Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use

Emily G Jacobs,Elissa S Epel,Heather A Kenna,Jue Lin,Elizabeth H Blackburn,Candyce Kroenke,Natalie L Rasgon,Stefan Ft Weiss

doi:10.1371/journal.pone.0054713

Abstract

Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR = 6.26, 95% CI = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.

Highlights

Telomeres are DNA-protein complexes that cap the ends of eukaryotic chromosomes and protect against genomic instability
Participants randomized into hormone ‘ON’ and hormone ‘OFF’ groups did not differ significantly in age, years of education, body mass index (BMI) or baseline cognitive function
Hormonal variables, including age at menarche, age at menopause and number of years on hormone replacement therapy (HT) at enrollment, did not differ between groups except in one case: women randomized off HT were more likely to have been on an HT regimen that included 17b-estradiol

Summary

Introduction

Telomeres are DNA-protein complexes that cap the ends of eukaryotic chromosomes and protect against genomic instability. Leukocyte telomere length (TL) has emerged as a putative index of cellular age that predicts the incidence of agerelated diseases [4,5,6,7,8,9,10] as well as all-cause and disease-specific mortality in older adults [11,12,13,14,15]. Recent evidence from a telomerase-deficient mouse model demonstrates the widespead consequences of telomere attrition on neurodegeneration, including reduced proliferation of neural progenitor cells, restricted neurogenesis, and atrophy of white matter tracts. These age-related degenerative phenotypes were reversed following reactivation of endogenous telomerase activity [20]

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