Rapamycin and Two Other Drugs Extends Lifespan Twice As Much As Any Other Drug Combo

A triple drug combination has been used to extend the lifespan of fruit flies by 48% in a new study led by UCL and the Max Planck Institute for Biology of Aging.

The three drugs are all already in use as medical treatments: lithium as a mood stabilizer, trametinib as a cancer treatment and rapamycin as an immune system regulator.

Rapamycin has undesirable effects on fat metabolism, which can be similar to insulin resistance in people, but lithium appeared to cancel out this effect when the two drugs were given together.

A combination of drug treatment may one day be helpful at preventing age-related diseases in people.

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

The researchers were building on previous studies finding that lithium, trametinib, and rapamycin can each extend lifespan in fruit flies (Drosophila),* which is supported by other preliminary evidence in mice, worms, and cells, and observational findings in people.

The three drugs all act on different cellular signaling pathways that together form the nutrient-sensing network, which is conserved across evolution from worms and flies all the way to humans. This network adjusts what the body is doing in response to changes in nutrient levels. The three drugs in question act on different proteins of this network to slow the ageing process and delay the onset of age-related death.

For the latest study, the researchers gave fruit flies doses of lithium, trametinib and rapamycin, separately and in combination. Each drug individually extended lifespan by an average of 11%, while pairing two drugs extended lifespan by roughly 30%. When the three drugs were combined, the fruit flies lived 48% longer than flies in a control group that were not given the treatment.

“Previous studies in fruit flies have achieved lifespan extensions of about 5-20%, so we found it was quite remarkable that this drug combination enabled them to live 48% longer,” Dr Castillo-Quan said.

Principal investigator, Professor Linda Partridge (UCL Institute of Health Ageing and Max Planck Institute for Biology of Ageing), said: “There is a growing body of evidence that polypills – pills that combine low doses of multiple pharmaceutical products – could be effective as a medication to prevent age-related diseases, given the complex nature of the aging process. This may be possible by combining the drugs we’re investigating with other promising drugs, but there is a long way to go before we will be able to roll out effective treatments.”

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.

SOURCES- UCLA, PNAS
Written By Brian Wang, Nextbigfuture.com

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