Abstract
Across organisms, manipulation of biosynthetic capacity arrests development early in life, but can increase health- and lifespan post-developmentally. Here we demonstrate that this developmental arrest is not sickness but rather a regulated survival program responding to reduced cellular performance. We inhibited protein synthesis by reducing ribosome biogenesis (rps-11/RPS11 RNAi), translation initiation (ifg-1/EIF3G mutation and egl-45/EIF3A RNAi), or ribosome progression (cycloheximide treatment), all of which result in a specific arrest at larval stage 2 of C. elegans development. This quiescent state can last for weeks—beyond the normal C. elegans adult lifespan—and is reversible, as animals can resume reproduction and live a normal lifespan once released from the source of protein synthesis inhibition. The arrest state affords resistance to thermal, oxidative, and heavy metal stress exposure. In addition to cell-autonomous responses, reducing biosynthetic capacity only in the hypodermis was sufficient to drive organism-level developmental arrest and stress resistance phenotypes. Among the cell non-autonomous responses to protein synthesis inhibition is reduced pharyngeal pumping that is dependent upon AMPK-mediated signaling. The reduced pharyngeal pumping in response to protein synthesis inhibition is recapitulated by exposure to microbes that generate protein synthesis-inhibiting xenobiotics, which may mechanistically reduce ingestion of pathogen and toxin. These data define the existence of a transient arrest-survival state in response to protein synthesis inhibition and provide an evolutionary foundation for the conserved enhancement of healthy aging observed in post-developmental animals with reduced biosynthetic capacity.
Highlights
The differing phenotypes stemming from the loss of essential cellular functions, such as protein synthesis, are specific to the time in life when the deficit occurs
Protein synthesis inhibition induces a stress resistant developmental arrest state To elucidate the possible connection between the developmental arrest and longevity-promoting effects of protein synthesis inhibition [16, 19,20,21, 29], we first defined the nature of the developmental arrest in C. elegans
We targeted the translation initiation factor, egl-45/EIF3A, or the small ribosomal protein, rps-11/RPS11, by RNA interference (RNAi), so that we could control the strength and duration of inhibition, thereby avoiding the constitutive arrest that can occur when protein synthesis is inhibited by genetic mutation [31]
Summary
The differing phenotypes stemming from the loss of essential cellular functions, such as protein synthesis, are specific to the time in life (development or adulthood) when the deficit occurs. Two other arrest states are adult reproductive diapause, which is induced by L4 starvation and results in an early-adult arrest state capable of surviving long periods of nutrient deprivation with the ability to later resume reproduction, and impaired mitochondria arrest, induced by deficiency in mitochondrial respiration and resulting in L3 arrest [4, 8]; these two states have not yet been directly shown to have stress resistance phenotypes These examples suggest the existence of cellular programs that function as checkpoints throughout development that stall reproduction to promote fitness [9]
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