Hormone actions controlling sex-specific life-extension

Garratt, Michael; Stout, Michael J.

doi:10.18632/aging.101396

Cited by 5 publications

(3 citation statements)

References 8 publications

(11 reference statements)

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“…Collectively, our findings strongly suggest that 17α-E2 acts through ERα in the liver and/or hypothalamus to modulate metabolic parameters. However, our findings are in contrast to other reports suggesting that 17α-E2 elicits health benefits by modulating androgen metabolism ( Garratt et al, 2017 ; Garratt et al, 2018 ; Garratt and Stout, 2018 ). Garratt et al reported that responsiveness to 17α-E2 was significantly attenuated in castrated male mice ( Garratt et al, 2018 ), which the authors proposed may indicate 17α-E2 acts as a 5α-reductase inhibitor ( Schriefers et al, 1991 ) to prevent the conversion of testosterone into dihydrotestosterone (DHT).…”

Section: Discussioncontrasting

confidence: 99%

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

Mann

Hadad²,

Holte

et al. 2020

eLife

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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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Section: Discussioncontrasting

confidence: 99%

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

Mann

Hadad²,

Holte

et al. 2020

eLife

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“…17α-E2 has recently been shown to induce considerable benefits on healthspan and lifespan in male mice ( Harrison et al, 2014 ; Strong et al, 2016 ; Stout et al, 2017a ; Garratt et al, 2017 ; Mann et al, 2020 ; Garratt et al, 2018 ), although little benefit has been observed in females receiving the compound ( Garratt et al, 2017 ; Garratt et al, 2018 ). We have postulated that the lack of beneficial effects of 17α-E2 in females may be due to the high levels of endogenous 17β-E2, which may outcompete the less-potent 17α-E2 at estrogen receptors ( Mann et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the collective evidence outlined above, it must be noted that most of the studies to date have evaluated health parameters that deteriorate to a greater degree in male mammals with advancing age ( Garratt and Stout, 2018 ), including nutrient-sensing pathway perturbations, systemic metabolic parameters, and pro-inflammatory stress ( Stout et al, 2017a ; Steyn et al, 2018 ; Garratt et al, 2017 ; Mann et al, 2020 ; Garratt et al, 2018 ). In fact, it is well-established that female mammals possess an inherent advantage as compared to their male counterparts with regard to metabolic plasticity, immunological responses, and DNA damage ( Austad and Fischer, 2016 ; Moran et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

17α-Estradiol prevents ovariectomy-mediated obesity and bone loss

Mann

Pitel

Nelson-Holte

et al. 2020

Experimental Gerontology

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Menopause is a natural physiological process in older women that is associated with reduced estrogen production and results in increased risk for obesity, diabetes, and osteoporosis. 17α-estradiol (17α-E2) treatment in males, but not females, reverses several metabolic conditions associated with advancing age, highlighting sexually dimorphic actions on age-related pathologies. In this study we sought to determine if 17α-E2 could prevent ovariectomy (OVX)-mediated detriments on adiposity and bone parameters in females. Eight-week-old female C57BL/6J mice were subjected to SHAM or OVX surgery and received dietary 17α-E2 during a six-week intervention period. We observed that 17α-E2 prevented OVX-induced increases in body weight and adiposity. Similarly, uterine weight and luminal cell thickness were decreased by OVX and prevented by 17α-E2 treatment. Interestingly, 17α-E2 prevented OVX-induced declines in tibial metaphysis cancellous bone. And similarly, 17α-E2 improved bone density parameters in both tibia and femur cancellous bone, primarily in OVX mice. In contrast, to the effects on cancellous bone, cortical bone parameters were largely unaffected by OVX or 17α-E2. In the non-weight bearing lumbar vertebrae, OVX reduced trabecular thickness but not spacing, while 17α-E2 increased trabecular thickness and reduced spacing. Despite this, 17α-E2 did improve bone volume/tissue volume in lumbar vertebrae. Overall, we found that 17α-E2 prevented OVX-induced increases in adiposity and changes in bone mass and architecture, with minimal effects in SHAM-operated mice. We also observed that 17α-E2 rescued uterine tissue mass and lining morphology to control levels without inducing hypertrophy, suggesting that 17α-E2 could be considered as an adjunct to traditional hormone replacement therapies.

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Hormone actions controlling sex-specific life-extension

Cited by 5 publications

References 8 publications

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

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

17α-Estradiol prevents ovariectomy-mediated obesity and bone loss

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