C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals
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
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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Research Article Aging Cell biology

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

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 1

C16orf70 encodes a protein named MYTHO that is expressed in different tissues and upregulated in aging.

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C16orf70 encodes a protein named MYTHO that is expressed in different t...
(A) PBI-eGFP/3xFlag-MYTHO vector or PBI-eGFP/3xFlag–empty vector was transfected into HEK293A cells. 3×FLAG-MYTHO expression was observed using an anti-FLAG antibody. The blot shown in the image represents the results of 4 independent transfections. (B) Quantitative RT-PCR of Mytho in different organs and muscles from 5-month-old male mice. mRNA expression was calculated by the ΔCt method and expressed as fold increase from the tissue where Mytho is less expressed (small intestine). SOL, soleus muscle; GNM, gastrocnemius muscle; EDL, extensor digitorum longus muscle; TA, tibialis anterior muscle; QUAD, quadriceps muscle; WAT, white adipose tissue; BAT, brown adipose tissue. n = 3 for all tissues, n = 2 only for WAT and lung. (C) Quantitative real-time PCR of Mytho from mice of different ages (3–4 months, n = 5; 7 months, n = 4; 10 months, n = 6; and >2 years old, n = 4). Expression was normalized to that of Gapdh and is expressed as fold increase (1-way ANOVA with Tukey’s multiple-comparison test). (D) Quantitative real-time PCR of MYTHO in muscle biopsies from patients of different ages: 24–38 years old (n = 8), 45–64 years old (n = 7), 67–75 years old (n = 7), and 84–95 years old who underwent surgery for hip replacement (n = 8). All data were normalized to GAPDH and are expressed as fold increase from the 24- to 38-year-old control group (1-way ANOVA with Tukey’s multiple-comparison test). (E) Immunoblot of homogenates from GNM muscle from 5-month-old mice (n = 4) and >24-month-old (n = 6) mice. Anti-C16orf70 antibody was used to detect MYTHO endogenous protein. Normalization was performed using GAPDH and data are expressed as fold increase (2-tailed Student’s t test). All bars indicate SEM. *P < 0.05; **P < 0.01.