Starvation causes comprehensive metabolic changes, which are still not fully understood. Here, we used quantitative proteomics and RNA sequencing to examine the temporal starvation responses in wild-type Caenorhabditis elegans and animals lacking the transcription factor HLH-30. Our findings show that starvation alters the abundance of hundreds of proteins and mRNAs in a temporal manner, many of which are involved in central metabolic pathways, including lipoprotein metabolism. We demonstrate that premature death of hlh-30 animals under starvation can be prevented by knockdown of either vit-1 or vit-5, encoding two different lipoproteins. We further show that the size and number of intestinal lipid droplets under starvation are altered in hlh-30 animals, which can be rescued by knockdown of vit-1. Taken together, this indicates that survival of hlh-30 animals under starvation is closely linked to regulation of intestinal lipid stores. We provide the most detailed poly-omic analysis of starvation responses to date, which serves as a resource for further mechanistic studies of starvation.

Highlights d Autophagy regulates steroid production d Autophagosomes sequester and traffic cholesterol substrate for steroid production d The Warts effector microRNA bantam regulates autophagy via the EcR and Tor pathways d Autophagy-dependent steroid regulation adjusts growth to nutrient availability

Decline of cellular functions especially cognitive is a major deficit that arises with age in humans. Harnessing the strengths of small and genetic tractable model systems has revealed key conserved regulatory biochemical and signaling pathways that control aging. Here, we review some of the key signaling and biochemical pathways that coordinate aging processes with special emphasis on Caenorhabditis elegans as a model system and discuss how nutrients and metabolites can regulate lifespan by coordinating signaling and epigenetic programs. We focus on central nutrient-sensing pathways such as mTOR and insulin/insulin-like growth factor signaling and key transcription factors including the conserved basic helix-loop-helix transcription factor HLH-30/TFEB.

SummaryOne of the most fundamental challenges for all living organisms is to sense and respond to alternating nutritional conditions in order to adapt their metabolism and physiology to promote survival and achieve balanced growth. Here, we applied metabolomics and lipidomics to examine temporal regulation of metabolism during starvation in wildtype Caenorhabditis elegans and in animals lacking the transcription factor HLH-30. Our findings show for the first time that starvation alters the abundance of hundreds of metabolites and lipid species in a temporal- and HLH-30-dependent manner. We demonstrate that premature death of hlh-30 animals under starvation can be prevented by supplementation of exogenous fatty acids, and that HLH-30 is required for complete oxidation of long-chain fatty acids. We further show that RNAi-mediated knockdown of the gene encoding carnitine palmitoyl transferase I (cpt-1) only impairs survival of wildtype animals and not of hlh-30 animals. Strikingly, we also find that compromised generation of peroxisomes by prx-5 knockdown renders hlh-30 animals hypersensitive to starvation, which cannot be rescued by supplementation of exogenous fatty acids. Collectively, our observations show that mitochondrial functions are compromised in hlh-30 animals and that hlh-30 animals rewire their metabolism to largely depend on functional peroxisomes during starvation, underlining the importance of metabolic plasticity to maintain survival.Abstract Figure

One of the most fundamental challenges for all living organisms is to sense and respond to alternating nutritional conditions in order to adapt their metabolism and physiology to promote survival and achieve balanced growth. Here, we applied metabolomics and lipidomics to examine temporal regulation of metabolism during starvation in wild‐type Caenorhabditis elegans and in animals lacking the transcription factor HLH‐30. Our findings show for the first time that starvation alters the abundance of hundreds of metabolites and lipid species in a temporal‐ and HLH‐30‐dependent manner. We demonstrate that premature death of hlh‐30 animals under starvation can be prevented by supplementation of exogenous fatty acids, and that HLH‐30 is required for complete oxidation of long‐chain fatty acids. We further show that RNAi‐mediated knockdown of the gene encoding carnitine palmitoyl transferase I (cpt‐1) only impairs survival of wild‐type animals and not of hlh‐30 animals. Strikingly, we also find that compromised generation of peroxisomes by prx‐5 knockdown renders hlh‐30 animals hypersensitive to starvation, which cannot be rescued by supplementation of exogenous fatty acids. Collectively, our observations show that mitochondrial functions are compromised in hlh‐30 animals and that hlh‐30 animals rewire their metabolism to largely depend on functional peroxisomes during starvation, underlining the importance of metabolic plasticity to maintain survival.