Males and females pursue different reproductive strategies, which often bring them into conflict-many traits exist that benefit one sex at a cost to another [1]. Decreased female survival following mating dramatically demonstrates one aspect of this phenomenon [2-5]. Particularly intriguing is the evidence that secreted compounds can shorten lifespan of members of the opposite sex in Drosophila [6] and Caenorhabditid nematodes [7] even without copulation taking place. The purpose of such signals is not clear, however. While it is possible that they could limit subsequent mating with competitors or hasten post-reproductive demise, thus decreasing competition for resources, they are also likely to harm unmated individuals. Why would a system exist that reduces the vigor of potential mates prior to mating? Addressing this question could provide insights into mechanisms and evolution of sexual conflict and reveal sensory inputs that regulate aging. Here, we describe two distinct ways in which Caenorhabditis elegans males cause faster somatic aging of hermaphrodites but also manipulate different aspects of their reproductive physiology. The first, mediated by conserved ascaroside pheromones, delays the loss of germline progenitor cells. The second accelerates development, resulting in faster sexual maturation. These signals promote male reproductive strategy and the effects harmful to hermaphrodites appear to be collateral damage rather than the goal.

Significance Aging animals, particularly females, suffer from diminished reproductive ability, likely due to high costs of germline maintenance. Potential remedies may be found in signals exchanged by members of opposite sexes to promote reproductive success. We show that in the nematode Caenorhabditis elegans , male pheromone facilitates healthy oocyte aging. This pheromone increases germline proliferation and physiological cell death, which is required to maintain oocyte quality. We show that young adults that have not yet commenced reproduction are particularly sensitive to signals from mates and nutrients, likely because during this narrow time window, they set an environment-appropriate balance between germline and soma investment. We advocate the study of social signals as a productive avenue for identifying regulators of physiology and aging.

Highlights d C. elegans male pheromone promotes hermaphrodite reproductive success d Serotonin is required for hermaphrodites to respond to male pheromone d The same neuronal circuit mediates behavioral and physiological responses d Circuit sharing coordinates distinct phenomena occurring on different timescales

Sex pheromones facilitate reproduction by attracting potential mates and altering their behavior and physiology. In C. elegans, males and hermaphrodites secrete similar blends of pheromone molecules, two of which are present in different relative concentrations: ascr#3, which is more abundant in hermaphrodites, and ascr#10, which is more abundant in males. It is not currently understood how this compositional difference results in sex-specific effects, for example, the slower aging of the hermaphrodite germline in the presence of physiologically relevant concentrations of male pheromones. Here we report three key elements of the mechanism responsible for this phenomenon. First, ascr#3 counters the activity of ascr#10. This antagonism decreases the magnitude and the sensitivity of the hermaphrodite response to the male pheromone, restricting it to situations in which the presence of a male could be inferred with high confidence. Second, hermaphrodites recognize pheromone as male if the concentration of ascr#10 is higher than that of ascr#3. Third, the response to ascr#10 requires TRPV channel function in the ADL neurons and the daf-7 signaling from the ASI neurons, whereas the response to ascr#3 relies on cyclic guanosine monophosphate (cGMP)-gated channels and activity of the ASJ, AWB, and AWC neurons. These results argue that the counteracting activities of distinct neuronal circuits determine the sexual identity of the pheromone. The parallels between this mechanism and other signaling systems suggest that diverse organisms may perform particular neuronal computations using similar general principles.

Excreted small-molecule signals can bias developmental trajectories and physiology in diverse animal species. However, the chemical identity of these signals remains largely obscure. Here we report identification of an unusual N -acylated glutamine derivative, nacq#1, that accelerates reproductive development and shortens lifespan in C. elegans . Produced predominantly by C. elegans males, nacq#1 hastens onset of sexual maturity in hermaphrodites by promoting exit from the larval dauer diapause and by accelerating late larval development. Even at picomolar concentrations, nacq#1 shortens hermaphrodite lifespan, suggesting a trade-off between reproductive investment and longevity. Acceleration of development by nacq#1 requires chemosensation and depends on three homologs of vertebrate steroid hormone receptors. Unlike ascaroside pheromones, which are restricted to nematodes, fatty acylated amino acid derivatives similar to nacq#1 have been reported from humans and invertebrates, suggesting that related compounds may serve signaling functions throughout Metazoa.

To ensure long-term reproductive success organisms have to cope with harsh environmental extremes. A reproductive strategy that simply maximizes offspring production is likely to be disadvantageous because it could lead to a catastrophic loss of fecundity under unfavorable conditions. To understand how an appropriate balance is achieved, we investigated reproductive performance of C. elegans under conditions of chronic heat stress. We found that following even prolonged exposure to temperatures at which none of the offspring survive, worms could recover and resume reproduction. The likelihood of producing viable offspring falls precipitously after exposure to temperatures greater than 28°C primarily due to sperm damage. Surprisingly, we found that worms that experienced higher temperatures can recover considerably better, provided they did not initiate ovulation. Therefore mechanisms controlling this process must play a crucial role in determining the probability of recovery. We show, however, that suppressing ovulation is only beneficial under relatively long stresses, whereas it is a disadvantageous strategy under shorter stresses of the same intensity. This is because the benefit of shutting down egg laying, and thus protecting the reproductive system, is negated by the cost associated with implementing this strategy – it takes considerable time to recover and produce offspring. We interpret these balanced trade-offs as a dynamic response of the C. elegans reproductive system to stress and an adaptation to life in variable and unpredictable conditions.

Pheromones are secreted molecules that mediate animal communications. These olfactory signals can have substantial effects on physiology and likely play important roles in organismal survival in natural habitats. Here we show that a blend of two ascaroside pheromones produced by C. elegans males primes the female reproductive system in part by improving sperm guidance toward oocytes. Worms have different physiological responses to different ratios of the same two molecules, revealing an efficient mechanism for increasing coding potential of a limited repertoire of molecular signals. The endogenous function of the male sex pheromones has an important side benefit. It substantially ameliorates the detrimental effects of prolonged heat stress on hermaphrodite reproduction because it increases the effectiveness with which surviving gametes are used following stress. Hermaphroditic species are expected to lose female-specific traits in the course of evolution. Our results suggest that some of these traits could have serendipitous utility due to their ability to counter the effects of stress. We propose that this is a general mechanism by which some mating-related functions could be retained in hermaphroditic species, despite their expected decay.

A major goal of systems biology is to understand how organism-level behavior arises from a myriad of molecular interactions. Often this involves complex sets of rules describing interactions among a large number of components. As an alternative, we have developed a simple, macro-level model to describe how chronic temperature stress affects reproduction in C. elegans. Our approach uses fundamental engineering principles, together with a limited set of experimentally derived facts, and provides quantitatively accurate predictions of performance under a range of physiologically relevant conditions. We generated detailed time-resolved experimental data to evaluate the ability of our model to describe the dynamics of C. elegans reproduction. We find considerable heterogeneity in responses of individual animals to heat stress, which can be understood as modulation of a few processes and may represent a strategy for coping with the ever-changing environment. Our experimental results and model provide quantitative insight into the breakdown of a robust biological system under stress and suggest, surprisingly, that the behavior of complex biological systems may be determined by a small number of key components.