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

Richard A Miller,David B Lombard,Daniel L Smith,Vivian Diaz,Hashan Jayarathne,Adam B Salmon,Marianna Sadagurski,Jessica M Snyder,Francesca Macchiarini,David B Allison,Navasuja Kumar,Martin A Javors,W Timothy Garvey,David E Harrison,Randy Strong,James F Nelson ,Lucas Kniess Debarba ,Andrzej T Gałecki ,Peter C Reifsnyder ,Elízabeth Fernández ,Nadia Rosenthal ,Warren Ladiges ,Molly A Bogue

doi:10.1172/jci.insight.140019

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.

Highlights

Aging is the dominant risk factor for most chronic diseases that afflict people in industrialized societies
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
Acarbose, 17aE2, and rapamycin can each produce significant life span extension even when started at ages 60%–70% of the median survival age of controls, i.e., 16–20 months of age [13, 14]

Summary

Introduction

Aging is the dominant risk factor for most chronic diseases that afflict people in industrialized societies. There is ample evidence, in mice, that the process of aging can be delayed or retarded by low-calorie diets [1,2,3,4,5], by natural or engineered mutations in any of several genes that modify growth hormone and IGF-1 signals [6, 7], and, more recently, by drugs added to food [8] Each of these approaches has been shown to extend life span and to delay multiple forms of late-life illness, including both neoplastic and degenerative diseases. These drugs may provide a starting point for development of antiaging interventions in humans

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Conclusion