期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 42, 页码 20817-20819出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1913212116
关键词
aging; polypharmacology; trametinib; rapamycin; lithium
资金
- University College London Scholarships
- American Federation for Aging Research/Glenn Foundation for Medical Research Postdoctoral Fellowship [PD18019]
- Max Planck Society
- National Institutes of Health [AG54215, GM122610]
- European Research Council under the European Union [741989]
- European Research Council [311331]
- Research Into Ageing
- Parkinson's UK
- Wellcome Trust Clinical Career Development Fellowship [214589/Z/18/Z]
- Wellcome Trust Strategic Award [WT098565/Z/12/Z]
- Academy of Medical Sciences
- European Research Council (ERC) [311331, 741989] Funding Source: European Research Council (ERC)
- Wellcome Trust [214589/Z/18/Z] Funding Source: Wellcome Trust
Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Drosophila. Remarkably, the triple drug combination increased lifespan by 48%. Furthermore, the combination of lithium with rapamycin cancelled the latter's effects on lipid metabolism. In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health.
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