Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice

Abstract

Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.

Figure 1.

Survival curves comparing control to rapamycin-treated mice, pooled across sites. The p values reflect outcome of stratified log-rank test. The arrows at 270 days indicate the age at which rapamycin treatment was initiated.

Figure 2.

Survival curves for control and rapamycin-treated mice, each site plotted individually. The p values reflect outcome of log-rank tests. The arrows at 270 days indicate the age at which rapamycin treatment was initiated.

Figure 3.

Raw (left) and smoothed (right) plots of the logarithm of the mortality risk for control and rapamycin-treated mice as a function of age. Data have been pooled across gender and test site. Dashed diagonal lines on the right panel indicate fits to the Gompertz model. Arrows at 39 weeks indicate start of rapamycin exposure.

Figure 4.

Comparison of survival for rapamycin administered from 9 or from 20 months of age in separate yearly cohorts, pooled across sites. See text for discussion of statistical significance tests. Data for the mice exposed to rapamycin from 20 months of age are from Harrison and colleagues (2).

Figure 5.

Body weight values for control mice and for mice exposed to rapamycin from 9 months of age. The p values reflect t tests, pooling across sites, for the hypothesis that rapamycin has no effect on body weight.

Figure 6.

Survival curves for mice exposed to simvastatin from 10 months of age (top), or to resveratrol from 12 months (bottom). Data are pooled across sites. Males are shown in the left panels, and females in the right panels. Each curve shows results for both high and low doses. The p values reflect log-rank tests, stratified by test site. None of the agents had a significant effect on life span, compared with control mice, at any dose tested. The arrows indicate the age at which the drug treatment was initiated.

Figure 7.

Age effects on total activity in male mice, comparing control to rapamycin-treated mice. The y-axis shows change score, calculated as (activity at 18 months) minus (activity at 7 months in the same mouse). A negative score indicates that the mouse was less active at 18 than at 7 months. (For comparison, the number of beam breaks at 7 months of age for males was approximately 45,000 at The Jackson Laboratory [TJL], 75,000 at University of Michigan [UM], and 71,000 at University of Texas [UT].) The bars show mean and SEM for the change scores. Number of mice tested: 35, 43, and 43 controls and 19, 19, 24 rapamycin-treated mice at TJL, UM, UT, respectively. Asterisks indicate a significant difference between control and rapamycin males at p = .004 at UM and p = .04 at UT.