Battle of the sexes - why male worms make their mates age (and die) faster

In the presence of males, females trade longevity for fertility.

In C. elegans, a species of worm frequently used in molecular biology research, females are subject to a strange effect: the presence of males accelerates their death. Recent research sheds new light on why: males’ molecular signals cause females to shift resources to reproduction, at the cost of maintaining their bodies. We speak with Ilya Ruvinsky, who authored the paper together with Erin Aprison, to learn more about his findings, and what they can tell us about male-female relationships in other species—including our own.

ResearchGate: What are C. elegans, and why did you look at this species in particular?

Ilya Ruvinsky: For the last 40 years or so, a worm called Caenorhabditis elegans has been one of the major stalwarts of molecular biology research, along with the mouse and the fly. The reason it’s so popular is that it’s fantastic for genetics. It has a small genome and only 1,000 somatic cells. They’re either males or self-fertile hermaphrodites. I’m going to slip and call the hermaphrodites females, but they’re technically hermaphrodites, because they make a little bit of sperm.

Because this species is so simple, it’s wonderful for molecular and developmental biology research. You can manipulate individual cells, either physically or with mutations, and study the effects. Manipulability and simplicity are extraordinarily attractive, because C. elegans have all the tissues that we care about: nervous cells, muscle cells, a digestive system. Very simple of course, but nevertheless recognizable. We can get to the basics of how these cells are organized and how they function without great expense, very rapidly, and with terrific precision.

RG: If the “females” are actually hermaphrodites and produce sperm, do they even need the males for reproduction?

Ruvinsky: Yes and no. A safe way of thinking about hermaphrodites in C. elegans is that they are females that make sperm early on. Basically, they make a fixed number of sperm, and that’s it. Once they switch to producing eggs, they only produce eggs from that point on. So for early reproduction, they strictly speaking do not need males. For late reproduction, they certainly do—they’ve run out their own sperm, and have no way of switching back to producing it.

“Females literally wrinkled faster, started moving less, and died sooner.”

C. elegans hermaphrodite
Adult hermaphrodite C. elegans. Credit: Bob Goldstein

RG: How does the presence of males affect females in this species?

Ruvinsky: C. elegans males leave behind substances that shorten the lifespan of females. If you let male worms dwell on plates for a while, and then remove them and place females on the plates, you can see this effect. Compared to females on untreated plates, they do in fact age faster. Other researchers have shown that females literally wrinkled faster, started moving less, and died sooner after mating with males and in the presence of male-secreted compounds. But we also saw—quite surprisingly—that while this rapid aging was happening, the germline (cells that give rise to eggs) was more like that of younger worms. So there’s this paradox: in one way, they age faster; in another, they age slower.

Males exude libraries of small molecules that make up their pheromone cocktails. When we took two of these molecules chemically synthesized by a colleague, we were able to recapitulate this slower aging of the female reproductive system, confirming it’s these molecules that cause this change.

RG: And what’s the impact on females’ reproductive maturity?  

Ruvinsky: We found that females on plates that had previously been populated by males started to make eggs sooner, reaching reproductive maturity at an earlier age. This is tremendously interesting, because everyone has always suspected that males are trying to manipulate females, and this is a classic way to do it, to get females ready for reproduction. We also found that it’s only just before becoming sexually mature, that the male substances matter.

Mice share a similar phenomenon. If you take naïve female mice and introduce them to cages in which older, sexually mature males have lived, they achieve reproductive maturity faster, but it’s not known how or why. So it’s striking that we find a similar phenomenon in worms, a very distant species. We don’t yet know whether the mechanisms that achieve this affect in both species are the same. But it is certainly tantalizing to think about what these males of either species might be saying to females with them.

“Males signal to females to shift all of their resources into reproduction even if at the cost of the upkeep of their bodies.”

RG: And what do you think they’re saying?

Ruvinsky: Females have to achieve a balance in terms of resource allocation. It costs a lot of energy to upkeep the body, and it costs a lot of energy to upkeep reproductive cells. You wouldn’t want to overcommit to one over the other unless you are absolutely certain that the conditions are right for reproduction. So males use their pheromones to signal to females: “I’m nearby. There will be sperm around. Commit to reproduction. This is the time to go.” Of course, whenever there are different interests between members of different sexes, there’s a conflict. In this case, males signal to females to shift all of their resources into reproduction even if at the cost of the upkeep of their bodies.

RG: Beyond worms and mice, are there other species this effect has been documented in?

Ruvinsky: A lot of work on this has been done in insects—particularly flies—where pheromones have been studied to the hilt. What’s a little different in our study compared to what’s been done in flies and mammals is that we study physiological changes rather than behavior. I want to be careful not to suggest perfect parallelism of mechanisms between flies, worms, mice, and other animals. But there are parallels that reveal a general principal about the kinds of things males say to females in these chemical languages. The languages themselves could be very different, but the message is likely similar.

“In biomedical research, every time we discover a basic general principal, it’s true in humans in one way or another.”

RG: What about in humans?

Ruvinsky: Looking for these parallels, particularly if we can study something in great detail in a model organism like C. elegans, can tell us more about how our own physiology is constructed. I’m not suggesting that humans do exactly the same thing in exactly the same way, because we simply don’t know. But in biomedical research, every time we discover a basic general principal, it’s also true in humans in one way or another. Sometimes in ways we didn’t quite anticipate, sometimes in ways that are different than in the model systems we studied, but the general principals are there.

RG: What’s the next step in research in this area?

Ruvinsky: There are a couple of really fascinating questions. For one, we’re pretty sure that some of these male signals are sent via females’ neurons. Because there are so few neurons in the worm—there are only 300 neurons altogether and maybe two dozen that could even conceivably be sensing chemicals like this—we’re very close to identifying exactly how these signals get in. Then there’s got to be some sort of relay of information from a sensory neuron to the germline. We would really like to know how that happens and whether there are ways to bypass it and go straight to the germline.

Another interesting consideration is that two of the molecules that make up C. elegans’ sex pheromones exist in different concentrations in the two sexes—males have more of one, and females have more of the other. That’s fascinating, because it means that worm brains—simple as they are—can detect not only presence or absence of molecules but also their relative concentrations. They know how to tell them apart, and we’d like to find out how.

Finally, we want to understand how developmental speedup happens generally. That can provide all kinds of insights about regulation of development and how environmental factors affect it. Determining that would be really important. The research we’ve been doing on C. elegans is a great entryway into this very exciting question.

Featured image courtesy of Francesco Falciani.