OR2H2 Activation Suppresses Cellular Senescence and Aging by Activating AMPK and Inducing Senolysis in VK2/E6E7 Cells

Abstract Background Olfactory receptors are expressed in multiple extra-nasal tissues and these ectopic olfactory receptors mediate tissue specific functions and regulate cellular physiology. Ectopic olfactory receptors may play key roles in tissues constantly exposed to odorants, thus functionality of these receptors in genital tissues are of particular interest. The functionality of ectopic olfactory receptors expressed in VK2/E6E7 human vaginal epithelial cells was investigated. Results OR2H2 was functionally expressed in VK2/E6E7 cells and activation of OR2H2 by aldehyde 13–13, a ligand of OR2H2, increased the intracellular calcium and cAMP concentrations. Immunoblotting demonstrated that activation of OR2H2 by aldehyde 13–13 stimulated the CAMKKβ-AMPK-mTOR-autophagy signaling axis, and that these effects were negated by OR2H2 knockdown. Autophagy activation suppressed aging and cellular senescence. Activation of OR2H2 by aldehyde 13–13 restored proliferation, reduced the expression of senescence markers, P16 and P19 in H2O2-induced senescent cells. Additionally, aldehyde 13–13 showed senolytic activity by predominantly inducing apoptosis of H2O2-induced senescent cells compared with non-senescent normal cells. In vivo, aldehyde 13–13 increased the lifespan of Caenorhabditis elegans and budding yeast. Conclusions These findings demonstrate that OR2H2 is a functional receptor in VK2/E6E7 cells and activation of OR2H2 activates AMPK-autophagy axis, suppresses cellular aging and senescence, thus may increase cellular lifespan.