Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α
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Abstract
Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on August 18 2020, follows. The decision letter below relates to version 1 of the preprint.
Summary
This work has the potential to make an important original contribution to the aging biology literature and includes interesting new findings regarding the role of 17a-E2 in lifespan extension. The authors provide persuasive evidence of the role of classic estradiol receptor ERa in 17a-E2 signaling and mediating the metabolic effects of 17a-E2. However, far reaching and unsupported claims are made regarding the central tenets of this manuscript as is stated in their abstract: namely sex-specific differences and that of tissue specific mediation of 17a-E2 effects facilitating the therapeutic benefit. While the tissue specific data are …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on August 18 2020, follows. The decision letter below relates to version 1 of the preprint.
Summary
This work has the potential to make an important original contribution to the aging biology literature and includes interesting new findings regarding the role of 17a-E2 in lifespan extension. The authors provide persuasive evidence of the role of classic estradiol receptor ERa in 17a-E2 signaling and mediating the metabolic effects of 17a-E2. However, far reaching and unsupported claims are made regarding the central tenets of this manuscript as is stated in their abstract: namely sex-specific differences and that of tissue specific mediation of 17a-E2 effects facilitating the therapeutic benefit. While the tissue specific data are suggestive that the liver and hypothalamus facilitate the beneficial effects of 17a-E2, these data do not appear to have been appropriately statistically analyzed. These need to be addressed prior to publication.
The authors need to provide additional evidence for the tissue-specific nature of 17a-E2s effects on metabolism and lifespan, as well as correct/redo/undertake their statistical analyses using appropriate methods. Moreover, the experimental design needs to be more clearly documented and the data presented in a legible and interpretable manner. As such, the manuscript requires a complete reanalysis of current data and a complete rewrite, before we could consider its publication in eLife.
Essential Revisions
The experimental design needs to be more clearly documented, and the data presented in legible figures with detailed legends that alert the reader to the salient methods and findings. The authors should include a brief rational for each of the experiments used and their choice of cells and provide a concise description of the methods used, and sample size. The authors need to articulate how the significance for RNA-seq and CHIP-seq data was assessed.
If the authors already have the complementary data on female mice on a high fat diet (rather than on normal chow) to facilitate a direct comparison with the male mice on a high fat diet and, thereby, support their sex-specific claims, it would strengthen the paper considerably, if not their claims on sex specificity should be removed from this paper as one cannot directly compare females on normal chow with males on a HFD.
The authors state that their ChIP-seq data reveal nearly identical ERa binding patterns with17a-E2 and 17b-E2, however these have not been rigorously analyzed. The authors need to undertake actual statistical comparisons across groups rather than rely solely on qualitative assessments.
The authors need to provide additional evidence for the tissue-specific nature of 17a-E2s effects on metabolism and lifespan. While they present convincing data that administration of 17a-E2 has direct effects on liver and hypothalamus, they have not provided definitive evidence that these tissues are directly responsible for the beneficial effects on metabolism and lifespan. The abstract and results section should be appropriately tempered.
The authors claim that 17a-E2 reverses cellular senescence in the liver but provide limited conclusive supporting data. The authors need to provide additional evidence to support these claims.
The motif comparison for the ChIP-seq data in Fig. 1B is not described sufficiently to allow for evaluation by readers. Moreover, the authors do not appear to have employed appropriate statistical analyses. Please describe the statistical tests employed.
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