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

aging polypharmacology trametinib rapamycin lithium

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#1 Engadin

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Posted 01 October 2019 - 09:39 PM


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F U L L   T E X T   S O U R C E :   PNAS

 

 

 

 

 

 

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.

 

 

Aging is a complex process of progressive cell, tissue, and systemic dysfunction that is involved in the etiology of age-related diseases (1). Genetic, dietary, and pharmacological interventions can ameliorate the effects of aging in laboratory animals and may lead to therapies against age-related diseases in humans (24).

 

In organisms ranging from invertebrates to mammals, reducing the activity of the nutrient-sensing mechanistic target of rapamycin (mTOR) and insulin/insulin-like growth factor signaling (IIS) network can promote longevity and health during aging (23). Lowering network activity can also protect against the pathology associated with genetic models of age-related diseases (12). The network contains many drug targets, including mTOR, mitogen-activated protein kinase kinase (MEK), and glycogen synthase kinase-3 (GSK-3) (Fig. 1A). Down-regulation of mTOR activity by rapamycin, GSK-3 by lithium, or MEK by trametinib can each individually extend lifespan in laboratory organisms (511), and brief inhibition of mTOR has recently been shown to increase the response of elderly people to immunization against influenza (12). In addition, both mTOR and MEK inhibitors have been shown to reduce senescent phenotypes in human cells (13), while increasing concentrations of lithium levels in drinking water correlate with reduced all-cause mortality in a Japanese population (10). An advantage of pharmacological interventions is that the timing and dose of drug administration are relatively simple to optimize, and drugs can be easily combined (41416). Combination drug treatments also have the potential to counter resistance from feedback and to reduce each other’s side effects (17). Rapamycin, trametinib, and lithium each target different kinases and transcription factors to extend lifespan (5811), and therefore their effector mechanisms are at least partially different from each other. Simultaneous inhibition of multiple targets within the nutrient-sensing network may hence be needed to optimize effector outputs and health benefits. Here, we measure the effects of combination treatments of rapamycin, lithium, and trametinib on lifespan and other traits, using Drosophila as a model organism.

 

 

F1.large.jpg

 

FIGURE 1.

Lithium blocks negative side effects of mTORC1 and IIS inhibition. (A) A simplified diagram of the Drosophila nutrient-sensing network showing the target kinases of rapamycin, trametinib, and lithium. Lithium reversed the (B) hypertriglyceridemia (n = 6 replicas of 5 flies per condition, 1-way ANOVA) and (C) starvation resistance induced by rapamycin (50 µM) (n = 75). (D) Lithium treatment significantly extended lifespan of both wDah and dilp2-3,5 mutant flies. Neither (E) rapamycin (P = 0.58) nor (F) trametinib (P = 0.14) further extended lifespan of dilp2-3,5 mutant flies [log-rank test (n = 150)]. Cox Proportional Hazard analysis showed a significant genotype by treatment interaction for rapamycin (P = 0.002) and trametinib (P = 0.0018). Error bars represent SEM. ***P < 0.001 (1-way ANOVA or log-rank test).

 

 

 

 

Results and Discussion

 

Rapamycin treatment, from Caenorhabditis elegans to humans, is associated with altered metabolism, including hypertriglyceridemia and obesity (518). Alone, a lifespan-extending dose of lithium (11) did not alter triglyceride levels, but simultaneous treatment with both lithium and rapamycin reversed the dyslipidemia caused by rapamycin (Fig. 1B). To confirm that this change in lipid levels was physiologically relevant, we pretreated (14 d) flies with lithium, rapamycin, or a combination, and assessed their survival under starvation. Lithium did not alter survival under starvation conditions, while rapamycin increased it (Fig. 1C). Consistent with their effects on lipid levels, combining lithium and rapamycin treatment resulted in control levels of starvation resistance (Fig. 1C). Lithium can therefore reverse metabolic storage alterations associated with mTOR inhibition.

 

Lithium inhibits GSK-3 activity to extend lifespan (11), implying that activation of GSK3 is likely, if anything, to shorten lifespan. Inhibition of IIS in the canonical PI3K pathway can extend lifespan and health span, but reduces inhibitory phosphorylation of GSK3 by Akt (Fig. 1A), and hence activates GSK3 (4), a potentially deleterious side effect of lowered IIS (19). We therefore tested whether lithium could have additive effects in combination with genetic inhibition of IIS upstream of Akt. Lithium was able to further extend the lifespan of flies lacking the insulin-like peptides 2, 3, and 5 (dilp2-3,5) (Fig. 1D) (20). In contrast, rapamycin or trametinib, neither of which inhibit GSK3, were not able to extend the lifespan of dilp2-3,5 flies (Fig. 1 E and F). Lithium thus reverses an adverse side effect of inhibition of the canonical IIS pathway.

 

 

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Edited by Engadin, 01 October 2019 - 09:40 PM.

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Also tagged with one or more of these keywords: aging, polypharmacology, trametinib, rapamycin, lithium

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