Here we report the first study to examine the relationship between estimated endogenous and exogenous estrogen exposure, telomere length, and telomerase activity. Greater endogenous estrogen exposure, as measured by longer duration of the reproductive years, was related to longer PBMC telomere length and lower telomerase activity. In contrast, exogenous exposure to estrogen, as measured by length of HT use, was not associated with longer TL or telomerase.
Our finding that duration of endogenous estrogen exposure is negatively correlated with telomerase activity in this group of postmenopausal women at risk for cognitive decline may appear contradictory to reports that estrogen upregulates telomerase activity in vitro
. However, in the present study, telomerase activity was measured several years after menopause occurred. Given that PBMC telomerase can respond rapidly (over minutes to hours) to changing physiological conditions (32
), it was not surprising that telomerase activity did not show a close relationship to the estrogen status years earlier. Thus, from these data, it was not possible to directly evaluate the association of endogenous estrogens with telomerase activity, since telomerase was measured years after the greatest exposure.
High telomerase activity, however, may be a cellular response to inflammation and may thus indicate compromised health. For example, the proinflammatory cytokine IL-6 has been shown to upregulate telomerase activity in in vitro
cultured cells (33
). Elevated levels of another proinflammatory cytokine, TNF-alpha, were also reported in cells from these caregivers in response to stimulation in vitro
). Thus, the inverse finding between endogenous estrogen exposure and telomerase activity may be due in part to the reported anti-inflammatory effects of estrogen. Our finding that higher telomerase is associated with fewer reproductive years is consistent with previous in vivo
findings suggesting that telomerase may augment the proliferative capacity of lymphocytes, macrophages, and smooth muscle cell in atherosclerosis development (12
). Thus, these data are consistent with the notion that longer reproductive years of life (and later age at menopause) could delay the development of cardiovascular disease associated with menopause.
Estimated duration of endogenous estrogen exposure was inversely associated with the state of combined short TL and high telomerase activity. Although the implications of this finding are not fully understood, we note that telomerase activity is highly regulated by a large number of mechanisms, including, in non-human model systems, DNA damage responses that act to enhance the action of telomerase on telomeres (35
). Hence our finding, taken together with previous preclinical reports (36
) is consistent with the possibility that telomerase activity in PBMCs may increase in response to the damage signaling from too-short telomeres, although this mechanism remains to be further elucidated.
Endogenous estrogen has been associated with lower cardiovascular disease risk in women (38
) and with lower risk of cognitive decline (39
). Possible mechanisms involved in the protective role of estrogen include its ability to lower oxidative stress, reduce inflammation, improve vasodilation, and alter gene expression profiles in vasculature and the heart (40
). Correspondingly, both oxidative damage and proinflammatory cytokines have been associated with telomere shortening (42
). Our findings suggest that one possible mechanism through which endogenous estrogens may exert both cardioprotective and cognitive effects may be through deceleration of telomere shortening and hence cellular aging. The effects may be unique to endogenous hormones however. While endogenous bioavailable estradiol levels have been beneficially related to cognitive function and cardiovascular outcomes, exogenous estrogen use has been linked to earlier dementia (44
) and coronary events.
The only published study examining the in vivo
relationship between estrogens and telomere length found that women who had been on HT for more than five years had longer TL compared to age-matched women who had not used HT (45
). However, the authors noted that women who exercised regularly and took daily vitamins were better represented in the group of women using HT. Both exercise and vitamin intake have been reported to be associated with longer TL (46
). The positive correlation between TL and HT in that report therefore may be at least partially accounted for by the difference in exercise and vitamin intake between the two groups or may also be accounted for by other unmeasured variables representing good self care over the life course which may lead to residual confounding even with adjustment for these other variables. Thus, it is not clear from current data whether exogenous estrogen exposure in women is associated with TL.
There were several limitations to this study. First, all participants in this study were prescribed HT by their doctors, with at least one risk factor for cognitive decline as described in the methods, including the possibility of increased risk of cognitive decline which was reported to be associated with short TL (48
). Therefore, these study results may not extend to the general population. Future studies should examine this association in women who have never used HT, without risk factors for cognitive decline. The small sample size limited our ability to explore the more complex influence of the combinations of reproductive factors, including oral contraceptive and different types of HT regimens.
As in all observational studies, we cannot rule out the possibility that the observed relationship between estrogen exposure and TL was due to some unmeasured factor related to both longer reproductive years and reduced cell aging. Socioeconomic status is a major factor which should theoretically influence both reproductive history and cell aging, but adjustment for education had little influence on our associations. Telomere length is also 30–70% genetically determined (49
); genetic factors might ultimately be responsible for both long TL and long reproductive years. We were not able to address this issue, but longitudinal studies that examine the relationship between reproductive years and changes in telomere length over time, as well as genome-wide genetic analysis, may help address these limitations in the future.
In summary, we provide preliminary evidence that endogenous estrogen is associated with longer telomere length and lower telomerase activity in PBMCs. Larger studies are needed to draw more definitive conclusions about the relationship between estrogen, telomeres and telomerase.