Telomerase as a Therapeutic Target in Cardiovascular Disease

Abstract

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials.

Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

“…Shorter leukocyte telomere length (LTL) is linked with CVD clinically. Short LTL is predictive of higher overall mortality in over 60-year-olds, an increased risk of death from heart disease, severe HF, atherosclerosis and the development of ischaemic heart disease and may be predictive for ventricular arrhythmias in patients with ischaemic heart disease, as reviewed previously ( Fernández-Alvira et al, 2016 ; Hoffmann et al, 2021 ; Valdes et al, 2005 ). Furthermore, short LTL is also associated with cardiovascular risk factors such as hypertension, stress, smoking, or obesity ( Valdes et al, 2005 ).…”

“…Furthermore, statins, one of the most potent drugs in delaying age-related inflammatory changes in the arterial vessel wall and that slow the progression of atherosclerosis have been shown to stimulate telomerase activity ( Bennaceur et al, 2014 ). While telomerase has enzymatic functions beyond those of telomere maintenance ( Hoffmann et al, 2021 ), supporting the hypothesis that oxidative stress mediates T-cell telomere shortening inducing senescence which in turn promotes atherogenesis are the observations that CD8 + T-cells become functionally senescent with age ( Callender et al, 2018 ). T-cell senescence is implied by proliferative arrest and the increased production and secretion of inflammatory mediators characteristic of a SASP ( Callender et al, 2018 ), and once senescent, cytotoxic terminally differentiated CD8 + T cells (TEMRA) are pro-atherosclerotic and an independent predictor of all-cause mortality in the elderly ( Martin-Ruiz et al, 2020 ).…”

Telomeres and Age-Related Diseases

“…Despite their significant results, meta-analyses should be interpreted with caution as the studies included varied substantially in study design and patient characteristics. This is particularly important when considering that CVD is a highly multifactorial entity that is associated with multiple risk factors, such as age, gender, obesity, physical inactivity, genetic predisposition, and others, and involves several pathomechanisms including inflammation, oxidative stress, and dyslipidemia [100,101].…”

Inhibiting the Priming for Cancer in Li-Fraumeni Syndrome

“…Intriguingly there are also indications that many of the ‘off-target’ effects of statins may reduce elements of the pre-cancer niche and thereby reduce carcinogenesis in LFS. Data from studies in cardiovascular disease show that statin treatment may reduce the risk of cardiovascular disease by targeting telomere shortening, which is a risk factor [ 88 , 89 ]. Telomere shortening, exacerbated by mitochondrial dysfunction and oxidative stress, causes DNA damage, cellular senescence and further inflammation in cardiomyocytes, ultimately leading to cardiovascular events.…”