Rapamycin extends murine lifespan but has limited effects on aging
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
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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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 4

Rapamycin did not improve age-related reductions in grip strength and cross-sectional muscle fiber area.

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Rapamycin did not improve age-related reductions in grip strength and cr...
(A–F) Aging-related decline in muscle strength was assessed using 2-paw (A, C, and E) and 4-paw (B, D, and F) grip strength tests in the 16-month (A and B; young control, n = 10; vehicle, n = 18; rapamycin, n = 20), 25-month (C and D; young control, n = 10; vehicle, n = 11; rapamycin, n = 16), and 34-month (E and F; young control, n = 10; vehicle, n = 9; rapamycin, n = 14) cohorts. (G and H) Muscle fibers were automatically identified on H&E-stained sections of quadriceps femoris muscle of the 16-month (G; young control, n = 786 muscle fibers from 5 mice; vehicle, n = 534 muscle fibers from 6 mice; rapamycin, n = 600 muscle fibers from 8 mice) and 25-month (H; young control, n = 330 muscle fibers from 6 mice; vehicle, n = 741 muscle fibers from 4 mice; rapamycin, n = 1,371 muscle fibers from 5 mice) cohorts using image segmentation and analysis software. Shown are examples of histological images and classification maps (generated via automated segmentation of histological images) along with quantification of cross-sectional muscle fiber area. Scale bar: 400 μm. Whisker plots display 25th percentile, median, and 75th percentile as well as minimum-to-maximum (A–F) or 10th to 90th percentile (G and H). P values and fit coefficients with 95% confidence intervals are shown; statistically significant differences (P < 0.05) are denoted by bold font.