Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype

Authors

Yaosi Liang
Christopher Pan
Tao Yin
Lu Wang
Xia Gao
Ergang Wang
Holly Quang
De Huang
Lianmei Tan
Kun Xiang
Yu Wang
Peter B Alexander
Qi-Jing Li
Tso-Pang Yao
Zhao Zhang
Xiao-Fan Wang

Publication Date

1-1-2024

Journal

Advanced Science

DOI

10.1002/advs.202303489

PMID

37964763

PMCID

PMC10787106

PubMedCentral® Posted Date

11-15-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Senescence-Associated Secretory Phenotype, Amino Acids, Branched-Chain, Leucine, Mechanistic Target of Rapamycin Complex 1, Energy Metabolism, Mammals, age‐related inflammation, BCAA, mTORC1, SASP, senescence

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.