YTHDF1 differentiates the contributing roles of mTORC1 in aging.

The mechanistic target of rapamycin (mTOR) serves as an essential hub in sensing metabolic stress and regulating aging, although the differential contributions of mTOR-regulated protein and cholesterol synthesis are unclear. Post-transcriptional modifications of mRNAs, such as N6-methyladenosine (m6A), occur rapidly in response to acute environmental changes to maintain tissue homeostasis. Here, we showed that loss of YTH m6A RNA-binding protein 1 (YTHDF1) accelerated murine aging. Mechanistically, YTHDF1 is anchored to the lysosome surface by lysosome-associated membrane protein (LAMP2), whereby it recruits tuberous sclerosis complex (TSC2) to inhibit mTOR complex 1 (mTORC1). Ythdf1 loss activated mTORC1-sterol regulatory element-binding protein 2 (SREBP2)-axis-mediated cholesterol biosynthesis but not m6A-reader-regulated protein translation. Rapamycin restored murine healthspan in contrast to the maximum lifespan shortening caused by Ythdf1 depletion. Our data reveal an m6A-independent function of YTHDF1, which differentiates the contributing roles of mTORC1 in the regulation of aging.