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Behavior Genetics, Vol. 33, No. 2, March 2003 (© 2003) Mate Choice, Sexual Conflict, and Evolution of Senescence Daniel Promislow1,2 Sex-related differences in longevity are common throughout the animal kingdom. Previous studies have suggested that at least part of these differences may be due to sex-specific costs of reproduction. Recently, workers have recognized that sexual conflicts of interest between males and females may play a significant role in the evolution of sexually dimorphic traits. Here I explore the possibility that sexual conflict may explain sex-specific differences in longevity and may act as a driving force in the evolution of senescence. I present comparative evidence for this hypothesis and discuss the potential relevance of sexual conflict theory to the search for specific genes that influence longevity. One implication of a sexual conflict theory of aging is that genes that influence senescence, and in particular those that affect sex differences in aging, may evolve very rapidly and so be difficult to detect. KEY WORDS: Sexual conflict; senescence; aging; sex-specific mortality; cost of reproduction. 2001). Whatever the cause for these sex differences, they are apparent even among fetuses and newborns (McMillen, 1979). Differences in survival between males and females turn out to be widespread in the animal kingdom, though patterns vary among taxonomic groups. In most mammal species, females live longer than males (Promislow, 1992), whereas in birds, males typically outlive females (Promislow, Montgomerie, and Martin, 1992). In fruit flies, patterns of sex-specific survival vary from species to species (Promislow and Haselkorn, 2002) and depend on whether one is comparing longevity in mated individuals or in virgin flies (e.g., Partridge and Andrews, 1985; Partridge, Green, and Fowler, 1987; Sgrò and Partridge, 1999). In the following paper, I discuss three aspects of reproductive behavior that might influence sex-specific differences in mortality. These factors include the short-term physiological costs of reproduction and the longer-term evolutionary consequences of female mate choice and sexual conflict. I will also discuss evidence for sex-specific genes that influence fitness and how reproductive behavior might affect the evolution of these genes. An earlier study (see Svensson and Sheldon, 1998) noted that sexual conflict could lead to increased INTRODUCTION Women have longer life expectancies than men in 190 of 205 populations around the world, with an average advantage of 4.4 years (2002 data, Population Reference Bureau, http://www.prb.org). In developed countries, this difference may exceed a decade. Of course, this dramatic difference has not gone unnoticed, as shown by the very popularity of the title “Why Do Women Live Longer Than Men?” in the scientific literature (e.g., Epstein, 1983; Grut, 1998; Hazzard, 1989; Holden, 1987; Promislow, 1991b; Schneider, Cebrat, and Stauffer, 1998; Seely, 1990; Waldron, 1976, 1978). In humans, one common answer to the question of why females live longer than males is that they differ in their hormone profiles. For example, high levels of testosterone are associated with increased aggression, which could lead to higher mortality among males (Book, Starzyk, and Quinsey, 2001). At the same time, high levels of estrogen in women may actually reduce mortality rates (Reis et al., 2000; Rodriguez et al., 1 2 Department of Genetics, University of Georgia, Athens, GA 30602– 7223, USA. To whom correspondence should be addressed at Tel: (706) 5428000. Fax: (706) 542–3910. e-mail:[email protected] 191 0001-8244/03/0300-0191/0 © 2003 Plenum Publishing Corporation 192 mortality rates. Here I develop this argument more fully, arguing that sexual conflict between males and females may account not only for sex differences in mortality but also for the evolution of senescence itself. Given recent advances in our theoretical understanding of sexual conflict, its macroevolutionary patterns and molecular genetic consequences, the ideas presented here should soon be experimentally testable. MORTALITY AND COSTS OF REPRODUCTION The most direct effects of reproduction on mortality rates are seen in the physiological costs of mating, gamete production, and parental care. In many species, behaviors associated with reproduction have been shown to decrease life expectancy (Reznick, 1985). Studies in Drosophila, in particular, have demonstrated that courtship behavior, copulation, and gamete production can all lead to higher mortality rates in both males and females (Partridge, 1980, 1987; Partridge and Andrews, 1985; Partridge and Farquhar, 1981; Partridge and Harvey, 1985; Sgrò and Partridge, 1999). All of these behaviors are energetically costly, so it is not surprising that they have deleterious effects on longevity. There is some debate as to whether costs of reproduction affect humans as well. In wealthy societies, high resource levels may offset any costs of reproduction. However, throughout human history, there has clearly been an increased risk of mortality during childbirth (Loudon, 1993), and comparisons both within and among populations point to a negative correlation between number of children and life span (Lycett, Dunbar, and Voland, 2000; Thomas et al., 2000; Westendorp and Kirkwood, 1998). Although it is likely that increased reproductive output increases mortality rates, it is not clear how these costs could account for the greater life expectancy seen in women. Perhaps in the absence of reproductive costs, the sex difference in longevity would be even greater. Nevertheless, many of the most successful attempts to extend longevity in model organisms point to the importance of reproduction in the aging process. For example, studies in both flies and rodents have demonstrated that caloric restriction can dramatically extend life span (Masoro, 2000; Nusbaum and Rose, 1999). Animals that are fed a calorically restricted diet have not only higher survival but also increased stress resistance and increased activity levels (e.g., McCarter et al., 1997). However, calorically restricted individuals also Promislow show a dramatic reduction in reproductive capacity. This loss of reproductive ability could account for the increase in longevity. In fact, some have argued that this may be an adaptive response to living through lean times (Holliday, 1989; Masoro and Austad, 1996). More recently, biogerontologists have shown that diapause, in which an animal enters a state of reproductive stasis, can also stop or slow the aging process (Herman and Tatar, 2001; Tatar et al., 2001; Tatar and Yin, 2001). For example, many of the genes that have been shown to extend longevity are involved in dauer formation in nematodes (Guarente and Kenyon, 2000) (the nematode equivalent of diapause) or in adult diapause in flies (Clancy et al., 2001; Tatar et al., 2001). Given that reproduction may mediate the ties between aging and both caloric restriction and diapause, it may turn out that scientists working on the genetics of aging may actually be working on the genetics of reproduction. This claim is further supported by the finding that some loci are associated with longevity in one sex but not the other (Nuzhdin et al., 1997). These sex differences may well be due to sex-specific differences in reproductive physiology. Experimental evidence suggests that reproductive behaviors can both increase and decrease longevity. Some studies suggest that mate choice, whereby females choose to mate with fitter-than-average males, can increase life span, though the effect is relatively weak (Partridge, 1980; Promislow, Smith, and Pearse, 1998). On the other hand, genotypes that increase fitness in one sex may actually reduce fitness in the opposite sex (Rice and Chippindale, 2001). These sex-specific genetic effects may arise due to reproductive conflicts of interest between males and females. In the following sections, I explore how costs and benefits of reproductive behaviors might influence the evolution of sex differences in life span. MATE CHOICE, SEXUAL CONFLICT, AND SEX DIFFERENCES IN AGING Mate Choice Over a century ago, Charles Darwin and Alfred Russell Wallace recognized that female mate choice of males and male-male competition for access to females played an important role in the evolution of sexually dimorphic traits (Darwin, 1871; Wallace, 1889). These elaborate traits include a range of morphological and behavioral factors, such as large antlers in deer, elaborate and colorful plumage in birds, and the complex, Mate Choice, Sexual Conflict and Senescence ritualized courtship behaviors found throughout the animal kingdom. These traits may allow males to attract females or to compete successfully against other males and so increase reproductive success, but they also can exact costs. A brightly colored bird not only is more likely to attract females but also must pay the physiological costs of producing and maintaining the bright plumage and will be more conspicuous to predators (Andersson, 1994). Biologists have explored a range of possible explanations to try to understand the forces that could maintain these costly traits. One argument is that males vary in quality (e.g., viability, fertility, or competitive ability), and elaborate traits signal a male’s quality to the female (Andersson, 1994). From a gerontological perspective, this model has interesting implications. If a cohort of young males varies in some aspect of quality, and if this quality influences the probability of survival, then as males get older, their underlying viability (notwithstanding the effects of aging) should improve. As a cohort ages, the lowest-quality individuals will die off first. On average, older males will have better-quality genes to pass on to their offspring. Thus, if a female can choose among males based on age, by choosing to mate with an older male, she is more likely to pass on high-quality viability genes to her offspring. Theoreticians have examined the conditions under which preference for old mates can evolve (Beck and Powell, 2000; Hansen and Price, 1995; Kokko and Lindström, 1996). Only recently, however, have biologists asked whether preference for older males can actually influence the evolution of aging. In a recent theoretical study, Beck et al. (2002) carried out simulations in which a cohort of females was allowed to evolve varying degrees of preference for males of different ages. Typically, after many hundreds of generations, females would evolve a bias against young males and in favor of older males (Fig. 1). But there was an interesting consequence of this preference. The authors compared mortality rates in cohorts where females were allowed to exercise their age-specific mate preference with cohorts of females that were forced to mate at random. After many generations, the mortality rates in the “choosy” cohort were significantly lower than in the random mating cohort (Fig. 2). By choosing to mate preferentially with older males, females can improve the chances that they produce high-quality offspring. At the same time, female preference for older males can increase the frequency of genes for high viability and the strength of selection acting at late ages, thereby 193 Fig. 1. Female preference based on male age. In a genetic algorithm simulation, Beck et al. (2002) found that females evolved a preference for older males, except at very high mortality rates, where females preferred to mate with males of intermediate age. Preference refers to the probability that a female will mate with a randomly encountered male of a particular age. The three curves represent simulations for populations with low (thick line), medium (thin line), or high (dashed line) rates of increase in age-specific mortality (figure based on data reported in Beck et al. 2002). Fig. 2. Effect of female preference on average mortality in populations with and without age-specific mate preference. The y-axis shows the natural log of the initial mortality rate in the population, where mortality rates increase exponentially with age. Smaller (more negative) values imply lower mortality rates. Comparisons between populations with and without female preference are shown for three levels of senescence, with senescence determined by the rate of increase in mortality rates with age. In populations where females are allowed to choose mates, mortality rates evolve to a lower equilibrium value (figure based on data reported in Beck et al. 2002). 194 having the long-term, unintended consequence of increasing life span of the entire cohort. The theoretical finding that female choice can extend longevity over evolutionary time is supported by experimental and comparative data. Promislow, Smith, and Pearse (1998) used artificial selection to create divergent lines with high and low levels of opportunity for mate choice and male-male competition. They found that populations with greater levels of sexual selection evolved a longer life span. In a comparative study of mortality rates and plumage coloration, Promislow, Montgomerie, and Martin (1992) found that bright coloration was more likely to be found in species with high female survival rates. At the time, the authors drew the causal arrow from mortality to coloration, arguing that high mortality rates would act as a constraint on the evolution of costly secondary sexual characteristics. However, Beck et al. (2002) suggest another possibility. If bright plumage is an indicator of quality, then in brightly colored species, females will have the opportunity to choose males with genes that increase viability, and over evolutionary time, survival rates will increase. Sexual Conflict Mating behavior may reduce mortality rates over evolutionary time, but it is not without costs. These costs may arise due to inherent conflicts of interest between the sexes. In mating contests between males and females, what is optimal for one sex may be suboptimal for the other sex. Consider sperm competition as an example. In many species, females will mate with two or more males in relatively quick succession. Sperm from multiple males are thus competing for access to the female’s eggs. Selection will favor males that are most able to displace sperm from previous males, and to avoid being displaced by subsequent males. At the same time, selection may favor females that are able to control which sperm fertilizes their eggs. Due to these conflicts of interest between the sexes, traits that increase fitness in males could, theoretically, decrease fitness in females. A series of studies has now shown that natural selection can favor males that actually harm their mates, reducing their survival rates quite dramatically (Chapman et al., 1995; Rice, 1996). In many circumstances, mating behaviors, and even specific genes, that are optimal for one sex may be deleterious for the other sex, leading to sexual conflict (Partridge and Hurst, 1998; Rice, 2000; Rice and Chippindale, 2001). Promislow These conflicts between the sexes could potentially lead to increased mortality rates in females (Svensson and Sheldon, 1998). Fruit flies provide a powerful model to study the genetics and evolution of sexual conflict and aging. Female fruit flies typically mate with two or more males. In the race to fertilize eggs, males have evolved proteins that appear to incapacitate sperm from previous males (Price, Dyer, and Coyne, 1999) or to prevent their sperm from being displaced by subsequent males (Clark et al., 1995). But a male can also improve his fitness by manipulating female behavior. In flies, the last male to mate with a female fertilizes most of the eggs the female is carrying at that time. To increase the probability of fertilizing a female’s eggs, males produce specialized substances (accessory gland proteins, or Acps—Wolfner et al., 1997) that reduce receptivity of the female to subsequent courting males and force the female to lay more eggs than might be optimal from the female’s perspective (Wolfner et al., 1997). In this way, a male can increase the relative number of eggs fertilized by his sperm. However, Acps not only alter a female’s mating behavior but also increase her risk of dying. In a 1995 study of Drosophila, Tracy Chapman and colleagues (1995) mated females with normal males and with males that do not produce Acps. Only females exposed to Acps showed increased mortality. At least one candidate gene, Acp62F, has been identified as a possible cause of increased female mortality. The Acp62F protein is similar to proteinase inhibitors found in nematodes (Lung et al., 2002), and part of its structure is similar to a neurotoxin produced by the Brazilian armed spider, Phoneutria nigriventer (Wolfner et al., 1997). It is unlikely that natural selection has led to the evolution of proteins whose sole purpose is to increase female mortality rate. Rather, the benefits that Acps provide in terms of increased male reproductive success outweigh the costs (from the male’s perspective) of increased female mortality. Since females do not appear to benefit from this situation, should they not evolve some response to disable the effect of male Acps? In fact, a study by Rice suggests that such coevolutionary responses do occur. Rice (1996) developed an experimental procedure in which males were selected for high mating success in competition with other males, but females were prevented from responding genetically to changes in males. Within a few tens of generations, he found that males had evolved much higher reproductive success than unselected control lines. More important, when mated with females, Mate Choice, Sexual Conflict and Senescence experimental males induced much higher female mortality rates than did the control males. Thus, it appears that males are continually evolving ways to maximize their sperm competitive ability, including processes that manipulate female behavior or physiology, and females are evolving counteradaptations to prevent being manipulated by the male. These conditions set the stage for a continual arms race between males and females. At times, we expect males to gain the upper hand, while at other times females will have the advantage (Fig. 3). This arms race points to one possible reason why in some species males might have higher mortality than females, whereas in other species the reverse would be true, depending on which sex has the current advantage. This pattern of males winning the arms race in some species and females in others is illustrated by a recent study across species of water strider (Arnqvist and Rowe, 2002). Male water striders have evolved grasping hooks to hold on to females during copulation, and females have evolved spines to ward off unwanted suitors. In species where females have the upper hand in competition with males, females have large spines, and copulations are relatively short. When males hold the advantage, hooks are proportionately larger than spines, and copulation duration increases. The size of hooks and spines is easy to measure. The biochemical shape of Acps that influence mating behavior in flies is not so easily measured but may exhibit the same pattern of adaptation and counteradaptation as seen in water striders. At present, we can- Fig. 3. Sexual conflict can lead to states where females have higher fitness than males or vice versa. This may account, at least in part, for the sex bias in adult mortality (Chippindale, Gibson, and Rice, 2001). 195 not take a biochemical snapshot of the arms race among different species of Drosophila, though experiments such as that of Rice (1996), described earlier, provide evidence that genetic variation exists for such macroevolutionary patterns to arise. It remains to be determined, however, if we can extrapolate from fruit flies to humans. Like flies, human males have an impressive assortment of glands that contribute to seminal fluid. Birkhead (2000) makes a fairly convincing argument that at least some of these glands have evolved under the force of sexual conflict. We do not yet know whether human males produce seminal products that manipulate females, though other sorts of manipulation is certainly likely (Gowaty, 1997). Interestingly, a comparative study in primates provides some evidence that these accessory glands play a role in sperm competition (Dixson, 1998). By definition, sexual conflict implies that one sex suffers when the other gains. Until now, we have considered the possibility that sexual conflict may influence sex biases in mortality. But it might also lead to the evolution of senescence itself. Just as sexual conflict has driven the evolution of ever-increasing trait size in male and female water striders (Arnqvist and Rowe, 2002), the same process could lead to increasing mortality rates in both sexes of a species where sexual conflict is pervasive. In the context of sexual conflict, males and females not only will evolve traits that harm one another but also will pay the cost of bearing these complex traits. As the sexual conflict arms race progresses, the costs of these traits should continually increase, so that species with relatively high levels of sexual conflict would have relatively high mortality rates (see Johnstone and Keller, 2000). Most evolutionary models of aging suggest that high intrinsic mortality rates will select for high rates of senescence (Charlesworth, 1994; Ricklefs, 1998; but see Abrams, 1993). (By “rate of senescence,” we mean the rate at which mortality rates increase with age [Finch, Pike, and Witten, 1990; Promislow, 1991a]). Thus, if sexual conflict increases mortality rates, this could lead indirectly to the evolution of senescence. At the same time, in a process that is akin to Medawar’s mutation accumulation model, females may counteract the costs of male traits arising due to sexual conflict by delaying their effects until later in life. This could lead to increased mortality rates at late age in females, though it is not clear how this might translate into higher rates of aging in males. The interrelationships of female preference, male ornaments, sexual conflict, underlying demography, 196 and so forth are likely to be rather complex (Fig. 4). In the future, formal mathematical models should explore the demographic and behavioral conditions under which sexual conflict could lead to the evolution of senescence. For now, the following section provides examples from various species suggesting that sexual conflict could explain interspecific variation in life history strategies in general, and life span in particular (see also Svensson and Sheldon, 1998). Sexual Conflict and the Evolution of Aging— Comparative Evidence Arnqvist and Rowe (2002) demonstrated how comparative approaches could be used to examine the consequences of varying degrees of sexual conflict among species of water strider. To test the hypotheses presented here, ideally we would compare the extent of sexual conflict among species with measures of mean life span, sex-specific mortality rates, and rates of senescence. While there are plenty of published data on survival rates, measuring sexual conflict turns out Promislow to be rather difficult (water striders notwithstanding). Bearing this challenge in mind, I discuss several biological factors that may lead to reduced levels of sexual conflict and that also appear to be associated with reduced mortality rates. Eusociality In eusocial species of ants, bees, and termites, queens can be extremely long-lived, surviving upwards of 20 years (Keller and Genoud, 1997). Keller and Genoud (1997) suggest that long life span in eusocial species is due to the highly sheltered environment in which queens live. Carey (2001) places the cause directly in the behavioral realm. I extend his explanation to include the possibility of sexual conflict. While conflicts of interest between queens and workers or between workers and males are common (Hamilton, 1964; Sundstrom and Boomsma, 2001), species with single queens tend to have extremely low levels of sexual conflict between the queen and her Fig. 4. Possible pathways for mate choice and sexual conflict to influence the evolution of senescence. For example, female mate choice could increase mortality rates if mate choice led to the evolution of costly secondary sexual characteristics. On the other hand, females choice could decrease mortality if females selected males with genes for high viability. Sexual conflict could lead to high mortality rates (see text), but in species where females have relatively high levels of control over the conflict, the consequences of sexual conflict might be reduced. Mate Choice, Sexual Conflict and Senescence mates. Queens typically mate with one or multiple males on a single mating day, after which the queen founds a colony. To fertilize offspring, the queen uses sperm that have been stored for years or even decades after this first mating bout. In this situation, there should be strong selection on males to prevent them from evolving mechanisms that kill off or displace sperm from other males and that harm the female, and strong selection on females to evolve countermeasures to harmful male traits. A queen’s fitness depends on her ability to produce a large colony and to have sperm in sufficient numbers to last many years. Thus, a male may actually benefit by deliberately not increasing female mortality or, in the case of polyandrous queens, by not displacing sperm from previous males. The more sperm a female carries and the longer she lives, the greater the chance that a male’s sperm will fertilize offspring that will, themselves, eventually become queens. Monogamy In a lifelong monogamous species, males and females will have concordant strategies to maximize fitness, and sexual conflict should be absent or slight (Rice, 2000). Even when there is some conflict, such as in socially monogamous species that seek extrapair copulations outside the pair bond (Gowaty, 1996), levels of conflict are still likely to be lower than in polygamous species, so we would expect monogamous species to be longer-lived or to have lower rates of aging. Some evidence from mammals supports this argument. While most mammals are polygynous and show significant evidence of aging, in monogamous species of canids, rates of senescence are conspicuously low (Promislow, 1991a). Postreproductive Survival Over the past decade, biodemographic studies have shown that at very late ages, the age-related rate of increase in mortality slows and may show a reversal in fruit flies, nematodes, and even humans (Carey et al., 1992; Curtsinger et al., 1992; Vaupel et al., 1998). As reproduction slows down or ceases altogether at late age, so, too, does the amount of sexual conflict. In Drosophila, for example, if older females no longer mate (or are housed with males that no longer mate), they may no longer pay the cost of exposure to Acps. Thus, sexual conflict could account for mortality deceleration seen in many species. 197 Cooperative Breeding In many species of birds, mature offspring forgo the opportunity to breed and instead remain at the natal nest for one or more seasons, helping their parents to rear younger siblings or half siblings. Work on the extraordinarily promiscuous Australian fairy wren suggests one way in which helpers at the nest can reduce the costs of sexual conflict. If females mate outside the pair bond, males may be less likely to help rear offspring due to uncertain paternity (Møller and Birkhead, 1993). In the fairy wren, it appears that this cost is offset by the presence of helpers at the nest (Mulder et al., 1994), giving females an advantage in conflicts with mates. Within the general framework of cooperative breeding, there is a wide range of mating systems (Cockburn, in press). Whether the costs to females of sexual conflict are generally reduced in cooperative breeders remains to be seen. But in line with the theory developed here, comparative evidence shows that cooperative species do tend to have lower mortality rates (Arnold and Owens, 1998; Møller and Birkhead, 1993). Sexual Conflict and the Evolution of Aging— Experimental Tests At least one study in fruit flies has shown experimentally that increasing the opportunity for sexual selection leads to an increase in adult survival (Promislow, Smith, and Pearse, 1998). However, this study was not a test of a sexual conflict theory of aging per se, since flies were not allowed to mate multiply. In the absence of multiple mating, sexual conflict is greatly reduced, at least in flies. Fortunately, there are several ways in which we can reduce opportunity for sexual conflict. Using a variety of techniques, several studies have shown that increased conflict shortens life span (Chapman et al., 1995; Holland and Rice, 1999; Rice, 1996). These studies suggest a way that might explore directly the relationship between sexual conflict and rates of aging. Earlier, I noted that Acps play a central role in the Drosophila male’s ability to manipulate female reproductive behavior and physiology. Wolfner et al. (1997) have created strains in which males do not produce any Acps. To test the idea that sexual conflict leads to the evolution of aging, one could simply maintain large, outbred populations of flies with and without the presence of Acps. If sexual conflict increases mortality rates, then the populations without Acps 198 should gradually evolve longer life span relative to those that do produce Acps. Challenges for a Sexual Conflict Theory of Aging The link between sexual conflict and senescence is still conjectural at this point. The examples discussed here provide support for the novel hypothesis that increases in sexual conflict play an important role in the evolution of increased rates of aging and/or decreased longevity (see also Svensson and Sheldon, 1998). However, we have yet to obtain direct experimental evidence, and there are alternative explanations for each of the comparative examples presented here. For example, eusocial ants tend to live in environments that are well protected from predators and climatic fluctuations. In cooperatively breeding species, individuals may live longer simply because they can help each other with the important tasks of daily living. The advantage of the sexual conflict hypothesis is that it pertains to multiple ecological situations and is experimentally testable. In fact, there are three distinct cross-specific patterns that need to be explained. Species differ in mean life span (e.g., Gaillard et al., 1989), in the degree to which mortality rates increase with age (Promislow, 1991a; Ricklefs, 1998), and in the degree of sex bias in mortality (Clutton-Brock, Albon, and Guinness, 1985; Promislow, 1992; Promislow, Montgomerie, and Martin, 1992). Future theory should consider the possibility that each of these three patterns could be influenced by interspecific variation in the strength of sexual conflict. Promislow for longevity and may also suggest something about the nature of genes that influence aging. When genes increase or decrease fitness equally in both sexes, natural selection leads to the fixation or loss of these genes. Genes involved in sexual conflict, however, increase fitness in one sex at the expense of fitness in the opposite sex. This antagonistic effect is expected to generate negative genetic correlations for adult fitness in males and females and can maintain polymorphisms for fitness-related genes in natural populations. Rice and Chippindale (2001) use the example of the human hip to illustrate this argument. Natural selection should favor relatively large hip size in women to facilitate easy passage of the fetus through the birth canal. Increased hip width may decrease locomotor performance, but females gain the benefit of decreased complications at birth. Males, on the other hand, gain no such direct benefit. Thus, selection should favor alleles that increase hip width in females but decrease hip width in males, setting the stage for conflict. In an experimental test of this idea, Chippindale, Gibson, and Rice (2001) used “clone generator” females to create large numbers of males and females that shared an identical set of major chromosomes. This allowed the researchers to determine the effects on fitness of identical genotypes in a male or female background. Consistent with sexual conflict theory, Chippindale, Gibson, and Rice (2001) found that among forty different Drosophila genomes, genotypes that increased relative fitness in males tended to decrease fitness in females. Although not the focus of their study, this result supports the contention that sexual conflict could maintain genetic variation for longevity in natural populations. Sexual Conflict and Genetic Variation The strength of selection tends to be strongest on fitness traits, such as fecundity or survival, and so over time, selection should erode genetic variation for these traits as deleterious alleles are lost and beneficial ones go to fixation (Fisher, 1930). But there remains plenty of genetic variation for life span (Rose, 1991). What maintains this variation? Classic evolutionary theories of senescence suggest two possibilities. Genetic variation for longevity is maintained either by the lack of selection acting on genes whose effects are limited to late ages (mutation-selection balance; Medawar, 1952) or because some genes that decrease survival late in life have beneficial effects early in life (antagonistic pleiotropy; Williams, 1957). Sexual conflict provides a third hypothesis for the maintenance of genetic variation Sexual Conflict: Why Should Molecular Biogerontologists Care? We have established that costs of reproduction can increase mortality rates. We have seen how one sex can manipulate the other, using either morphological or biochemical means, and so increase the mortality rate of the manipulated sex. And recent studies have demonstrated that at least some genes that increase fitness in one sex may decrease it in the other. These results suggest three ways in which gerontological research could benefit from thinking about the causes and consequences of sexual conflict. First, studies on the genetics of sexual conflict (Chippindale, Gibson, and Rice, 2001; Rice, 1992, 1998) point out that many important genes may have Mate Choice, Sexual Conflict and Senescence sex-specific effects and may even increase fitness in one sex while decreasing it in the other. The search for aging genes is often confined to the study of a single sex. In several recent, widely cited examples of genes that extend longevity (Lin et al., 1998; Parkes et al., 1998; Rogina et al., 2000), data on survival were provided for males only. More comprehensive experiments are necessary. Second, we have identified numerous genes that appear to be involved in sexual conflict, including accessory gland proteins in Drosophila (Wolfner et al., 1997), and recent studies suggest that both X- and Ylinked loci may be especially important for sex-specific fitness traits (Chippindale and Rice, 2001; Gibson, Chippindale, and Rice, 2002). These may be useful candidate loci in the search for longevity genes. Finally, classical population genetics theory suggests that genes that extend longevity should go to fixation. Thus, we should expect to find little genetic variation for life span in natural populations. Data from humans and many other species contradict this expectation, so we are left with the problem of what maintains this variation. One possibility is that genes that extend longevity have antagonistic pleiotropic effects, decreasing fertility or fecundity. However, some studies have found genes that increase life span but do not decrease reproductive capacity (Lin, Seroude, and Benzer, 1998). It may turn out that a significant amount of segregating genetic variation for life span is maintained by balancing selection created by sexual conflict. Genes involved in sexual conflict may turn out to be excellent candidates for studies on the genetics of aging. However, this also points to a very important caveat. Genes involved in sexual conflict tend to evolve very quickly (Swanson et al., 2001). To the extent that these rapidly evolving genes influence longevity, the search for aging genes may turn out to be the search for a moving target. ACKNOWLEDGMENTS Thanks to A. Keyser and C. Spencer, who provided helpful comments on an earlier draft of this manuscript. Useful comments were also provided by J. 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