Immune drug Rapamycin boosts lifespan
Dave Saum
Immune drug boosts lifespan
Posted by Bob Grant
[Entry posted at 8th July 2009 06:00 PM GMT]
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).
"This is pretty remarkable," Panjak Kapahi, a geneticist at the Buck
Institute for Age Research in California told The Scientist. "There might be
more to gain in understanding the downstream effects, but this is already a
wonderful start." Kapahi, who was not involved with the study, added that,
though preliminary, the finding opens the door for further research into the
drug's use for an anti-aging intervention in humans. "It should be
applicable to humans, I think."
David Harrison, a gerontologist at The Jackson Laboratory in Bar
Harbor Maine and lead author on the paper, told The Scientist that 9%,
though seemingly a modest life span increase, is significant when compared
to the effect of eradicating some of the most common age-related diseases in
humans. "If you prevented all deaths from cancer and atherosclerosis,"
Harrison said, "it would be a little less than that."
Rapamycin works by inhibiting the target of rapamycin (TOR) signaling
pathway, which plays a role in the translating mRNA into proteins and
inhibits processes that degrade cellular waste. The drug has been found to
extend the life spans of yeast, fruit flies, and nematodes. "This is really
the first demonstration that inhibiting TOR also increases lifespan in
mammals," said Matt Kaeberlein, a pathologist at the University of
Washington in Seattle who was not involved with the study.
Kapahi, who discovered in 2004 that the TOR pathway played a role in
extending the life spans of fruit flies, said that Harrison's study is both
a "great victory for the invertebrate models of aging," and a fruitful way
forward to investigate a potential anti-aging treatment in humans. "You
would put your money on a pathway that you know has worked in four different
organisms," he said. "This is as good as it gets."
As rapamycin has previously been shown to increase the life spans of
invertebrate model organisms, its effect in mice is not entirely surprising,
according to Kaeberlein, who wrote a commentary that accompanies the Nature
paper. More surprising is the fact that the longer-lived mice in the study
were not given rapamycin until they were 600 days old. "That is very
surprising to myself and to a lot of people," Kaeberlein told The Scientist.
"And it's a very important result." A 600-day-old mouse is roughly
equivalent to a human that is 60 years of age, and other successful
anti-aging interventions have not proved effective so late in an organism's
life.
Kaeberlein said that rapamycin's effectiveness in middle aged mice
represents an interesting therapeutic opportunity in humans, because "almost
everything that has been found to significantly increase lifespan in model
organisms leads to some sort of fitness costs" -- usually by stunting growth
or reducing reproductive capacity. A rapamycin-based anti-aging pill
administered later in life might circumvent these problems.
Harrison agreed. "It's certainly possible that there may be optimal
times to start things when you're old that might be deleterious when you're
young," he said. But he joined Kaeberlein and Kapahi in cautioning that the
findings should not be interpreted as an invitation for age-conscious humans
to ingest the drug. "It's not time to start popping rapamycin for
anti-aging," Harrison said, adding that taking rapamycin likely carries
significant risks common to other immune suppressants or immunocompromising
diseases.
Several questions surrounding the results and rapamycin's impact on
the TOR pathway and aging remain to be answered. "What's happening in these
animals that are given rapamycin and are living a long time?" asked
Kaeberlein. "That's going to be important for the next set of experiments to
look at."
Harrison said that he and other researchers collaborating in the
National Institute on Aging's Interventions Testing Program are examining
the drug's cellular effects and testing a suit of other compounds suspected
to increase the longevity of mammals. The effect of rapamycin and the
indication that the TOR pathway is important in mammalian aging is a major
step towards developing a drug that might prolong human life, he said. "I
think this makes us a lot closer than we were before," he said. "Who knows
what's going to work, but we have a point here that's ever so much more
specific and interesting than we had to start with."
--------------------
Rating: 4.90/5 (10 votes )
comment:
Is mitochondrial function (respiration) a cause for ageing??
by anonymous poster
[Comment posted 2009-07-08 14:45:32]
J Biol Chem. 2006 Sep 15;281(37):27643-52. Epub 2006 Jul 17.Related
Articles, Links
The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial
oxygen consumption and oxidative capacity.
Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel
T.
Cardiology Branch, Laboratory of Cardiac Energetics, Flow Cytometry Core
Facility, NHLBI, National Institutes of Health, Bethesda, Maryland 20892,
USA.
Metabolic rate and the subsequent production of reactive oxygen species are
thought to contribute to the rate of aging in a wide range of species. The
target of rapamycin (TOR) is a well conserved serine/threonine kinase that
regulates cell growth in response to nutrient status. Here we demonstrate
that in mammalian cells the mammalian TOR (mTOR) pathway plays a significant
role in determining both resting oxygen consumption and oxidative capacity.
In particular, we demonstrate that the level of complex formation between
mTOR and one of its known protein partners, raptor, correlated with overall
mitochondrial activity. Disruption of this complex following treatment with
the mTOR pharmacological inhibitor rapamycin lowered mitochondrial membrane
potential, oxygen consumption, and ATP synthetic capacity. Subcellular
fractionation revealed that mTOR as well as mTOR-raptor complexes can be
purified in the mitochondrial fraction. Using two-dimensional difference gel
electrophoresis, we further demonstrated that inhibiting mTOR with rapamycin
resulted in a dramatic alteration in the mitochondrial phosphoproteome. RNA
interference-mediated knockdown of TSC2, p70 S6 kinase (S6K1), raptor, or
rictor demonstrates that mTOR regulates mitochondrial activity independently
of its previously identified cellular targets. Finally we demonstrate that
mTOR activity may play an important role in determining the relative balance
between mitochondrial and non-mitochondrial sources of ATP generation. These
results may provide insight into recent observations linking the TOR pathway
to life span regulation of lower organisms.
See more work from this group.
comment:
Life-prolonging pill
by Hans Weber
[Comment posted 2009-07-08 14:13:27]
In the chapter "Death" in his new book, "Life Ascending", Nick Lane mentions
TOR and the potential benefits of rapamycin to delay aging. Since aging is
associated with cancer, cardiovascular, and other degenerative diseases, its
delay would keep such diseases at bay, thus assuring a longer healthier
life. Lane considers an anti-aging pill a real possibility.
rs1...@yahoo.com
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.
Inhibition of the TOR signalling pathway by genetic or pharmacological
intervention extends lifespan in invertebrates, including yeast,
nematodes
and fruitflies; 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.
======================
From full text:
The rapamycin was microencapsulated by Southwest Research Institute
(San Antonio, Texas), using a spinning disk atomization coating
process with the enteric coating material Eudragit S100 (Röhm Pharma).
This thermoplastic coating material increased the fraction of
rapamycin that survived the food preparation process by three- to
fourfold. Because the coating material is water soluble only in non-
acidic conditions, the encapsulated rapamycin is released in the small
intestine rather than in the stomach. A pilot study showed that
encapsulated rapamycin led to blood concentrations approximately
tenfold higher than achieved by equivalent doses of non-encapsulated
rapamycin. The encapsulated rapamycin was administered at 14 mg per kg
food (2.24 mg of rapamycin per kg body weight per day).
Thomas Carter
Hi,
The NIA has an ongoing multi center testing program for possible life
extending interventions in mice. I think this is their third success
in just a few tries.
A newly approved cancer drug, Afinitor, is a better inhibitor of mTOR
than rapamycin. I would guess this will be tested soon in mice.
Resveratrol, curcumin, green tea, a combination of lycopene and EPA,
metformin, silibinin, and melatonin also inhibit mTOR according to
some reports listed below.
Adiponectin, which is produced by fat cells when body weight is
reduced protects against heart disease, but surprisingly has been
linked to excess mortality. Interestingly it ACTIVATES mTOR.
Thomas
XXXX
(2) NEW FDA APPROVED DRUG BLOCKS mTOR BETTER THAN RAPAMYCIN. LIKELY TO
BE ANTI-AGING AND STRONGLY ANTICARCINOGENIC. SHOULD BE ADDITIVE TO
PUTATIVE ANTI-AGING INTERVENTIONS THAT DON’T ATTENUATE THE
SOMATOTROPHIC AXIS, SUCH AS MELATONIN, METOPROLOL, ACEi, AND EXERCISE.
Drug combo cuts pancreatic tumour size
Last Updated: 2009-06-24 13:08:32 -0400 (Reuters Health)
ZURICH (Reuters) - A combination of two drugs from Novartis AG cut the
size of pancreatic neuroendocrine tumours in more than 80 percent of
patients in a mid-stage study, the Swiss group said on Wednesday.
Patients who received a once-daily pill Afinitor in combination with
Sandostatin LAR had no progression in their disease for a median of
16.7 months, according to results from the so-called RADIANT-1 study
of 160 patients.
Afinitor is one of Novartis's most important new drugs and is being
tested for use against several different types of cancer, which could
help it achieve sales of more than $1 billion annually.
It works by blocking a protein known as mTOR and disrupting the
growth, division and metabolism of cancer cells and is a key plank of
Novartis's strategy to expand in cancer drugs.
A late stage trial evaluating Afinitor as a potential treatment option
for patients with pancreatic neuroendocrine tumours is already
underway, Novartis said.
Pancreatic neuroendocrine tumours are an uncommon form of the disease,
a cancer formed from cells that have roles both in the endocrine and
nervous systems
At the time of diagnosis nearly 60 percent of all patients have
advanced disease, meaning the cancer has spread to other parts of the
body and has become more difficult to treat.
The U.S. Food and Drug Administration approved Afinitor earlier this
year for use in advanced kidney cancer and European regulators have
also recommended it. Novartis expects a filing for use in
neuroendocrine tumours within the next year.
Sandostatin LAR is already approved for symptom control in certain
types of neuroendocrine tumours
XXXX
1: Oral consumption of pomegranate fruit extract inhibits growth and
progression of primary lung tumors in mice.
Khan N, Afaq F, Kweon MH, Kim K, Mukhtar H.
Cancer Res. 2007 Apr 1;67(7):3475-82. Epub 2007 Mar 27.
PMID: 17389758 [PubMed - indexed for MEDLINE]
Related Articles Free article at journal site
2: Green tea extract and (-)-epigallocatechin-3-gallate inhibit mast
cell-stimulated type I collagen expression in keloid fibroblasts via
blocking PI-3K/AkT signaling pathways.
Zhang Q, Kelly AP, Wang L, French SW, Tang X, Duong HS, Messadi DV, Le
AD.
J Invest Dermatol. 2006 Dec;126(12):2607-13. Epub 2006 Jul 13.
PMID: 16841034 [PubMed - indexed for MEDLINE]
Related Articles Free article at journal site
3: Rapamycin inhibits hTERT telomerase mRNA expression, independent of
cell cycle arrest.
Bae-Jump VL, Zhou C, Gehrig PA, Whang YE, Boggess JF.
Gynecol Oncol. 2006 Mar;100(3):487-94. Epub 2005 Oct 24.
PMID: 16249016
1: At concentrations that inhibit mTOR, resveratrol suppresses
cellular senescence.
Demidenko ZN, Blagosklonny MV.
Cell Cycle. 2009 Jun 15;8(12):1901-4. Epub 2009 Jun 21.
PMID: 19471118 [PubMed - in process]
Related Articles
2: Curcumin disrupts the Mammalian target of rapamycin-raptor complex.
Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S.
Cancer Res. 2009 Feb 1;69(3):1000-8. Epub 2009 Jan 27.
PMID: 19176385 [PubMed - indexed for MEDLINE]
Related Articles
3: The antidiabetic drug metformin suppresses HER2 (erbB-2)
oncoprotein overexpression via inhibition of the mTOR effector p70S6K1
in human breast carcinoma cells.
Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA.
Cell Cycle. 2009 Jan 1;8(1):88-96. Epub 2009 Jan 1.
PMID: 19106626 [PubMed - indexed for MEDLINE]
Related Articles Free article at journal site
4: Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/
4E-BP1 signalling pathway in human cervical and hepatoma cancer cells:
implications for anticancer therapy.
García-Maceira P, Mateo J.
Oncogene. 2009 Jan 22;28(3):313-24. Epub 2008 Nov 3.
PMID: 18978810 [PubMed - indexed for MEDLINE]
Related Articles
5: Concomitant supplementation of lycopene and eicosapentaenoic acid
inhibits the proliferation of human colon cancer cells.
Tang FY, Cho HJ, Pai MH, Chen YH.
J Nutr Biochem. 2009 Jun;20(6):426-34. Epub 2008 Aug 15.
PMID: 18708285 [PubMed - in process]
Related Articles
6: Melatonin represses oxidative stress-induced activation of the MAP
kinase and mTOR signaling pathways in H4IIE hepatoma cells through
inhibition of Ras.
Kimball SR, Abbas A, Jefferson LS.
J Pineal Res. 2008 May;44(4):379-86.
PMID: 18410586 [PubMed - indexed for MEDLINE]
Related Articles Free article in PMC | at journal site
7: Adiponectin signals in prostate cancer cells through Akt to
activate the mammalian target of rapamycin pathway.
Barb D, Neuwirth A, Mantzoros CS, Balk SP.
Endocr Relat Cancer. 2007 Dec;14(4):995-1005.
PMID: 18045951
Dave Saum
Antibiotic Delayed Aging in Experiments With Mice
a..
By NICHOLAS WADE
Published: July 8, 2009
A new star has appeared in the field of drugs that delay aging in laboratory
animals, and are therefore candidates for doing the same in people.
The drug is an antibiotic, rapamycin, already in use for suppressing the
immune system in transplant patients and for treating certain cancers.
Rapamycin treatment had the remarkable effect of extending life even though
it was not started in the right dose until the mice had lived 600 days �
equivalent to a person at age 60. Most interventions that prolong life in
mice, including a very low-calorie diet, need to be started early in life to
show any effect.
Experts warn that this should not be tried at home. No one knows yet if
rapamycin slows aging in people or at what dose it might be effective. And
any drug that suppresses the immune system is not to be trifled with.
The finding was reported online Wednesday in Nature by researchers at three
institutions working in parallel. The teams were led by David E. Harrison of
the Jackson Laboratory, a mouse-breeding powerhouse in Bar Harbor, Me.;
Richard A. Miller of the University of Michigan; and Randy Strong of the
University of Texas Health Science Center.
The researchers do not know how rapamycin secures its anti-aging effect. It
could be just halting tumors rather than delaying the aging process in
general.
The three teams were sponsored by the National Institute of Aging as part of
a program to test possible anti-aging drugs much more rigorously.
�One of the nasty secrets of the field is that most mouse longevity
experiments are done only once in one lab on one genetic background,� said
Steven Austad, an expert on aging at the University of Texas Health Science
Center, who was not involved in the research.
The National Institute of Aging program includes a test of two doses of
resveratrol, the ingredient of red wine that is thought to mimic the effects
of caloric restriction on longevity. The results have not been published,
but Christoph Westphal, chief executive of Sirtris, a company exploring the
health effects of resveratrol and similar chemicals, said the tests �are
seeing quite modest effects of resveratrol.�
The effectiveness of rapamycin in extending the life of elderly mice was
discovered by accident. The researchers found that the mice fed rapamycin
were not getting the proper dose in their bloodstream. They reformulated the
drug in the form of capsules that fed slow doses to the intestine, but by
that time the mice were elderly. Nonetheless, life span increased by 14
percent in the females and 9 percent in the males.
�It�s no longer irresponsible to say that following these up could lead to
medicines that increase human life span by 10, 20 or 30 percent,� Dr. Miller
said.
It will be at least 10 years before matters are sorted out, he said, but, as
of right now, �I don�t think there�s any evidence for people that there�s
any drug that can slow aging down.�
An earlier version of this article gave an incorrect middle initial for
Richard Miller.
A version of this article appeared in print on July 9, 2009, on page A20
of the New York edition.
Dave Saum
JULY 9, 2009
Two Mammals' Longevity Boosted
Transplant Drug Lengthens Lives of Mice, and Fewer Calories Benefit Monkeys
By KEITH J. WINSTEIN
A study published Wednesday found that rapamycin, a drug used in organ
transplants, increased the life span of mice by 9% to 14%, the first
definitive case in which a chemical has been shown to extend the life span
of normal mammals.
Anti-aging researchers also expect a second study, to be released this week,
will show that sharply cutting the calorie intake of monkeys extends their
lives substantially. The experiment is said to be the first technique shown
to retard aging in primates.
Rhesus monkeys, 27-year-old Canto, left, and Owen, 29, are among the oldest
surviving subjects in a study of the links between diet and aging.
The prospect of a reliable human longevity pill is still distant. A
commentary released with the rapamycin study strongly cautioned against
taking the drug to prolong life because of potentially deadly side effects.
Rapamycin suppresses the immune system and carries strong warnings about the
resulting risk of infections and death.
But the mouse and monkey findings appear to mark the most substantial
scientific progress yet in the search for ways to extend human life spans --
once viewed as a fringe area of study.
"It's time to break out of our denial about aging," said Aubrey de Grey, a
British gerontologist who has drawn controversy for his suggestions on how
to forestall death. "Aging is, unequivocally, the major cause of death in
the industrialized world and a perfectly legitimate target of medical
intervention."
The studies boost the notion that restricting metabolic activity -- whether
through a drug or calorie restriction, which involves sharply reducing food
intake -- lengthens life span.
"It's all consistent with what human practitioners of calorie restriction
have always believed," said Brian Delaney, president of the North
Carolina-based Calorie Restriction Society, which claims 3,000 members. "Any
degree of restriction beyond what you're currently eating will confer health
benefits and will slow the aging process." Many of the society's members
restrict their eating to a level not much above starvation levels in the
hope of living longer.
The monkey study, which will be published in Science magazine, will report
on about 40 rhesus monkeys at a University of Wisconsin lab who have been
calorie-restricted for 20 years. Several longevity researchers who have seen
pre-released copies of the study described its findings.
The mouse study, published in the journal Nature, is part of a systematic
search by the federal government's National Institute on Aging, and was
conducted by biologists and university researchers in Maine, Michigan and
Texas. The study group has so far tried seven different chemicals, including
aspirin and the cardiovascular drug enalapril, generally with middling
results.
But rapamycin, a fungus-fighting bacterial secretion originally discovered
in the soil of Easter Island, showed a marked effect. The compound is
branded by drug maker Wyeth as Rapamune and is used to suppress the immune
system and ward off rejection after organ transplants and in heart stents.
A Wyeth spokesman called it an "interesting preclinical study" and said
Wyeth just became aware of the finding Wednesday.
Mice given rapamycin -- starting when they were 600 days old, or roughly the
equivalent of 60 human years -- lived longer on average than mice who didn't
get the drug. Their "maximal life span" -- meaning the age at which 10% of
the mice were still alive -- increased to 1,245 days for females, compared
with 1,094 days for those not fed the drug, or a 14% increase. For males,
the maximal life span was 1,179 days, a 9% increase over the 1,078 days for
those not fed the drug.
"This is really extreme," said David Harrison, who led the group studying
the drug at Maine's Jackson Laboratory, in Bar Harbor. "No other
intervention that I know of has been effective starting so late in life."
Several researchers, and the editorial in Nature, cautioned people about
taking rapamycin, which is available only by prescription. The drug carries
a so-called black box warning about side effects.
Three years ago, when a Harvard University team reported that resveratrol, a
compound found in red wine, increased the life spans of obese mice, it
touched off a wave of consumer use of the drug. But the team's follow-up
findings in regular mice showed no significant longevity gains -- even with
a massive dose of the over-the-counter drug.
The Wisconsin study, which began in 1989 with 30 monkeys and added 46 more
in 1994, is an effort to test calorie restriction in an animal genetically
closer to humans. Researchers have known since the 1930s that eating 30%
fewer calories than normal lengthens the life span of mice. Half the monkeys
were given a normal diet, and half had their food intake cut back by 30% at
roughly age 10.
The Calorie Restriction Society's Mr. Delaney, who has seen the results,
said that after 20 years, only 20% of the calorie-restricted monkeys had
died, compared with half of the monkeys on a normal diet. He said calorie
restriction seemed to slow down the loss of nerve cells in the brain.
Write to Keith J. Winstein at keith.w...@wsj.com