Gap junctions in theC. elegansnervous system regulate ageing and lifespan

Abstract

The nervous system is a central regulator of longevity, but how neuronal communication interfaces with ageing pathways is not well understood. Gap junctions are key conduits that allow voltage and metabolic signal transmission across cellular networks, yet it has remained unexplored whether they play a role in regulating ageing and longevity. We show that the innexin genes encoding gap junction subunits in Caenorhabditis elegans have extensive and diverse impacts on lifespan. Loss of the neural innexin unc-9 increases longevity by a third and also strongly benefits healthspan. Unc-9 acts specifically in a glutamatergic circuit linked to mechanosensation. Absence of unc-9 depends on a functional touch-sensing machinery to regulate lifespan and alters the age-dependent decline of mechanosensory neurons. The life extension produced by removal of unc-9 requires reactive oxygen species. Our work reveals for the first time that gap junctions are important regulators of ageing and lifespan.is currently unknown whether gap junction coupling as a key intercellular communication channel contributes to the regulation of ageing and longevity.Here we set out to explore if gap junctions affect ageing using the nematode Caenorhabditis elegans, an outstanding model for studies on ageing 14,15 . We assayed the lifespan of loss-offunction mutants of most of the 25 C. elegans innexins and discovered that innexins have a significant impact on lifespan, some leading to an extension of lifespan while others shorten it. Surprisingly, most null mutations of neural innexins extended lifespan, with loss of unc-9, the most widely expressed innexin in the nervous system, increasing longevity by a third. Its selective removal from glutamatergic neurons led to an increase in lifespan and points to a mechanosensory circuit where UNC-9 regulates ageing. Our results show that UNC-9 alters the age-dependent decline of touch-sensing neurons and depends on functional touch sensation as well as reactive oxygen species to modulate lifespan. This study gives strong evidence to suggest an important and previously unknown role for gap junction intercellular communication in shaping ageing and longevity. ResultsThe C. elegans gap junction genes regulate longevity As there is extensive intercellular gap junction coupling in all organs of C. elegans, we hypothesised that gap junction channels may play specific roles in organismal ageing and longevity. The channel subunits encoded by 25 innexin genes show diverse, highly combinatorial, plastic and dynamic expression in virtually all organs and cells of this animal.The gap junction channels these innexins form play key roles in intercellular communication [16][17][18] . We asked if innexins influence longevity, which has not been known. To this end we performed lifespan assays in loss-of-function mutants of all innexins except inx-3, inx-12 and inx-13; these genes are essential for embryonic development or osmoregulation and their loss confers a lethal phenotype 18,19 . Loss-of-function mutants are availab...

A gonadal gap junction INX-14/Notch GLP-1 signaling axis suppresses gut defense through an intestinal lysosome pathway

“…The innate immune response induced by bacterial infection occurs primarily in the gut ( 6 ) or epidermal tissue ( 11 ) of C. elegans . Remarkably, inx-14 is mainly expressed in the germline, neurons and muscle cells ( 34 , 40 ). To determine in which tissue inx-14 acts to reduce intestinal defense, we treated animals with tissue-specific inx-14 RNAi prior to PA14 infection.…”

“…We demonstrate that inx-14 , a heterotypic and heteromeric gap junction subunit, suppresses intestinal defense, as mutants lacking this gene showed strongly increased resistance to PA14 infection. Recent studies have demonstrated that INX-14 is widely expressed in the germline, neurons and muscle ( 34 , 40 ). To determine the tissue in which INX-14 functions, we performed tissue-specific RNAi and rescue assays and remarkably found that INX-14 primarily acts in the germline.…”

“…We demonstrate that inx-14, a heterotypic and heteromeric gap junction subunit, suppresses intestinal defense, as mutants lacking this gene showed strongly increased resistance to PA14 infection. Recent studies have demonstrated that INX-14 is widely expressed in the germline, neurons and muscle (34,40) Previous work demonstrates that insulin/IGF-1 signals from the reproductive system shorten longevity. In C. elegans, prevention of germline stem cell proliferation results in the extension of lifespan, which requires the activity of DAF-16, a member of the forkhead/ winged-helix family of transcriptional regulators (70,71).…”