Every person is born with a specific telomere length (TL) that ranges between 5 to 15 kb, which is affected as the years go by [28]. The rate of TL shortening hovers at 20–50 bp while it is dependent on several factors such as the end-replication phenomenon, oxidative stress, and other DNA-damaging agents [29,30,31,32]. According to the above-mentioned loop formation hypothesis, telomeric regions can form loops having a minimum length of about several thousand nucleotides, which can be used by the cell to quickly detect DNA breaks in this area [33]. By the end-replication phenomenon, a small telomeric DNA fragment is lost in every cell division due to the inability of transcription of the free 3′-chain. So naturally, telomeres reach a critical length and to such an extent that no loop can be formed. Telomere shortening is thought to be the cause of the restricted number of divisions in most human cells. Hayflick was the first to describe this occurrence and this phenomenon was later called the “Hayflick Limit” [34]. A DNA damage signal is received by the cell at this time, and telomeres lose their protective role. This critical shortening of TL leads the cell into senescence, and causative cell death, which is regulated by inner biochemical and pro-inflammatory changes via the transition of the cell into a senescence-associated secretory phenotype (SASP) [35,36]. The DNA-damage signal becomes permanent, leading to activation of cyclin-dependent inhibitor pathways, including either the p53/p21Cip or p16Ink4a/Rb while transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), CCAAT/enhancer-binding protein (C/EBP), and tumor protein p53 are controlling the procession [31,32,36]. Although TL varies along the tissue types due to the altered proliferation rates, a correlation has been observed between TL in different tissues and peripheral blood leucocytes [28,29,30,37,38].

Telomeres, called the “biological clock” of cells, are a recognized marker of cell senescence. They are widely affected by a variety of intrinsic and environmental factors via the upregulation of oxidative stress levels. It is a condition in which increased levels of reactive oxygen species (ROS), such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are present due to a biological imbalance [39]. Dysfunctional mitochondria and immune cells are responsible for the main expression of ROS . The high guanine content of telomeres makes telomeres an easy target for ROS, leading to guanine oxidation. These point mutations and single or double DNA breaks affect telomeres’ function and cell proliferation [40,41]. Consequently, oxidative stress leads to TL shortening which is closely associated with tissue age-related decline regardless of the telomerase function [42]. When a critical TL is reached, apoptotic mechanisms and molecular paths such as p53, MAP kinase (mitogen-activated protein kinase), and transcription factor kappa B are activated, leading to cell senescence [43]. Cells with SASP secrete a variety of pro- and inflammatory cytokines well known for their atherosclerotic effect [44]. SASP cells have been identified in vasculature regions with atherosclerotic plaques as well as in cardiomyocytes in biopsies of patients with heart failure [45,46,47]. In both conditions, the SASP phenotype was followed by significant short TL [45]. As a result, factors that induce oxidative stress and telomere shortening can lead to a vicious cycle that promotes a state of chronic inflammation, which causes vascular endothelial dysfunction and contributes to the development of atherosclerotic plaques.

Atherosclerosis is a multifactorial condition whose progression is affected by a variety of cardiovascular risk factors [2]. Recently, short LTL has been positively associated with cardiovascular risk factors such as high BMI, waist circumference, high levels of blood C-reactive protein, low levels of HDL (high-density lipoprotein), high levels of cholesterol and triglycerides, as well as insulin resistance and blood pressure [48,49,50]. In another study, although no association was observed between classical cardiovascular risk factors and short LTL, when the results were adjusted to smokers a strong statistical significance was detected [51]. Benetos et al. previously verified the link between hypertension and shorter telomeres [52]. In the same regard, Morgan et al. discovered that the exposed telomere ends led to arterial cell senescence in individuals with hypertension [53]. Finally, Haycock et al. concluded that patients with diabetes mellitus presented shorter LTL than their healthy counterparts [54]. Short telomeres have been linked to increased arterial stiffness, preclinical atherosclerosis, and poor diabetes management. This might be owing to the harmful consequences of persistent hyperglycemia and the accumulation of advanced glycation end products (AGEs) [55].

Atherosclerosis is characterized by the formation of plaques in the vessel wall. These emerge as a result of complex pathophysiological pathways involving pro- and anti-inflammatory cytokines [1,56]. Given the elevated cardiovascular risk in people with short LTL, it would be rational to assume that there is a connection between short LTL and subclinical atherosclerosis. Since the investigation of potential indicators of atherosclerosis progression constitutes a huge challenge worldwide, several studies are trying to detect the exact role of LTL in this context. Until now, the landscape has been quite hazy with the results from a number of studies being inconsistent. In 2016, a large study including 1459 middle-aged adults found no statistically significant link between shortened LTL and subclinical atherosclerosis [57,58]. Thus, TL does not seem to have a prognostic value in individuals without clinical signs of disease. Indeed, Nzietchueng and Nguyen et al. showed a significantly shorter TL in aortic cells with atherosclerotic lesions as well as in vasculature regions with low elasticity [59,60]. A possible explanation is that local vascular alterations affect TL as a result of oxidative stress. In the Framingham study, internal carotid artery intima-media thickness was linked with short LTL among obese males (BMI > 30 kg/m²) but not in the whole cohort. No association was observed between short LTL and common carotid artery intima-media thickness or carotid artery stenosis [61]. Trying to connect LTL with potential modifiable behavioral factors, Bountziouka et al. analyzed 422.797 patients from the UK Biobank. Although lifestyle changes appear to be quantitatively related with LTL, the magnitude of these effects is insufficient to appreciably affect the connection between LTL and various diseases or life expectancy [62]. In another study, Schellnegger et al. highlighted the detrimental role of sedentary life, not only in cardiovascular risk induction but also in LTL attrition. More specifically, a regular basis aerobic physical activity at a moderate to high level tends to help LTL preservation, while it is still unclear as to the optimal type and duration of exercising [63]. LTL was also not a significant predictor of intima-media thickness or plaque formation in the Asklepios study [57]. However, Panayiotou et al. showed an inverse association between LTL and common carotid artery intima-media thickness [64]. In the same aspect, the Strong Heart Study examined 2819 Americans without known cardiovascular risk factors for a follow-up period of 5.5 years to assess the predictive role of LTL in the occurrence and progression of carotid atherosclerosis. The shortest LTL had a 49% and 61% greater incidence of plaque formation and plaque development, respectively, than the longest LTL [65]. Finally, a strong association of carotid atherosclerosis with short LTL has been established in hypertensive patients, highlighting the unfavorable impact of hypertension on TL [66].

Since observational studies illustrated that attrition of LTL is related to mortality, physicians are trying to investigate its role in cardiovascular disease (CVD), which is the leading cause of death worldwide [67]. The Hutchinson–Guilford Progeria Syndrome constitutes a striking example of age-related LTL shortening, in which the majority of the patients die from a myocardial infarction or stroke in their teenage years [68]. Premature senescence of fibroblasts as well as rapid TL shortening was observed in the cell cultures of these patients [68]. As such, there was a rationale for further exploration of LTL’s role in CVD, especially since studies showed that shorter LTL is associated with higher mortality rates. Indeed, in the Bruneck and LURIC studies, patients with a lower relative LTL presented higher death incidences in a 10-year follow-up [67,69,70]. In the same vein, multiple studies reported an increase in all-cause mortality risk, ranging from 17% to 66%, when patients with the longest telomeres were compared to subjects with the shortest telomeres [67,69,70,71,72]. However, some studies could not confirm the hypothesis of the association between LTL and CVD or mortality. This might be partially explained by the fact that some of these studies focused on low-risk populations with a modest number of events [73,74,75].

Several studies also investigated the association of LTL shortening with the presentation and progression of CAD. In two studies conducted in 2010 and 2021, physicians found that LTL in patients with stable CAD was significantly shorter than in healthy individuals of the same age (1.13 ± 0.52 CU in patients with CAD vs. 1.52 ± 0.81 CU in healthy individuals) which was further extended to sex analysis. It was interesting that men presented with shorter LTL than women, which could partially be related to the effect of estrogen, but this is an observation that remains hazy [70,76]. Trying to investigate the genetic background of premature CAD onset, Tian et al. compared Chinese patients with healthy individuals. It was shown that patients with premature CAD presented shorter LTL and higher circulating levels of oxidative stress components [77]. In another study, men with arterial hypertension, CAD, and early vascular aging (defined as arterial hypertension or CAD debut at young age—before 45 years, increased vascular wall stiffness according to the cardio-ankle vascular index), the LTL was significantly shorter than in men with arterial hypertension and CAD but without early vascular aging [78]. Haycock et al. conducted a meta-analysis on 43,000 individuals, including over 8000 patients with cardiovascular disease. It was demonstrated that, regardless of other risk factors, people with a shorter LTL were more likely to develop CAD [54]. In another meta-analysis published in 2020, shorter LTL was shown to be strongly connected to CAD severity, with Asians presenting the shortest LTL after ethnicity adjustment [79]. However, regarding the association of function stages of stable angina I–III (according to the Canadian Cardiovascular Society classifications) and LTL, no significant relation was observed [67,78].

One of the major manifestations of CAD is myocardial infarction (MI), and the development of biomarkers for early prognosis is referred to as mandatory [80,81,82,83,84]. LTL has been investigated as a potential biomarker with controversial results. A significantly shorter LTL has been observed in individuals with MI compared to healthy individuals even after adjustment for sex, body mass, and age [80]. Similarly, a study from the United Kingdom in 2017 demonstrated that in patients suffering from MI, LTL may be a useful prognostic biomarker for cardiovascular outcomes after the event, regardless of age. More particularly, MI patients with short LTL (defined as less than 0.96 CU in the study) presented significantly higher rates of all-cause and cardiovascular mortality within the first year after the event [85,86]. On the other hand, Russo et al. found no significant association between LTL and MI occurrence in young Italians [87]. Neither could Chan et al. confirm the hypothesis, as no statistically significant association was observed between relative LTL and adverse MI outcomes (death, recurrent MI, unplanned percutaneous coronary intervention revascularization, stroke, significant bleeding) in elderly Chinese patients, one year after their percutaneous coronary intervention [88]. Finally, while there was initially a connection between LTL and MI incidence in Czech women, the significance was lost after adjusting for major cardiovascular risk factors [86]. LTL has also been explored as a potential biomarker for the prognostication of stroke. The vast majority of the trials, which included over 37,000 and 25,000 people, respectively, could not establish a link between stroke risk and LTL [89,90].