Identification the Role of BCAT1 and SLC6A14/15 in Cellular Senescence and Aging

Abstract

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, the comprehensive impacts of BCAAs on mammalian physiological aging process remain uncertain due to the complexities of BCAA metabolic regulation. Cellular senescence is a phenotype of stable cell cycle arrest that contributes to aging and age-related diseases. Senescent cells accumulate in aged tissues and drive age-related disorders through the senescence-associated secretory phenotype (SASP), a process whereby a spectrum of proteins including inflammatory cytokines are secreted into the extracellular space. However, the molecular mechanisms controlling SASP induction remain incompletely understood. On a mechanistic front, while the activity of the mammalian target of rapamycin complex 1 (mTORC1) signaling has links to cellular senescence, the exact events leading to mTORC1 activation are not clear. Here we report that alterations in BCAA metabolism, which are mediated by the BCAA transporters Solute Carrier Family 6 Members 14 and 15 (SLC6A14 and SLC6A15) and the enzyme BCAA transaminase 1 (BCAT1), trigger the SASP program during senescence. Increased expression of SLC6A14/15, with a concomitant reduction in BCAT1, contributes to elevated intracellular BCAAs in senescent cells; this in turn activates mTORC1 signaling to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous of mammalian SLC6A15 are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during the aging process. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.