Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans
Biguanides, including the world’s most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the inc...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/82210 |
| _version_ | 1797739406391508992 |
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| author | Lucydalila Cedillo Fasih M Ahsan Sainan Li Nicole L Stuhr Yifei Zhou Yuyao Zhang Adebanjo Adedoja Luke M Murphy Armen Yerevanian Sinclair Emans Khoi Dao Zhaozhi Li Nicholas D Peterson Jeramie Watrous Mohit Jain Sudeshna Das Read Pukkila-Worley Sean P Curran Alexander A Soukas |
| author_facet | Lucydalila Cedillo Fasih M Ahsan Sainan Li Nicole L Stuhr Yifei Zhou Yuyao Zhang Adebanjo Adedoja Luke M Murphy Armen Yerevanian Sinclair Emans Khoi Dao Zhaozhi Li Nicholas D Peterson Jeramie Watrous Mohit Jain Sudeshna Das Read Pukkila-Worley Sean P Curran Alexander A Soukas |
| author_sort | Lucydalila Cedillo |
| collection | DOAJ |
| description | Biguanides, including the world’s most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in Caenorhabditis elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor skn-1/Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging. |
| first_indexed | 2024-03-12T13:57:45Z |
| format | Article |
| id | doaj.art-5f9402d37613409b85d1992e1eaa7bee |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T13:57:45Z |
| publishDate | 2023-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5f9402d37613409b85d1992e1eaa7bee2023-08-22T11:30:33ZengeLife Sciences Publications LtdeLife2050-084X2023-08-011210.7554/eLife.82210Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegansLucydalila Cedillo0Fasih M Ahsan1https://orcid.org/0000-0001-8031-7056Sainan Li2https://orcid.org/0000-0002-1880-6294Nicole L Stuhr3https://orcid.org/0000-0003-2537-7114Yifei Zhou4https://orcid.org/0000-0003-0088-6262Yuyao Zhang5Adebanjo Adedoja6Luke M Murphy7https://orcid.org/0000-0002-2784-6255Armen Yerevanian8Sinclair Emans9Khoi Dao10Zhaozhi Li11Nicholas D Peterson12https://orcid.org/0000-0003-4157-8119Jeramie Watrous13Mohit Jain14Sudeshna Das15Read Pukkila-Worley16https://orcid.org/0000-0001-5340-8294Sean P Curran17https://orcid.org/0000-0001-7791-6453Alexander A Soukas18https://orcid.org/0000-0002-9100-2436Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United StatesLeonard Davis School of Gerontology, University of Southern California, Los Angeles, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United States; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United StatesDepartment of Medicine and Pharmacology, University of California San Diego, San Diego, United StatesBiomedical Informatics Core, Massachusetts General Hospital and Harvard Medical Schoo, Cambridge, United StatesProgram in Innate Immunity, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, United StatesDepartment of Medicine and Pharmacology, University of California San Diego, San Diego, United StatesDepartment of Medicine and Pharmacology, University of California San Diego, San Diego, United StatesBiomedical Informatics Core, Massachusetts General Hospital and Harvard Medical Schoo, Cambridge, United StatesProgram in Innate Immunity, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, United StatesLeonard Davis School of Gerontology, University of Southern California, Los Angeles, United StatesCenter for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Broad Institute of Harvard and MIT, Cambridge, United StatesBiguanides, including the world’s most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in Caenorhabditis elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor skn-1/Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.https://elifesciences.org/articles/82210metforminagingether lipidsC. elegansmetabolism |
| spellingShingle | Lucydalila Cedillo Fasih M Ahsan Sainan Li Nicole L Stuhr Yifei Zhou Yuyao Zhang Adebanjo Adedoja Luke M Murphy Armen Yerevanian Sinclair Emans Khoi Dao Zhaozhi Li Nicholas D Peterson Jeramie Watrous Mohit Jain Sudeshna Das Read Pukkila-Worley Sean P Curran Alexander A Soukas Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans eLife metformin aging ether lipids C. elegans metabolism |
| title | Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans |
| title_full | Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans |
| title_fullStr | Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans |
| title_full_unstemmed | Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans |
| title_short | Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans |
| title_sort | ether lipid biosynthesis promotes lifespan extension and enables diverse pro longevity paradigms in caenorhabditis elegans |
| topic | metformin aging ether lipids C. elegans metabolism |
| url | https://elifesciences.org/articles/82210 |
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