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Background <p>The apolipoprotein ε4 allele (<i>APOE4</i>) is associated with decreased longevity and 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 of <i>APOE4</i>-associated aging phenotypes. Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in <i>APOE4</i> versus the predominant <i>APOE3</i> genotype using early middle-aged mice with knock-in of human <i>APOE</i> alleles.</p> Methods <p>Beginning at age 10 months, male <i>APOE3</i> or <i>APOE4</i> mice were treated for 20 weeks with 17αE2 or vehicle then compared body-wide for indices of middle-aged phenotypes.</p> Results <p>Across peripheral and neural measures, <i>APOE4</i> associates with poorer outcomes. Notably, 17αE2 treatment generally improves outcomes in a genotype-dependent manner, favoring <i>APOE4</i> mice, including reductions in body weight, plasma leptin, hepatic steatosis, learning and memory, and oxidative damage in the brain. Plasma lipidomics and microglial transcriptomics show reductions in genotype-specific differences with 17αE2 treatment.</p> Conclusions <p>These findings demonstrate that <i>APOE4</i> promotes systemic and neural aging phenotypes linked to AD and that 17αE2-mediated healthspan actions show a positive <i>APOE4</i> bias. Collectively, the findings suggest that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with the <i>APOE4</i> genotype.</p>

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Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Cassandra J. McGill,
  • Amy Christensen,
  • Wenjie Qian,
  • Max A. Thorwald,
  • Jose Godoy Lugo,
  • Sara Namvari,
  • Olivia S. White,
  • Caleb E. Finch,
  • Bérénice A. Benayoun,
  • Christian J. Pike

摘要

Background

The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and 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 of APOE4-associated aging phenotypes. Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles.

Methods

Beginning at age 10 months, male APOE3 or APOE4 mice were treated for 20 weeks with 17αE2 or vehicle then compared body-wide for indices of middle-aged phenotypes.

Results

Across peripheral and neural measures, APOE4 associates with poorer outcomes. Notably, 17αE2 treatment generally improves outcomes in a genotype-dependent manner, favoring APOE4 mice, including reductions in body weight, plasma leptin, hepatic steatosis, learning and memory, and oxidative damage in the brain. Plasma lipidomics and microglial transcriptomics show reductions in genotype-specific differences with 17αE2 treatment.

Conclusions

These findings demonstrate that APOE4 promotes systemic and neural aging phenotypes linked to AD and that 17αE2-mediated healthspan actions show a positive APOE4 bias. Collectively, the findings suggest that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with the APOE4 genotype.