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C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals
Anais Franco-Romero, … , Eva Trevisson, Marco Sandri
Anais Franco-Romero, … , Eva Trevisson, Marco Sandri
Published June 13, 2024
Citation Information: J Clin Invest. 2024;134(15):e165814. https://doi.org/10.1172/JCI165814.
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Research Article Aging Cell biology Article has an altmetric score of 258

C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals

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Abstract

The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.

Authors

Anais Franco-Romero, Valeria Morbidoni, Giulia Milan, Roberta Sartori, Jesper Wulff, Vanina Romanello, Andrea Armani, Leonardo Salviati, Maria Conte, Stefano Salvioli, Claudio Franceschi, Viviana Buonomo, Casey O. Swoboda, Paolo Grumati, Luca Pannone, Simone Martinelli, Harold B.J. Jefferies, Ivan Dikic, Jennifer van der Laan, Filipe Cabreiro, Douglas P. Millay, Sharon A. Tooze, Eva Trevisson, Marco Sandri

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Figure 9

Scheme of MYTHO function in mammalian cells and C. elegans.

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Scheme of MYTHO function in mammalian cells and C. elegans.
Left panel s...
Left panel shows the effects of MYTHO inhibition in mammalian cells. The ablation of the Mytho gene causes autophagic impairment, mitochondrial dysfunction with increased ROS production, accumulation of β-galactosidase, upregulation of p21, and reduced cell proliferation. These features belong to the hallmarks of aging, supporting a MYTHO role in preventing cellular senescence. The right panel describes the consequences of myt-1 deletion in C. elegans. Consistently, autophagic flux, resistance to oxidative stress, life span, and health span were reduced in the absence of myt-1. The myt-1 contribution to life span was dissected by genetic interaction studies that identified myt-1’s involvement in glp-1– and eat-2–mediated longevity.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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