Quinoline-4-carboxylic acid inhibits autophagic degradation of YBX1 to promote anti-aging and liver regeneraton (PRJCA021573)
DDR), or reversely to DNA repair/regeneration remain unclear. Studying senescence/aging-triggered loss of proliferation/regeneration in human mesenchymal stem cell (hMSC) cultures and mouse livers, accumulated N-acetylhistamine, phosphatidylethanolamines, and DNA damage-regulated autophagy modulator 1 (DRAM1) proteins were found associated with DDR-induced autophagy (DDRIA). Feeding hMSCs with N-acetylhistamine alone induced DNA damage, DRAM1 and early senescence, but not DDRIA. Nonetheless, DDRIA constitutes a downward spiral towards senescence/aging by corroding the YBX1-NRF2 axis. Seeking protection strategies from the induced pluripotent stem cells of a DNA damage-tolerant hibernator, metabolite quinoline-4-carboxylic acid (QCA) was found to prevent DDRIA degradation of YBX1, which then enhanced the expression of DNA repair proteins and NRF2 functions. Thus, QCA supplements reversed senescent/aging phenotypes in hMSCs, Drosophila and mice, and promoted liver regeneration in aged mice also by rewiring metabolism and augmenting ATP production. Overall, QCA may represent a pharmacophore for developing anti-aging treatments.