The drug rapamycin is known to increase lifespan in mice. Whether rapamycin slows down aging, however, remains unclear. A team of researchers from the German Center for Neurodegenerative Diseases (DZNE) and the Helmholtz Zentrum München has now found that rapamycin extends lifespan -- but its impact on aging itself is limited. The life-extending effect seems to be related to rapamycin's suppression of tumors, which represent the main causes of death in these mouse strains.
The findings are reported in the current issue of the Journal of Clinical Investigation.
The body's repair mechanisms begin to fail with increasing age. As a result, signs of wear and tear appear and the risk for many diseases, including Alzheimer's disease, diabetes, cardiovascular disorders and cancer, increases. "Current efforts to develop therapies against age-related diseases target these disorders one by one," says Dr. Dan Ehninger, research group leader at the DZNE site in Bonn. "Influencing the aging process itself may be an alternative approach with the potential to yield broadly effective therapeutics against age-related diseases."
In this context, the substance rapamycin is noteworthy. Rapamycin is used in recipients of organ transplants, as it keeps the immune system in check and can consequently prevent rejection of the foreign tissue. In 2009, US scientists discovered another effect: Mice treated with rapamycin lived longer than their untreated counterparts. "Rapamycin was the first drug shown to extend maximal lifespan in a mammalian species. This study has created quite a stir," says Ehninger.
For Ehninger and his team, this finding motivated further studies: "We wanted to address if rapamycin slows down aging in mice or, alternatively, if it has an isolated effect on lifespan -- without broadly modulating aging."
Not a youth elixir
Together with scientists from the Helmholtz Zentrum München and other colleagues, Ehninger's group investigated if rapamycin influences aging in mice. The results are sobering: "Our results indicate that rapamycin extends lifespan, but it has only limited effects on the aging process itself," is Ehninger's summary of the findings. "Most aging traits were not affected by rapamycin treatment. Although we did observe positive effects on some aging traits, such as memory impairments and reduced red blood cell counts, our studies showed that similar drug effects are also seen in young mice, indicating that rapamycin did not influence these measures by slowing aging, but rather via other, aging-independent, mechanisms."
The researchers believe that such aging-independent drug effects also underlie rapamycin's effect on lifespan. "We assume that the lifespan of mice is extended because rapamycin inhibits tumor formation. This is a well-known rapamycin effect, which we were able to confirm. Cancer is the leading cause of death in the relevant mouse strains" says the specialist in molecular medicine. "Rapamycin, therefore, seems to have isolated effects on specific life-limiting pathology, but lacks broad effects on aging in mice."
A comprehensive assessment of aging
The research team assessed more than 150 traits, which typically change during the course of aging. These analyses included an assessment of vision, reflexes, cardiovascular function, learning and behavior, immune functions and the integrity of the arterial wall, to just name a few. "Aging is a complex process, which cannot be captured by assessing a single parameter. This is why we analysed a large number of structural and functional signs of aging," explains Ehninger. "The present study is one of the most comprehensive assessments of a putative anti-aging intervention."
The analysis comprised three different age cohorts, in which rapamycin treatment was either initiated in young adulthood, in midlife or late in life. "At the time, the US study showed that rapamycin extends lifespan irrespective of whether the treatment is given to young or aged animals," says the Bonn-based researcher. "We, therefore, chose a study design, in the context of which we also investigated rapamycin's effects on different age groups. This enabled us to examine whether the possible effects of rapamycin depend on the age at which treatment started."
The animals were genetically identical twin mice. All of the animals received rapamycin regularly over a period of approximately one year. For each age cohort there was also a control group, which did not take the substance.
Need for comprehensive analyses
"Generally speaking, our studies show that a number of different parameters have to be considered when assessing the efficacy of possible anti-aging interventions. The interpretation of the data depends heavily on the overall picture of findings. Lifespan measures alone are not a reliable indicator of anti-aging effects," emphasises Ehninger. "This makes the search for anti-aging medicines tedious, but it is also very promising, because such substances could open up new possibilities for medicine. However, this is still some way off."
- Frauke Neff, Diana Flores-Dominguez, Devon P. Ryan, Marion Horsch, Susanne Schröder, Thure Adler, Luciana Caminha Afonso, Juan Antonio Aguilar-Pimentel, Lore Becker, Lillian Garrett, Wolfgang Hans, Moritz M. Hettich, Richard Holtmeier, Sabine M. Hölter, Kristin Moreth, Cornelia Prehn, Oliver Puk, Ildikó Rácz, Birgit Rathkolb, Jan Rozman, Beatrix Naton, Rainer Ordemann, Jerzy Adamski, Johannes Beckers, Raffi Bekeredjian, Dirk H. Busch, Gerhard Ehninger, Jochen Graw, Heinz Höfler, Martin Klingenspor, Thomas Klopstock, Markus Ollert, Jörg Stypmann, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabe de Angelis, Dan Ehninger. Rapamycin extends murine lifespan but has limited effects on aging. Journal of Clinical Investigation, 2013; DOI: 10.1172/JCI67674
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