Aging and atrial fibrillation: Role of telomere dysfunction

To the Editor: Atrial fibrillation (AF) is a prevalent arrhythmia, with aging recognized as a major risk factor. As the global population ages, the incidence of AF has been steadily increasing, particularly among individuals aged ≥65 years. AF increases the risk of stroke and heart failure and is strongly associated with cognitive impairment, frailty, and reduced quality of life. A comprehensive understanding of the mechanisms through which aging contributes to AF, particularly the role of telomere dysfunction, is crucial for identifying novel therapeutic targets. Structure and function of telomeres: Human telomeres consist of telomeric DNA and telomere protective protein complexes, which form cap-like protective structures at the ends of eukaryotic linear DNA molecules. These structures are critical for maintaining genome stability by protecting eukaryotic genetic material from nucleolytic attack and preventing DNA repair system activation. Telomeric DNA consists of highly repetitive TTAGGG DNA sequences that form a distinct telomeric loop (T-loop) structure. This structure protects loose DNA ends from being mistakenly recognized as double-strand breaks requiring repair. Telomeric DNA is surrounded by a complex of six proteins collectively known as the telomere protection protein complex. These proteins include telomeric repeat binding factor 1 (TRF1), TRF2, repressor/activator protein 1, TRF1 interacting nuclear protein 2 (TIN 2), telomere protection protein 1 (POT1), and POT1 interacting protein 1 (TPP1). This complex is essential for stabilizing the T-loop structure. Telomere length is maintained by the enzyme telomerase, a ribonucleoprotein complex that prevents telomere shortening and extends them by providing a template sequence for telomeric repeats. Telomerase comprises telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and telomerase-associated protein.[1] Link between aging and telomere dysfunction: In human somatic cells, telomere length progressively shortens with each cell division. When telomere length reaches a critical threshold, the cell loses its ability to divide and undergoes replicative senescence or death. Cardiomyocytes (CMs) are terminally differentiated cells that do not undergo further mitosis. Their telomere shortening is not significantly influenced by replication-related factors. However, telomere shortening in these cells is associated with CM abnormalities and functional impairments. Mitochondrial reactive oxygen species (ROS) can induce telomere shortening in vitro, with the telomere region being susceptible to oxidative damage. In senescent endothelial cells, telomere dysfunction contributes to the development of a senescence-associated secretory phenotype, which is characterized by increased inflammation and oxidative stress. Both human and mouse CMs exhibit ROS-induced DNA damage in the telomere region, which is irreparable and persistent. Telomeric DNA is more susceptible to cleavage by ROS than non-telomeric DNA, resulting in single-strand breaks. ROS damage telomeres through the formation of 8-oxo-7,8-dihydroguanine, a modified base that acts as a telomerase chain terminator. This impairs telomerase-mediated telomere elongation and causes single-strand breaks in telomeric DNA. With advancing age, both telomerase activity and the expression of telomere protective proteins decline. The reduced expression levels of three key telomere protective proteins, namely, Trf1, Tpp1, and Pot1, have been associated with telomere shortening in CMs.[2] Evidence from clinical and experimental studies: In patients with AF, little substantial evidence indicates relative telomere shortening in atrial cells. However, leukocyte telomere length (LTL) shortening has been associated with the development of paroxysmal AF (PAF). LTL shortening is a predictor of progression from PAF to persistent AF (PsAF) and might serve as a biomarker for predicting post-ablation AF. An in vitro study found that silencing TERT in HL-1 cells results in shortened action potential duration (APD), intracellular Ca2+ overload, decreased L-type calcium currents, and increased ROS levels. In a mouse model of hypertensive heart failure, myocardial regions with pronounced fibrosis had significantly shorter total telomere lengths. Taken together, telomere dysfunction may contribute to AF pathogenesis through electrophysiological alterations and structural remodeling. Mechanisms by which telomeres affect AF: The telomere protective protein TRF2 positively regulates telomere length and inhibits ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling in the telomeric region. The downregulation of TRF2 expression leads to telomere dysfunction and ATM activation.[1] Meanwhile, telomere shortening inhibits peroxisome proliferator-activated receptor γ-coactivator 1-α (PGC-1α) through ATM activation and p53 phosphorylation by the ataxia-telangiectasia and RAD3-related kinase (ATR) checkpoint kinase via the “telomere-p53-PGC axis”. This regulatory axis, involving p53 and PGC-1α, is thought to contribute to decreased L-type calcium currents and intracellular calcium overload in aged atrial cell membranes. These alterations trigger electrical and structural remodeling of the atrium, thereby promoting AF.[3] p53 directly binds to sarcoplasmic reticulum Ca2+-ATPase 1 (SERCA1), thereby altering its oxidative state and increasing Ca2+ loading. The reduced expression of pGC-1α, along with impaired type 1 ryanodine receptor function, exacerbates intracellular calcium overload by increasing calcium release. Additionally, senescence increases type 2 ryanodine receptor (RyR2) oxidation and phosphorylation, leading to intracellular calcium overload by increasing sarcoplasmic reticulum Ca2+ release. The reduced expression of PGC-1α inhibits SERCA1, thereby slowing intracellular calcium ion recycling and further exacerbating intracellular Ca2+ accumulation. Severe intracellular calcium overload enhances the action of sodium-calcium exchangers on the cell membrane, thereby increasing the transient inward current and inducing delayed afterdepolarization and triggered activity (TA), thus causing AF. Additionally, the reduced expression of PGC-1α directly decreases the cytosolic L-type calcium currents, thus shortening the plateau phase of the cardiac potential. This decreases the duration of the action potential and increases the risk of AF. Furthermore, the reduced expression of PGC-1α can directly reduce the L-type calcium current in the cell membrane, further shortening the action potential plateau period in CMs. This process shortens the APD, increases the incidence of afterdepolarizations and TAs, and triggers AF. Telomere shortening inhibits PGC-1α expression along with its downstream TERT expression. This, in turn, impairs mitochondrial function by damaging mitochondrial DNA (MtDNA). Oxidative stress induces mitochondrial outer membrane permeabilization, causing the oligomerization of voltage-dependent anion channel proteins (VDAC1 and VDAC3). This leads to pore formation and allows MtDNA fragments to reach the cytoplasm. Simultaneously, the activation of pro-apoptotic proteins Bak and Bax facilitates the formation of a channel structure that allows MtDNA protrusion and release into the cytoplasm. When MtDNA is released into the cytoplasm and extracellular matrix, it activates NOD-like receptor protein 3 (NLRP3) inflammatory vesicles. TERC, a long-stranded non-coding RNA, promotes the activation of the NF-κB signaling pathway, further exacerbating oxidative stress-related mitochondrial damage. Meanwhile, telomere dysfunction caused by decreased TERC expression leads to the overactivation of NLRP3 inflammatory vesicles. Activated NLRP3 signaling enhances RyR2 expression, increasing sarcoplasmic reticulum Ca2+ release. This leads to delayed afterdepolarization and TA by amplifying sodium-calcium exchanger activity, ultimately triggering AF. Additionally, activated NLRP3 inflammatory vesicles increase interleukin (IL)-1b and IL-18 production. This is positively correlated with the progression from paroxysmal to persistent AF and the development of persistent AF. The pathophysiological changes associated with aging create an environment conducive to the development of AF. Atrial fibrosis is a hallmark of structural remodeling in AF. Senescence activates the TGF-β/Smad signaling pathway, promoting the formation of Smad2, Smad3, and Smad4 trimeric complexes and their translocation to the nucleus and subsequently inducing the expression of fibrosis-related genes. Moreover, p53, activated by telomere shortening, directly interacts with the trimeric complexes, further exacerbating myocardial fibrosis and the inflammatory response.[4] Telomeric zinc finger-associated protein (TZAP) is a negative regulator of telomere length maintenance. Its overexpression has been associated with a significant increase in the expression of the transient receptor potential cation channel subfamily M member 7, a gene implicated in cellular responses. TZAP may contribute to telomere shortening and the activation of the TGF-β/Smad signaling pathway, thereby exacerbating fibrosis. Ultimately, TZAP may promote the progression of atrial fibrosis by enhancing TGF-β1 activity in atrial fibroblasts, thereby inducing AF. Therapeutic approaches targeting telomeres: Recent studies show that silent information regulator 1 (SIRT1) inhibits p53, stabilizing telomeres through deacetylation. Statins prevent telomere shortening by reducing oxidative stress, thereby preventing AF by blocking DNA damage and inflammatory responses. Inflammatory responses activated by telomere dysfunction can be attenuated by inhibiting or deleting the NLRP3 gene. The adeno-associated virus serotype 9-mediated knockdown of NLRP3 prevents AF, suggesting that NLRP3 inhibition may be a viable strategy for prevention. MCC950, a selective NLRP3 inhibitor, shows promise in treating AF by directly inhibiting NLRP3. SIRT3 reduces oxidative stress by promoting the production of reduced glutathione. Antioxidants such as vitamins C and E neutralize ROS, reducing telomeric DNA damage and decreasing AF incidence. Pim-1 activators inhibit the TGF-β pathway by decreasing Smad phosphorylation and upregulating TERT to maintain telomere length. Clustered regularly interspaced short palindromic repeats gene editing aims to precisely repair telomere DNA, maintaining genomic stability and cardiomyocytes function to prevent or treat AF. Therapeutic approaches targeting telomere maintenance, oxidative stress, and inflammation show promise in slowing cardiac aging and preventing AF. In conclusion, telomere shortening and dysfunction affect atrial electrophysiological properties, contributing to fibrosis and abnormal calcium handling, potentially precipitating AF. Oxidative stress and inflammation contribute to telomere shortening, further promoting AF development. Although not routinely used for diagnosis, telomere length holds potential as a biomarker and therapeutic target for AF. Strategies like antioxidants, NLRP3 inhibitors, and SIRT1 activators have shown promise, but their long-term safety and efficacy require further validation. However, telomere length is not significantly associated with AF development or maintenance. AF is primarily associated with structural remodeling, inflammation, oxidative stress, and electrophysiological changes in the atria, rather than being directly determined by telomere length. Clinical trials have shown no consistent correlation between telomere length and AF manifestations or pathogenesis. Some studies fail to find significant differences in telomere length between patients with AF and controls. AF is multifactorial, influenced by risk factors like hypertension, diabetes, and coronary artery disease, which can all contribute to telomere shortening. Although telomere shortening is linked to aging, AF persistence and recurrence are more influenced by electrophysiological characteristics and external stimuli. Despite the role of telomere shortening in aging, clinical evidence supporting its direct link to AF remains lacking. Future studies may provide new therapeutic options for older patients with AF, improving their quality of life and alleviating the social and economic burden. Conflicts of interest None.