Males deploy multifaceted strategies and hijack longevity pathways to induce premature demise of the opposite sex

Abstract

<jats:title>Abstract</jats:title><jats:p>Interactions between the sexes negatively impact health in many species, including mammals<jats:sup>1–9</jats:sup>. In mice, sexual interactions induce weight gain and shorten lifespan in females, independent of fertilization<jats:sup>6,9</jats:sup>. In <jats:italic>Caenorhabditis</jats:italic>, males shorten the lifespan of the opposite sex (females or hermaphrodites)<jats:sup>1–3,8</jats:sup>. However, the mechanisms underlying the negative influence of males on lifespan – and their overlap with known longevity pathways – are still largely unknown. Here, we use transcriptomic profiling and targeted screens to systematically uncover new conserved genes involved in male-induced demise. Interestingly, deficiency of these genes individually, and especially in combination, induces strong protection, highlighting the benefit of combining interventions to extend lifespan. Some genes (e.g. <jats:italic>acbp-3, col-43</jats:italic>) only extend hermaphrodite lifespan when knocked-down in the presence of males, suggesting specific protective mechanisms against male-induced demise. However, we also uncover two previously unknown longevity genes (<jats:italic>sri-40</jats:italic> and <jats:italic>delm-2</jats:italic>) that, when knocked-down, extend hermaphrodite lifespan both with and without males, which points to new broad mechanisms of resistance. In sharp contrast, many classical long-lived mutants are actually short-lived in the presence of males, suggesting that males hijack and suppress known longevity pathways. This systematic analysis reveals striking differences in longevity in single sex versus mixed sex environments and uncovers the elaborate network of functional regulation elicited by sexual interactions, which could extend to other species.</jats:p>

Oleic Acid Protects Caenorhabditis Mothers From Mating-Induced Death and the Cost of Reproduction

“…Correlation coefficients are listed next to the corresponding branches/nodes. (Booth et al, 2020). Genes that regulate mitochondrial fatty acid beta oxidation, such as acdh-8, decr-1.2, and decr-1.3, were specifically up-regulated in mated worms with oleic acid supplementation, suggesting that oleic acid's unique ability to modulate lipid homeostasis might contribute to its specificity in regulating the longevity of mated worms.…”

“…To better understand how fat metabolism is altered after mating, we performed transcriptional analysis of mated vs. unmated glp-1 hermaphrodites (Booth et al, 2020). glp-1 mothers lack a germline to produce any eggs, which allowed us to disregard transcriptional changes in eggs, and instead focus on somatic changes.…”

“…Microarray data of mated and unmated glp-1(e2141) was retrieved from the previous publication (Booth et al, 2020). glp-1(e2141) hermaphrodites grown at the restrictive temperature (25 • C) were mated on day 1 of adulthood for 24 h in a 2:1 male:hermaphrodite ratio.…”

piRNAs regulate a Hedgehog germline-to-soma pro-aging signal

“…Reasoning that the signal should be amplified after mating, we started with the list of 666 genes that are significantly up-regulated in the mated germlines we identified in our mRNA-seq analysis. First, since the pro-aging signal originates from the germline, it must be germline-specific: we subtracted those genes that are also up-regulated in mated glp-1 germlineless worms (Booth et al, 2020) from the original list, reducing the number of candidates to 418 ( Figure S2C, 3A, Table 3). Next, we reasoned that the amplified germline signal should be robust enough to be identified in the transcriptome of whole worms with an intact germline, since the germline accounts for a significant proportion of the whole worm biomass.…”

“…Microarray data of mated and unmated glp-1 ( e2141 ) was retrieved from the previous publication (Booth et al, 2020). Microarray data of mated and unmated fog-2 ( q71 ) was retrieved from the previous publication (Choi et al, 2021).…”