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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

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 8

myt-1 controls longevity through the eat-2 and glp-1 signaling pathways.

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myt-1 controls longevity through the eat-2 and glp-1 signaling pathways...
(A) Survival curves of fer-15(b26) II (n = 140), myt-1(pan8) I; fer-15(b26) II (n = 140), fer-15(b26) II; daf-2(e1370) III (n = 141), and myt-1(pan8) I; fer-15(b26) II, daf-2(e1370) III worms (n = 179) (N = 2). (B) Survival curves of fer-15(b26) II (n = 216), myt-1(pan8) I; fer-15(b26) II (n = 244), fer-15(b26) II; eat-2(ad1116) II (n = 171), and myt-1(pan8) I; fer-15(b26) II; eat-2(ad1116) II (n = 263) worms (N = 2/3). (C) Survival curves of fer-15(b26) II (n = 135), myt-1(pan8) I; fer-15(b26) II (n = 162), fer-15(b26) II; glp-1(e2141) III (n = 163), myt-1(pan8) I; fer-15(b26) II; glp-1(e2141) III (n = 162) (N = 2). Raw data of fer-15(b26) II and myt-1(pan8) I; fer-15(b26) II worms are the same in B and C (experiments were performed in parallel). Cox proportional hazards analysis was performed for the interaction of terms genotypes myt-1 and daf-2 (0.00018), eat-2 (0.00004), glp-1 (0.0007). (D and E) Life span of young adult fer-15(b26) II and myt-1(pan8) I; fer-15(b26) II worms fed with empty pL4440 vector or pL4440 expressing the atg-18 coding sequence [atg-18(RNAi)] (n = 260–340 worms/condition) (D) or bec-1 coding sequence [bec-1(RNAi)] (n = 228–290 worms/condition) (E) following the adulthood RNAi protocol (see Methods) (N = 3). Cox proportional hazards analysis was performed for the interaction of terms genotypes myt-1 and atg-18 RNAi (P < 0.0001), bec-1 RNAi (P = 0.01466). Raw data of fer-15(b26) II and myt-1(pan8) I; fer-15(b26) II worms are the same in D and E (experiments were performed in parallel). Log-rank test was used to compare longevity curves (see Supplemental Figure 6A for life span experimental details and statistics). (F) Body and head bends, reversals, and duration of stillness periods were quantified for 30 seconds in 10-day-old fer-15(b26) II animals (WT) and fer-15(b26) II; oxTi0882; syls321 (OE myt-1) worms fed with atg-18(RNAi) (n = 38 [WT]/n = 51 [OE myt-1]) or control bacteria (n = 33 [WT]/n = 76 [OE myt-1]) after a harsh touch stimulus at the tail (N = 2). *P < 0.05; ***P < 0.001; ****P < 0.0001. N = number of independent experiments; n = total worm number.

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