Rapamycin reviewed

One of 2009’s most significant breakthroughs in biogerontology (or in any field; q.v. Science, WIRED) last year was the announcement that the macrolide drug rapamycin can extend longevity in mice.

More specifically, rapamycin can accomplish this when administered to adult, wildtype mice. In other words, no genetic modification or early-life intervention is necessary, making rapamycin one of the first compounds that meets the criteria for an anti-aging drug that could be used for people who are already alive and well down the road toward aging themselves.

The lifespan extension achieved is modest (~10%), but this is more impressive in light of the fact that the mice were quite old at the time treatment began, and the study used only a single dose rate. Future studies will undoubtedly seek to optimize the dose and regimen with the goal of achieving greater enhancement of lifespan.

How does it work? As the saying goes, further study is required, and at multiple levels.

• Organism: It is possible that rapamycin acts by delaying the onset of cancer, frankly slowing the aging process, or a combination of both. (This issue could be addressed by using genetically engineered mouse strains that exhibit very little cancer.)

• Tissue: Rapamycin might decelerate cellular senescence, which could fight aging in two ways: by maintaining cells in a division-competent state (and thereby increasing the pool of cells available to regenerate tissues), and by ameliorating the damaging effects of deleterious inflammatory secretion by senescent cells. This is complicated by the fact that senescence is itself a tumor-suppressor pathway; in the absence of data to the contrary, one might have expected the drug to have a modest oncogenic effect, but that doesn’t seem to be the case in the mouse studies. (It’s worth mentioning that the author of that first senescence study prognosticated the efficacy of rapamycin as an anti-aging drug several years ago).

• Cell: With respect to cellular and molecular mechanisms, all eyes are on the TOR pathway (“target of rapamycin”; the protein is inhibited by rapamycin) . The TOR kinase, which has been implicated in lifespan control in smaller organisms, regulates translation by modulating the activity of ribosomal proteins and elongation factors. Deleting the S6 kinase gene (a target of TOR; eliminating S6K is like selectively turning off a specific arm of the TOR pathway) extends lifespan in rodents – consistent with the idea that TOR exerts its effects on aging by controlling translation.

There’s a good deal left to discover about the rapamycin’s effects on aging in general — and regarding the specific mechanistic relationship between translational control, senescence, and organismal aging — but I have it on good authority that there’s a great deal of effort being exerted in that direction. Watch this space for future developments.

If you’re interested in reading more, there’s a nice post on the issue over at Fight Aging!

Oh, I almost forgot – impending pun alert – in the “cruel irony” department, rapamycin may inhibit the formation, consolidation and preservation of long-term memory; it’s even been proposed as a treatment for PTSD. (To make a very long story short, protein translation is required for establishment and maintenance of memories.) It’s not yet clear whether the doses of rapamycin that extend lifespan will have an effect on memory, but it’s clearly crucial to figure that out. It would be a damn shame to live an extra ten or twenty years at the cost of slowly forgetting one’s past. I’ll be following that emerging story with interest.

More elsewhere:



  1. Glad to see that you have resurected your blog.

    TOR signaling is one of the most exciting fields – it is also one of the most ancient (if not the most ancient) eukaryotic signaling pathways. There are deep ties between it and cancer as half of the nastiest oncogenes and tumor supressors are prt of this cascade. And in the end the biggest target of TOR is ribosome biogenesis and translational control.

    To encourage you a bit, I would like to see your take on the growing connections between cell polarity and aging. Specifically I saw a new paper from the Nystrom group in the last issue of Cell.

  2. One more follow up study came up 3 months ago in Science Signaling – blogged Therapeutic rejuvenation of aging hematopoietic stem cells.

    This is the first study, which showed a link between adult stem cell (HSC) disfunction and aging of organism and involvement of mTOR activation. Before was just speculations. This is the one possible mechanism which could explain results published in Nature.
    This is the 2nd study, confirmed that Rapamycin is able to extend life of mice (mammals), so results published in Nature is reproducible independently.
    They also showed that Rapamycin actually decelerate senescence in aged HSC and level of Ink4a goes down.

  3. Thanks Alex, Спасибо Alexey.

    Dr. Palazzo – I checked out the Nystrom lab article and will definitely cover it at some point soon.

  4. I read your post with great interest; it certainly broadened my existing knowledge on mTOR’s role in the aging process (Alexey, I also saw your journal club ppt on the topic too).

    I would just like to comment on your
    “impending pun alert”. I find it interesting that mTOR inhibition would suppress reconsolidation of an established fear memory, and agree that protein translation is an important for strengthening synaptic connections.

    What I find curious, are the reports that have detailed enhanced memory formation due to mTOR’s inhibition by rapamycin, or it’s analogs. Here is a study in a heterozygous TSC mouse model that suggests strengthening of neurocognition and hippocampal-dependent learning following rapamycin treatment. http://www.nature.com/nm/journal/v14/n8/abs/nm1788.html

    Through a series of elegant experiments, these authors suggest enhanced hippocampal-dependent learning in normal mice with mTOR activation (glucose), and not inhibition (rapamycin and AICAR). http://www.ncbi.nlm.nih.gov/pubmed/16885218?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=6

    Of note, is that if tumor suppressors of the PI3K pathway are defective and you get aberrant phosphorylation and activation of mTOR, generally neurocognition / learning and memory is impaired (eg. TSC 1/2; LKB1; NF1; PTEN). So in essence, if mTOR’s activity is hyperactive in these disease states, then memory formation is decreased.

    So really, does mTOR’s role in memory formation just come down to a balancing act? Too much activity being deleterious in harmatoma disease states? However, in the normal adult individual, when mTOR functions typically at basal levels, or at slightly increased levels of activity in the aging adult, then mTOR-dependent protein translation can be beneficial in memory maintenance?

    Yes, very intriguing developing story, and one that is near and dear.

  5. Again, so nice that you are back. I can’t tell you how refreshing and inspiring your writing is.

    In regards to the review I was surprised to see no mention of rapamycin being an immunosuppresant. I was under the impression that the greater chance of infection and disease was the main trade off for the extension in lifepsan.
    Per MIT Tech Review:

    Though I have to admit that the long term memory loss was a nice suprise. Kind of like a pill that lets you forget your mistakes and get those years back. I don’t know about everyone here, but if that pill was on the market I would take it. 😉

  6. It would be a damn shame to live an extra ten or twenty years at the cost of slowly forgetting one’s past.

    Forgetting one’s past? Or one’s present? If rapamycin keeps people from forming new memories, then it is problematic. But if it simply causes us to forget the past, then surely that is a lessor concern? Given enough time, we all forget the past anyway. And, regardless of what people say, most act in a manner consistent with the belief that gaining more of a future is more important to them than hanging onto the past.

    I could imagine some future technology that allows us to renew our cells in ways which we today can not easily foresee. To the extent that such renewal lead to the formation of either new nerve cells or a re-invigoration of old nerve cells, then we’d have to expect a loss of memories – a natural occurrence when nerve cells are changing. Possibly amnesia is the price of renewal. It would be a bit of creative destruction, of the biological kind. I think many people would regard that as a fair price to pay.

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