# End-of-life pathology in UM-HET3 mice treated with 16 α‑hydroxyestradiol or late‑start canagliflozin

## TL;DR

This study examines how two drugs affect lifespan differently in male and female mice, finding complex but unexplained sex-specific effects.

## Contribution

The study reveals sex-specific responses to drugs in mice lifespan extension, with complex but non-obvious histopathological patterns.

## Key findings

- 16 α-hydroxyestradiol and late-start canagliflozin increased male mouse lifespan but decreased female lifespan.
- Histopathological analysis showed complex, sex-specific lesion changes but no clear cause for sex differences.
- Female-specific negative effects may involve non-histopathological toxicities.

## Abstract

Canagliflozin (Cana) started  at 16 months of age and 16-hydroxy-estradiol (OH_Est) started at 12 months each led to significant increases in lifespan in male UM-HET3 mice but significant decreases in female lifespan. To seek insights into the basis for these sex-specific effects, we performed end-of-life histopathological analyses of control and treated mice for all three interventions testing program sites. There were no significant drug-induced alterations in inferred cause of death, although statistical power was low for such comparisons. Tabulation of incidental lesions (i.e., combining lethal and non-lethal lesions) revealed a complex set of significant and near-significant changes caused by each of the two agents, in some cases absent, or even opposite in direction, in one of the two sexes. The analysis did not, however, reveal a clear pattern that would explain the selective sex-specific effects of either agent on lifespan. It is plausible that the female-specific harm induced by each of these agents could reflect harmful or toxic effects that are not easily detectable by histopathological examination.

The online version contains supplementary material available at 10.1007/s11357-025-01741-3.