α-Estradiol, a natural form of the hormone lacking estrogenic effects, inhibits the activity of 5-alpha reductase enzymes [1]. α-Estradiol can cross the blood-brain barrier and bind to the brain-specific estrogen receptor ER-X, thereby influencing the regulation of energy metabolism in the central nervous system [2]. α-Estradiol has been widely used to extend the lifespan of male mice and reduce the neuroinflammatory response in the hypothalamus of mice[3].
In vitro, α-Estradiol (10nM) treatment for 24 hours significantly inhibited H2O2-induced cell death in SN4741 cells[4]. Treatment with 100nM α-Estradiol for 24 hours significantly reduced the death of PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP) and restored the expression of dopamine transporter proteins[5].
In vivo, α-Estradiol treatment via oral administration at a dose of 4.8mg/kg daily for 12 months significantly prolonged the lifespan of male mice[6]. Oral administration of α-Estradiol at a dose of 14.4mg/kg/day for 8 months significantly altered hepatic metabolism and increased the levels of multiple amino acids in male mice [1]. Oral administration of α-Estradiol at a dose of 14.4mg/kg daily for 6 months significantly improved skeletal muscle and myofiber phenotype as well as physical function in male mice[7].
References:
[1] Garratt M, Lagerborg K A, Tsai Y M, et al. Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice[J]. Aging Cell, 2018, 17(4): e12786.
[2] Garratt M, Bower B, Garcia G G, et al. Sex differences in lifespan extension with acarbose and 17‐α estradiol: gonadal hormones underlie male‐specific improvements in glucose tolerance and mTORC 2 signaling[J]. Aging cell, 2017, 16(6): 1256-1266.
[3] Debarba L K, Jayarathne H S M, Miller R A, et al. 17-α-Estradiol has sex-specific effects on neuroinflammation that are partly reversed by gonadectomy[J]. The Journals of Gerontology: Series A, 2022, 77(1): 66-74.
[4] Biewenga E, Cabell L, Audesirk T. Estradiol and raloxifene protect cultured SN4741 neurons against oxidative stress[J]. Neuroscience letters, 2005, 373(3): 179-183.
[5] Gélinas S, Martinoli M G. Neuroprotective effect of estradiol and phytoestrogens on MPP+‐induced cytotoxicity in neuronal PC12 cells[J]. Journal of Neuroscience Research, 2002, 70(1): 90-96.
[6] Harrison D E, Strong R, Allison D B, et al. Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males[J]. Aging cell, 2014, 13(2): 273-282.
[7] Garratt M, Leander D, Pifer K, et al. 17‐α estradiol ameliorates age‐associated sarcopenia and improves late‐life physical function in male mice but not in females or castrated males[J]. Aging Cell, 2019, 18(2): e12920.