Protection againstAPOE4-associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice

Abstract

SummaryThe apolipoprotein ε4 allele (APOE4) is associated with decreased longevity, increased vulnerability to age-related declines, and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development ofAPOE4-associated aging phenotypes. Here we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against age-related impairments inAPOE4versus the predominantAPOE3genotype using early middle-aged mice with knock-in of humanAPOEalleles. Beginning at age 10 months, maleAPOE3orAPOE4mice were treated for 20 weeks with 17αE2 or vehicle then compared for indices of aging phenotypes body-wide. Across peripheral and neural measures,APOE4was associated with poorer outcomes. Notably, 17αE2 treatment improved outcomes in a genotype-dependent manner favoringAPOE4mice. These data demonstrate a positiveAPOE4bias in 17αE2-mediated healthspan actions, suggesting that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated withAPOE4genotype.