Telomer length, integrity vs. telomerase-activity: who is to blame for heart failure?

This editorial refers to ‘Integrative transcriptomic profiling links telomere dysfunction to cGAS–STING activation in heart failure signatures in mice and humans’, by M. Brandt et al., https://doi.org/10.1093/cvr/cvag013. Is reduced telomere length truly a hallmark across cardiovascular disease (CVD)? Observations of shorter telomeres in heart failure, coronary artery disease (CAD), and hypertension are common, but the mechanistic and pathophysiological context remains underdeveloped. Several gaps limit progress. First, few studies distinguish the subcellular localization of telomerase reverse transcriptase (TERT), despite its compartment—specific roles: nuclear TERT (nucTERT) supports telomere maintenance and prevents replicative senescence, whereas mitochondrial TERT (mtTERT) binds mitochondrial DNA, protects it from oxidative stress, and enhances respiratory chain function.1 Second, the underlying mechanism of ‘how’ TERT protects mitochondrial integrity especial in the cardiovascular system, remains ill defined. Lastly, it is difficult to ascertain between telomer erosion/shortening or uncapping that precedes shortening in in a clinical setting. Since TERTs discovery in the mid-1980s, research has linked telomere erosion to diverse pathologies, while increased telomerase-activity and telomere (in)stabilization have been tied to cancer and cell proliferation. Strategies to inhibit TERTs catalytic activity to counter proliferation (as means to inhibit tumor growth) or increase activity to counter cellular aging, have largely fallen short in clinical setting. In the early 2010s, two independent groups described non-canonical roles of TERT in protecting mitochondrial integrity and function.2,3 This mitochondrial axis has since been linked to CVD, neurological disorders, inflammatory responses, and beyond. A striking paradox also persists: slow or non-dividing cells such as neurons, cardiac myocytes, endothelial cells exhibit relatively high telomerase-activity compared with more replicative somatic cells like smooth muscle cells. In addition, in preclinical models the role of telomer uncapping in progression of cardiovascular pathology, independent of telomer erosion has been established.4 This fuels a central controversy: which event is causative—telomere erosion, uncapping or reduced telomerase activity? Species specific differences in telomer biology complicate translation of preclinical models into human pathology. In rodents, telomeres are 5–10 times longer than in humans, and telomere-dependent phenotypes often require 3–5 generations of TERT or telomerase RNA component (TERC) null intercrosses. Loss of telomerase-activity leads to telomere erosion in actively dividing cells, though for minimally dividing cardiac myocytes, this should be less consequential. This suggest reduced telomerase-activity itself or telomer uncapping can cause cellular senescence, decreased autophagy (including mitophagy), and mitochondrial damage—all key contributors to heart failure? Inflammation and aging are both critical factors in progression of heart disease, promoting the hypothesis that preventing telomere shortening might support cardiomyocyte proliferation and cardiac repair. Loss of telomeric repeat-binding factor (TRF)2 results in rapid telomer uncapping, promoting blunt end telomer fusion and contributes to decline in cardiovascular function, however it is unclear if telomer shortening per se is causative. In human pathology increased TERT results in a rapid (hours to days)5 improvement in vascular function following acute or sub-acute interventions—timelines incompatible with physiologically meaningful telomere elongation. Conversely, systemic TERT knockout mice exhibit protection from atherosclerosis6 (associated with smooth muscle cell proliferation) yet develop microvascular dysfunction (due to loss of NO-mediated vasodilation) consistent with CAD—even without critically short telomeres.5,7 Recent evidence from tissue/cell specific8–10 TERT knockout models suggests telomere erosion is a secondary effect and anti-senescence therapy (senolytics) show promising results to counteract cardiovascular aging events despite reductions in telomere length.4 While age-related telomere shortening and cellular senescence are indisputable, no telomere shortening is observed in the cardiac tissue and micro-vessels of patients with CAD compared with healthy controls,5 however in immune cells telomere shortening10 has been widely documented. Yet acute suppression of telomerase-activity in a timely manner not compatible with significant telomer erosion, can induce CAD-like vascular phenotypes in the human coronary microcirculation.5,11 Further, mtTERT alone is sufficient to protect against ischemia/reperfusion injury in rodent and patient myocardium,12 and overexpression of TERT with a mutated nuclear localization signal, but not with a mutated mitochondrial targeting sequence, restores normal vasodilator function in human vessels,11 underscoring the primacy of telomer independent effects that leads to pathology. Both mechanisms, nucTERT and mtTERT, converge on improving cardiovascular resilience but act through distinct pathways. NucTERT primarily counters replicative aging, while mtTERT mitigates oxidative stress and metabolic changes (Figure 1). Therapeutic strategies that target TERT localization and activation may therefore offer synergistic benefits in preventing and treating CVD. Similarly, use of senolytics shows promising results to combat CVD. There are compartment-specific roles of telomerase reverse transcriptase (TERT): nuclear TERT (nucTERT) supports telomere maintenance, the canonical role, regulates gene expression via chromatin remodeling and prevents replicative senescence. In contrast, mitochondrial TERT (mtTERT, the non-canonical role) binds to mitochondrial DNA, protects it from oxidative stress, and enhances respiratory chain function. These two mechanisms converge on improving cardiovascular resilience. NucTERT primarily counters replicative aging, while mtTERT mitigates oxidative stress and metabolic changes. However, telomere shortening is also supposed to act as an active signal that reprograms cardiomyocytes/cardiovascular cells toward inflammation and dysfunction. Alternatively, loss of telomerase activity primes cells for secondary insults that activate innate immunity and culminate in heart failure (created with BioRender). ATP, adenosine triphosphate; Cyt C, cytochrome C; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; TERC, telomerase RNA component; TRF2, telomeric repeat-binding factor 2. Telomere dysfunction contributes to heart failure largely by promoting replicative senescence and apoptosis in cardiomyocytes. Critical short telomeres DNA damage responses, activating checkpoint proteins such as Chk2 and down-regulating telomere-binding proteins like TRF2 (loss of which causes telomer uncapping). This cascade leads to telomere dysfunction, genomic instability, and increased cell death—even in non-dividing heart cells—promotes decline in cardiac function. In heart failure patients, reduced TRF2 expression and telomere attrition correlate with increased cardiomyocyte apoptosis. Experimental models mechanical or oxidative stress down-regulates TRF2, resulting in telomer uncapping and activation of Chk2, while forced TERT expression counteracts uncapping to possibly overwrite the effects of reduced TRF2 resulting in reduced cell death and preserving cardiac function. Telomere shortening and uncapping contributes to pathological remodeling—hypertrophy and ventricular dilation—that characterize heart failure. In TERC deficient mice, progressive telomere shortening leads to impaired regeneration, increased apoptosis, and ultimately heart failure. No endothelial dysfunction is observed in early generations of TERC deficient mice, however the vascular phenotype of TERT knock outs mimics that observed in patients with CAD.7 Together these findings suggest that loss of telomerase activity (TERT) or telomer uncapping (independent of telomer length) promotes pathology. The study by Brandt13 used TERC-deficient mice—thereby avoiding confounding effects of non-canonical TERT—to examine how telomere integrity contributes to cardiac pathology. In these TERC-deficient mice telomere shortening triggers transcriptional reprogramming that leads to cardiac dysfunction and overlaps extensively with the regulatory networks driving murine and human HF, including pathways related to mitochondrial dysfunction, neurohumoral stress, inflammation, and genomic instability. These findings suggest that telomere erosion can destabilize cardiac tissue, impair repair processes, and accelerate heart failure progression. However, they do not rule out telomer uncapping and/or reduced telomerase activity as causative event(s). Thus, targeting different telomer erosion and/or reduced telomerase activity per se may hold therapeutic promise CVD. The overexpression of TERT, especially mtTERT, in the setting of uncapped or critically short telomeres, may be a means of answering the question of causality. To strengthen mechanistic insights, robustness, and translational impact, key aspects to consider in future approaches are: (ⅰ) Increase the tissue specificity: To avoid a mixture of cardiac-intrinsic effects with systemic consequences (e.g. bone marrow or immune dysfunction) as seen in current models of full-body telomerase-deficient mice, use cardiomyocyte- and fibroblast-specific deletions/rescues. (ⅱ) Improve the temporal resolution: Measure telomere length and telomerase activity, mitochondrial function, and inflammatory activation at multiple stages of dysfunction to distinguish cause vs. consequence within the telomere–p53–mitochondria–immune cascade. (ⅲ) Reduce the cellular heterogeneity: Apply single-cell transcriptomics to dissect telomere-driven changes across cell types (myocytes, fibroblasts, immune cells). Bulk RNA-seq may obscure these contributions. (ⅳ) Identify downstream effectors: E.g. molecular drivers of fibrosis, hypertrophy, and contractile failure. (ⅴ) Test causality: Define how telomere shortening interacts with TERT activity, integrating canonical (telomere maintenance) and non-canonical (mitochondrial protection) actions. (ⅵ) Increase the translational relevance: Verify TERT-related pathways whenever possible in human tissue/material. Clarifying the controversy of whether telomere shortening acts as an active signal of reprogramming cardiomyocytes/cardiovascular cells toward inflammation and dysfunction, or whether loss of telomerase-activity primes cells for secondary insults that activate innate immunity and culminate in heart failure should be addressed in future studies. Canonical and non-canonical TERT pathways converge on cardiovascular resilience but through distinct molecular routes—offering opportunities for precision therapies targeting TERT localization and function (Figure 1). This work was supported by the National Institutes of Health Grants R01-HL- HL157025, R01-HL- HL157025, R01-HL-173549 (A.M. Beyer) and by the German Research Foundation RTG 2989 P5 (P. Kleinbongard).