Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype
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 B...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202303489 |
| _version_ | 1797356388188422144 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Yaosi Liang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T14:25:53Z |
| format | Article |
| id | doaj.art-31eefbea3ab7422289b0a16e728f1a35 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T14:25:53Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-31eefbea3ab7422289b0a16e728f1a352024-01-13T04:23:06ZengWileyAdvanced Science2198-38442024-01-01112n/an/a10.1002/advs.202303489Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory PhenotypeYaosi Liang0Christopher Pan1Tao Yin2Lu Wang3Xia Gao4Ergang Wang5Holly Quang6De Huang7Lianmei Tan8Kun Xiang9Yu Wang10Peter B. Alexander11Qi‐Jing Li12Tso‐Pang Yao13Zhao Zhang14Xiao‐Fan Wang15Department of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USAChildren's Nutrition Research Center Department of Pediatrics Baylor College of Medicine Houston TX 77030 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USACenter for Regenerative Medicine Massachusetts General Hospital Harvard Medical School Boston MA 02114 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Immunology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USADepartment of Pharmacology and Cancer Biology Duke University Medical Center Durham NC 27710 USAAbstract 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.https://doi.org/10.1002/advs.202303489age‐related inflammationBCAAmTORC1SASPsenescence |
| spellingShingle | 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 Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype Advanced Science age‐related inflammation BCAA mTORC1 SASP senescence |
| title | Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype |
| title_full | Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype |
| title_fullStr | Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype |
| title_full_unstemmed | Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype |
| title_short | Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype |
| title_sort | branched chain amino acid accumulation fuels the senescence associated secretory phenotype |
| topic | age‐related inflammation BCAA mTORC1 SASP senescence |
| url | https://doi.org/10.1002/advs.202303489 |
| work_keys_str_mv | AT yaosiliang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT christopherpan branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT taoyin branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT luwang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT xiagao branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT ergangwang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT hollyquang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT dehuang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT lianmeitan branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT kunxiang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT yuwang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT peterbalexander branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT qijingli branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT tsopangyao branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT zhaozhang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype AT xiaofanwang branchedchainaminoacidaccumulationfuelsthesenescenceassociatedsecretoryphenotype |