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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #416714
Research Project: Molecular, Cellular, and Regulatory Aspects of Obesity Development

Location: Children's Nutrition Research Center

Title: Branched-chain amino acid accumulation fuels the senescence-associated secretory phenotype

Author
item LIANG, YAOSI - Duke University
item PAN, CHRISTOPHER - Duke University
item YIN, TAO - Duke University
item WANG, LU - Duke University
item GAO, XIA - Children'S Nutrition Research Center (CNRC)
item WANG, ERGANG - Duke University
item QUANG, HOLLY - Children'S Nutrition Research Center (CNRC)
item HUANG, DE - Duke University
item TAN, LIANMEI - Duke University
item XIANG, KUN - Duke University
item WANG, YU - Massachusetts General Hospital
item ALEXANDER, PETER - Duke University
item LI, QI-JING - Duke University
item YAO, TSO-PANG - Duke University
item ZHANG, ZHAO - Duke University
item WANG, XIAO-FAN - Duke University

Submitted to: Advanced Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2023
Publication Date: 11/15/2023
Citation: Liang, Y., Pan, C., Yin, T., Wang, L., Gao, X., Wang, E., Quang, H., Huang, D., Tan, L., Xiang, K., Wang, Y., Alexander, P.B., Li, Q., Yao, T., Zhang, Z., Wang, X. 2023. Branched-chain amino acid accumulation fuels the senescence-associated secretory phenotype. Advanced Science. 11(2):Article 2303489. https://doi.org/10.1002/advs.202303489.
DOI: https://doi.org/10.1002/advs.202303489

Interpretive Summary: 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, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here we identified a novel mechanism linking intrinsic alterations in BCAA metabolism cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases.

Technical 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, BCAAs’ full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.