C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals

• Published in: The Journal of clinical investigation 2024-08, Vol.134 (15)
• Main Authors: Franco-Romero, Anais, Morbidoni, Valeria, Milan, Giulia, Sartori, Roberta, Wulff, Jesper, Romanello, Vanina, Armani, Andrea, Salviati, Leonardo, Conte, Maria, Salvioli, Stefano, Franceschi, Claudio, Buonomo, Viviana, Swoboda, Casey O, Grumati, Paolo, Pannone, Luca, Martinelli, Simone, Jefferies, Harold Bj, Dikic, Ivan, van der Laan, Jennifer, Cabreiro, Filipe, Millay, Douglas P, Tooze, Sharon A, Trevisson, Eva, Sandri, Marco
• Format: Article
• Language: English
• Subjects: Aging; Analysis; Caenorhabditis elegans; Cells; DNA sequencing; Genetic transcription; Gerontology; Nucleotide sequencing; Pharmaceutical industry; Physiological aspects; RNA; Scientific equipment and supplies industry
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI165814

The identification of genes that confer either extension of lifespan or accelerate age-related decline was a step forward in understanding the mechanisms of ageing and revealed that it is partially controlled by genetics and transcriptional programs. Here we discovered that the human DNA sequence C16ORF70 encoded for a protein, named MYTHO (Macroautophagy and YouTH Optimizer), which controls life- and health-span. MYTHO protein is conserved from C. elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the ortholog myt-1 gene in C. elegans dramatically shortened lifespan 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 ageing.