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.

No abstract

During ageing, preservation of locomotion is generally considered an indicator of sustained good health, in elderlies and in animal models. In C. elegans, mutants of the insulin receptor DAF-2 represent a paradigm of healthy ageing, as their increased lifespan is accompanied by a delay in age-related loss of mobility. However, these animals are less mobile than wild-type animals in early adulthood. Here we investigated the DAF-2-dependent relationship between longevity and mobility using an auxin-inducible degron to trigger tissue-specific degradation of endogenous DAF-2. As previously reported, inactivation of DAF-2 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 prevented the age-related loss of mobility. In 1-day-old adults, DAF-2 depletion in neurons reduced mobility, while muscle depletion had no effect. By contrast, DAF-2 depletion in the muscle of middle-age animals improved their mobility. The combination of neuronal and muscle effects thus mimics the global locomotor phenotype of daf-2 mutants. Yet, we observed that neuronal or muscle DAF-2 depletion both preserved the mitochondria network in ageing muscle. Overall, these results show that the mobility 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.