Role of arterial telomere dysfunction in hypertension

Morgan, R. Garrett; Ives, Stephen J.; Walker, Ashley E.; Cawthon, Richard M.; Andtbacka, Robert H.I.; Noyes, Dirk; Lesniewski, Lisa A.; Richardson, Russell S.; Donato, Anthony J.

doi:10.1097/hjh.0000000000000157

Cited by 62 publications

(34 citation statements)

References 29 publications

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“…This was the first piece of evidence that suppression of selective Nox isoforms could be instrumental in the maintenance of vascular longevity. Finally, redox activation of p53/p21 cip signalling leading to senescence is evident in murine models of hypertension [151,152], diabetes [153,154], atherosclerosis [155,156] and pulmonary hypertension [121,157]. …”

Section: Role Of Ros Signalling In Proteins Involved In Agingmentioning

confidence: 99%

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

2016

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Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of ‘longevity genes’ and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population.

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Section: Role Of Ros Signalling In Proteins Involved In Agingmentioning

confidence: 99%

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

2016

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“…Previously, in a group of both women and men, we determined that arterial telomere uncapping was greater in subjects with hypertension, which by definition includes subjects both with a blood pressure >140/90 mmHg, as well as those receiving anti-hypertensive medication (Morgan and others 2014). In the present study, in subjects that include both users and non-users of anti-hypertensive medications, we find that systolic blood pressure and pulse pressure relate to resistance artery telomere uncapping among men, but not women.…”

Section: Discussionmentioning

confidence: 99%

“…ChIPs were performed to assess hTERT (Abcam) bound to telomeres as described above (Morgan and others 2013; Morgan and others 2014). …”

Section: Methodsmentioning

confidence: 99%

“…Telomere ends form a loop structure, known as a cap, which prevents the chromosome ends from being recognized as double-stranded DNA breaks and initiating a DNA damage response (Griffith and others 1999; Stansel and others 2001; Takai and others 2003). In human arteries, telomere uncapping from loss of the loop structure increases with advancing age and is associated with hypertension (Morgan and others 2013; Morgan and others 2014). In arteries, greater telomere uncapping, independent of mean telomere length, is associated with increased markers of cellular senescence and inflammation (Morgan and others 2013).…”

Section: Introductionmentioning

confidence: 99%

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Age-related arterial telomere uncapping and senescence is greater in women compared with men

Walker

Morgan

Ives

et al. 2016

Experimental Gerontology

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Telomere uncapping increases with advancing age in human arteries and this telomere uncapping is associated with increased markers of senescence, independent of mean telomere length. However, whether there are sex specific differences in arterial telomere uncapping is unknown. We found that telomere uncapping (serine 139 phosphorylated histone γ-H2A.X in telomeres) in arteries was ~2.5 fold greater in post-menopausal women (n=17, 63±2 yrs) compared with premenopausal women (n=11, 30±2 yrs, p=0.02), while there was only a trend towards greater telomere uncapping in older men (n=26, 66±2 yrs) compared with young men (n=11, 31±2, p=0.11). Senescence markers, p53 bound to the p21 gene promoter and p21 gene expression, were 3-4 fold greater in post-menopausal compared with premenopausal women (p=0.01-0.02), but only 1.5-2 fold greater in older compared with young men (p=0.02-0.08). Blood glucose was related to telomere uncapping in women, while systolic blood pressure, pulse pressure and serum creatinine were related to telomere uncapping in men. Mean arterial telomere length decreased similarly in women and men with age (p<0.01). Thus, the age-related increase in arterial telomere uncapping and senescence is greater in women than men, despite similar age-related reductions in mean telomere length in both sexes.

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“…To estimate chromosomal content, we measured mean telomere length (mTL) as we have previously described at length[28–30]. We believe mTL represents a good estimate of chromosome content, as telomeres are present on every chromosome.…”

Section: Methodsmentioning

confidence: 99%

Age-Associated ALU Element Instability in White Blood Cells Is Linked to Lower Survival in Elderly Adults: A Preliminary Cohort Study

et al. 2017

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BackgroundALU element instability could contribute to gene function variance in aging, and may partly explain variation in human lifespan.ObjectiveTo assess the role of ALU element instability in human aging and the potential efficacy of ALU element content as a marker of biological aging and survival.DesignPreliminary cohort study.MethodsWe measured two high frequency ALU element subfamilies, ALU-J and ALU-Sx, by a single qPCR assay and compared ALU-J/Sx content in white blood cell (WBCs) and skeletal muscle cell (SMCs) biopsies from twenty-three elderly adults with sixteen healthy sex-balanced young adults; all-cause survival rates of elderly adults predicted by ALU-J/Sx content in both tissues; and cardiovascular disease (CVD)- and cancer-specific survival rates of elderly adults predicted by ALU-J/Sx content in both tissues, as planned subgroup analyses.ResultsWe found greater ALU-J/Sx content variance in WBCs from elderly adults than young adults (P < 0.001) with no difference in SMCs (P = 0.94). Elderly adults with low WBC ALU-J/Sx content had worse four-year all-cause and CVD-associated survival than those with high ALU-J/Sx content (both P = 0.03 and hazard ratios (HR) ≥ 3.40), while WBC ALU-J/Sx content had no influence on cancer-associated survival (P = 0.42 and HR = 0.74). SMC ALU-J/Sx content had no influence on all-cause, CVD- or cancer -associated survival (all P ≥ 0.26; HR ≤ 2.07).ConclusionsThese initial findings demonstrate that ALU element instability occurs with advanced age in WBCs, but not SMCs, and imparts greater risk of all-cause mortality that is likely driven by an increased risk for CVD and not cancer.

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Role of arterial telomere dysfunction in hypertension

Cited by 62 publications

References 29 publications

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

Age-related arterial telomere uncapping and senescence is greater in women compared with men

Age-Associated ALU Element Instability in White Blood Cells Is Linked to Lower Survival in Elderly Adults: A Preliminary Cohort Study

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