Rapamycin extends murine lifespan but has limited effects on aging
Frauke Neff, … , Martin Hrabe de Angelis, Dan Ehninger
Frauke Neff, … , Martin Hrabe de Angelis, Dan Ehninger
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3272-3291. https://doi.org/10.1172/JCI67674.
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Research Article

Rapamycin extends murine lifespan but has limited effects on aging

Abstract

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin’s effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin’s longevity effects from effects on aging itself.

Authors

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

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Figure 8

Rapamycin treatment had no significant effect on age-related changes in maximal O2 consumption and body temperature, but increased RER.

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Rapamycin treatment had no significant effect on age-related changes in ...
(A–C) Findings from a metabolic assessment (indirect calorimetry) of the 25-month cohort (young control, n = 10; vehicle, n = 10; rapamycin, n = 14). (A) Body temperature. (B) Maximal O2 consumption. (C) Average RER. Data were analyzed by fitting them with a linear model against the factors of age (young vs. old), treatment (rapamycin vs. vehicle), and body weight. (D) Effects of rapamycin on RER in young mice (control, n = 9; rapamycin, n = 8). Whisker plots display minimum, 25th percentile, median, 75th percentile, and maximum. P values and fit coefficients with 95% confidence intervals are shown; statistically significant differences (P < 0.05) are denoted by bold font. See Supplemental Tables 11 and 12 for complete findings.