Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice

Abstract

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.

Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo

“…(C) Telomerase activity in the GC was quantified by the amount of [α- telomerase activity is readily measurable, our findings that estrogen deficiency results in telomerase inhibition in the ovary highlight a tissue-specific stimulatory effect of estrogen on telomerase. Our recent studies showing that estrogen deficiency caused telomerase inhibition in the adrenal gland (Bayne et al, 2008) suggest that estrogen links the regulation of telomere homeostasis in steroidogenic organs in mice. The regulation of ovarian telomerase, present in a number of species including mice, rats, cows, pigs and humans (Lavranos et al, 1999;Rodgers et al, 2001;Yamagata et al, 2002;Baykal et al, 2004;Russo et al, 2006), is likely to be physiological, underlying major functions of the ovary.…”

“…Telomerase activity was determined by a TRAP assay performed essentially as described (Bayne et al, 2008). Whole frozen ovaries were homogenized in 10 µL pre-chilled TRAP lysis buffer (0.5% CHAPS, 10 mmol/L Tris-HCl pH 7.5, 1 mmol/L MgCl 2 , 1 mmol/L EGTA, 5 mmol/L β-mercaptoethanol, 10% glycerol and 1 mmol/L AEBSF) per mg tissue.…”

“…Recent evidence suggests that estrogen may regulate telomerase, the enzyme that controls the proliferative lifespan of cells by maintaining telomeres (reviewed in (Bayne et al, 2008;). In vitro, estrogen stimulates telomerase activity in human breast cancer cells (Kyo et al, 1999), ovarian cancer cells (Misiti et al, 2000) and vascular endothelial cells (Ling et al, 2006).…”

“…However, little is known about the effect of endogenous estrogen on telomerase activity in vivo and the consequence of estrogen regulation of telomerase for telomeres and cell proliferation under physiological conditions. While absent from most human somatic tissues, telomerase is present in some mouse tissues (Blasco, 2007), although little is known of how telomerase is regulated and the role of estrogen in regulating telomerase in mice (Bayne et al, 2008;. In the present study, we used estrogen-deficient ArKO mice to investigate the roles of estrogen in regulating telomerase activity and granulosa cell proliferation in the ovary in vivo.…”

Sexual dimorphism in cancer

“…17β-estradiol, the most potent form of estrogen, can also counteract senescence through p53-antagonizing mechanisms and/or control of telomerase expression 33,34 .…”