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DAF‐2/insulin IGF‐1 receptor regulates motility during aging by integrating opposite signaling from muscle and neuronal tissues
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DAF‐2/insulin IGF‐1 receptor regulates motility during aging by integrating opposite signaling from muscle and neuronal tissues
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Journal Article
DAF‐2/insulin IGF‐1 receptor regulates motility during aging by integrating opposite signaling from muscle and neuronal tissues
2022
Overview
During aging, preservation of locomotion is generally considered an indicator of sustained good health, in elderlies and in animal models. In Caenorhabditis elegans, mutants of the insulin‐IGF‐1 receptor DAF2/IIRc represent a paradigm of healthy aging, as their increased lifespan is accompanied by a delay in age‐related loss of motility. Here, we investigated the DAF‐2/IIRc‐dependent relationship between longevity and motility using an auxin‐inducible degron to trigger tissue‐specific degradation of endogenous DAF‐2/IIRc. As previously reported, inactivation of DAF‐2/IIRc in neurons or intestine was sufficient to extend the lifespan of worms, whereas depletion in epidermis, germline, or muscle was not. However, neither intestinal nor neuronal depletion of DAF‐2/IIRc prevented the age‐related loss of motility. In 1‐day‐old adults, DAF‐2/IIRc depletion in neurons reduced motility in a DAF‐16/FOXO dependent manner, while muscle depletion had no effect. By contrast, DAF‐2 depletion in the muscle of middle‐age animals improved their motility independently of DAF‐16/FOXO but required UNC‐120/SRF. Yet, neuronal or muscle DAF‐2/IIRc depletion both preserved the mitochondria network in aging muscle. Overall, these results show that the motility pattern of daf‐2 mutants is determined by the sequential and opposing impact of neurons and muscle tissues and can be dissociated from the regulation of the lifespan. This work also provides the characterization of a versatile tool to analyze the tissue‐specific contribution of insulin‐like signaling in integrated phenotypes at the whole organism level. In C. elegans, age‐associated regulation of motility by the DAF‐2/insulin‐IGF‐1 receptor is determined by the sequential and opposing impact of neurons and muscle and can be dissociated from the lifespan phenotype. Intestinal and neuronal DAF‐2 activities modulate lifespan, whereas muscle DAF‐2 does not. Neuronal DAF‐2 promotes motility in early adulthood through inhibition of DAF‐16/FOXO, whereas muscle DAF‐2 decreases motility in middle age through inactivation of UNC‐120/SRF.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Animals
/ Caenorhabditis elegans - metabolism
/ Caenorhabditis elegans Proteins - genetics
/ Caenorhabditis elegans Proteins - metabolism
/ daf‐2
/ Food
/ Forkhead Transcription Factors - metabolism
/ Insulin
/ lifespan
/ Mammals
/ Motility
/ Mutants
/ Mutation
/ Neurons
/ Proteins
/ Receptor, IGF Type 1 - genetics
/ Receptor, Insulin - genetics
/ Receptor, Insulin - metabolism
/ Worms
