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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.

Author information

1
Barshop Institute for Longevity and Aging Studies, San Antonio, Texas.
2
Department of Cell Systems and Anatomy, UTHSCSA, San Antonio, Texas.
3
Department of Molecular Medicine, UTHSCSA, San Antonio, Texas.
4
Center for Healthy Aging, UTHSCSA, San Antonio, Texas.
5
Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, UTHSCSA, San Antonio, Texas.
6
GRECC, South Texas VA Healthcare System, San Antonio, Texas.

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.

KEYWORDS:

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

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