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Aging and Lifespan

Rapamycin And Aging: The Spotlight Shines

Rapamycin gets the spotlight in Bloomberg Businessweek here. This is a look at what’s been set in motion by the 2009 report that the compound notably extended the life of rodents in long-term feeding studies. It’s a good article, and gets some interesting quotes from Mark Fishman of Novartis and many others.
One of the big questions is how rapamycin exerts its effects. It’s certainly an inhibitor of the mTOR pathway (and it was actually used to discover and define it, since the TOR part stands for “target of rapamycin”). That’s going to do a lot, including immune suppression, which is one of the reasons that people are a bit leery of using the drug in otherwise healthy people. However, this study, from late last year, suggested that the closely related everolimus actually improved immune function in elderly human patients, so the last word on this has definitely not been written.
There was a study in 2013 which suggested that the lifespan enhancement seen in rapamycin animal studies was largely (or completely) due to tumor suppression, rather than any general anti-aging effect, but (as this Bloomberg story shows), this is still an open topic. A group at the University of Washington is planning a study in aging dogs that might help answer the question.
What seems certain is that companies are taking on the idea of treating aging more openly. GSK got pretty badly burned with Sirtris and the follow-up from resveratrol, or so it most certainly appears from the outside, but Novartis is clearly interested, and you have AbbVie’s recent deal with Google’s Calico as well. The idea will not be so much as to move right in and say “We’re going to reverse aging”, but to go after diseases associated with aging, whose mechanisms of treatment might be more general. This is partly just prudent practice, and partly regulatory caution, since the FDA has no way to deal with a proposal to treat people who, by current medical definitions, have no disease but are “merely” growing old. With any luck, that “merely” will come to seem odd.
I can’t resist quoting James Blish here (and I couldn’t last time, either). In his 1950s Cities in Flight books, one of the key technologies that made the plot run (along with a handy and vividly described faster-than-light drive), was the discovery of a suite of therapies that nearly prevented aging. Blish himself studied as a biologist, and worked for Pfizer in the 1950s for a while, although not as a scientist. That accounts for a scene early on when a returning space pilot is delivering exotic samples for testing to “Pfiztner”, a large drug company in New York City:

The door closed, leaving Paige once more with nothing to look at but the motto written over the entrance in German black-letter:
Wider den Tod ist kein Kräutlein gewachsen!
Since he did not know the language, he had already translated this by the If-only-it-were-English system, which made it come out “The fatter toad is waxing on the kine’s cole-slaw.” This did not seem to fit what little he knew about the eating habits of either animal, and it was certainly no fit admonition for workers.

That motto, of course, turns out to be an old herbalist saying that “Against Death doth no simple grow”, and the characters in the story are busy proving that to be incorrect. (That’s also a good example of the peculiar things that Blish would drop into his science fiction stories, odd little asides done in omniscient-author voice that give his writing an unmistakeable tone.) We’ll see how prescient he was about the natural products for aging, and if that works out, perhaps we’ll have enough time to start in on the faster-than-light drive.

23 comments on “Rapamycin And Aging: The Spotlight Shines”

  1. NMH says:

    I suspect Rapamycin, in the end, will be similar in effect to Calorie Restriction: if you have a crappy high calorie diet with plenty of sugar and fat then both will work, but if your diet is pretty good then the affect will be nominal.
    Since diet/lifestyle is increasing crappy in the west, Rapamycin development should be winner for big Pharma. We can’t seem to convince people to eat right.
    And the stupid feed back cycle continues….

  2. translate me says:

    that doesn’t say something more like ‘no herb washes away death’?

  3. Kismet says:

    Except this is not how calorie restriction works.
    There is some controversy whether CR translates to primates and in turn humans, but the idea that the increase in lifespan is proportional to the degree of restriction was never in doubt.
    Or put another way: the scaling with degree of restriction has been demonstrated convincingly in mice and the primate studies are currently unable to rule out any such effect.

    It translates to: “There grows no herb to treat [against] aging”

  4. kk says:

    Living long is no fun if you get dementia.
    I have seen a lot of news articles about T-817MA for Alzheimers recently. I am unable to understand what it is or how it works.
    Does anyone here have an opinion on T-817MA ?

  5. Anonymous says:

    @4 Kismet: The Wisconsin primate study saw an effect on CR on monkeys (not counting the monkeys that died to unnatural causes), while the NIH study did not. Speculation is that the Wisconsin study worked because of the relatively bad diet that these monkey’s were on (25% sucrose ad libitum), while the NIH study the diet was not as high in sucrose and was not ad libritum. So my guess would be that restriction is not as effective when someone is on a better diet.

  6. Cato the Elder says:

    You should curate a Derek Lowe suggested reading list, as so far your book references are always spot on!

  7. anchor says:

    @ kk..Hello, hola! Calling Simonian, calling Simonian!

  8. Dr. Manhattan says:

    Nice to know there is another Blish fan out there. I first read the Cities in Flight Series when I was a teenager in the 1960’s. As Derek mentioned, Blish actually worked for Pfizer right after WWII in public relations and used his contacts and biology experience to get the screening part correct in the search for what he called anti-agathics, the first of which he named ascomycin. In their search for novelty Pfitzner is screening soil from the Moons of Jupiter. There is also a backstory which clearly is linked to the McCarthy era of the 1950’s as well. The last book in the series “The Triumph of Time” has a stunning ending.
    Derek, ever wonder why some bright bulb in Hollywood has never tapped into the Cities in Flight for a series of films? Infinitely better than rebooting Spiderman…

  9. Dr. Manhattan says:

    “We’ll see how prescient he was about the natural products for aging, and if that works out, perhaps we’ll have enough time to start in on the faster-than-light drive.”
    No, remember that spindizzy (Dillon-Wagoner gravitron polarity generator) works in its own continuum, following the Blackett-Dirac equation, which was tested in Jupiter’s gravity field on the Bridge. Being in their own field, the spindizzy therefore “have little regard for any legislation about the speed of light”

  10. Derek Lowe says:

    8/9 Dr. Manhattan
    Yeah, I’ve wondered about a film, too. With modern special effects, there really aren’t “unfilmable” science fiction scenes any more, and the “Earthman, Come Home” part has enough action to keep things zipping along. It’s weird to see more-detailed-than-needed made-up chemistry and physics and nods to Spengler’s theories of history mixed in with slam-bang space opera, but that’s Blish all over. That also meant that his bad stuff is very bad indeed, also in its own special way.
    Your point about the spindizzy is valid, too. But out here in the rest of universe, it was, for practical purposes, an inertialess FTL drive. And an antigravity device, too!

  11. Morten G says:

    Life-extension with caloric restriction makes good sense in rodents and worms. But for longer living animals that are likely to see more breeding seasons whether or not bad years extend their lives… I don’t think we’ll see much use of it for humans.
    Btw, Google does a very reasonable job of translating the German:
    “Against the death no herb is grown”. So he wasn’t 100% profetic.
    Autophagy seems like a reasonable mechanism for letting people live healthier, longer. But a short fast is free. Heck, it’ll even save you money.

  12. cdsouthan says:

    Kräutlein is a diminutive so “herblet” or “little herb” comes closer (cf Fraulein = little woman = girl) but, hey, its clear enough

  13. Bruce Hamilton says:

    8. Ascomycin is an ethyl analog of tacrolimus, and has similar properties to rapamycin. Another Blish fan contribution?.

  14. steve says:

    #3, I would temper your remark by saying that there’s no doubt that caloric restriction works for animals in a laboratory environment. It turns out that caloric restriction also inhibits immune responses (maybe through mTOR, the target of rapamycin); when put into a natural environment, caloric-restricted animals actually die faster due to a reduced ability to fight infection.

  15. lynn says:

    I’m happy to be taking rapamycin daily for its immunosuppressive properties keeping my kidney transplant happy – and it would be nice to think it will be life extending. But there are side effects. High triglycerides, hyperglycemia and, most important, retardation of wound and bone healing and many more. Be wary of the free lunch.

  16. anon the II says:

    at Bruce #13
    Depends on how you look at it. If you’re a chemist, tacrolimus and rapamycin look very similar. However, if you’re a biologist, tacrolimus looks a lot more like cyclosporin.

  17. Lane Simonian says:

    #4 T-817MA [1-{3-[2-(1-benzothiophen-5-yl) ethoxy]propyl}azetidin-3-ol maleate] is an aromatic compound and at least certain aromatic compounds can be used to treat Alzheimer’s disease not so much because they inhibit the aggregation of amyloid, but because they act as antioxidants.

  18. Lane Simonian says:

    Yes, be careful of what you wish for. The AMP-activated protein kinase is another avenue that has been suggested for life extension, but activation of this kinase under conditions of oxidative stress actually contributes to Alzheimer’s disease.

  19. simpl51 says:

    I dislike the concept of “the Patient”, who passively lets the experts treat his diagnosed disease with a potential cure, neither of which he can expect to fathom, so he must accept the decision of a risk-balancing insurer.
    This doesn’t fit well with several recent themes in this blog – vaccines, preventative medicine (no disease) neurologicals and alzheimer’s (the experts aren’t good enough) and psychotherapy.
    So I see his counterpart on the internet as the Impatient, an Indiana Jones type who grows his own hemp and ergot, who keeps a lump of rapamycin in the fridge next to the maggots, who can transcend borders when he needs TCM or phages, and whose condition has an activist group before the first treatments are on the market.
    To win time and outsmart lobbies, the Impatient might sign up to crowdfund a lifelong study of the obvious, that nicotine vapes are less carcinogenic than smokey old cigarettes.
    As for vaccines, the Great Impatients of Washington State are going for the kill on 5(?) great scourges of humankind, since Pharma can’t take the uncertainty any more.

  20. cancer_man says:

    Wait, how does Derek know “GSK got pretty badly burned with Sirtris?”
    SRT2104 appears to be doing well in trials.
    I have no idea. I’m just curious why GSK has been deemed down for the count in this early round of anti aging pills.

  21. Rene says:

    I really enjoyed Blagosklonny’s earlier Aging as well as his oxidation and aging review (spoiler, oxidative damage isn’t the cause of aging despite what the pom juice people say). He didn’t have an RO1 to defend at that time…

  22. one man CRO says:

    i developed some novel (composition of matter) mTOR inhibitors. they all work as advertised. one of them works better than rapamycin. the biologists working on the screen saw something shiny and just walked away. this was 3 yrs ago and they have no interest in doing anything more with my compounds. obviously we’re early here but there is something interesting. i don’t have any biology tools here, just chemistry
    anyone interested in a partnership??

  23. Henri says:

    I wandered into this blog while trying to find out about Revalesio, which certainly triggered my crap detectors. However my feedback is in appreciation of James Blish’s approach to translation. I thought I was the only person to use this approach.

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