Rapamycin Increases Mice Longevity
maxwatt 08 Jul 2009
A pill for longer life?
A drug slows the march of time in middle-aged mice.
Kerri Smith
Could a pill one day slow ageing in humans?
Rapamycin, a drug commonly used in humans to prevent transplanted organs from being rejected, has been found to extend the lives of mice by up to 14% — even when given to the mice late in life.
In flies and worms, drug treatments have been shown to prolong lifespan, but until now, the only robust way to extend life in mammals has been to heavily restrict diet.
The researchers caution, however, that using this drug to extend the lifespan of humans might be problematic because it suppresses the immune system — potentially making people who take it more susceptible to infectious diseases.
Research teams at three different US institutions — the University of Texas Health Science Center in San Antonio, the University of Michigan in Ann Arbor and the Jackson Laboratory in Bar Harbor, Maine — ran the same experiment in parallel, splitting nearly 2,000 mice between them. The mice were bred to ensure that they were genetically different enough that no single strain would be more or less susceptible to ageing-related diseases or the effects of the drug. They then gave the mice food that included rapamycin.
Problems formulating the feed meant that the teams couldn't start the treatment until the mice were rather older than they had planned — 20 months of age, or the equivalent of about 60 years in human terms.
As it happened, this delay was a fortuitous accident. Compared with the non-drug-taking group, the lifespans of the mice given rapamycin increased by up to 14%, even though they were middle-aged when treatment began. Their life expectancy at 20 months shot up by 28% for the males and 38% for the females.1
"You've probably heard the phrase 'chance favours the prepared mind', and this is an example of it," says David Harrison, who led the arm of the experiment that took place at the Jackson Laboratory.
Calorie control link?
An independent initiative, the Interventions Testing Program overseen by the US National Institute of Aging, chose rapamycin for the three labs to test because it's known to have effects on a cellular pathway called TOR (for target of rapamycin). This pathway is known from studies in mice, flies and worms to be involved in the age-defying effects of calorie-restricted diets.
“I wouldn't do it myself and wouldn't encourage anyone to do it at this point.”
David Harrison
Jackson Laboratory
This link could mean that rapamycin is mimicking the effects of dietary restriction, says Matt Kaeberlein, whose group at the University of Washington in Seattle works on ageing in mice, yeast and worms. "All the arrows are going in the right direction," he says.
Harrison isn't so sure, however — none of the mice lost body weight during their experiments, he says, and dietary restriction usually works best when started early in life, not in middle age as the rapamycin treatment was.
The big question, of course, is whether this drug could extend human life. Both Harrison and Kaeberlein are cautious. "I wouldn't do it myself and wouldn't encourage anyone to do it at this point," says Harrison.
Getting the dose correct is another problem. A normal human dose of rapamycin is between 2 and 5 milligrams per day, much lower than the dose given to the mice, which was 2.24 milligrams per kilogram of body weight per day.
Perhaps rapamycin could be altered somehow, to reduce its effects in the immune system while keeping its anti-ageing effects? "It's an open question whether you can uncouple that from immune suppression," Kaeberlein says. But in future, he says, it's likely that it will be possible to tweak rapamycin in this way, or to target the other molecules in the pathway instead. Kaeberlein's lab is already working on these downstream targets.
Several other compounds are currently being tested by the three US centres as part of the Interventions Testing Program, including resveratrol, a compound found in red wine and thought to have beneficial effects on the heart, and simvastatin, one of a family of compounds called statins, also used for heart conditions.
For now, the researchers won't be trying out their anti-ageing drug on themselves. But that hasn't stopped them daydreaming about it. "Of course, you can imagine we've been considering it ourselves," laughs Harrison. "I'm 67, so it's just about time for me to start my treatment, isn't it?"
References
Harrison, D. E. et al. Nature advance online publication doi:10.1038/nature08221 (2009).
Abstract:
Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies1, 2, 3, 4, 5; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
brunotto 08 Jul 2009
Edited by brunotto, 08 July 2009 - 08:11 PM.
Michael 08 Jul 2009
Holy shit!
For some time, there's been evidence for involvement of activation of autophagy in the life-extending effects of CR, including in particular via inhibition of TOR (an autophagy-inhibitor protein) -- ie, that unblocking the inhibition of autophagy retards aging. Most of the evidence comes from life extension in invertebrates, including both knockout and siRNA studies as well as studies using the TOR inhibitor drug rapamycin]. As some of you will know, I have a very low opinion of the relevance of invertebrate models in biogerontological research, and especially for any putative life-extension intervention.
We were discussing this just a couple of days ago on the Calorie Restriction Society listserv, and I wrote:
I'd remind everyone that ... we don't have a full LS study in any mammal for curcumin or any other modulator of mTOR. ... I'd enjoy an occasional curry and await further evidence in otherwise-normal, healthy rodents.
Then, just moments ago, someone posts this:
Immune drug boosts lifespan
The Scientist blog
Posted by Bob Grant
[Entry posted at 8th July 2009 06:00 PM]
A drug used to prevent the rejection of transplanted organs and as an experimental cancer treatment in humans can significantly increase lifespan when given to adult mice, researchers have found. Mice that were administered the immunosuppressant rapamycin lived an average of 9-14% longer than mice that were not fed the drug, according to a paper published online in Nature today (July 8th).
I was initially sure that this was going to be 'the usual nonsense': so-called 'life extension' in some short-lived, genetically-screwed-up and/or carcinogen-fed and/or obese and/or diabetic and/or poorly-husbanded bunch of mice. Well, no siree!
People, this is for REAL! The above snip actually downplays the significance of the report, because (a) the animals didn't even get started on the stuff until age 20 mo -- definitely the beginning of the 'golden years' in mice; (b) this wasn't 'the usual nonsense,' but was reported in perfectly healthy animals; and © this was the freakin' NIA's Intervention Testing Protocol, which is being run at 3 of the most respectable labs for such purposes in the world, and includes some of the most hard-nosed biogerontologists out there (Richard Miller and David Harrison) -- and all 3 sites independently reported the result, and in both genders!!
The difference isn't massive, and indeed, if I have 1 quibble, it's that the controls' max LS were not quite as long as is generally achieved in the best labs (Weindruch, Spindler, and the sadly-departed Walford): control groups were all in the 1000-1200 d max LS range, where the latter investigators' control animals generally push 1200 days -- but the result is too robust to dismiss. (As a result, sadly, it can't win the Rejuvenation MPrize: Spindler's late-onset CR animals, initiated a full month younger, had a max LS of 1319 d (website says 1356) -- but this is a completely novel result, and the first real pharmacological one).
No, I am not recommending we all start popping rapamycin (let alone megadose curcumin): they're 'just' rodents, after all, and the stuff is a toxic immunosuppressant; indeed, while humans are normally administered 2-5 mg/d, the mice got 2.24 mg per kg of body weight/d, which even after adjusting for metabolic scaling is presumably a huge dose. Plus, while it's excellent to see this done (by logistical serendipity, as it turns out) in such late-onset animals, it's possible that the effect is somehow countering something that you wouldn't want to counter earlier on in life.
But make no mistake: this is a robust breakthrough in pharmacological biomedical gerontology. Something useful can come of this. I'm dancing in my little chair .
Yee-haw!
-Michael
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
David E. Harrison, Randy Strong, Zelton Dave Sharp, James F. Nelson, Clinton M. Astle, Kevin Flurkey, Nancy L. Nadon, J. Erby Wilkinson, Krystyna Frenkel, Christy S. Carter, Marco Pahor, Martin A. Javors, Elizabeth Fernandez & Richard A. Miller
Nature advance online publication 8 July 2009
Received 9 April 2009; Accepted 24 June 2009; Published online 8 July 2009
maxwatt 08 Jul 2009
At concentrations that inhibit mTOR, resveratrol suppresses cellular
senescence.
Demidenko ZN, Blagosklonny MV.
Oncotarget, Albany, New York, USA.
PMID: 19471118 [PubMed - as supplied by publisher]Here we demonstrated that, at cytostatic, near-toxic concentrations,
resveratrol inhibited S6 phosphorylation and prevented the senescence
morphology in human cells. Using a sensitive functional assay, we
found that resveratrol partially prevented loss of the proliferative
potential associated with cellular senescence. Resveratrol was less
effective than rapamycin, because aging-suppression by resveratrol was
limited by its toxicity at high concentrations. We discuss whether
concentrations of resveratrol that inhibit mTOR (target of rapamycin)
and suppress cellular senescence are clinically achievable and whether
partial inhibition of mTOR by resveratrol might be sufficient to
affect organismal aging.
So resveratrol inhibits mTOR, sort of. It is just possible, but unlikely, that partial inhibition of mTOR at low doses that are phenomenologically feasible might extend life.
Curcumin inhibits mTOR, at high doses, but bioavailability is poor:
Carcinogenesis
Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells
Christopher S. Beevers, Fengjun Li, Lei Liu, Shile Huang *
Department of Biochemistry and Molecular Biology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA
email: Shile Huang (shuan1@lsuhsc.edu)
*Correspondence to Shile Huang, Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932
Fax: +318-675-5180
Funded by:
Feist-Weiller Cancer Research Award
Edward P. Stiles Award
Start-up Fund
Louisiana State University Health Sciences Center in Shreveport, LA
KEYWORDS
curcumin • mTOR • S6K1 • 4E-BP1 • Akt • apoptosis • motility • rhabdomyosarcoma
ABSTRACT
Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Here we show that curcumin inhibited growth of rhabdomyosarcoma cells (Rh1 and Rh30) (IC50 = 2-5 M) and arrested cells in G1 phase of the cell cycle. Curcumin also induced apoptosis and inhibited the basal or type I insulin-like growth factor-induced motility of the cells. At physiological concentrations (2.5 muM), curcumin rapidly inhibited phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and Hela). Curcumin also inhibited phosphorylation of Akt in the cells, but only at high concentrations (>40 M). The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells. © 2006 Wiley-Liss, Inc.
Received: 6 December 2005; Accepted: 2 February 2006
Is a level of (2.5 muM) achievable from reasonable oral dosing?
Caffeine also inhibits mTOR, but mega-dosing caffeine is probably not a good idea either.
stephen_b 08 Jul 2009
In this paper, the plasma concentrations in subjects taking 2g of BCM-95 were measured. The peak achieved was 456.88 ng/g. Can someone convert to micromoles?Is a level of (2.5 muM) achievable from reasonable oral dosing?
I've been taking 2 caps of the LEF product by emptying them into a tablespoon of coconut oil.
StephenB
Boondock 09 Jul 2009
Scientists discover Easter Island 'fountain of youth' drug that can extend life by ten years
kismet 09 Jul 2009
I'm not sure how we translate immuno-suppressant doses to humans but a simple BSA dose translation gives ~13mg for a 70kg human. That is indeed quite a lot. It also seems that as expected lymphoma incidence was increased in the rapamycin group and overall cancer incidence also seems to be increased*. We definitely need mTOR inhibitors without those side-effects (I'm assuming immuno-suppression is unrelated to mTOR signalling per se).No, I am not recommending we all start popping rapamycin (let alone megadose curcumin): they're 'just' rodents, after all, and the stuff is a toxic immunosuppressant; indeed, while humans are normally administered 2-5 mg/d, the mice got 2.24 mg per kg of body weight/d, which even after adjusting for metabolic scaling is presumably a huge dose. Plus, while it's excellent to see this done (by logistical serendipity, as it turns out) in such late-onset animals, it's possible that the effect is somehow countering something that you wouldn't want to counter earlier on in life.
*I guess rapamycin increases incidence due to immuno-suppression (or did the incidence merely increase because the mice lived longer?) but postpones progression due to its neoplastic activity, does it? Afterall it's known to increase cancer risk in humans.
I'm wondering if the guys over at Pfizer (et al.) are screening their compounds for mTOR activity right now.
Edited by kismet, 09 July 2009 - 12:59 AM.
kismet 09 Jul 2009
I'm assuming that 1g of blood = 1ml. Molecular weight of curcumin is 368.38 g/mol. 2.5mcM = 925 mcg/L = 925ng/ml (which is pretty close to their peak value of 456 ng/ml) if I did not screw up my maths -- but I certainly did as it sounds too good to be true.In this paper, the plasma concentrations in subjects taking 2g of BCM-95 were measured. The peak achieved was 456.88 ng/g. Can someone convert to micromoles?
tunt01 09 Jul 2009
it's nice to see confirmation of what we everyone suspected already, but I'd personally like to see more practical studies. i get somewhat tired of seeing these individual studies which examine one substance in isolation. i'd like to see a mouse study, which has AOR Ortho-Core vitamins, Revgenetics resveratrol + LEF Curcumin vs. a mouse with just AOR Ortho Core vs. a mouse w/ mediterannean supplements vs. control. more real world applications...
kismet 09 Jul 2009
Actually they also tested enalapril and CAPE (caffeic acid phenethyl ester) which did not affect life span. Basically every compound (ever) tested but rapamycin failed in rigorous testing so far. Although, I second the sentiment that we need more applicable real world research in many regards.i get somewhat tired of seeing these individual studies which examine one substance in isolation. i'd like to see a mouse study, which has AOR Ortho-Core vitamins, Revgenetics resveratrol + LEF Curcumin vs. a mouse with just AOR Ortho Core vs. a mouse w/ mediterannean supplements vs. control. more real world applications...
Edited by kismet, 09 July 2009 - 02:04 AM.
manofsan 09 Jul 2009
http://www.technolog...medicine/22974/
100YearsToGo 09 Jul 2009
I posted some time ago about this here.
SquareTheCurve 09 Jul 2009
A team of 14 researchers from three institutions, led by David Harrison from the Jackson Laboratory at Bar Harbor in Maine, fed rapamycin to mice late in their life – at 600 days of age – and showed that both the median and maximal lifespan of treated animals were considerably extended. Currently, the only way to extend the life of a rodent is by severely restricting its diet, so this marks the first report of a pharmacological intervention that lengthens the life of mammals – with clear implications for humans.
The results, published today in an online paper on the website of the journal Nature, are attracting considerable excitement, and an accompanying article in Nature by two of the world's leading experts on the ageing process, Matt Kaeberlein and Brian K Kennedy from the University of Washington, Seattle, headed "A Midlife Longevity Drug?" openly asks the question: "Is this the first step towards an anti-ageing drug for people?"
The article then goes on to point out that rapamycin is immuno-suppressive, so it still has "unwanted side effects". Still, the maximum lifespan of female mice increased 38%, and of male mice 28%, so good news if you're an otherwise-healthy mouse.
Can someone provide pointers to the articles in Nature?
maxwatt 09 Jul 2009
Edited by maxwatt, 09 July 2009 - 06:43 PM.
maxwatt 09 Jul 2009
I'm assuming that 1g of blood = 1ml. Molecular weight of curcumin is 368.38 g/mol. 2.5mcM = 925 mcg/L = 925ng/ml (which is pretty close to their peak value of 456 ng/ml) if I did not screw up my maths -- but I certainly did as it sounds too good to be true.
I think your math was correct, but I think the blood serum levels are a bit optimistic, even with a formulated curcumin. Even two gram doses show little in the blood. Would that it were so simple as to OD curcumin.
AgeVivo 09 Jul 2009
1. will rapamycin also extend lifespan of not-so-old mice? (eg young adult or 1 year old)
2. curcumin is on the list of things tested by the NTP. Do you bet that it will extend lifespan as well?
3. rapamycin is an immunosuppressant; will it extend mouse lifespan in our houses? (= non-pathogen-protected environments)
Edited by AgeVivo, 09 July 2009 - 08:17 PM.
AgeVivo 09 Jul 2009
I'll start:1. will rapamycin also extend lifespan of not-so-old mice? (eg young adult or 1 year old)
2. curcumin is on the list of things tested by the NTP. Do you bet that it will extend lifespan as well?
3. rapamycin is an immunosuppressant; will it extend mouse lifespan in our houses? (= non-pathogen-protected environments)
1: my guess is no for young adults, slightly for 1 year old mice. Indeed i guess that cancers would prevail before non-autoimmunity
2: my guess is slightly, like aspirin or NDGA
3: depends on 1. If rapamycin largely extends lifespan in young mice, then my guess is yes.
Edited by AgeVivo, 09 July 2009 - 08:33 PM.
Cyberbrain 09 Jul 2009
Anthony_Loera 09 Jul 2009
http://cancerres.aac...stract/59/4/886
http://clincancerres...ract/10/23/8059
For Cardiac function:
http://circ.ahajourn...act/109/24/3050
The more I search in google scholar, the more I like it...
A
VidX 10 Jul 2009
It's funny, I was talking how awesome it wouldbe to have a CR mimicker without actual CR and now this *hint* justa few days later. I hope it won't end as a "usual" so called breaktrhoughs.
Edited by VidX, 10 July 2009 - 12:10 AM.
VictorBjoerk 10 Jul 2009
The effect is still less than severe CR, isn't it?
VidX 10 Jul 2009
PWAIN 10 Jul 2009
I note Vidx got in before me about the starting age.
This is amazing. However I wonder, what is the highest attained age for a CR mouse? Yoda still holds the total record with 1462 days, right?
The effect is still less than severe CR, isn't it?
Edited by resvhead, 10 July 2009 - 02:38 AM.
maxwatt 10 Jul 2009
Well it was started at an old age so it's hard to conclude anything yet. What's unclear for me - how inhibition of protein sythesis helps to get rid of these "bad" proteins? Shouldn't this be a vice versa? Sorry for my possible stupid question, I'm not an expert, but try to understand as much as possible.
One explanation I've seen is that slowing protein turnover slows the rate at which defective proteins are formed. One mTOR inhibitor is being investigated for its potential to treat prion diseases.