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.

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