Canagliflozin shares common mTOR and MAPK signaling mechanisms with other lifespan extension treatments

Long-lived mouse models and treatments that extend lifespan, such as Rapamycin, acarbose and 17 & alpha;- -estradiol, lead to reduction in mTORC1 activity, declines in cap-dependent translation and increases in cap-independent translation. In addition, these treatments reduce the MEK-ERK-MNK (ERK1-2) signaling cascade, leading to reduction in eIF4E phosphorylation, which also regulates mRNA translation. Here, we report that Canagliflozin, a drug that extends lifespan only in male mice reduces mTORC1 and ERK1-2 signaling in male mice only. The data suggest reduction in mTORC1 and ERK pathways are common mechanisms shared by both genetic and pharmacological models of slowed aging in mice. Our data also reveal a significant sexual dimorphism in the ERK1-2 signaling pathway which might help to explain why some drugs can extend lifespan in males but have no effects in female mice.

Automated summary

Long-lived mouse models and certain treatments like Rapamycin, acarbose and 17α-estradiol, which extend lifespan, reduce mTORC1 and ERK1-2 signaling pathways. Canagliflozin, a drug that only extends lifespan in male mice, was found to have the same effect. This suggests a common mechanism in genetic and pharmacological models of slowed aging in mice, as well as a sexual dimorphism in the ERK1-2 pathway.