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. 2020 Nov;19(11):e13269.
doi: 10.1111/acel.13269. Epub 2020 Nov 4.

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects

Randy Strong  1   2 , Richard A Miller  3 , Molly Bogue  4 , Elizabeth Fernandez  1   2 , Martin A Javors  5 , Sergiy Libert  6 , Paul Anthony Marinez  1   2 , Michael P Murphy  7 , Nicolas Musi  8   9 , James F Nelson  10 , Michael Petrascheck  11   12 , Peter Reifsnyder  4 , Arlan Richardson  13   14 , Adam B Salmon  8   15 , Francesca Macchiarini  16 , David E Harrison  4
Affiliations

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects

Randy Strong et al. Aging Cell. 2020 Nov.

Abstract

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex.

Keywords: 17-DMAG; MitoQ; minocycline; rapamycin; survival; β-GPA.

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Conflict of interest statement

The University of Texas Health Science Center at San Antonio has applied for a patent, U.S. Patent Application No. 13/128,800, by inventors Zelton Dave Sharp and Randy Strong, for an encapsulated rapamycin formulation used in this paper. Under a licensing agreement between Emtora Biosciences (formerly Rapamycin Holdings, Inc.) and the University of Texas Health Science Center San Antonio, R. Strong, and Z.D. Sharp, the University is entitled to milestone payments and royalty on sales of microencapsulated rapamycin. The university has a plan for managing conflicts of interest under its “Policy and Procedures for Promoting Objectivity in Research by Managing, Reducing or Eliminating Conflicts of Interest.” Michael P. Murphy consults for Antipodean Pharmaceuticals Inc., which is developing MitoQ as a potential therapy and also holds patents in the use of MitoQ.

Figures

FIGURE 1
FIGURE 1
Kaplan–Meier survival plots for female and male mice exposed to different Rapa treatment schedules. Green circles: Rapa given from 22 months until death. Red squares: Rapa given from 20–21, 22–23, 24–25, etc., until death. Cyan diamonds: Rapa given for 3 months only, starting at 20 months. Data are pooled from all three test sites
FIGURE 2
FIGURE 2
Weight at 6–24 months of age for Control and Rapa‐treated mice, pooled across sites. Each symbol represents the mean of 295 male and 298 female control mice at 6 months, falling to 125 males and 210 females at 24 months. Corresponding values for each Rapa group are an average of 150 males and 135 females at 6 months, falling to an average of 81 males and 102 females at 24 months. SEM values ranged from 0.3 to 0.8 g. All groups of Rapa males differed from Controls at p < 0.014 at ages 12, 18, and 24 months (Tukey's post hoc test after ANOVA, stratified by site.) All Rapa females differed from Controls at p < 0.001 at 24 months only. The “Rapa 20–23” group of females also differed from Controls (p = 0.03) at 12 months
FIGURE 3
FIGURE 3
Kaplan–Meier survival plots for female and male mice treated with 17‐DMAG, Min, bGPA, or MitoQ
See this image and copyright information in PMC

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