Rapamycin slows aging in mice

Abstract

Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action.

Fig. 1

Incidence of liver degeneration (males only), myocardial nuclear atypia, endometrial hyperplasia (females only), and adrenal tumor in young, old, and rapamycin-treated mice. Group sizes were as follows: young, old, and Rapa-Low, 15 of each sex; Rapa-Mid 14 females and 12 males; Rapa-High, 13 females and nine males. Fisher's Exact Test was used to evaluate the significance of age effects (young vs. old untreated), to compare Rapa (all doses) vs. old (untreated), or to compare old untreated vs. Rapa-high as indicated in the figure panels. Cuzick's nonparametric test for trends (Cuzick, 1985) was used to evaluate significance of differences among the four groups of old mice at rapamycin doses (zero, low, mid, or high).

Fig. 2

Incidence of adrenal hyperplasia, adrenal telangectasia, ovarian cyst (females only), thyroid cold follicles, and lung tumor in young, old, and rapamycin-treated old mice (pooled across rapamycin doses). The bracket in each figure indicates a significant difference between young and untreated old mice by Fisher's Exact Test.

Fig. 3

Maximum tangent modulus (left) and hysteresis area (right) for tibialis anterior tendons. Bars show mean ± SEM for N = 6 young, 9 old, and 17–20 old rapamycin-treated mice. Young values differed from old at P = 0.002 for each endpoint by t-test. Old differed from rapamycin treatment group at P = 0.036 for maximum tangent modulus and at P < 0.001 for hysteresis area.

Fig. 4

Cataract severity in mice evaluated by slit lamp examination at 20 months of age. Each eye was scored on a scale of 0–3, and the mean value of the left and right eye was used as the index of severity for each mouse. Bars shown mean ± SEM for groups of 25–29 female mice or 17–30 male mice. Significance of the trend among four groups of 20-month-old mice (old, Rapa-low, Rapa-mid, and Rapa-high) was evaluated by the nonparametric method of Cuzick (Cuzick, 1985).

Fig. 5

Testicular degeneration in males. Group sizes as in Fig. 1, with statistical evaluation as in (Cuzick, 1985).

Fig. 6

Age-associated decline of spontaneous in-cage activity, calculated as a change score (× 10^–3) for each mouse tested at both 7 and 18 months of age. Bars show means ± SEM, and asterisks indicate significant effects of rapamycin treatment at P < 0.05, as estimated using a two-factor anova with Site (UT, UM, TJL) and Rx (rapamycin or untreated) as the predictor variables.

Fig. 7

Rapamycin levels in blood of mice tested at age 8–9 months after consumption of rapamycin for 5 months. Each symbol shows an individual mouse, and horizontal bars indicate means.