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Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity

Marzia Savini, Jonathon D. Duffy, Andrew Folick, Yi-Tang Lee, Pei-Wen Hu, Isaiah A. Neve, Feng Jin, Qinghao Zhang, Matthew Tillman, Youqiong Ye, William B. Mair, Jin Wang, Leng Han, Eric A. Ortlund, Meng C. Wang
doi: https://doi.org/10.1101/2021.06.10.447794
Marzia Savini
1Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Jonathon D. Duffy
1Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Andrew Folick
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
6Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
7Department of Medicine – Endocrinology and Metabolism – University of California San Francisco, San Francisco, CA, 94143, USA
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Yi-Tang Lee
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
8Integrative Program of Molecular and Biochemical Sciences, Baylor College of Medicine, Houston, TX 77030, USA
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Pei-Wen Hu
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Isaiah A. Neve
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Feng Jin
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
5Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Qinghao Zhang
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
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Matthew Tillman
11Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA, 30322, USA
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Youqiong Ye
9Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, 77030
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William B. Mair
10Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, 02115
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Jin Wang
5Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Leng Han
9Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, 77030
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Eric A. Ortlund
11Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA, 30322, USA
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Meng C. Wang
1Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
2Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
4Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
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  • For correspondence: wmeng@bcm.edu
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Abstract

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in aging-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate aging remains unclear. Here, we report a fat-to-neuron lipid signaling pathway induced by lysosomal metabolism and its longevity promoting role in Caenorhabditis elegans. We discovered that lysosomal lipolysis in peripheral fat storage tissue up-regulates the neuropeptide signaling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation requires the secretion from the fat storage tissue of a lipid chaperone protein LBP-3 and polyunsaturated fatty acids (PUFAs). LBP-3 binds to specific PUFAs, and acts through a nuclear hormone receptor NHR-49 and neuropeptide NLP-11 in neurons to extend lifespan. Together, these results reveal lysosomes as a signaling hub to coordinate metabolism and aging, and a lysosomal signaling mechanism that mediates intertissue communication to promote longevity.

Competing Interest Statement

The authors have declared no competing interest.

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Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity
Marzia Savini, Jonathon D. Duffy, Andrew Folick, Yi-Tang Lee, Pei-Wen Hu, Isaiah A. Neve, Feng Jin, Qinghao Zhang, Matthew Tillman, Youqiong Ye, William B. Mair, Jin Wang, Leng Han, Eric A. Ortlund, Meng C. Wang
bioRxiv 2021.06.10.447794; doi: https://doi.org/10.1101/2021.06.10.447794
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Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity
Marzia Savini, Jonathon D. Duffy, Andrew Folick, Yi-Tang Lee, Pei-Wen Hu, Isaiah A. Neve, Feng Jin, Qinghao Zhang, Matthew Tillman, Youqiong Ye, William B. Mair, Jin Wang, Leng Han, Eric A. Ortlund, Meng C. Wang
bioRxiv 2021.06.10.447794; doi: https://doi.org/10.1101/2021.06.10.447794

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