Combining Strategies to Slow Aging to Increase Life Span in Flies by 48%

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The research and development communities have little incentive to try combinations of approaches when it comes to intervening in the aging process, or indeed to treat any medical condition. There is little funding and large barriers stand in the way of any effort to combine either existing or novel therapies, such as issues with intellectual property rights. Thus few groups undertake such work. Which is a pity, because one would expect there to be synergies between therapies targeting two different mechanisms affecting the same condition in many cases, or at least for the treatments to be additive in effect.

The example here is interesting as a demonstration of such synergies between approaches, but it is worth recalling that the upregulation of stress response mechanisms via nutrient sensing used as a target here is a strategy known to have a far smaller impact on life span in long-lived species than in short-lived species. Extending life in flies by 48% is still not something that would necessarily indicate that any significant gains in human life span are possible via this methodology.

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. 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. Lowering network activity can also protect against the pathology associated with genetic models of age-related diseases. The network contains many drug targets, including mTOR, mitogen-activated protein kinase kinase (MEK), and glycogen synthase kinase-3 (GSK-3). Down-regulation of mTOR activity by rapamycin, GSK-3 by lithium, or MEK by trametinib can each individually extend lifespan in laboratory organisms, and brief inhibition of mTOR has recently been shown to increase the response of elderly people to immunization against influenza.

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. Here we show that trametinib, rapamycin, and lithium act additively to increase longevity in Drosophila. Because rapamycin, lithium, and trametinib extend lifespan by at least partially independent mechanisms, we investigated the effects on lifespan of their double and triple combinations.

Double combinations of lithium and rapamycin, lithium and trametinib, or rapamycin and trametinib produced a reproducibly greater lifespan extension than controls, on average 30%, compared to each compound alone, which extended lifespan by an average of 11%. 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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