m⁶A epitranscriptomic regulation of tissue homeostasis during primate aging.

Abstract

How N⁶-methyladenosine (m⁶A), the most abundant mRNA modification, contributes to primate tissue homeostasis and physiological aging remains elusive. Here, we characterize the m⁶A epitranscriptome across the liver, heart and skeletal muscle in young and old nonhuman primates. Our data reveal a positive correlation between m⁶A modifications and gene expression homeostasis across tissues as well as tissue-type-specific aging-associated m⁶A dynamics. Among these tissues, skeletal muscle is the most susceptible to m⁶A loss in aging and shows a reduction in the m⁶A 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 m⁶A levels are both decreased in senescent myotubes. Our study provides a resource for elucidating m⁶A-mediated mechanisms of tissue aging and reveals a METTL3-m⁶A-NPNT axis counteracting aging-associated skeletal muscle degeneration.