m6A epitranscriptomic regulation of tissue homeostasis during primate aging

The authors characterized m(6)A dynamics in primate tissue aging and revealed a new role for the METTL3-m(6)A-NPNT axis in maintaining skeletal muscle homeostasis, thereby providing insight into the epitranscriptomic machinery underlying 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.