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...  Read more

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

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...  Read more

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. Abstract

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. Abstract

View all comments by Edwin J. Weeber