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

Aiping Xu, Zhao Zhang, Su Hyuk Ko, Alfred L. Fisher, Zhijie Liu, Lizhen Chen

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere12884
JournalAging cell
Volume18
Issue number2
DOIs
StatePublished - Apr 2019

Keywords

  • daf-16
  • efa-6
  • fat metabolism
  • longevity
  • microtubules
  • neuronal aging

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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