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

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.

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Castillo-Quan et al 2019 - Triple drug combination.pdf (Postprint), 799KB
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Castillo-Quan et al 2019 - Triple drug combination.pdf
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 Creators:
Castillo-Quan, Jorge1, Author
Tain, Luke S.1, Author           
Kinghorn, Kerri J., Author
Li, Li, Author
Grönke, Sebastian1, Author           
Hinze, Yvonne2, Author           
Blackwell , T. Keith, Author
Bjedov, Ivana, Author
Partridge, Linda1, Author           
Affiliations:
1Biological Mechanisms of Ageing, Department Partridge, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_1942294              
2Bio-MS, Core Facilities, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_1942305              

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Free keywords: aging, lithium, poly-pharmacology, rapamycin, trametinib, triglycerides
 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.

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Language(s): eng - English
 Dates: 2019-08-012019-09-162019-09-30
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1073/pnas.1913212116
 Degree: -

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Project name : GeroProtect
Grant ID : 741989
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)
Project name : Biological determinants of ageing and late life health, and their pharmacological manipulation
Grant ID : WT098565/Z/12/Z
Funding program : Wellcome Trust Funding (Wellcome Trust Strategic Award)
Funding organization : Wellcome Trust (WT)

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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Acad. Sci. USA
  Other : Proc. Acad. Sci. U.S.A.
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : PNAS
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 116 (42) Sequence Number: - Start / End Page: 20817 - 20819 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230