Stressed Out Cells: Chronic Stress and Telomere Shortening

While many of us can resonate with the negative impacts of stress on our day-to-day lives, from a qualitative basis, chronic psychological stress also has far-reaching consequences on cellular and molecular health, contributing to accelerated biological aging. One of the most prominent biomarkers of this aging process is telomere shortening—a phenomenon driven in part by decreased activity of telomerase, the enzyme responsible for maintaining telomere length. For starters, it’s important to know what telomeres are, before understanding how they are indicators for stress in the body [1]. 

Telomeres are specialized DNA-protein structures located at the ends of chromosomes. They consist of repetitive DNA base pair sequences (TTAGGG in humans) that protect chromosome ends from being degraded, fused, or abnormally recombined. Each time a cell divides during mitosis, telomeres naturally shorten due to the inability of DNA polymerase to fully replicate the 3′ ends of a DNA strand [1]. This process is partially counteracted by telomerase, an enzyme that works against this process by adding telomeric repeats to chromosome ends.

In normal physiology, telomerase is tightly regulated. Its activity is modulated by a variety of transcription factors, signaling pathways, and epigenetic mechanisms. Any disruption in these regulatory processes—such as those induced by chronic stress—can suppress telomerase activity and lead to accelerated telomere loss [2]. This is truly the crux of how chronic stress impacts cellular activity. 

With this background in mind, this article further explores the molecular mechanisms by which chronic stress leads to reduced telomerase activity and subsequent telomere shortening. Emphasis is placed on the roles of the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, and epigenetic modifications in mediating this relationship [3]. The long-term effects of stress-induced telomerase inhibition are discussed in the context of aging and disease, highlighting the critical importance of stress management in promoting quality of life, in ways we might not expect.

Cortisol and the HPA Axis

One of the central biological pathways activated during chronic psychological stress is the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, the hypothalamus releases corticotropin-releasing hormone (CRH), which in turn stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH then prompts the adrenal cortex to release cortisol, the primary stress hormone we are most familiar with [4]. Persistently elevated cortisol levels have several long-term consequences that negatively impact telomerase activity.

Firstly, when cortisol enters cells, it can bind to glucocorticoid receptors (GRs), which can then move to the nucleus of a cell, where DNA is stored, and influence gene expression. This Glucocorticoid signaling has been shown to reduce expression of the TERT gene, which is responsible for making the telomere-rebuilding enzyme telomerase. When TERT expression is “turned off” by the interaction of glucocorticoid receptors and cortisol, telomeres are less protected. In cells with high turnover, meaning they move through the cell cycle and replicate quickly, particularly lymphocytes, cortisol-induced suppression of telomerase leads to increased telomere shortening during cell proliferation [5].

Interestingly enough, a landmark study by Epel et al. (2004) demonstrated that women experiencing high levels of perceived stress had significantly lower telomerase activity and shorter telomeres in peripheral blood mononuclear cells compared to low-stress controls. This study provided some of the first direct evidence linking chronic stress to suppressed telomerase function in humans [6].

Oxidative Stress

Telomeric DNA, the sequences that cap the ends of a chromosome, is particularly vulnerable to oxidative damage because of its high guanine content. Guanine is one of the four nucleotide bases in DNA. Guanine is particularly susceptible to oxidation, leading to the formation of 8-oxoguanine and DNA strand breaks. Oxidative damage at telomeres is difficult to repair efficiently, leading to the erosion of telomeric sequences. Reactive oxygen species (ROS) also directly inhibit the expression of telomerase by affecting redox-sensitive (chemical reactions that involve oxygen species) transcription factors that can also regulate TERT expression [7].
In vitro studies have shown that oxidative stress leads to a marked reduction in telomerase activity and an increase in cellular senescence (aging) markers. Thus, oxidative stress, linked with chronic mental stress and inflammation, serves both as a direct driver of telomere damage and an indirect suppressor of telomerase.

Chronic psychological stress is associated with increased systemic inflammation, characterized by elevated levels of cytokines, which are proteins released by your immune system. Pro-inflammatory cytokines have been shown to inhibit telomerase activity in various cell types, including immune cells themselves [8]. Some pro-inflammatory cytokines negatively regulate the transcription of TERT and may also impair the assembly or function of the telomerase enzyme complex. Inflammatory conditions promote increased proliferation of immune cells to combat perceived threats, resulting in more frequent cell division and faster telomere reduction. Studies in both animal models and human populations have consistently found correlations between elevated inflammatory markers and reduced telomerase activity.

Epigenetics

Epigenetic modifications refer to changes in gene expression that do not involve alterations in the actual DNA sequence. These include DNA methylation and non-coding RNA interactions. DNA methylation occurs when DNA is wrapped around histone proteins that become bonded to methyl groups. This leads to the DNA becoming more tightly bound, and, as a result, “unreadable” by key enzymes. Under the physiological conditions of chronic stress, several epigenetic changes can suppress telomerase’s telomere-restoring function. Hypermethylation of the TERT promoter leads to transcriptional silencing of the gene encoding the telomerase reverse transcriptase [9]. Epigenetic repression of telomerase is often sustained, which may explain why even past exposure to stress can result in lasting telomere shortening later in life.

Why does this matter?

Telomerase suppression and the resultant telomere shortening have broad implications for aging and the development of age-related diseases. When telomeres become critically short, cells enter a permanent state of arrested growth, or senescence, contributing to tissue dysfunction and the accumulation of senescent cells that secrete pro-inflammatory factors. Stem and progenitor cells, types of cells in our body that replicate the most often and are responsible for differentiating into specific cell types, rely on telomerase for long-term self-renewal. Telomerase inhibition limits their regenerative capacity, impairing tissue repair and the cell differentiation often involved in maturing the immune cells that “remember” pathogens. Short telomeres are also generally associated with increased risk of cardiovascular disease, neurodegenerative disorders, diabetes, and certain cancers, which can cyclically promote the chronic stress and inflammation that leads to telomere shortening in the first place [10]. By the opposite token, in some cancers, stress may contribute to abnormal telomerase reactivation, allowing damaged, cancerous cells to bypass cell aging and continue dividing, thereby promoting tumor growths.

Evidently, stress initiates a complex cascade of biological responses that converge on the inhibition of telomerase activity and the acceleration of telomere shortening. This process is mediated through multiple interconnected mechanisms, including activation of the HPA axis, elevation of cortisol, increased oxidative stress, systemic inflammation, and stress-induced epigenetic modifications. The suppression of telomerase in stressed individuals contributes to premature cellular aging, reduced regenerative potential, and heightened disease risk [11]. As such, mitigating chronic stress through behavioral, pharmacological, and lifestyle interventions plays a far more critical role in preserving telomere integrity and promoting long-term health than once expected.