Date Published: January 14, 2019
Publisher: John Wiley and Sons Inc.
Author(s): Aiping Xu, Zhao Zhang, Su‐Hyuk Ko, Alfred L. Fisher, Zhijie Liu, Lizhen Chen.
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.
Microtubules (MTs) are essential cytoskeletal structures for most eukaryotic cells and MT regulators have been implicated in many human diseases. MTs are polymeric hollow rods built from dimers of α‐ and β‐tubulin that are arranged in a head‐to‐tail manner. MTs are highly dynamic structures that constantly undergo growth and shrinkage/catastrophe (Mitchison & Kirschner, 1984). MT dynamics and stability can be modulated by a large number of MT‐interacting proteins. Some MT‐associated proteins (MAPs), such as Tau, bind along the MT structure to promote MT assembly and stability by protecting MTs from severing by destabilizing factors (Kapitein & Hoogenraad, 2015). Due to the larger cytoplasmic volume and polarized morphology, neurons rely more on MT function compared with other cell types. MTs serve as tracks for long‐distance transport and play a critical role in the establishment and maintenance of neuronal structure and polarity (Kapitein & Hoogenraad, 2015). Consequently, abnormalities in MT organization and dynamics, as well as MT protein expression or distribution, have been observed in many neurological disorders. Mutations in tubulin genes or MAPs have also been reported to affect neuronal integrity during aging (Chew, Fan, Gotz, & Nicholas, 2013; Pan, Peng, Chen, & McIntire, 2011). The importance of MT regulation in healthy neuronal aging is underscored by the critical role of Tau in MT stabilization and its dysfunction related to neurodegenerative diseases where the impairment of axonal transport is a common factor (Baird & Bennett, 2013).
Conceived and designed the experiments: AX, AF, ZL, and LC. Performed the experiments: AX, SK, and LC. Analyzed the data: AX, ZZ, and LC. Wrote the paper: AX, ZZ, ZL, and LC.