The Role of Telomerase in Maintaining Telomere Length and Preventing Cellular Aging

At a glance:

• Definition and Structure of Telomerase
• The Function of Telomerase in Telomere Maintenance
• Telomerase and Cellular Aging
• Telomerase Activity Regulation
• Application of telomerase in disease and anti-aging strategies
• Conclusion

At the extremities of chromosomes lie specialized structures called telomeres that safeguard genomic stability and influence cell lifespan. These protective sequences undergo progressive shortening during cellular replication cycles, ultimately leading to a state of senescence where cell division ceases-a phenomenon that plays a significant role in organismal aging and the development of multiple pathological conditions, from malignancies to disorders affecting neural function. The enzyme complex known as telomerase, composed of protein and RNA components, functions to counterbalance telomere attrition by synthesizing new telomeric sequences, which helps postpone cellular senescence. Our investigation examines how telomerase maintains DNA integrity, explores its differential regulation among various cellular populations, and evaluates its therapeutic applications in combating age-related conditions and treating disease.

Definition and Structure of Telomerase

Telomerase is a ribonucleoprotease that maintains the stability of chromosome ends by adding guanine-rich repeats to lengthen telomeres. This enzyme plays a key role in cell division, especially in preventing chromosome end shortening and end-to-end fusion.

Telomerase definition

Telomerase is a complex of RNA and protein that can synthesize and lengthen telomeric DNA repeats using its own RNA as a template. Its main function is to maintain telomere length, thereby maintaining the ability and stability of cells to divide. Telomerase is highly active in germ cells, stem cells and certain cancer cells, but is less active or completely inactive in most somatic cells.

Telomerase structure

Telomerase consists of telomerase RNA (TER) and telomerase reverse transcriptase (TERT). TERT contains multiple functional domains, such as the N-terminal TEN domain, the RNA binding domain (TRBD), the reverse transcriptase domain (RT), and the C-terminal CTE domain. These domains have different functional and structural characteristics in different species. TER contains a template region and multiple functionally important secondary structural elements, such as pseudo-junctions, 5 'boundary elements, etc. These elements play an important role in the catalytic function of telomerase and TERT binding.

Figure1.Human telomere structure and telomerase recruitment. (Boccardi, V.,et.al,2024)

The Function of Telomerase in Telomere Maintenance

Telomere Shortening Mechanism

Telomeres are DNA sequences located at the ends of chromosomes. Their main function is to protect chromosomes from damage and maintain their integrity. The chromosomes of eukaryotes are linear, and DNA polymerases cannot synthesize DNA from scratch and require an existing nucleotide chain as a starting point. In the replication of the lagging strand, the primer for the last Okazaki fragment cannot be replaced with DNA, resulting in the end not being fully replicated. As a result, a length of telomeres is lost every time a cell divides, a phenomenon called the "end-replication problem." In addition, telomeres are also susceptible to oxidative stress, further accelerating their shortening.

The Function of Telomerase

Telomerase can synthesize telomeric DNA through its RNA template, thereby lengthening telomeres at the ends of chromosomes. The core component of telomerase is the RNA template, which provides a 3' "primer" that allows DNA polymerase to synthesize repetitive sequences (such as TTAGGG). It lengthens telomeres by binding to the single-stranded overhangs of telomeres and using an RNA template to add new nucleotides. In addition to directly lengthening telomeres, telomerase has also been found to have other non-telomeric functions, such as regulating gene expression and participating in cell cycle regulation. These functions may further affect the biological behavior of cells and the occurrence of diseases.

In germ and stem cells, high telomerase activity enables indefinite cellular division by preserving the length of chromosomes. The limited expression of telomerase in somatic cells results in progressive telomere shortening during cell division cycles. Malignant cells demonstrate renewed telomerase function, which contributes to their unlimited replicative potential and perpetual growth capacity.

Telomerase and Cellular Aging

Telomere Shortening and Cellular Aging

As telomeres progressively shorten, they reach a critical threshold that prompts cells to initiate protective mechanisms aimed at mitigating DNA damage accumulation. This telomere shortening induces cellular senescence by activating DNA damage responses, including the p53 and p16INK4a pathways, which halt cell proliferation to prevent the replication of compromised cells. While this mechanism is essential for preserving genomic integrity, it simultaneously plays a significant role in the aging process and the development of age-related diseases.

The senescence triggered by telomere shortening is regarded as a pivotal element in aging. However, the interplay between telomere length and aging extends beyond a simple cause-and-effect relationship. Telomere length acts as a regulatory factor, orchestrating alterations in gene expression associated with aging. Among the extensive array of gene expression changes linked to aging, nearly a thousand are influenced by variations in telomere length.

Studies have also shown that telomere shortening is associated with a variety of aging-related diseases, including cardiovascular diseases, neurodegenerative diseases, pulmonary fibrosis, etc. For example, in heart disease, shortening of telomeres is associated with aging of cardiomyocytes, which can lead to reduced heart function. In neurodegenerative diseases, telomere dysfunction may lead to a decline in cognitive function and affect memory and learning abilities.

Figure2.TL in human tissues. (Demanelis, K,et.al,2020)

Telomerase in Preventing Cellular Aging

Telomerase lengthens telomeres by adding repetitive sequences, thereby maintaining telomere length and cell proliferation ability. Activating telomerase can extend the life of cells and has been shown to prolong life and delay aging-related pathology in animal models.

Figure3.Characteristics of hTERT make it an ideal therapeutic target for human cancers. (Lü, M., V.,et.al,2012)

Although telomerase activation can extend cell life, potential risks include increased risk of cancer development and uneven effects on different cell types. In addition, the impact of long-term activation of telomerase on tissue function and overall health still needs further study.

Normal somatic cells have a limited number of divisions, which is called the Hayflick limit. Telomere shortening is one of the important mechanisms leading to this limit. Many cancer cells have short telomeres, but telomerase is active in these cells, allowing cancer cells to divide indefinitely. Inhibiting telomerase activity through drugs may help prevent excessive division of cancer cells, thereby inhibiting tumor growth.

Telomerase Activity Regulation Regulation Mechanisms

Regulation of telomerase activity is a complex process involving multiple molecular mechanisms and signaling pathways. Telomerase consists of hTERT (catalytic subunit), hTR (RNA subunit) and hTEP1 (regulatory protein). Its activity is regulated by cell cycle, environmental factors and multiple regulatory factors.

Cell cycle regulation:

Telomerase activity shows obvious dynamic changes during the cell cycle. Telomerase activity is higher in the S phase of the cell cycle, but lower in the G1 and G2 phases. This change is closely related to the need for cell proliferation and DNA replication. In multicellular organisms, telomerase activity is flexibly regulated in germ cells to maintain telomere length, but at a lower level in somatic cells.

Environmental factors:

Telomerase activity may increase temporarily during environmental factors such as oxidative stress, inflammatory responses and tissue repair, but the increase is not unlimited.

Regulating factors:

Protein kinases: such as PKC and Akt regulate the activity of hTERT, the catalytic subunit of telomerase.

Transcription factors: such as P53, NF-κB, Wnt/β-catenin, etc. affect telomerase activity by regulating the transcription of the hTERT gene.

Post-translational modifications: For example, PP2A inhibits hTERT activity by dephosphorylating it.

Protein-protein interactions: For example, Plk1 stabilizes hTERT protein, enhancing its stability and upregulating telomerase activity.

Measurement of Telomerase Activity

Measurement of telomerase activity is an important means to study telomerase function. Common measurement methods include:

TRAP test (telomere repeat amplification protocol):

The TRAP test is a PCR-based technique used to detect extension products of specific oligonucleotide substrates. This technology can amplify and detect the signal of telomerase activity, providing a powerful tool for studying telomerase activity.

The TRAP test can be used clinically to diagnose tumors and evaluate treatment effectiveness. For example, in endometrial cancer, the TRAP method showed that normal endometrium expresses telomerase activity and is regulated by steroid hormones.

Real-time RT-PCR: Used to detect the expression level of hTERT mRNA and indirectly reflect telomerase activity.

Immunofluorescence staining: Used to detect the location and expression level of telomerase protein in cells.

Application of telomerase in disease and anti-aging strategies

Telomerase and age-related diseases

Telomere shortening is associated with a variety of diseases, such as cardiovascular diseases, neurodegenerative diseases, etc. The relationship between abnormal activation of telomerase activity and cancer occurrence has also attracted widespread attention. Therefore, the potential application of telomerase in disease treatment has important research value.

Telomerase activation and anti-aging strategies

The research progress of telomerase activators provides new ideas for anti-aging strategies. Some low-molecular-weight compounds, such as cycloAstragenol and its derivatives extracted from traditional Chinese medicine, have been shown to activate telomerase activity. These compounds may have potential therapeutic effects on restoring telomere length in stem cells and lymphocytes. However, the potential risks of telomerase activation cannot be ignored, such as increasing the risk of tumor development. Therefore, when considering telomerase activation as an anti-aging strategy, its potential side effects must be weighed.

Conclusion

Telomerase plays a key role in maintaining telomere length and preventing cell aging. Telomerase research provides new ideas for anti-aging and disease treatment. By studying the function and activity of telomerase in depth, we can better understand its role in cell aging and disease. Future research needs to further explore the regulatory mechanism of telomerase. Developing more effective telomerase regulators is the key to realizing the use of telomerase in disease treatment and anti-aging strategies. Through continuous exploration and innovation, we are expected to develop safer and more effective telomerase regulators, contributing to human health and longevity.