (12)]. The few comparative studies on sex differences in longevity highlight the importance of sexual selection in influencing survival rates (13). Some comparative studies have pointed fingers at sex differences in body size, costs of reproduction, and mating behavior (6, 14). Several analyses of quantitative trait loci for longevity have identified genes that appear to act in a sex-specific manner. For example, Mackay and colleagues have identified quantitative trait loci that are associated with an increase in male life span but a decrease in female life span (15-17). And a few intriguing studies suggest that some genes that are beneficial in one sex may be deleterious in the other, such as genes for male accessory gland proteins in Drosophila, whose products can enhance male reproductive success at the expense of female longevity (18-20). However, we know little about the genetic basis of these sex differences and about why the sexes might differ in how they respond to longevity-altering interventions.

In recent years, geneticists have identified single-gene mutations acting in a variety of different pathways that can dramatically extend life span in model organisms [for example, (21-24)]. Perhaps the most successful manipulation known to extend longevity is dietary restriction (DR) (25), which functions in diverse taxa, including yeast, worms, flies, mice, and rats [for a critical review of DR, see "Dietary Drawbacks" (26) and the Masoro Review]. A recent study by Magwere and colleagues (27) illustrated that DR experiments may help us to understand sex differences in longevity. Magwere et al. found that the effect of DR is highly sex-specific in the fruit fly Drosophila melanogaster. Previous studies typically have tested just two conditions: ad libitum feeding versus reduced nutrients. Magwere et al. tested for enhanced life span under eight different nutrient conditions, from 20 to 160% of normal yeast and sucrose concentrations. In their study, both males and females exhibited an enhanced life span under conditions of DR. However, the food concentrations that maximized life span were slightly greater in females than in males. More important, female flies subjected to DR showed up to a 60% increase in life span as compared to controls that were not subjected to DR, whereas male flies subjected to DR exhibited only a 30% increase in life span as compared with male controls. These findings suggest that variations in the response of flies to DR may result from sex differences either in resource acquisition and allocation or in the insulin/IGF-1 signaling pathway. Some researchers have suggested that DR extends life span by reducing reproduction, and the cost of reproduction is higher in females than in males (28). However, subsequent work carried out in the Partridge lab (29) showed that the increase in female life span with DR occurs even in sterile females (ovoD mutants). A similarly sex-specific response was found in a recent study of fly mutants in which superoxide dismutase (SOD) was overexpressed in the motor neurons (30). The SOD mutant was crossed into 10 different wild-caught genetic backgrounds. The authors found that in 6 of 10 genetic backgrounds, SOD significantly increased life span in females. However, SOD increased male life span in only 1 of 10 genotypes. These findings suggest that other biological manipulations can also give rise to sex differences related to life span. Understandably, the current focus in biology of aging research is on genetic and environmental interventions that extend life span. One might argue that the sex-specificity of such a response is of secondary interest to whether there is a response at all. But understanding sex differences in the response to life span-extending manipulations should lead to novel insights about the basic mechanisms that underlie the biology of aging in both sexes.

The timely study of Magwere et al. suggests the need for a broader review of sex differences in response to genetic or environmental manipulations. With this in mind, we review the literature on sex-specific effects of interventions that extend life span in D. melanogaster and carry out a simple metaanalysis. In addition, we discuss possible explanations for the observed sex-specific differences and suggest various ways in which we might test these hypotheses.

Do the Sexes Respond Differently to Life-Extending Manipulations?

Both Magwere et al. (27) and Spencer et al. (30) found that female life span is increased to a significantly greater extent than male life span in response to manipulations. We first set out to determine whether this is a general phenomenon. We examined data from all of the sources listed in the SAGE KE genes/interventions database, as well as other articles on D. melanogaster that cited an increase in life span in response to genetic or environmental interventions. To standardize the response variable, we calculated the change in median or mean life span for males and females. If neither mean nor median life span was given in the articles, we calculated the mean life span from the Gompertz parameters. The results of these analyses are shown in Supplementary Table 1 for 56 genetic and 41 environmental interventions. The sex-specific effects are plotted in Fig. 1. More detailed measures of aging are given in Supplementary Table 2.

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Fig. 1. Sex-specific effects of interventions that extend life span in Drosophila. Plotted is the percentage change in median or mean life span caused by a genetic or environmental intervention in males against the percentage change in median or mean life span caused by a genetic or environmental intervention in females. Numbers correspond to those in the first column of Supplementary Tables 1 and 2. Numbers 1 to 24 are genetic interventions, and numbers 25 to 46 are environmental interventions. Sex-specific effects were either significant (red), not tested (blue), or not significant (black). Data points above the diagonal represent male-biased effects; data points below the diagonal represent female-biased effects.

The first conclusion that can be drawn from Supplementary Tables 1 and 2 is that in about half of the experiments (50 of 97), either only one sex was tested (44 experiments) or the sex was not specified (6 experiments). This includes well-known genetic interventions such as the methuselah mutant (mth) and overexpression of heat shock protein genes (hsp) and the manganese superoxide dismutase gene (SOD). In the majority (41) of the 44 single-sex studies, only males were studied, but this choice is made without giving any rationale. As an exception, Marden et al. (31) explicitly stated that they used only males to avoid confounding factors associated with female reproduction. In all other cases, it is not clear whether the opposite sex was omitted because it showed no effect or because it was simply easier to work with only one sex. Second, in 31 of the 47 interventions where both males and females were tested, no attempt was made to determine whether the sexes showed significant differences in their responses (that is, changes in life span) (Fig. 1). This suggests that sex-specific effects have been largely ignored. Third, when researchers explicitly measured the responses of male and female flies to the treatment, the effect was greater in females than in males (female-biased) in 8 of 16 cases [virginity, InR, chico, DTS- (encodes a protein involved in ecdysone biosynthesis), dietary epithalamin, DR, and overexpression of human cytosolic Cu/Zn superoxide dismutase (SOD)]; male-biased in 5 of 16 cases [exposure to hypergravity, dietary epitalon (a synthetic peptide related to epithalamin), selection for desiccation resistance, and dietary silkworm moth extract], and not significantly different in only 3 of 16 cases (EcR, PCMT, and selection for longevity).

Two notes of caution should be given here. First, a strong positive effect on mean life span is often caused by a reduction in the age-independent baseline mortality rate (that is, the intercept of the Gompertz curve, plotting the log-transformed mortality rate versus age). However, some interventions, such as mutations in the methionine sulfoxide reductase gene (MSRA) and DR in female flies also increase the rate of age-specific mortality (that is, the slope of the Gompertz curve) (see Supplementary Table 2). Thus, by definition, these flies live longer but age faster. Second, whether a sex-specific effect is observed may depend on the nature of the control fly line that is used in the experiment. For example, Orr et al. (32) showed that overexpression of the antioxidative enzymes Cu/ZnSOD, MnSOD, catalase, and thioredoxin reductase did not extend life span when the control strains were relatively long-lived; and Spencer et al. (30) found that the life span extension in flies that overexpress human SOD depends on the genetic background of the flies. In the Magwere et al. study (27), flies subjected to DR lived 65% (females) and 32% (males) longer than flies cultured on high concentrations of sucrose and yeast. However, the life span extension was only 9% (females) and 11% (males) when compared with flies that were fed standard fly food medium. Perhaps the pertinent question in their study is not why DR enhances life span in females more than in males, but why females, which normally live longer than males, show a much greater reduction in life span than do males when cultured on high-concentration sucrose/yeast medium.

Why Do the Sexes Differ in Response to Life-Extending Manipulations?

We are left with a conundrum. Where researchers have bothered to measure the effects of a genetic or phenotypic manipulation in both sexes, they have found that sometimes males respond more than females and sometimes the opposite is true. Given this substantial variation in sex-specific response, it will be no easy task to determine just what genetic or environmental factors are responsible for the observed differences in the response of male and female flies. However, at this point we can at least put forward a few general classes of hypotheses that we think are worth exploring. These are not meant to be mutually exclusive or exhaustive.

Genetic differences between the sexes. Work in Trudy Mackay's lab (15-17) has demonstrated that there are genes with sex-specific effects on life span. Genetic manipulations could result in sex-specific effects either directly by changing the expression of such genes or indirectly through epistasis (for example, see the Omholt Perspective). Environmental manipulations could result in sex-specific effects through interactions between the environment and genes with sex-specific effects.

Physiological differences between the sexes. Females have a higher nutrient demand than males, because egg production is energetically more costly than sperm production. Moreover, females distribute resources mainly to eggs, whereas males allocate resources mainly to activity and courtship (33). If life span extension is caused by a down-regulation of reproduction, then the response is expected to be female-biased. The sexes may also differ in the physiology of pathways known to be important in the determination of longevity. For example, Drosophila males are smaller than females and have reduced insulin/IGF signaling, and are thus more sensitive to mutations that reduce insulin/IGF function during development, which can retard growth and delay pupation (34).

Sexual selection. Female choice of mates and male-male competition can lead to the evolution of elaborate and costly traits and behaviors in males (35). An intervention that reduces the expression of such a costly trait would be expected to increase male life span disproportionately.

Sexual conflict. Genes that increase fitness in one sex can reduce fitness in the other sex (18). Promislow (14) suggested that sexual conflict could lead to the evolution of sex differences in life span. If an intervention alters the expression of a sexually antagonistic gene, the intervention may extend life span in one sex but reduce life span in the opposite sex.

Sex linkage. In Drosophila, most genes from the male X chromosome are hyperactivated to compensate for gene-dose differences between males and females [for example, see (36)]. This hyperactivation is carried out by the male-specific lethal (MSL) complex (37, 38). A sex-biased response could result from an intervention that modifies the MSL complex. In addition to the evolution of sex-specific gene expression, genes that enhance male fitness at the expense of reduced female fitness may have transposed from autosomes onto the Y chromosome (39, 40). Thus, a sex-biased response could result from an intervention that changes the expression of genes on the Y chromosome, which are mainly male fertility genes in Drosophila (41). Similarly, a sex-biased response could result from an intervention that changes the expression of genes on the X chromosome, where male-biased genes are underrepresented and female-biased genes are overrepresented in Drosophila (42, 43).

Testing the Hypotheses

There are several ways to further our understanding of why one sex might respond more strongly to a genetic or environmental alteration than the other. First, we need more data. Only one-sixth of the 97 experiments we reviewed here provided statistical tests of differences in response between males and females.

Second, genome-scale gene expression microarray studies could be used to compare gene expression levels in males and females with and without a particular intervention. Such analyses should tell us not only which genes show different expression patterns in the presence and absence of an intervention, but also whether these patterns differ between the sexes. Similarly, microarray or quantitative trait loci studies could be used to determine whether sex-linked loci are associated with sex-specific responses to interventions that extend life span.

Third, research on the biology of aging frequently mentions resource acquisition and allocation, but these important traits are rarely measured in the lab. Isotope-labeled nutrients could be used to quantify these traits and determine whether they really do differ between males and females under different circumstances.

Finally, the role of sexual conflict and sexual selection could be considered by comparing strains that have been selected for decreased or enhanced levels of sexual conflict or competitive ability (13).


The recent study by Magwere et al. (27) highlighted a striking difference in how males and females respond to at least one intervention known to extend life span. Perhaps the longest-lasting value of their study will be that it forces us to consider just how widespread sex-specific responses to interventions are, and ultimately to determine why sex-specific responses occur. The sex-specific effects of interventions that extend life span in Drosophila have not received enough attention and need more exploration. The extent to which sex-specific effects of interventions that increase life span exist in other taxa remains to be addressed. We are confident that studies testing hypotheses about these sex-specific effects will, in turn, increase our understanding of the basic biology of aging.

July 14, 2004
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Citation: J. M. S. Burger, D. E. L. Promislow, Sex-Specific Effects of Interventions That Extend Fly Life Span. Sci. Aging Knowl. Environ. 2004 (28), pe30 (2004).

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