A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.
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.
['Castillo-Quan|Jorge Iván|JI|0000-0002-6324-2854', 'Tain|Luke S|LS|', 'Kinghorn|Kerri J|KJ|', 'Li|Li|L|', 'Grönke|Sebastian|S|0000-0002-1539-5346', 'Hinze|Yvonne|Y|', 'Blackwell|T Keith|TK|', 'Bjedov|Ivana|I|', 'Partridge|Linda|L|0000-0001-9615-0094']
D000368:Aged D000375:Aging D000818:Animals D004330:Drosophila D029721:Drosophila Proteins D004338:Drug Combinations D005260:Female D038362:Glycogen Synthase Kinase 3 D006801:Humans D008094:Lithium D008136:Longevity D000076222:Mechanistic Target of Rapamycin Complex 1 D008875:Middle Aged D000078622:Nutrients D011728:Pyridones D011744:Pyrimidinones D015398:Signal Transduction D020123:Sirolimus
aging rapamycin trametinib lithium polypharmacology