The continuous presence of young males significantly shortened the lifespan of hermaphrodites (>20% decrease) (, ). The male-induced shortening of lifespan was seen whether males were placed with hermaphrodites at the beginning of their life (day 1) or at sexual maturity (day 4) (). This lifespan shortening was not a result of crowding because the total numbers of worms were the same in all conditions. Males also induced behavioral and morphological phenotypes characteristic of an advanced age in these hermaphrodites: movement was slowed, paralysis increased, and a general decrepitude was observed, as exemplified by increased incidence of vacuole-like structures and structural decline within the cuticle, muscle, pharynx, and intestine (, ; and ) (–). We termed this phenomenon male-induced demise (MID).

To understand how males restrict the lifespan of the opposite sex, we assessed genome-wide changes in hermaphrodite gene expression triggered by males. To avoid expression changes due to fertilized embryos in the mother, we used sterile hermaphrodites (glp-1). We placed glp-1 young adult hermaphrodites with wild-type young males for 8 days, then removed the males and collected the hermaphrodites’ RNA for microarray analysis (). As a control, we collected RNA from glp-1 hermaphrodites that were not placed in the presence of males but were grown at the same density with other hermaphrodites (). Unbiased clustering of the microarray data revealed that the presence of males induced large changes in gene expression in hermaphrodites (, , ). Genes whose expression was increased in response to males were enriched for insulin signaling (P = 4.3×10⁻³) (e.g. insulin peptides (ins-4, ins-11, ins-23 and ins-31), which are expressed in neurons), transthyretin-related family members (P = 4.3×10⁻³) (which are involved in neurodegenerative diseases in mammals ()), and G-protein coupled chemoreceptors (P = 1.9×10⁻³) (which are expressed in sensory neurons) (). In contrast, genes whose expression was decreased in response to males were enriched for C-type lectins and the cuticle (). That the presence of males triggered changes in the expression of neuronally-expressed genes suggests that mechanisms other than structural damage resulting from copulation also contribute to MID.

Because MID could be rescued by manipulating a single gene in the hermaphrodites, the phenomenon seems unlikely to solely result from structural damage caused by copulation. To more directly test whether males could shorten the lifespan of hermaphrodites without being in physical contact with them, we placed males on plates for 2 days, removed these males, and then added hermaphrodites to the male-conditioned plates (). Conditioning the plates with males shortened the lifespan of wild-type hermaphrodites, in a manner that depended on the number of males used to make the conditioned medium (). Hermaphrodites placed on male-conditioned plates underwent signs of MID (). While there may be a physical component to MID, one or more diffusible substances secreted or released by males on the plate is sufficient to decrease lifespan of hermaphrodites.

Is the male-induced demise a more general, conserved phenomenon? The genus Caenorhabditis includes several distantly related species, each of them with different strains (). Similar to what we observed in the long-domesticated strain of C. elegans (N2), males from a wild C. elegans strain, AB1, also shortened the lifespan of hermaphrodites of that strain (). Males from the species C. briggsae, which diverged from C. elegans about 20–30 million years ago (), decreased the lifespan of hermaphrodites of two different C. briggsae isolates (). Males from the species C. remanei, which has obligate males and females, led to lifespan shortening of females (). Together, these results indicate that MID is conserved at least over 20–30 million years of evolution and is not linked to hermaphroditism. The evolutionary conservation of MID raises the possibility that this phenomenon has adaptive value and may be caused by conserved mechanisms.