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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 10, 2009

mTOR, Rapamycin, and Lifespan: A Startling Study

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Posted by Derek

A new paper coming out in Nature is getting a lot of attention, and well it should. This is some of the more dramatic anti-aging news that's been reported to date. (The accompanying editorial is also surely the first time anyone's quoted "Stairway to Heaven" in Nature).

The work hinges on a kinase enzyme called TOR (you often see an "m" in front of it, for "mammalian"). TOR, in accordance with the best gotta-name-it-something traditions of biochemistry, stands for "target of rapamycin", by which you would deduce (correctly) that rapamycin was discovered well before TOR. Rapamycin's a complex natural product first isolated from bacteria in a soil sample from Easter Island (Rapa Nui) - right here, in fact. In the late 1980s and early 1990s it was (along with another macrolide immunosuppresant, FK-506) the subject of a huge amount of research. (Note that FK-506 and rapamycin, though similar, still have some major differences in mechanism - unraveling these was most definitely nontrivial). Both compounds have strong immunosuppressive properties - the hope was that one or the other might prove to be some sort of universal transplant drug, among other things.

Rapamycin isn't that, but it's still useful, particularly in kidney transplants. And since TOR is involved in a lot of important cellular processes (brace yourself), inhibition of it by rapamycin and synthetic molecules has been studied extensively for other actions. The most interesting (well, perhaps until now) has been as an anticancer therapy. That alone illustrates the trickiness of this area, since one problem with any immunosuppressive therapy is a significantly higher risk of cancer. Decoupling these two effects has occupied a lot of time and effort over the years; that last link should give you an idea of the magnitude of the task.

But rapamycin has also shown life-extending properties in simple organisms, and this latest paper extends this effect to mice. The NIH group studying this had their problems, though - just adding the compound to rodent chow wasn't enough to achieve useful blood levels. More formulation work had to be done to produce an encapsulated version that could make it past the upper gut, and by the time that was worked out, the large cohort of mice set aside for the experiment was. . .well, rather more aged than planned.

But they went ahead with the experiment anyway, starting them off at 600 days old, which is roughly a 60-year-old human. Startlingly, the compound still extends life span, by about 14% in the female mice and 9% in the males. At ages where about 5% of the control mice were still alive, some 20% of the treated mice were still going. That's a very significant result, especially considering the late start. All in all, this looks like the most dramatic mid-to-later lifespan intervention that anyone's ever seen in a mammal. (Caloric restriction, for example, has been basically useless if started at the 600 day mark in mice, and no weight losses were seen here). There's a rapamycin study under way with mice in the prime of rodent life (starting at 270 days), and the preliminary results look quite similar (with again a stronger effect in the females).

The causes of death don't seem to have altered. A good sample of animals from both groups were checked by necropsy, and nothing significant was noted. That seems rather surprising, because the blood levels of the compound are (at least from what I can see) rather high. The paper mentions that the mice had 60 to 70 ng/mL rapamycin, and looking around, I find blood levels of 15 ng/mL mentioned as effective in tumor suppression in one mouse model, and the immunosuppressive doses seem to be similar. I'd be glad to hear from anyone who knows more about rapamycin dosing in mice, though; it's definitely outside my range of experience.

Are people going to run out and start taking the stuff? It wouldn't surprise me, although I'd have to say that that's a bad idea at the moment. There's an awful lot that we don't understand about the tradeoffs between aging, cancer, and the immune response, and I'd hate to end up on the wrong side of that bet. Jumping straight to humans is too big a leap for now, but remember - there are a lot of other mTOR inhibitors out there in development (try this paper for starters). If we can narrow down which pathways are important for lifespan (and believe me, there are people thinking hard about this right now, especially after this paper), then there could be some very interesting opportunities

Comments (13) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. Lucifer on July 10, 2009 10:10 AM writes...

Talking about longevity. Why not study the Naked Mole-Rat (Heterocephalus glaber)?

This small mammal lives over 28 years in captivity. The best part- it's body does not seem to age. A 27 year old female rat is just as fertile as a 2 year old. Same for many systems such as the cardiovascular system.

A few interesting publications.

Vascular aging in the longest-living rodent, the naked mole rat: Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H919-27.

Disparate patterns of age-related changes in lipid peroxidation in long-lived naked mole-rats and shorter-lived mice. Aging Cell. 2006 Dec;5(6):525-32.

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3059-64.

Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B. 2008 May;178(4):439-45.

Permalink to Comment

2. Anonymous on July 10, 2009 10:19 AM writes...

Kinase inhibitors for life span? That is a big bet.

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3. tom on July 10, 2009 10:36 AM writes...

Nice review but it's also worth mentioning that unlike most small molecules rapamycin is extremely selective so its effects can, as-near-as-dammit, be wholly assigned to TOR inhibition. Another intriguing fact is that it only inhibits a subset of TOR functions and by a mechanism that is poorly understood. Neither of these properties is likely to be matched by TOR kinase inhibitors so its definitely "game on" for Pharma

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4. DT on July 10, 2009 11:44 AM writes...

There are two complexes of mTOR, and the Sabatini lab has been studying these for years. complex one contains raptor, while two contains rictor; rapamycin specifically inhibits complex one in acute treatments(Rapamycin inhibits mTORC1, but not completely. Autophagy. 2009 Jul;5(5):725-6. Epub 2009 Jul 22). In that paper, they bring up another drug worth noting named Torin1 which inhibits both complexes. He has many other valuable papers pertaining to these complexes.

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5. Kismet on July 10, 2009 12:03 PM writes...

The causes may be similar but it seems that cancer incidence was increased by quite a lot (e.g. Lymphoma 10 vs 15) (1) Perhaps cancer incidence was higher (immunosuppression), but mortality lower.
The causes of death stayed the same? But wouldn't we actually expect the causes to stay the same if the drug really postpones aging? They die from the same, just later on. I suppose histopathology will show the important differences (if any)...

By the way, I don't think CR is necessarily useless at this age. Generally, it is said that late life CR simply requires *very* careful and slow initiation. Apparently late-life CR started in mice just 1 month younger than those, still holds the (late-onset) life extension record. (2)

Additionally this is not the only recent result of importance to biogerontology & life extension. It seems that another important paper was published around the same time. More preliminary and promising data from the CRd'd primates. (3)
I don't think that's a coincidence. But it certainly makes for good publicity (and hopefully more funding in the future).

(1) http://www.nature.com/nature/journal/vaop/ncurrent/extref/nature08221-s1.pdf
(2) http://mfoundation.org/forums/showpost.php?p=7001&postcount=1
(3) Science, 325 (5937), 201-204
Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys.
Colman et al.

Permalink to Comment

6. eb on July 10, 2009 12:47 PM writes...

The side effects of rapamycin might be a problem http://tinyurl.com/mb2g2s

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7. drcharles on July 12, 2009 12:57 AM writes...

I read one article about this that suggested the increase in longevity might be due to decreases cancer incidence (while on a chemotherapy med)? I'll go read more about this, thanks for the summary.

Interesting how "TOR" is used differently in two adjacent posts! thanks for your efforts to facilitate free speech.

Permalink to Comment

8. Kismet on July 12, 2009 11:14 AM writes...

Nope, it's definitely not cancer incidence (which seems to have increased drastically, see the pdf from nature I linked to). If anything it is cancer mortality, but the authors haven't provided definite data yet.
As a rule of thumb: "chemothapy meds" increase incidence but decrease progression of cancer.

Permalink to Comment

9. bcpmoon on July 13, 2009 1:26 AM writes...

Boy, talk about a marketing bonanza! A life-prolonging, natural miracle drug from easter island? I bet the first ads are out at whale.to

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10. alig on July 13, 2009 6:54 AM writes...

So you can live longer as long as you live in a plastic bubble sealed off from all pathogens? Immunosuppresives will have trouble in the real world because they will reduce the ability of the body to fight infections. Fine if you are a mouse in a cage in a clean room, not so ok if you come into contact with people everyday. (I can't remember exactly, but I believe CR is immunosuppressive as well).

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11. Bill Sardi on July 13, 2009 7:25 AM writes...

The dosage of rapamycin used in these lab mice was around 156 mg human equivalent whereas about 2-5 mg is used in humans for immunosuppression. There is no practical application of this discovery at the present time. Resveratrol has been compared with rapamycin and should be the logical direction for future research of the mTOR pathway. http://www.ncbi.nlm.nih.gov/pubmed/19471118

Permalink to Comment

12. passionlessDrone on July 13, 2009 9:25 AM writes...

Hello friends -

Is there any chance that we observed increased lifespan without apparent problems with immunosuppression because the rats didn't start getting the drug until later in life? In other words, maybe things would have evened out lifespan wise if the problems with immunosuppression were lifelong.

Very nice post.

- pD

Permalink to Comment

13. Kismet on July 13, 2009 12:54 PM writes...

The real Bill Sardi promoting resveratrol? (it's slightly funny considering the conflicts of interest involved)
I've been told the resveratrol concentrations used in this stuy are near-toxic and can be only reached in vitro... either way we need more specific inhibitors of mTOR, but first we need more proof that rapamycin slows aging per se and that we really want to target mTOR (and how).

alig, nope, CR is not necessary immunsuppressive. There's data supporting both sides and CRONies are not known to suffer from too many infections FWIW.

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