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Canagliflozin extends life span in genetically heterogeneous male but not female mice
Richard A Miller1, David E Harrison2, David B Allison3
1Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan, USA.
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.
Insights
Canagliflozin (Cana), a diabetes drug, extended median survival in male mice by 14% by inhibiting glucose reuptake. This suggests controlling peak glucose levels may offer longevity benefits against age-related diseases.
Area of Science:
- Gerontology
- Pharmacology
- Metabolic Diseases
Background:
- Canagliflozin is an FDA-approved medication for type 2 diabetes.
- It functions by inhibiting the sodium-glucose cotransporter 2 (SGLT2).
- SGLT2 inhibition blocks renal glucose reabsorption and intestinal glucose absorption.
Purpose of the Study:
- To investigate the effects of canagliflozin on lifespan and healthspan in genetically heterogeneous mice.
- To explore the potential of glucose-lowering interventions for promoting longevity.
Main Methods:
- Genetically heterogeneous mice were administered canagliflozin (180 ppm) in their chow from 7 months of age until death.
- Lifespan, survival curves, and age-related pathologies were assessed.
- Metabolic parameters including fasting glucose, glucose tolerance, and body composition were measured.
Main Results:
- Canagliflozin significantly extended median survival in male mice by 14% and increased 90th percentile survival by 9%.
- No significant lifespan benefits were observed in female mice.
- Canagliflozin reduced fasting glucose and improved glucose tolerance in both sexes, and decreased fat mass in females.
Conclusions:
- The lifespan extension in male mice suggests that blunting peak glucose levels may be a mechanism for longevity.
- Canagliflozin's effects on glucose metabolism warrant further investigation as a potential preventive strategy for age-related diseases.
- Interventions targeting daily peak glucose levels may hold promise for promoting healthspan and preventing late-life diseases.
