The target of rapamycin (TOR) protein, renowned for its highly conserved nature across species, plays a pivotal role in modulating signaling pathways via its multiprotein complexes, TORC1 and TORC2. The relationship between TOR and its inhibitor, rapamycin, especially in the context of lifespan extension, has earned significant attention. Unlike mammals, which have a single TOR gene, the budding yeast Saccharomyces cerevisiae features two TOR paralogs: TOR1 and TOR2. Non-essential TOR1 gene has been the focus of extensive research, whereas the essential TOR2 gene has received relatively little attention in lifespan studies. In our research, we engineered a point mutation (Ser-1975-Ile) within the FKBP12-rapamycin-binding (FRB) domain of Tor2p to block rapamycin binding. Remarkably, this mutation negated the lifespan-extending benefits of rapamycin, irrespective of the TOR1 gene status. Our findings indicate that the TOR2 gene likely serves as the primary mammalian ortholog, playing a crucial role in mediating the effects of rapamycin on lifespan extension. This discovery opens a new avenue for the development of innovative anti-aging agents targeting the TOR. complex.

• PMID: 39241621
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Seo D, Yalcin G, Jang H, Lee HJ, Kim DH, Lee CK

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