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Dose and sex-specificity in Canagliflozin-mediated neuroprotection in aging mice
Abstract:
Canagliflozin (Cana), an SGLT2 inhibitor prescribed for type 2 diabetes, extends median lifespan by 14% in male but not female UM-HET3 mice at 180 ppm, with male-specific neuroprotective effects, despite females accumulating higher drug concentrations in blood and brain. Here, we tested whether reducing the dose to a subclinical level of 60 ppm could provide neuroprotective benefits in females by reducing drug accumulation. Starting treatment at 7 months of age, Cana at 60 ppm improved glucose tolerance in both sexes at 18 months and increased water and food intake, consistent with SGLT2 inhibition, but produced only a transient reduction in fat mass in males after one month on diet, with no sustained effect on body weight in either sex. At 60 ppm, Cana did not improve cognitive function at 18 months or reduce neuroinflammation in males, whereas females showed reduced hippocampal microgliosis and astrogliosis at 24 months. Pharmacokinetic analysis demonstrated that females accumulated 3-to 5-fold higher Cana concentrations than males across brain regions, blood, and liver. Together, these findings demonstrate that neither dose reduction nor greater drug accumulation drives neuroprotective benefit in females, indicating fundamental sex differences in the biological response to SGLT2 inhibition and suggesting that the sex-specific longevity effects of Cana are not simply a matter of dose.
Insights
Lowering the dose of canagliflozin (Cana) did not confer neuroprotection in female mice. Despite higher drug accumulation, females showed reduced neuroinflammation, indicating sex-specific responses to SGLT2 inhibition.
Area of Science:
- Gerontology
- Neuroscience
- Pharmacology
Background:
- Canagliflozin (Cana), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, extends lifespan in male mice but not females.
- Sex-specific neuroprotective effects of Cana have been observed, with females accumulating higher drug concentrations.
Purpose of the Study:
- To investigate if reducing Cana dosage to a subclinical level (60 ppm) could induce neuroprotection in female mice by mitigating drug accumulation.
- To explore sex differences in response to SGLT2 inhibition at a lower dose.
Main Methods:
- UM-HET3 mice were treated with Cana (60 ppm) starting at 7 months of age.
- Physiological parameters (glucose tolerance, food/water intake, fat mass, body weight) and cognitive function were assessed.
- Neuroinflammation markers (microgliosis, astrogliosis) and drug concentrations in blood, brain, and liver were analyzed.
Main Results:
- Cana (60 ppm) improved glucose tolerance and increased water/food intake in both sexes but only transiently reduced fat mass in males.
- No cognitive improvements or reduced neuroinflammation were observed in males at 60 ppm.
- Females exhibited reduced hippocampal microgliosis and astrogliosis at 24 months.
- Females accumulated 3-to 5-fold higher Cana concentrations in brain, blood, and liver compared to males.
Conclusions:
- Dose reduction or increased drug accumulation does not drive neuroprotective benefits in female mice.
- Significant sex differences exist in the biological response to SGLT2 inhibition.
- The sex-specific longevity effects of Cana are not solely determined by dosage or drug accumulation levels.