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Aging Cell. 2019 Apr;18(2):e12884. doi: 10.1111/acel.12884. Epub 2019 Jan 14.

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

Xu A1,2, Zhang Z3, Ko SH1,2,3, Fisher AL4,5,6, Liu Z3, Chen L1,2,3.

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Barshop Institute for Longevity and Aging Studies, San Antonio, Texas.
Department of Cell Systems and Anatomy, UTHSCSA, San Antonio, Texas.
Department of Molecular Medicine, UTHSCSA, San Antonio, Texas.
Center for Healthy Aging, UTHSCSA, San Antonio, Texas.
Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, UTHSCSA, San Antonio, Texas.
GRECC, South Texas VA Healthcare System, San Antonio, Texas.


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.


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

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