Rapamycin: Extends Life in Mice, But Of Any Youth to Humans?
What's Hot in Biology, September/October 2010
By Dr. Jeremy Cherfas
Wired magazine and the journal Science both picked it as one of the top breakthroughs of 2009, and now Science Watch can confirm that the discovery that an antibiotic can prolong the life of laboratory mice is indeed a very hot topic. David Harrison of The Jackson Laboratory in Maine and a team of collaborators reported in Nature in July 2009 that rapamycin fed to mice increased their lifespan. More remarkable yet, the rapamycin regime did not start until the mice were already 600 days old, "roughly the equivalent of a 60-year-old person," according to the team, whose paper is at #3 in the Hot Topics list.
This is the first positive result to emerge from the National Institute on Aging Interventions Testing Program, which is examining the effect of a variety of substances on longevity in mice. Each compound is tested on a cohort of genetically heterogeneous mice at three independent laboratories: Harrison’s at Bar Harbor, Richard A. Miller’s at the University of Michigan, and Randy Strong’s at the University of Texas Health Science Center at San Antonio.
David E. Harrison
from the
Jackson Labratory.
There are various ways of measuring the effect on longevity, and while not all measures are equal at each site, overall the results are positive and impressive. Mean lifespan pooled over the three sites increased 13% for females and 9% for males. In terms of life expectancy at 600 days, the increase was 28% for males and 38% for females, and there was an associated increase in the maximum lifespan. The team undertook full autopsies on a sample of mice from each group; no differences were found, so although rapamycin delays death, it does not appear to affect the pattern of diseases associated with eventual death.
That said, rapamycin does seem to reduce the incidence of cancers, and is used as a therapeutic in some human tumors. It also seems to retard aging more generally, but a lot more work will be needed before researchers can say whether rapamycin works by delaying death from cancer or through more general effects on the mechanisms of aging—or both.
The decision to start feeding rapamycin when the mice were effectively already in late middle age was a happy accident. According to a related feature in the Nature issue containing paper #3, the original chow formulation did not maintain a sufficiently high level of rapamycin. It took more than a year to develop a formula in which the rapamycin was encapsulated, for timed release in the intestine. At that point the feeding regime started, with the remarkable results outlined above (M. Kaeberlein, B.K. Kennedy, Nature, 460[7253]: 331-2, 2009). A second cohort of mice started receiving rapamycin at nine months; an interim analysis indicated that these animals too are surviving longer than controls.
Sirolimus, also known as rapamycin, is an
immunosuppressant drug used to prevent rejection in organ
transplantation.
Image from the
Wikimedia Commons.
What is going on? Why rapamycin? In yeast, nematode worms, and Drosophila flies, defects in a cellular receptor called TOR are associated with increased longevity. TOR—which stands for "target of rapamycin"—promotes the translation of mRNA into proteins and is linked to cell growth and cell cycling, mitochondrial metabolism, and insulin-like signalling. With evidence of its importance in invertebrate aging, rapamycin was a natural early candidate for the Interventions Testing Program to examine.
There are also intriguing links between TOR and calorie restriction, which also promotes longevity in experimental conditions. In essence, TOR seems to be essential to balance the energy available, from the diet, and the energy needs of the growing cells. Harrison and his team point out that unlike calorie restriction, rapamycin does not result in weight loss, and calorie restriction that starts after 550 days seldom produces any increase in the longevity of mice.
Nevertheless, rapamycin may turn out to be a true dietary-restriction mimetic—a molecule that mimics the more general effects of calorie restriction. Rapamycin seems to reduce the prevalence of cancers in older mice, and so does dietary restriction. A lot more research is clearly needed to work out exactly how rapamycin extends longevity, from the level of cell-signalling mechanisms to changes in the nature and succession of age-related organ failures that normally bring death.
Are we, then, on the threshold of an immortality pill? Almost certainly not, although there may be other inhibitors of TOR waiting to be discovered. Rapamycin is known to inhibit the immune system, and is used to prevent the rejection of transplants, which currently makes it a liability. And one online commentator involved in aging research has pointed out what he calls "a cruel irony." Rapamycin "inhibits the formation, consolidation, and preservation of long-term memory." Of course, to do that it has to cross the blood-brain barrier. The Harrison et al. study did not investigate this, but the possibility remains. Would it be worth living another score of years at the cost of slowly forgetting the long preceding life?
Dr. Jeremy Cherfas is Science Writer at Bioversity International in Rome, Italy.
What's Hot in Biology | |||
---|---|---|---|
Rank | Paper |
Cites This Period Mar-Apr 10 |
Rank Last Period Jan-Feb 10 |
1 | J.C. Barrett, et al., "Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease," Nature Genetics, 40(8): 955-62, August 2008. [31 institutions worldwide] *331QF | 46 | 8 |
2 | D. Baek, et al., "The impact of microRNAs on protein output," Nature, 455(7209): 64-71, 4 September 2008. [Whitehead Inst., Cambridge, MA; Howard Hughes Med. Inst., MIT, Cambridge; Harvard Med. Sch., Boston, MA] *343XS | 40 | 1 |
3 | D.E. Harrison, et al, "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice," Nature, 460(7253): 392-5, 16 July 2009. [7 U.S. institutions] *470MO | 37 | † |
4 | E. Zeggini, et al., "Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes," Nature Genetics, 40(5): 638-45, May 2008. [5 U.S. and U.K. institutions] *293WS | 36 | 4 |
5 | A. Mortazavi, et al., "Mapping and quantifying mammalian transcriptomes by RNA-Seq," Nature Methods, 5(7): 621-8, July 2008. [Caltech, Pasadena] *319MC | 36 | † |
6 | V. Hornung, et al., "Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization," Nature Immunology, 9(8): 847-56, August 2008. [U. Massachusetts, Worcester; Ludwig-Maximilian U. Munich, Germany; Norwegian U. Sci. & Tech., Trondheim] *328EN | 35 | † |
7 | G.J.D. Smith, et al., "Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic," Nature, 459(7250): 1122-5, 25 June 2009. [U. Hong Kong, China; U. Edinburgh, U.K.; U. Arizona, Tucson] *466BX | 35 | † |
8 | T. Walsh, et al., "Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia," Science, 320(5875): 539-43, 25 April 2008. [9 U.S. institutions] *292EM | 34 | † |
9 | J.B. Kim, et al., "Oct4-induced pluripotency in adult neural stem cells," Cell, 136(3): 411-9, 6 February 2009. [6 German and U.S. institutions] *403ZN | 33 | † |
10 | M. Selbach, et al., "Widespread changes in protein synthesis induced by microRNAs," Nature, 455(7209): 58-63, 4 September 2008. [Max Delbruck Ctr. Molec. Med., Berlin, Germany; U. Glasgow, U.K.] *343XS | 31 | 3 |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |
KEYWORDS: Rapamycin, aging, extended lifespan, David Harrison, Richard A. Miller, Randy Strong, National Institute on Aging, NIA, Interventions Testing Program.