Canagliflozin extends life span in genetically heterogeneous male but not female mice

Abstract

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.

Keywords: Aging; Drug therapy; Glucose metabolism; Mouse models.

Figure 1. Survival curves for Cana-treated and sex-matched mice.

(A and B) Data pooled across sites. (C–H) Site-specific results. Female mice are shown on the left, and male mice are shown on the right. P values show results of log-rank tests, not adjusted for multiple comparisons, with site as covariate for the pooled data sets (top row). There were no remaining live mice at the time of analysis. The number of mice in each group is included in the count column of Table 1.

Figure 2. Cana levels in plasma, brain, and kidney of 22-month-old mice exposed to Cana from 7 months of age.

Scatterplots show kidney levels of Cana (top) or brain levels (bottom) versus plasma levels. Each symbol refers to 1 mouse (5 female mice and 8 male mice were included).

Figure 3. Mean weights for Cana and control mice, ages 6–24 months.

Values are mean levels for live mice, separately for each sex, pooled across sites. Cana treatment was initiated at 7 months. *P < 0.0002 for drug effect at ages 12–24 for female mice and 12–18 for male mice. N declined with age from 151–116 for Cana-treated male mice and from 136–107 for Cana-treated female mice, with approximately 2-fold higher numbers of control mice.

Figure 4. Body composition and glucose homeostasis in Cana versus control mice.

Each symbol represents a different mouse, with mean ± SEM also shown. Mice were given Cana from 7 months of age, and tested when 20–22 months old. (A–F, I, and J) The body composition and glucose tolerance data were obtained using 8–11 mice of each sex for each group, and (G and H) the fasting glucose data were obtained from 6 mice of each sex for each group. The glucose tolerance test data show results for 5 male mice and 6 female mice in each treatment group. *P < 0.05, **P < 0.01, ****P < 0.0001.