Bayne Sharyn, Jones Margaret Ee, Li He, Pinto Alex R, Simpson Evan R, Liu Jun-Ping
Department of Immunology, Central Eastern Clinical School, Monash University, Melbourne, Australia.
Cell Res. 2008 Nov;18(11):1141-50. doi: 10.1038/cr.2008.291.
Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.
雌激素缺乏介导衰老，但其潜在机制仍有待充分确定。我们在此报告，在小鼠中通过靶向破坏芳香化酶导致的雌激素缺乏会在体内显著抑制肾上腺中的端粒酶活性。基因表达分析表明，在缺乏雌激素的情况下，端粒酶逆转录酶（TERT）基因表达降低，同时肾上腺皮质中的细胞增殖受损以及肾上腺萎缩。已确定c-kit阳性的干细胞存在于肾上腺皮质实质中。对端粒的分析显示，雌激素缺乏导致肾上腺皮质中的端粒明显短于野生型（WT）对照小鼠。为了进一步确定雌激素的因果作用，我们对这些雌激素缺乏的动物进行了雌激素替代疗法。给雌激素缺乏的小鼠注射雌激素3周可恢复TERT基因表达、端粒酶活性和细胞增殖。因此，我们的数据首次表明，雌激素缺乏会在体内导致小鼠肾上腺中TERT基因表达、端粒酶活性、端粒维持和细胞增殖受到抑制，这表明端粒酶抑制和端粒缩短可能介导肾上腺中的细胞增殖停滞，从而在生理条件下导致雌激素缺乏诱导的衰老。
