m 6 A epitranscriptomic regulation of tissue homeostasis during primate aging

How N 6 -methyladenosine (m 6 A), the most abundant mRNA modification, contributes to primate tissue homeostasis and physiological aging remains elusive. Here, we characterize the m 6 A epitranscriptome across the liver, heart and skeletal muscle in young and old nonhuman primates. Our data reveal a positive correlation between m 6 A modifications and gene expression homeostasis across tissues as well as tissue-type-specific aging-associated m 6 A dynamics. Among these tissues, skeletal muscle is the most susceptible to m 6 A loss in aging and shows a reduction in the m 6 A methyltransferase METTL3. We further show that METTL3 deficiency in human pluripotent stem cell-derived myotubes leads to senescence and apoptosis, and identify NPNT as a key element downstream of METTL3 involved in myotube homeostasis, whose expression and m 6 A levels are both decreased in senescent myotubes. Our study provides a resource for elucidating m 6 A-mediated mechanisms of tissue aging and reveals a METTL3–m 6 A–NPNT axis counteracting aging-associated skeletal muscle degeneration.