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A triple drug combination targeting components of the nutrient-sensing network maximizes longevity

MPS-Authors

Castillo-Quan,  Jorge
Biological Mechanisms of Ageing, Department Partridge, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Tain,  Luke S.
Biological Mechanisms of Ageing, Department Partridge, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Grönke,  Sebastian
Biological Mechanisms of Ageing, Department Partridge, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Hinze,  Yvonne
Bio-MS, Core Facilities, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Partridge,  Linda
Biological Mechanisms of Ageing, Department Partridge, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Citation

Castillo-Quan, J., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., et al. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. Proceedings of the National Academy of Sciences of the United States of America, 116(42), 20817-20819. doi:10.1073/pnas.1913212116.


Cite as: http://hdl.handle.net/21.11116/0000-0004-F40A-E
Abstract
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.