Young Caenorhabditis elegans hermaphrodites use their own sperm to protect against the negative consequences of mating.
In popular culture, the phrase 'the battle of the sexes' conjures images of the complexities of dating, discussions about gender or, for some, a movie about the ultimate tennis grudge match. In the animal kingdom, the battle of the sexes can be much more visceral, and often deadly. Consider the roundworm Caenorhabditis elegans: hermaphrodite worms can reproduce through self-fertilization or by mating with male worms, but sexual interaction between males and hermaphrodites shortens the lifespan of both (Maures et al., 2014; Van Voorhies, 1992).
Self-fertilizing hermaphrodites enjoy a substantial post-reproductive lifespan, whereas those that mate with males typically only survive until they produce the last of their offspring (Shi and Murphy, 2014). The negative impact of sex on the lifespan of hermaphrodite worms is mediated by a number of molecular mechanisms including pheromones, the transfer of seminal fluid, and germline activation (Shi et al., 2017). Now, in two papers in eLife, researchers at Stanford University and Princeton University report that the 'self-sperm' produced by young hermaphrodites protects them from the dangers associated with mating. Each paper describes different signaling pathways involved in providing this protection.
In one paper Anne Brunet of Stanford University and co-workers – including Lauren Booth as first author with Travis Maures, Robin Yeo, and Cindy Tantilert – report that self-sperm protects C. elegans against aging by activating the 'sperm-sensing' pathway (Booth et al., 2019). Young hermaphrodite worms that mate have normal lifespans, while old worms die soon after mating. Booth et al. showed that, in young worms, normal lifespan after mating was the result of activating of the sperm-sensing pathway, which repressed the transcription factor CEH-18 and the ephrin receptor VAB-1 (Figure 1). In old worms, self-sperm was depleted and could no longer repress these proteins, leading to death. Booth et al. also investigated whether other species of roundworm were protected by self-sperm, discovering that Caenorhabditis briggsae shared this characteristic. However, this protection evolved relatively recently and independently from that of C. elegans, which suggests that roundworms continue to experience pressure from natural selection related to sexual interaction.
In the other paper Coleen Murphy of Princeton University and colleagues – including Cheng Shi as first author and Lauren Booth – explore the influence of male seminal fluid on the insulin and the mTOR signaling pathways (Shi et al., 2019). In particular, they find that the insulin signaling pathway is activated by two peptides present in male seminal fluid (INS-7 and INS-8) and repressed by INS-37, a peptide found in self-sperm. As aging hermaphrodite worms deplete their supply of self-sperm, they lose the protective repression of insulin signaling and only experience the mating-induced activation. Shi et al. also find that unknown molecules in male seminal fluid activate the mTOR signaling pathway, driving the removal of the pro-longevity transcription factor HLH-30 from the nucleus, which leads to mating-related death (Figure 1).
The work at Stanford and Princeton has broader relevance to our understanding of the molecular mechanisms of aging. To take one example, the drug fluorodeoxyuridine (FUdR) is widely used to prevent C. elegans reproduction during aging studies because it inhibits the production of eggs and sperm in hermaphrodites. The drug affects lifespan differently depending on the age of the worms (Wang et al., 2019), while also enhancing some pro-longevity treatments (Anderson et al., 2016). Understanding the relationship between FUdR, self-sperm, and signaling pathways involved in aging may lead to the development of new methods to study aging in C. elegans.
Sexual interactions also affect health in mammals, albeit in a less dramatic fashion. For example, the presence of male mice is sufficient to increase female body weight and stress while accelerating the onset of puberty (Garratt et al., 2016; Flanagan et al., 2011). Conversely, male mice maintained in the presence of females remain fertile substantially longer than those who live alone (Schmidt et al., 2009). While the specific role of self-sperm is not directly relevant to mammals, this work places evolutionarily conserved longevity pathways squarely at the intersection of sexual interaction and long-living invertebrates. Will the same be true for mammals?
C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuinsMechanisms of Ageing and Development 154:30–42.https://doi.org/10.1016/j.mad.2016.01.004
Age-dependent effects of floxuridine (FUdR) on senescent pathology and mortality in the nematode Caenorhabditis elegansBiochemical and Biophysical Research Communications 509:694–699.https://doi.org/10.1016/j.bbrc.2018.12.161
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Sexual interactions have a potent influence on health in several species, including mammals. Previous work in C. elegans identified strategies used by males to accelerate the demise of the opposite sex (hermaphrodites). But whether hermaphrodites evolved counter-strategies against males remains unknown. Here we discover that young C. elegans hermaphrodites are remarkably resistant to brief sexual encounters with males, whereas older hermaphrodites succumb prematurely. Surprisingly, it is not their youthfulness that protects young hermaphrodites, but the fact that they have self-sperm. The beneficial effect of self-sperm is mediated by a sperm-sensing pathway acting on the soma rather than by fertilization. Activation of this pathway in females triggers protection from the negative impact of males. Interestingly, the role of self-sperm in protecting against the detrimental effects of males evolved independently in hermaphroditic nematodes. Endogenous strategies to delay the negative effect of mating may represent a key evolutionary innovation to maximize reproductive success.