Paper #5 - A C elegans mutant that lives twice as long as wild type

Title: A C elegans mutant that lives twice as long as wild type

Year: 1993

Summary:  The authors investigated several genes that can lead to dauer formation (an alternative third larval stage induced by stress and whose entry is mediated by a pheromone during L1). They hypothesized that since dauers are so long-lived, perhaps some of the genes activated during dauer stage would confer longevity to the worm.

They used temperature sensitive dauer mutants (who would develop into dauers if grown at the non-permissive temperature, usually 20 or 25 C), but instead only subjected them to the non-permissive temperature after L4. Thus the worms did not enter the dauer phase, but  the mutations causing entry into dauer phase were activated as an early adult. Several genes did nothing (daf-11, daf-7, and daf-14), but all three daf-2 mutants had increased lifespans, from ~18 days to ~42 days for two of the three mutants.

As an aside, several years later it was discovered that daf-2 is an insulin receptor homolog, and that mutations that extend lifespan only require its loss of function in the nervous system specifically. Strikingly, its effects on lifespan could be separated from its effects on fat storage (as a general proxy for metabolism) depending on where the mutated gene was expressed (neurons vs muscle vs intestine).

The authors investigated whether daf-2 mutants were abnormal in their behavior, but they seemed to display similar pharyngeal pumping frequency and rates, and similar amounts of motion. They had slightly reduced brood sizes however (~20% reduction, questionably significant). I'm not clear on the preceding literature, but for some reason I guess others had thought that the reproductive cells were responsible for some sort of life-shortening effect. They therefore ablated the gonad precursor cells Z1 and Z4, as well as the germ-cell precursors Z2 and Z3 in order to establish whether this conferred a similar life-extending effect as daf-2, but they found these ablations had no effect.

Finally, they note that while daf-2 mutants live 42 days, a daf-2; daf-16 double mutant had a regular life-span. As another note, daf-16 was later discovered to be a downstream target of daf-2 and a FOXO ortholog that controls the expression of various antioxidative enzymes including catalase and superoxide dismutase, both of which are highly expressed in dauers.

Questions I still have:

The authors showed somewhat weak data to suggest that the behavior of these worms is normal. That's a kind of crazy thought. Somehow they get to live twice as long, and they get to do so in a seemingly healthy way. Could this be evolutionarily unfavorable? Do daf-2 mutations affect neuronal function or neuronal circuitry?

Potential follow-up articles: "daf-2, an insulin receptor-like gene that regulates longevity and diapause in C. elegans" (Kimura, Tissenbaum, Liu, and Ruvkun, 1997), and "Regulation of C. elegans lifespan by insulinlike signaling in the nervous system" (Wolkow, Kimura, Lee, and Ruvkun, 2000)