Brain–gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in <i>C. elegans</i>

Zhang, Bi; Gong, Jianke; Zhang, Wenyuan; Xiao, Rui; Liu, Jianfeng; Xu, X.Z. Shawn

doi:10.1101/gad.309625.117

Cited by 73 publications

(72 citation statements)

References 57 publications

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“…Serotonin signaling is known to regulate lipid metabolism, although the identity of specific neurons and specific stimulus (other than feeding itself) remains unknown (Murakami & Murakami, 2007; Srinivasan et al., 2008). Recently, glutamate and serotonin have been implicated in the IL1 sensory neuron cooling circuit and insulin‐like peptides have been implicated in the ASJ‐dependent warming circuit for longevity regulation (Zhang et al., 2018). Many mutations affecting AFD thermosensory neuron or the circuit, ttx‐1, gcy‐8, daf‐9 , regulate longevity at 25°C as shown earlier (Lee & Kenyon, 2009) but did not affect LD homeostasis in our analysis (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Neuronal control of lipid metabolism by STR‐2 G protein‐coupled receptor promotes longevity in Caenorhabditis elegans

et al. 2020

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The G protein‐coupled receptor (GPCR) encoding family of genes constitutes more than 6% of genes in Caenorhabditis elegans genome. GPCRs control behavior, innate immunity, chemotaxis, and food search behavior. Here, we show that C. elegans longevity is regulated by a chemosensory GPCR STR‐2, expressed in AWC and ASI amphid sensory neurons. STR‐2 function is required at temperatures of 20°C and higher on standard Escherichia coli OP50 diet. Under these conditions, this neuronal receptor also controls health span parameters and lipid droplet (LD) homeostasis in the intestine. We show that STR‐2 regulates expression of delta‐9 desaturases, fat‐5, fat‐6 and fat‐7, and of diacylglycerol acyltransferase dgat‐2. Rescue of the STR‐2 function in either AWC and ASI, or ASI sensory neurons alone, restores expression of fat‐5, dgat‐2 and restores LD stores and longevity. Rescue of stored fat levels of GPCR mutant animals to wild‐type levels, with low concentration of glucose, rescues its lifespan phenotype. In all, we show that neuronal STR‐2 GPCR facilitates control of neutral lipid levels and longevity in C. elegans.

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Section: Discussionmentioning

confidence: 99%

Neuronal control of lipid metabolism by STR‐2 G protein‐coupled receptor promotes longevity in Caenorhabditis elegans

et al. 2020

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“…Second, lifespan extension conferred by dietary restriction has been shown to be mediated by SKN‐1 that acts in the ASI sensory neurons (Bishop & Guarente, ). Finally, the AFD thermosensory neurons promote lifespan at warm temperature by up‐regulating the DAF‐9 sterol hormone signaling (Lee & Kenyon, ), while cool‐sensitive IL1 neurons promote lifespan at cool temperature through DAF‐16 in the intestine (Xiao et al, ; Zhang et al, ). Besides these direct effects of sensory neurons on longevity, neurons can also detect diverse cellular stressors and trigger animal‐wide stress responses to protect the animal and ensure survival (Durieux, Wolff, & Dillin, ; Prahlad, Cornelius, & Morimoto, ; Tatum et al, ; Taylor & Dillin, ).…”

Section: Discussionmentioning

confidence: 99%

Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans

Zhang

et al. 2019

Aging Cell

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Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age‐related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity. We find that loss of EFA‐6, a modulator of MT dynamics, can delay both neuronal aging and extend the lifespan of C. elegans. Through the use of genetic mutants affecting other MT‐regulating genes in C. elegans, we find that loss of MT stabilizing genes (including ptrn‐1 and ptl‐1) shortens lifespan, while loss of MT destabilizing gene hdac‐6 extends lifespan. Via the use of tissue‐specific transgenes, we further show that these MT regulators can act in the nervous system to modulate lifespan. Through RNA‐seq analyses, we found that genes involved in lipid metabolism were differentially expressed in MT regulator mutants, and via the use of Nile Red and Oil Red O staining, we show that the MT regulator mutants have altered fat storage. We further find that the increased fat storage and extended lifespan of the long‐lived MT regulator mutants are dependent on the DAF‐16/FOXO transcription factor. Our results suggest that neuronal MT status might affect organismal aging through DAF‐16‐regulated changes in fat metabolism, and therefore, MT‐based therapies might represent a novel intervention to promote healthy aging.

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“…Unc-9 is expressed in glutamatergic sensory neurons that respond to chemical, temperature and oxygen cues which are known to influence lifespan. However, these neurons do so by regulating daf-16 FOXO signalling 51,54,83 . Our data show that unc-9 acts independently of daf-16 to regulate longevity, making it unlikely that unc-9 regulates lifespan in these neurons.…”

Section: Discussionmentioning

confidence: 99%

Gap junctions in theC. elegansnervous system regulate ageing and lifespan

Vladis

Fischer

Digalaki

et al. 2019

Preprint

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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...

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Brain–gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in C. elegans

Cited by 73 publications

References 57 publications

Neuronal control of lipid metabolism by STR‐2 G protein‐coupled receptor promotes longevity in Caenorhabditis elegans

Neuronal control of lipid metabolism by STR‐2 G protein‐coupled receptor promotes longevity in Caenorhabditis elegans

Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans

Gap junctions in theC. elegansnervous system regulate ageing and lifespan

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