Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

Abstract

SummaryLongevity in mammals is influenced by sex, and lifespan extension in response to anti‐aging interventions is often sex‐specific, although the mechanisms underlying these sexual dimorphisms are largely unknown. Treatment of mice with 17‐α estradiol (17aE2) results in sex‐specific lifespan extension, with an increase in median survival in males of 19% and no survival effect in females. Given the links between lifespan extension and metabolism, we performed untargeted metabolomics analysis of liver, skeletal muscle and plasma from male and female mice treated with 17aE2 for eight months. We find that 17aE2 generates distinct sex‐specific changes in the metabolomic profile of liver and plasma. In males, 17aE2 treatment raised the abundance of several amino acids in the liver, and this was further associated with elevations in metabolites involved in urea cycling, suggesting altered amino acid metabolism. In females, amino acids and urea cycling metabolites were unaffected by 17aE2. 17aE2 also results in male‐specific elevations in a second estrogenic steroid—estriol‐3‐sulfate—suggesting different metabolism of this drug in males and females. To understand the underlying endocrine causes for these sexual dimorphisms, we castrated males and ovariectomized females prior to 17aE2 treatment, and found that virtually all the male‐specific metabolite responses to 17aE2 are inhibited or reduced by male castration. These results suggest novel metabolic pathways linked to male‐specific lifespan extension and show that the male‐specific metabolomic response to 17aE2 depends on the production of testicular hormones in adult life.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…Notably, arachidonic acid (AA, 20:4n6) and docosahexaenoic acid (DHA, 22:6n3), both of which are precursors for eicosanoid, resolvin, and protectin production [47,48], were found to be increased by 17α-E2 treatment in WT mice (Supplementary Figure 4). Our findings are aligned with a previous report by Garratt et al showing that 17α-E2 increases AA and DHA in liver [26]. None of the 17α-E2-mediated changes in fatty acid profiles were observed in ERα KO mice receiving 17α-E2.…”

“…We also performed similar analyses in female WT and ERα KO mice and determined that 17α-E2 failed to elicit improvements in mass, adiposity, calorie consumption, or metabolic parameters in either genotype (Supplementary Figure 2). This further supports previous data suggesting 17α-E2 improves health parameters in a sexually divergent manner [25,26]. Several studies have implicated ERα in the regulation of systemic metabolic parameters [42].…”

“…We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23][24]. Other groups have also determined that lifelong administration of 17α-E2 beneficially modulates metabolic outcomes, including glucose tolerance, mTORC2 signaling, and hepatic amino acid composition and markers of urea cycling, which were reported to be dependent upon the presence of endogenous androgens [25,26].…”

“…We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23][24]. Other groups have also determined that lifelong administration of 17α-E2 beneficially modulates metabolic outcomes, including glucose tolerance, mTORC2 signaling, and hepatic amino acid composition and markers of urea cycling, which were reported to be dependent upon the presence of endogenous androgens [25,26].Additionally, multiple lifespan extending compounds, including 17α-E2, exhibit similar modifications in liver function [27]. In all, recent studies by several independent laboratories strongly indicate that the lifespanextending effects of 17α-E2 are at least associated with, if not dependent on, metabolic improvements.Despite the mounting evidence demonstrating that 17α-E2 improves numerous health parameters, the signaling mechanism(s) and primary tissues through which 17α-E2 elicits these benefits remain unknown.Although 17α-E2 is a naturally-occurring enantiomer to 17β-estradiol (17β-E2), it has been postulated that 17α-E2 signals through a novel uncharacterized receptor [28][29][30][31] as opposed to classical estrogen receptors alpha (ERα) and beta (ERβ); which is due to 17α-E2 having significantly reduced binding affinity to ERα and ERβ as compared to 17β-E2 [32][33][34][35].…”

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

“…These hormonally-dependent sexspecific effects of 17aE2 for males suggest a potential mechanism of 17aE2 action that requires male-gonadal hormone production. These effects could still involve the estrogen signaling pathway, and possible interaction with the estrogen receptor (ER), but could be linked to steroid metabolism, particularly since 17aE2 leads to a male-specific increase in other estrogen steroids in the liver, particularly sulfated forms of estradiol (Garratt et al 2018). 17aE2 and estradiol both have the capacity to bind to ER, but with lower affinity than 17βE2 (Harrison et al 2014).…”