The nematode Caenorhabditis elegans exhibits rapid senescence that is promoted by the insulin/IGF-1 signalling (IIS) pathway via regulated processes that are poorly understood. IIS also promotes production of yolk for egg provisioning, which in post-reproductive animals continues in an apparently futile fashion, supported by destructive repurposing of intestinal biomass that contributes to senescence. Here we show that post-reproductive mothers vent yolk which can be consumed by larvae and promotes their growth. This implies that later yolk production is not futile; instead vented yolk functions similarly to milk. Moreover, yolk venting is promoted by IIS. These findings suggest that a self-destructive, lactation-like process effects resource transfer from postreproductive C. elegans mothers to offspring, in a fashion reminiscent of semelparous organisms that reproduce in a single, suicidal burst. That this process is promoted by IIS provides insights into how and why IIS shortens lifespan in C. elegans.

During aging, etiologies of senescence cause multiple pathologies, leading to morbidity and death. To understand aging requires identification of these etiologies. For example, Caenorhabditis elegans hermaphrodites consume their own intestinal biomass to support yolk production, which in later life drives intestinal atrophy and ectopic yolk deposition. Yolk proteins (YPs; vitellogenins) exist as three abundant species: YP170, derived from vit-1–vit-5; and YP115 and YP88, derived from vit-6. Here, we show that inhibiting YP170 synthesis leads to a reciprocal increase in YP115/YP88 levels and vice versa, an effect involving posttranscriptional mechanisms. Inhibiting YP170 production alone, despite increasing YP115/YP88 synthesis, reduces intestinal atrophy as much as inhibition of all YP synthesis, which increases life span. By contrast, inhibiting YP115/YP88 production alone accelerates intestinal atrophy and reduces life span, an effect that is dependent on increased YP170 production. Thus, despite copious abundance of both YP170 and YP115/YP88, only YP170 production is coupled to intestinal atrophy and shortened life span. In addition, increasing levels of YP115/YP88 but not of YP170 increases resistance to oxidative stress; thus, longevity resulting from reduced vitellogenin synthesis is not attributable to oxidative stress resistance.

Monocytes can develop immunological memory, a functional characteristic widely recognized as innate immune training, to distinguish it from memory in adaptive immune cells. Upon a secondary immune challenge, either homologous or heterologous, trained monocytes/macrophages exhibit a more robust production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, than untrained monocytes. Candida albicans, β-glucan, and BCG are all inducers of monocyte training and recent metabolic profiling analyses have revealed that training induction is dependent on glycolysis, glutaminolysis, and the cholesterol synthesis pathway, along with fumarate accumulation; interestingly, fumarate itself can induce training. Since fumarate is produced by the tricarboxylic acid (TCA) cycle within mitochondria, we asked whether extra-mitochondrial fumarate has an effect on mitochondrial function. Results showed that the addition of fumarate to monocytes induces mitochondrial Ca²⁺ uptake, fusion, and increased membrane potential (Δψm), while mitochondrial cristae became closer to each other, suggesting that immediate (from minutes to hours) mitochondrial activation plays a role in the induction phase of innate immune training of monocytes. To establish whether fumarate induces similar mitochondrial changes in vivo in a multicellular organism, effects of fumarate supplementation were tested in the nematode worm Caenorhabditis elegans. This induced mitochondrial fusion in both muscle and intestinal cells and also increased resistance to infection of the pharynx with E. coli. Together, these findings contribute to defining a mitochondrial signature associated with the induction of innate immune training by fumarate treatment, and to the understanding of whole organism infection resistance.