17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice
Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimer disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17-alpha-estradiol (17aE2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17aE2 healthspan benefits were modulated…
Research examining the impact of the hormone 17α-estradiol (17aE2) on aging phenotypes associated with the APOE4 gene variation in middle-aged female mice has revealed limited protective benefits. The NIA Interventions Testing Program previously identified 17aE2 as a compound that extends healthspan and lifespan, with more pronounced effects observed in male mice.
The study reveals that while APOE4 females exhibit more robust systemic aging-related phenotypes like increased adiposity, impaired glucose tolerance, and reduced energy expenditure, 17aE2 treatment yields modest improvements only in these females, including decreased adiposity, increased lean mass, enhanced glucose tolerance, and improved energy expenditure.
However, no significant benefits were observed in the central nervous system, as APOE4 females performed worse in cognitive tests and had higher levels of the Alzheimer's-related peptide soluble beta-amyloid. The findings emphasize the role of biological sex in determining the protective effects of longevity-promoting interventions against APOE4-associated conditions such as metabolic dysfunction, cognitive impairment, and vulnerability to Alzheimer's disease.
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