Bacterial Product Extends Mouse Life Spans
August 7, 2009
Research results by a collaborative team led by Jackson Laboratory Professor David Harrison, Ph.D., are receiving worldwide attention. Professor Harrison and colleagues recently reported that rapamycin, originally discovered as a bacterial product found in soil and now a synthetically produced immunosuppressant and cancer treatment, significantly extends the life span of mice (Harrison et al. 2009).
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| According to Professor Harrison, rapamycin is by far the most successful of the seven different treatments tested in the first two years of the ITP. |
The Interventions Testing Program
The research conducted by the Harrison team was part of The National Institute on Aging’s Interventions Testing Program (ITP), a multi-institutional program that investigates treatments that may potentially extend life span and delay disease and dysfunction in mice. For a treatment to be considered in the program, there must be strong evidence that it retards aging. Treatments that are easily obtainable, reasonably priced, and can be delivered in the diet or water are preferred. Any university, institute, or organization wishing to test a treatment’s effect on mouse life span may participate.
Currently, approved projects are conducted simultaneously at three sites: the University of Michigan, Ann Arbor, The Jackson Laboratory, Bar Harbor, ME, and the University of Texas Health Sciences Center, San Antonio. Each ITP site purchases the following F1 hybrids: BALB/cByJ (001026) x C57BL/6J (000664) females, distributed as CB6F1/J (100007), and C3H/HeJ (000659) x DBA/2J (000671) males, distributed as C3D2F1/J (100004). These F1 mice are mated to produce hybrid individuals, each genetically unique and heterogeneous, to which approved treatments are applied.
Rapamycin’s Effects
Harrison and his team chose to investigate rapamycin’s anti-aging effects in mice because of its action on a kinase called mechanistic target of rapamycin (mTOR), the inhibition of which had been shown to increase the life span of yeasts, nematodes, and fruitflies.
In one experiment, the team fed a group of mice standard mouse chow until they were 600 days old and rapamycin-laced chow thereafter. Pooled data from all three sites indicated that rapamycin increased the maximum life span (the 90th survival percentile) of female mice by 14% (from 1,094 to 1,245 days) and of male mice by 9% (from 1,078 to 1,179 days). Rapamycin-fed mice and controls died of comparable causes. In another experiment (ongoing as of 7/21/09), mice were fed rapamycin-laced chow starting at 270 days old. At the time of analysis, pooled data from all three sites indicated that rapamycin also reduces mid-life mortality.
Rapamycin was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island (Vézina et al. 1975), also known as "Rapa Nui" (hence the name rapamycin). It was originally developed as an antifungal agent, until its potent immunosuppressive and antiproliferative properties were discovered. Since then, it has been widely used to prevent organ transplant rejection and to treat cancer.
Rapamycin is by far the most successful of the seven different treatments tested in the first two years of the ITP. According to Professor Harrison, his team’s findings are significant for at least three reasons:
- The mice in the experiment were quite genetically diverse, the progeny of crossing four different strains, making it unlikely that rapamycin extended their lives merely by postponing a few strain-specific diseases
- Rapamycin treatment worked in 600-day old mice (equivalent to about 60-year old humans), making it the most effective anti-aging intervention so late in life and in such a genetically diverse mammal population
- Rapamycin treatment targets a single enzyme in a well-defined biochemical pathway
Professor Harrison and his colleagues speculate that rapamycin extends the lives of invertebrates and mammals by disrupting the mTOR pathway’s functions, though the nature and extent of those disruptions will have to be the subject of future research. Among its numerous functions, mTOR up-regulates protein synthesis, inhibits a pathway that degrades cellular products in lysosomes (these two functions are implicated in invertebrate aging), and influences cell growth, the cell-cycle, mitochondrial metabolism, and insulin-like signaling. Thus, mTOR inhibitors have been shown to reduce cell proliferation, angiogenesis, and glucose uptake. MTOR signaling can be reduced by dietary restriction, long known to increase life spans in invertebrates and rodents. In particular, cancer inhibition is a hallmark of dietary restriction in rodents, and rapamycin analogues are already used to treat certain forms of cancer (Kaeberlein and Kennedy 2009).
So, should you be taking rapamycin to lengthen your life? The study’s authors don’t recommend it - not before a great deal more is known about rapamycin’s benefits and side effects, especially its immunosuppressive activities, and not before it has been properly tested in clinical trials. Until then, rapamycin will continue to have important roles in ameliorating organ transplant rejections and treating cancer.
References
Authors in bold are Jackson Laboratory scientists.
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 60:392-5.
Kaeberlein M, Kennedy BK. 2009. A midlife longevity drug? Nature 60:331-2.
Vézina C, Kudelski A, Sehgal SN. 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. J Antibiot 28: 721–6.
