Does Estrogen Put the Brakes on Aging in ApoE4-Positive Cells?

White blood cells age quickly in post-menopausal women who carry the ApoE4 gene, but estrogen slows that decline, scientists report February 13 in PLoS ONE. Natalie Rasgon at Stanford University School of Medicine, California, and colleagues found that telomeres, the protective chromosome ends that are trimmed during DNA replication, shrank faster in aging women who carry at least one copy of this Alzheimer’s disease (AD) risk allele. Because shorter telomeres reflect more rounds of DNA replication, they are seen as an indirect measure of a cell’s age, though shrinking telomeres can also be an indication of oxidative stress or inflammation. Interestingly, women on hormone replacement therapy maintained longer telomeres. “It appears that ApoE4 carriers are at risk for accelerated cellular aging,” Rasgon told Alzforum. Further, she added, “Women receiving hormone therapy may have [ApoE] genotype-dependent responses.”

Some studies point to accelerated cell aging in AD. Patients have shorter white blood cell telomeres (see Honig et al., 2006) that dwindle further as the disease progresses (see Panossian et al., 2003). Other studies suggest this is only true in ApoE4 carriers (see Takata et al., 2012).

Rasgon previously reported that post-menopausal women who reported more years—and thus more estrogen exposure—between menarche and menopause have longer telomeres (see Lin et al., 2011), as do women on long-term hormone replacement therapy (see Lee et al., 2005). These were cross-sectional studies. No one had determined if the association holds up over time or if ApoE4 status influences it.

First author Emily Jacobs, University of California, San Francisco, and colleagues addressed both questions in a randomized, longitudinal trial. The research team measured the length of telomeres in white blood cells of 63 cognitively healthy, post-menopausal women, all of whom had started hormone replacement therapy at menopause and had been taking it for at least one year—one decade on average. Therapy consisted of either conjugated equine estrogen, estradiol, or either of those plus progesterone. Twenty-four participants carried at least one copy of the ApoE4 allele. Researchers randomized half the participants to continue hormone treatment and the other half to suspend it at the start of the trial.

Two years later, the scientists measured the chromosome ends again. ApoE4 carriers lost significantly more base pairs than did non-carriers. When estrogen entered the equation, it further divided the women. On average, those who remained on hormone therapy maintained their telomeres regardless of allele status. However, if the women stopped their treatments, ApoE4 carriers lost an average of 322 base pairs per telomere while non-carriers gained 490. The results imply that ApoE4 speeds up cell aging through loss of telomeres, and that estrogen’s impact depends on allele status. The mechanism of action is still unclear, wrote the authors.

The findings jibe with “numerous previous studies [that] suggest ApoE4 promotes oxidative stress and inflammation,” Mark Mattson, National Institute on Aging, Baltimore, Maryland, told Alzforum in an e-mail. Further studies will be needed to determine if the apolipoprotein exerts a direct influence on telomeres, and whether shorter telomeres in immune cells might mediate ApoE4’s effects on the aging brain and other organs, he wrote.

Results also indicate that if women with ApoE4 begin estrogen therapy as soon as menopause starts, they may be able to protect themselves against cell decline. “I find that fascinating,” said Phyllis Wise, University of Illinois at Urbana-Champaign. “We are learning that estrogen’s effects are pleiotropic, and this paper suggests they are even broader than we had appreciated before—they can get into the arena of chromosomal structure.” Estrogen’s precise influence on telomeres is unclear, wrote the authors, but previous studies reported that the hormone stimulates expression of part of the telomerase complex and raises the activity of telomerase, the enzyme that adds DNA to telomere ends (see Misiti et al., 2000, and Calado et al., 2009). Estrogen also has antioxidant properties (see Wong et al., 2008), which could indirectly stabilize telomeres.

Treatment does not seem to help non-carriers maintain their telomeres. In fact, stopping the treatment actually led to their growth, a phenomenon still under investigation by scientists, wrote the authors. Why might estrogen affect ApoE4 carriers and non-carriers differently? Rasgon and colleagues are unsure, but write that it could relate to ApoE gene expression. A previous study reported that estradiol boosts ApoE translation (see Srivastava et al., 1997).

Regardless of the mechanism, these findings may help experts make sense of contradictory evidence about the benefits and dangers of hormone replacement therapy. For example, some studies suggested that it decreases risk for dementia (see ARF related news story), while others indicated the opposite (see ARF related news story). ApoE status seems to define subsets of women who respond differently to estrogen, said Rasgon. “This study moves us a step closer to understanding which groups of women may benefit from hormone therapy versus those who will not.”

Because of the small sample size, this study was unable to tease apart whether different types of estrogen replacement have different effects. Rasgon said she plans to address that issue in future work, in addition to testing whether her findings hold up in a larger sample. As of now, results are too preliminary to make clinical recommendations about genetic testing for ApoE4, or about which subgroups should take supplemental estrogen, Rasgon told Alzforum.—Gwyneth Dickey Zakaib

Comments

  1. There has been a flurry of articles published within the past few years in which relatively shorter telomere length in lymphocytes has been associated with aging and numerous chronic diseases. A common factor in these conditions is that there is elevated cellular oxidative and inflammation. Therefore, one interpretation of this literature is that telomere length is an indicator of chronic cellular stress, much the same as accumulation of DNA damage and oxidized proteins are an indicator of chronic cellular stress. The present findings are consistent with the latter interpretation, because numerous previous studies have suggested that ApoE4 promotes accelerated oxidative stress and inflammation. What remains to be determined is: 1) what is the mechanism by which ApoE4 accelerates telomere attrition? Is it simply by increasing oxidative stress or is there a more direct mechanism; 2) does shorter telomere length in lymphocytes mediate any of the adverse effects of ApoE4 on the brain, heart and other organs during aging? The take home message is that the present findings reveal an interesting association between ApoE4 and lymphocyte telomere length, but its significance remains to be established.

    View all comments by Mark Mattson

  2. The elegant study by Rasgon and colleagues identifies yet another unknown consequence of ApoE4 expression: increased telomere (TL) shortening. Furthermore, this study suggests that hormone replacement therapy (HT) can effectively counteract these changes in a relatively short time. If a leap can be made that TL shortening is a metric for cell aging, and ApoE4 carriers show significant TL shortening, then a consequence of ApoE4 expression is acceleration of cellular aging. While this last assertion has yet to be tested, the rescue of ApoE4-dependent cellular aging with HT and potentially a rescue of overall cellular health would be an exciting possibility. To date, only animal studies have shown a connection between ApoE4 and synaptic function that can be modulated using estradiol. Pasternak and Trommer showed that estradiol treatment recovered the long-term potentiation (LTP) defects in the hippocampus of ApoE4 target replacement mice. The mechanism underlying the rescue of LTP is unknown, but is believed to be related to enhanced acetylcholine receptor function, and likely does not involve alterations in cellular aging.

    Kudos should be given to the authors for trying to account for established risk factors and potential confounds of the study. For example, exclusion criteria for participants with any significant cognitive disruption suggest that ApoE4 isoform effects on TL precede cognitive decline associated with ApoE4 inheritance.

    What would this work mean for male ApoE4 carriers? Currently, the use of estrogen as a therapeutic in men is limited to special circumstances, and potential increases in thrombo-embolic events are a major concern; however, studies like this may direct general investigational studies of HT in men and male cellular aging, and specifically in male ApoE4 carriers.

    References:

    Sayed Y, Taxel P. The use of estrogen therapy in men. Curr Opin Pharmacol. 2003 Dec;3(6):650-4. PubMed.

    Yun SH, Park KA, Kwon S, Woolley CS, Sullivan PM, Pasternak JF, Trommer BL. Estradiol enhances long term potentiation in hippocampal slices from aged apoE4-TR mice. Hippocampus. 2007;17(12):1153-7. PubMed.

    View all comments by Edwin J. Weeber

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References

News Citations

  1. Hormone Replacement Therapy Still up on Balance Beam
  2. Dementia Risk Increases, at Least in Those Who Start Hormone Therapy Late

Paper Citations

  1. Honig LS, Schupf N, Lee JH, Tang MX, Mayeux R. Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann Neurol. 2006 Aug;60(2):181-7. PubMed.
  2. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, Cummings JL, Effros RB. Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol Aging. 2003 Jan-Feb;24(1):77-84. PubMed.
  3. Takata Y, Kikukawa M, Hanyu H, Koyama S, Shimizu S, Umahara T, Sakurai H, Iwamoto T, Ohyashiki K, Ohyashiki JH. Association between ApoE phenotypes and telomere erosion in Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2012 Apr;67(4):330-5. PubMed.
  4. Lin J, Kroenke CH, Epel E, Kenna HA, Wolkowitz OM, Blackburn E, Rasgon NL. Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. Brain Res. 2011 Mar 16;1379:224-31. PubMed.
  5. Lee DC, Im JA, Kim JH, Lee HR, Shim JY. Effect of long-term hormone therapy on telomere length in postmenopausal women. Yonsei Med J. 2005 Aug 31;46(4):471-9. PubMed.
  6. Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW, Piaggio G, Sacchi A, Pontecorvi A, Bacchetti S, Farsetti A. Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol Cell Biol. 2000 Jun;20(11):3764-71. PubMed.
  7. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009 Sep 10;114(11):2236-43. PubMed.
  8. Wong CM, Yung LM, Leung FP, Tsang SY, Au CL, Chen ZY, Yao X, Cheng CH, Lau CW, Gollasch M, Huang Y. Raloxifene protects endothelial cell function against oxidative stress. Br J Pharmacol. 2008 Oct;155(3):326-34. PubMed.
  9. Srivastava RA, Srivastava N, Averna M, Lin RC, Korach KS, Lubahn DB, Schonfeld G. Estrogen up-regulates apolipoprotein E (ApoE) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor alpha-mediated pathway. J Biol Chem. 1997 Dec 26;272(52):33360-6. PubMed.

Further Reading

Papers

  1. Vierk R, Glassmeier G, Zhou L, Brandt N, Fester L, Dudzinski D, Wilkars W, Bender RA, Lewerenz M, Gloger S, Graser L, Schwarz J, Rune GM. Aromatase inhibition abolishes LTP generation in female but not in male mice. J Neurosci. 2012 Jun 13;32(24):8116-26. PubMed.
  2. Huang GZ, Woolley CS. Estradiol Acutely Suppresses Inhibition in the Hippocampus through a Sex-Specific Endocannabinoid and mGluR-Dependent Mechanism. Neuron. 2012 Jun 7;74(5):801-8. PubMed.
  3. Lee DC, Im JA, Kim JH, Lee HR, Shim JY. Effect of long-term hormone therapy on telomere length in postmenopausal women. Yonsei Med J. 2005 Aug 31;46(4):471-9. PubMed.
  4. Lin J, Kroenke CH, Epel E, Kenna HA, Wolkowitz OM, Blackburn E, Rasgon NL. Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. Brain Res. 2011 Mar 16;1379:224-31. PubMed.
  5. Jenkins EC, Ye L, Gu H, Ni SA, Velinov M, Pang D, Krinsky-McHale SJ, Zigman WB, Schupf N, Silverman WP. Shorter telomeres may indicate dementia status in older individuals with Down syndrome. Neurobiol Aging. 2010 May;31(5):765-71. PubMed.
  6. Lukens JN, Van Deerlin V, Clark CM, Xie SX, Johnson FB. Comparisons of telomere lengths in peripheral blood and cerebellum in Alzheimer's disease. Alzheimers Dement. 2009 Nov;5(6):463-9. PubMed.

Primary Papers

  1. Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL. Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use. PLoS One. 2013;8(2):e54713. PubMed.

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