C. elegans worms live up to 3 weeks, and for the last 2½ weeks, they are post-reproductive, unable to lay fertile eggs because they have run out of sperm to fertilize them. Why do they stop fertilizing their eggs, when sperm is metabolically ‘cheap’? Why has evolution endowed these nematodes with such an extended period of non-productive life? In mammals, it is common to speak of the “grandmother hypothesis”—that human females live on past menopause in order to have time to take care of their grandchildren. But worms haven’t been observed to care for their grandchildren.
My hypothesis is that, nevertheless, maybe they do. The service they provide to their grandchildren is in the form of pheromones.
Pheromones are powerful chemical signals. Incredibly small amounts can affect behavior. Hormones are chemical signals within the body, and pheromones are like external hormones, directed toward the behavior of other individuals. (When the individuals are of a different species, they are called kairomones.)
C. elegans is the lab worm that has been so useful in lifespan experiments. In the wild, it is thought that these millimeter-long worms live in the ground on rotting fruit or mushroom. What is clear is that their life history is exquisitely adapted to boom-and-bust cycles of food availability. Like many animals, they live a long time when they are waiting for food to appear, and a short time when they are eating and reproducing. And unique to C. elegans, the worm’s best trick is to go into a state of semi-dormancy, something like a spore, that can live for months at a time without food or water, and which resists heat, cold, chemical toxins and other insults. The spore-like state is called a dauer.
Young worm — Old worm
About 18-24 hours after a worm egg hatches, the stage-3 larva makes a decision whether to go for it, grow and eat and lay lots of eggs, or to become a dauer, to wait and bet on a better opportunity later on. My hypothesis starts with the idea that the dauer state represents the only way that a worm can hope to spread its progeny from one food site to another, which is essential if the lineage is to have a long-term future. “A chicken is an egg’s idea for making more eggs.” A colony of worms on one food source is a dauer’s way of making more dauers.
Come with me, and explore the dauer’s-eye perspective for a moment. You are a fraction of a millimeter long, and you weigh a few billionths of a gram. Imagine that you are carried by a bird or animal or by the wind, and you land on a piece of fruit. Your lucky day! Sensing food and moisture, you morph from the dauer state, turn yourself back into a larva, and you eat and eat, you grow and grow, and you lay several hundred eggs, all endowed for life with a copious food supply.
But if you’re thinking for the long term (all right, worms don’t have brains; but your genes can still be thinking) — if you’re thinking for the long term, your strategy will be to produce as many dauers as possible from this one piece of fruit. Each dauer is a lottery ticket for your future legacy. Remember that this piece of fruit is finite, and that when it’s gone, life beyond this one oasis is a very chancy proposition.
In the end, a good measure of your success in the evolutionary game—your fitness—is the number of dauers that come out of this piece of fruit.
With dauer number in mind as a goal, what’s your best strategy? Well, for the first generation, it’s to produce several hundred eggs. For the second generation, it’s to produce tens of thousands of eggs. For the third generation, several million eggs. But at that point (or possibly the fourth generation, depending on survival of your grandchildren) it will be important not to keep going with egg-laying, but to start generating dauers. The decision that every larva must make should, for optimal fitness, be NOW for the first generation, NOW for the second, NOW, for the third, and LATER for the fourth generation.
But how are you to know that it’s the fourth generation? Remember that you haven’t got eyes or ears or a brain. You might just keep choosing NOW while there’s food, and wait until there’s no more food to say LATER. This would be something you can sense for yourself, but (crucially) this is a flawed strategy. The problem is that your population is growing exponentially. Exponential population shoots up so quickly that there is no warning at the end. There might be a billion larvae all competing for the food that was perfectly adequate for the last generation, when the population was a hundred times smaller, but now there are so many mouths to feed that NONE of them will make it to Stage 3 Larvahood, when the worm is mature enough to become a dauer.
The population that can sense crowding and decide LATER before there is a food shortage has a big advantage in the number of dauers that will eventually be produced. This is where your grandmother can be of great assistance. She has stuck around, though she’s all done laying eggs, and has no prospects for herself, but she and her children can send pheromone signals to their grandchildren, warning them, “Don’t do it! Don’t grow up! Take refuge in dauerhood while there’s still time. If you wait until we run out of food, it will certainly be too late!”
My theory is that the reason that C. elegans goes on living so many days beyond its fertility is that she is sticking around to send pheromone signals to her great grandchildren. The 2-3 week lifespan is just sufficient to last through 4 generations. The theory makes predictions that are being tested in the Beijing lab of Meng-qiu Dong, where I am a visiting scholar this fall. Predictions are
- Life span should be extended in the presence of many old worms.
- The presence of just a few very old worms should be sufficient to bias a young larva’s decision toward becoming a dauer.
- Dauers should be hardy enough to survive the digestive tract of a mouse or bird, so that they can hitch a ride out into the wide world, looking for a new food source.
Here’s a 6-second movie of nictating behavior in a dauer of C japonica, a cousin of C. elegans. Does the dauer look like she’s hiding from predators, or does it look like she’s begging to be eaten? My guess is that worms depend on larger animals to reach new food sources that they could never find in a lifetime at their usual squirming pace in the ground.
Prediction (1) has already been tested in the Dong lab, with encouraging results. But the other two are stronger consequences of the theory, and I’ll be eager to see how the experiments fare.
Note on evolutionary theory and the state of the science
George Williams laid the foundation for the evolutionary theory of aging that is widely accepted and applied today. In his seminal paper of 1957, he was bold and astute enough to make 8 predictions that could be used to validate (or falsify) his theory. In the intervening years, only 2 of the 8 have been borne out, and 4 have been flat-out falsified. One of the predictions that turned out to be false was that death ought to ensue promptly when the capacity for reproduction is lost. Reproductive lifespan and actuarial lifespan should coincide closely, but they don’t.
Williams was, of course, aware that human females are an exception, handily explained by the “grandmother hypothesis” — older women are motivated to stick around because rearing young humans takes such a long time that a woman really needs to outlive her fertility. But he would be surprised to learn that chickens and whales, partridge and elephants, guppies and yeast cells all have substantial post-reproductive lifespans.
It is to Williams’s credit that he put out a well-reasoned theory and volunteered ways it could be put to the test. On the other hand, it reflects badly on the evolutionary scientists who came after him that as the theory was falsified time and again, they clung to the theory, patched it, made excuses for it, but never put it aside to look for a theory that aligns better with experimental reality.
With a lifespan eight times as long as their fertile life, C. elegans worms are in a class by themselves. Their post-reproductive life has been recognized as a scientific puzzle, and I look forward to finding out if my own theory will stand up to experimental tests.
I think it’s a brilliant theory!
There are a few species that grow faster and reproduce more the older they get.
Hello Joyce. Yes, Josh has a blog post about the myriad ways Aging occurs in the wild. What I would be really interested to study would be *how* evolutionary pressures gave rise to each one. Pretty sure we can learn A LOT this way on how to prevent the diseases of old age in humans. Cheers.
Clever solution Josh. You figured out how old worms might have a grandmother effect – and it makes sense. Would it matter that old worms stopped producing that pheromone (dafachronic acid) as they aged?
When you say that the dauer is the only way to spread from one food site to another, and say that the worms eat rotting fruit and mushrooms, that is not correct. The worms eat bacteria, bacteria are found in rotting fruits (not mushrooms) – but are not rotting fruits. Since bacteria are ubiquitous in the soil, there is no need to find discrete food sources. Yes the fact that large number of fellow worms are present in a spot will send the worm (third larval stage, after forming a pre-dauer which can revert to non-dauer) into the dauer state, but lack of food will do the same thing, so what is the advantage to high population indicating a lack of food, instead of lack of food directly turning the L3 into a dauer and sitting out the next three to four months till maybe a change of seasons brings it better luck?
The dauer is not quite a spore, it ages, slowly but it deposits lipofuscin and has a limit of about four months. And as your movie shows, it moves a bit.
That brings me to another inconvenient fact about the worm and I’m wondering if you know something about it: you say that in the final three quarters of its adult life the worm in incapable of reproducing, because it no longer has sperm, however that is the hermaphrodite form of the worm, and not the other, male form which produces only sperm and no eggs. It has a special apparatus for delivering sperm to the hermaphrodites. Might not this form act to inseminate hermaphrodites during their ‘post-reproductive’ phase, and thereby provide the surety of reproduction, provided by self-fertilization, (no chance you won’t find a mate), with the variety and evolvability conferred by sexual reproduction between genetically different individuals?
Hi Harold. Wouldn’t it be nice if we could measure lifespan on a re-emerging dauer? Even better, can we induce dauer state more than once on the same worm and then measure? I presume I don’t need to elaborate on the implications. 😉
Good points, Harold.
I think I answered one question above. It is important to become a dauer BEFORE running out of food, especially if generations are synchronized. Exponential growth makes the last generation so large that competition for food can prevent all the larvae from reaching L3.
Yes, the lucky hermaphrodite who finds a male can use all her eggs before she dies, but this is less than 1 worm in 1,000.
Interesting idea. This sounds analogous to quorum sensing in bacteria, except that instead of the signal just encoding population density, you have a signal that potentially encodes the age distribution of the population as well. Seems important, if confirmed.
Josh,have had a good dialogue with Alan Green,MD thanks to your referral.
Do you know if any of your readers are taking Rapamycin?