Metformin supplementation and life span in Fischer-344 rats

Abstract

Calorie restriction (CR) has been known for more than 70 years to extend life span and delay disease in rodent models. Metformin administration in rodent disease models has been shown to delay cancer incidence and progression, reduce cardiovascular disease and extend life span. To more directly test the potential of metformin supplementation (300 mg/kg/day) as a CR mimetic, life-span studies were performed in Fischer-344 rats and compared with ad libitum feeding and CR (30%). The CR group had significantly reduced food intake and body weight throughout the study. Body weight was significantly reduced in the metformin group compared with control during the middle of the study, despite similar weekly food intake. Although CR significantly extended early life span (25th quantile), metformin supplementation did not significantly increase life span at any quantile (25th, 50th, 75th, or 90th), overall or maximum life span (p > .05) compared with control.

Figures

Figure 1.

Food intake and body weight. (A) Food intake (mean ± SD in grams/rat/week) for CON, CR, MET, and PF–MET groups recorded every 3–4 weeks following group randomization. (B) Body weight (mean ± SD in grams/rat) for CON, CR, MET, and PF–MET groups every 4 weeks following group randomization. Note: CON = control; CR = calorie restriction; MET = metformin; PF–MET = pair fed to metformin.

Figure 2.

Glucose and insulin response. (A) Glucose levels (milligrams per deciliter) obtained at 06:00 hours during the indicated week (age 27, 39, 52, and 65 weeks) for CON, CR, MET, and PF–MET (mean ± SD for all surviving rats). (B) Insulin levels (nanograms per milliliter) obtained at 06:00 hours during the indicated week (age 27, 39, 52, and 65 weeks; mean ± SD for 12 rats per study group). *p < .05. Note: CON = control; CR = calorie restriction; MET = metformin; PF–MET = pair fed to metformin.

Figure 3.

Core body temperature (mean ± SD) at age 27, 39, 52, and 65 weeks (at 06:00 hours).

Figure 4.

Kaplan–Meier survival plots for CON, CR, MET, and PF–MET (CON: n = 31; CR: n = 40; MET; n = 40; and PF–MET: n = 40). Note: CON = control; CR = calorie restriction; MET = metformin; PF–MET = pair fed to metformin.