DAF‐2/insulin IGF‐1 receptor regulates motility during aging by integrating opposite signaling from muscle and neuronal tissues

Abstract

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.

Two Muscle-Specific and Direct Transcriptional Targets of DAF-16/FOXO Activated by Reduced Insulin/IGF-1 Signaling

“…Revealing its muscle-specific transcriptional activation by DAF-16 promotes several hypotheses on its potential role in aging-dependent physiological functions. For example, CEX-1 might contribute to the known effects of IIS on the age-dependent maintenance of muscle activity and muscle survival 44,46 . Intriguingly, impaired ryanodine receptor activity and reduced IIS have been reported to reduce heat shock-induced Ca 2+ overload in muscle cells 47 .…”

“…In motor neurons, decreased IIS and DAF-16 activation functions intrinsically to delay age-related decline in axon regeneration 43 . Age-dependent motility decline appears to be contributed by IIS from both neurons and muscles, in opposite ways at different phases of adults 21,44 .…”

“…In motor neurons, decreased IIS and DAF-16 activation functions intrinsically to delay age-related decline in axon regeneration 43 . Age-dependent motility decline appears to be contributed by IIS from both neurons and muscles, in opposite ways at different phases of adults 21,44 . DAF-16 regulates many physiological processes in muscles, including muscle arm extension 45 , neuromuscular junction development 34 , prevention of cell death 46 , and resistance to heat-induced calcium overload 47 .…”

Asperuloside, the bioactive compound in the edible Eucommia ulmoides male flower, delays muscle aging by daf-16 mediated improvement in mitochondrial dysfunction

“…Body bending frequency. The culture time points were the same as above and assays were performed as Roy et al 15 described with modifications. We placed 4-6 worms into a droplet of 5 μL M9 buffer.…”

Sea cucumber (Acaudina leucoprocta) peptides extended the lifespan and enhanced antioxidant capacity via DAF-16/DAF-2/SOD-3/OLD-1/PEPT-1 in Caenorhabditis elegans

“…It applies to utilizing molecular biology methods for genetic intervention and behavioral tracing ( 14 ). In C. elegans , IIS plays a key role in the regulation of development, metabolism, and aging ( 15 ). The IIS is a key pathway in the delayed aging of SCPs with the following key genes, ( daf-16, daf-2, sod-3 ).…”