Deregulated nutrient sensing is one of the hallmarks of aging. Phosphofructokinase 2 (PFK2) is a critical enzyme in glycolysis. Whether PFK2 can regulate lifespan remains unknown. PFK2 is encoded by 6-phosphofructo-2-kinase (Pfrx) in Drosophila. Here, we report that both Pfrx hypomorphic mutants PfrxEP1150 and PfrxKG02298 exhibit extended lifespan in Drosophila. RNAi specific knockdown of Pfrx in neurons reproduces the extended lifespan in flies. Interestingly, knockdown of
pfkb-1.1, the homolog of PFK2 in C. elegans, also increases lifespan in C. elegans. The extended lifespan by
pfkb-1.1 knockdown requires
let-363/TOR and its downstream target
rsks-1/S6K, but does not require
daf-16/FOXO and
aak-2/AMPK. Moreover, the levels of phosphorylated S6 kinase, the downstream effector of TOR (target of rapamycin) signaling, were reduced in PfrxEP1150 and PfrxKG02298. Furthermore, the treatment of rapamycin does not further prolong the extended lifespan in PfrxEP1150 and PfrxKG02298. Together, it suggests that Pfrx/pfkb-1.1 reduction enhances lifespan through reducing TOR signaling. In summary, our findings suggest the evolutionary conservation role of PFK2/pfrx/pfkb-1.1 in lifespan regulation in Drosophila and C. elegans.