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
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Veneto Institute of Molecular Medicine, Padova, Italy.
J Clin Invest. 2024 Jun 13;134(15):e165814. doi: 10.1172/JCI165814.
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.
鉴定出那些能够延长寿命或加速与年龄相关衰退的基因，是在理解衰老机制方面向前迈出的一步，并且揭示出衰老在一定程度上受遗传学和转录程序的控制。在此，我们发现人类DNA序列C16ORF70编码一种名为MYTHO（巨自噬与青春优化因子）的蛋白质，它控制寿命和健康寿命。MYTHO蛋白从秀丽隐杆线虫到人类都是保守的，并且其mRNA在老年小鼠和老年人中上调。在秀丽隐杆线虫中缺失直系同源的myt-1基因会显著缩短寿命，并降低动物在暴露于氧化应激时的存活率。从机制上讲，自噬需要MYTHO，可能是因为它作为一个支架，结合WIPI2和BCAS3，以在吞噬泡（新生自噬体）处招募和组装缀合系统。我们得出结论，MYTHO是一种转录调控的自噬起始因子，在促进应激抗性和健康衰老中起核心作用。
