OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes

Area of Science:

• Cell Biology
• Dermatology
• Molecular Biology

Background:

• Olfactory receptors (ORs) are the largest mammalian protein superfamily.
• Certain ORs, like OR2AT4, are found in extranasal tissues, including skin.
• OR2AT4 plays a role in skin cell functions, but its role in aging and senescence is unclear.

Purpose of the Study:

• To investigate the role of OR2AT4 in the aging and senescence of human keratinocytes.
• To explore the therapeutic potential of OR2AT4 activation for anti-aging and anti-senescence strategies.

Main Methods:

• Functional expression of OR2AT4 in human keratinocytes (HaCaT) was confirmed.
• The effects of the OR2AT4 ligand, sandalore, on cellular signaling pathways (calcium, cAMP) and senescence markers were analyzed.
• Gene knockdown of OR2AT4 was used to confirm ligand-mediated effects.
• Key signaling pathways, including CaMKKβ/AMPK/mTORC1/autophagy, were investigated.

Main Results:

• OR2AT4 activation by sandalore modulated intracellular calcium, inositol phosphate, and cAMP levels.
• Sandalore inhibited senescent cell phenotypes, restored cell proliferation, and increased Ki-67 expression.
• Sandalore reduced senescence-associated β-galactosidase and increased p21 expression in senescent cells.
• Sandalore activated the CaMKKβ/AMPK/mTORC1/autophagy axis, promoting autophagy.
• OR2AT4 knockdown attenuated sandalore-induced effects, confirming OR2AT4 mediation.

Conclusions:

• OR2AT4 activation by sandalore effectively combats aging and senescence in human keratinocytes.
• The observed effects are mediated through OR2AT4 and involve modulation of intracellular signaling and autophagy.
• OR2AT4 represents a promising therapeutic target for anti-aging and anti-senescence interventions in skin.