Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice

Abstract

Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90 th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in 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.

17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

“…Lifespan studies of the ITP demonstrate that, when following precise standards, mouse lifespan can be reproducibly extended by drugs in the diet (Harrison et al, 2009, 2014, 2019; Miller et al, 2011, 2014; Miller, Harrison, et al, 2020; Strong et al, 2008, 2016). Positive results are important, as showing here that 17aE2 is beneficial when started later in life.…”

“…The 2015 cohort of UM‐HET3 mice was also used to test the effects of canagliflozin, an inhibitor of SGLT2 (Miller, Harrison, et al, 2020).…”

“…Nine separate batches of diet pellets were tested with an average of 73% of expected amounts of GGA (range: 16%-123%). The 2015 cohort of UM-HET3 mice was also used to test the effects of canagliflozin, an inhibitor of SGLT2 (Miller, Harrison, et al, 2020).…”

Sodium‐glucose cotransporter‐2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body‐induced NRF2 activation

“…Moreover, SGLT2 inhibition leads to a negative energy balance due to its glycosuric effect, and therefore, SGLT2 inhibitors are potential calorie restriction mimetics 11 . Either calorie restriction or canagliflozin, an SGLT2 inhibitor, increased the life span and delayed the onset of age‐related disorders 12 . Intriguingly, both SGLT2 inhibitor and calorie restriction increase the plasma concentrations of ketone bodies, 13 which may share common mechanisms to relieve age‐related disorders.…”

“…11 Either calorie restriction or canagliflozin, an SGLT2 inhibitor, increased the life span and delayed the onset of age-related disorders. 12 Intriguingly, both SGLT2 inhibitor and calorie restriction increase the plasma concentrations of ketone bodies, 13 which may share common mechanisms to relieve agerelated disorders.…”