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).

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.

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.

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).

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.

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?

Scientists discover Easter Island 'fountain of youth' drug that can extend life by ten years

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.

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?

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...

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?"