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.”

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.

Written By Brian Wang, Nextbigfuture.com

14 thoughts on “Rapamycin and Two Other Drugs Extends Lifespan Twice As Much As Any Other Drug Combo”

  1. Looking at it another way, if every kg of blue whale tissue would generate just as many non-lethal tumors in the whale tissue as does every kilo of human tissue, then each 200 ton whale would generate about 18 non-lethal tumors each year. In the whales life span it would accumulate 3600 non-lethal tumors in its body. I find this highly unlikely, but it is also testable by performing autopsy on whale carcasses. Or you could trace tumor markers in the blood of living whales… At any rate, it should be pretty easy to find out.

  2. Very good point Brett. As you say, many grapefruit sized tumors would spawn new tumors in relation to their combined mass. I.e. the growth of tumor tissue should be exponential in the whale *unless* it has very good defenses against it. Elefants, whales, tortoises and some species of sharks are very good candidates for research.

    Just think that the blue whale weights up to 200 tons and can become up to 200 years old. That is 200 000 “tissue-kilo-years” before the onset of cancer (assuming that a large blue whale gets cancer once or less per life), whereas the same number for humans is about 50 000 “tissue-kilo-years” for deadly cancers, and about 15 000 “tissue-kilo-years” for non-leathal cancer (assuming the average human weights 50 kilos) [1]


  3. I concur with Brett Bellmore. Interesting point that should be validated by performing autopsy on dead whales. If possible, scientists should use carcasses rather than killing living whales.

  4. No disagreement with me there. I was summarising to save time and fit the text box limit.
    But I’ll point out that even if the blood vessels themselves are not cancerous, growing into a cancerous area means they are very likely to be overgrown and blocked by uncontrolled growth of the actual cancerous cells.

    Academic papers on the subject (https://academic.oup.com/icb/article/47/2/317/719209/) agree that the best way forward is careful analysis of whales for “benign” tumors.

  5. It’s a consequence of their shorter lifespan in the wild; Once you’ve knocked back a cause of death past the time when you’re likely to get eaten by a cat, there’s no particular evolutionary pressure to improve your defenses against that cause of death.

    Mice are prone to cancer because they don’t live long enough in the wild to die of it very often.

    That’s why you see particularly long lived species living in niches where they face little chance of death by predation, and the opportunity to keep reproducing into old age. They actually gain reproductive fitness by putting off dying.

    The species with natural longevity genes that are ripe for the plucking are the species that live as long as us, or longer. Tortoises. Parrots. Whales.

    We’ve already found some fascinating things looking at naked mole rats, which are the size of mice but live upwards of 50 years. We’re just not good enough at genetic engineering to apply those discoveries to ourselves. Yet.

  6. That’s an interesting hypothesis, which really calls for autopsy data to demonstrate whether whales actually do have grapefruit sized cancers in them.

    On the blood supply, the cancerous tissue doesn’t create the blood supply. All it does is secrete promoters that tell nearby blood vessels, not themselves cancerous, that they NEED a better blood supply. Starting to secrete “tumor angiogenesis factor” is a key developmental step between ‘benign’ tumors and cancer. Once a tumor does that, the rest is automatic on the part of non-cancerous tissue.

    Another key step is metastasis: The ability to shed cells into the blood and lymph which will start new tumors at distant locations. I bet even a whale would start to suffer as the number of grapefruit started mounting up.

    I’m not pre-judging why whales can create such a huge amount of tissue without dying of cancer. I’m just saying it cries out for research.

  7. Yes, smaller animals should be more susceptible to tumors.

    However, the smaller the animal, the less cells they have, so the smaller the chance that any one of those cells would go cancerous.

    Nonetheless, I believe that lab mice and rats have a cancer rate that is much, much higher than humans, which is confusing to people who naively look at the cancer rates of say mice exposed to “concerning new thing”.

  8. So conversely then, smaller animals like mice would succumb to tumors more quickly. And shouldn’t insects be even better test cases still?

  9. Looking for your keys under the street light:

    Yes, this is foolish if the keys are lost over in the dark.

    BUT, this assumes that you only have one set of keys, and you know where they are.

    In a lot of research, the actual situation is:

    • We don’t know how many keys there are, but there are probably dozens really. Just look at how many antibiotics have been found since penicillin. Look at the “me-too” drugs some people complain about.
    • We may have reason to suspect there are more keys in the dark, but there are probably some in the light as well.

    In this situation, looking in the light could well find you a key a lot faster than groping blindly in the dark, even if there are ultimately more keys out in the black areas.

  10. Whale cancer: The story I’ve heard is that

    • Cancer doesn’t set out to poison you or something, the way cancer kills is that tumours get big enough to physically prevent structures in your body from working. The tumors use up the physical size of your brain. They block needed bloodflow through other organs. etc.
    • Whales are big (citation needed). Therefore their organs, blood vessels etc. are big. A tumor the size of a grapefruit would shut down a human’s liver, but a whale can happily live with that and not even notice.
    • So for a cancer tumor to prove damaging/deadly to a whale, it has to grow very large.
    • For a tumor to grow very large, it has to develop internal structures that allow the cells to live. The tumor needs to build its own blood supply. It needs to transfer needed nutrients and oxygen in, and waste products out.
    • This does sort of happen, bodily tissues are preprogrammed to do this sort of thing, because all the normal tissue needs it too.
    • EXCEPT, that cancer cells, by definition, are cells that do not play well with others. That do not grow regularly and form nice, effective structures like blood supplies.
    • Therefore, the degree of cooperation and regular structure required to produce a whale-killing sized tumor is the sort of thing that is extremely hard for cancer cells to achieve. The unconstrained growth of cancer will block off the blood supply to the rest of the tumor. The tumor’s very behaviour will constrain its own growth.
    • The cancers get cancer.
  11. Historically, short lived animals have proven to be so biologically unlike humans that the longevity research on them has been practically useless.

    It’s the biomedical equivalent of looking for your car keys under the lamp post because the light is better there.

    Our best bet, IMHO, is good aging proxies to look for improvement in a short time, and research into naturally long lived species, particularly those that seemingly should not be long lived, (Naked mole rat, for instance.) so see what longevity strategies are working for them.

    How do whales manage to grow to such enormous size without dying of cancer, for instance? They must have extraordinarilly good defenses against it.

  12. I think that experimenting on short-lived animals is the
    fastest way to prove that something does not work at all.

  13. I got a bit excited until you mentioned fruit flies. There’s a long, long record of interventions in very short lived species not working in longer lived species, because those species have already in some way implemented them in order to be long lived.

    Inconvenient as it may be to conduct aging research in longer lived species, it tells us a lot more.

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