Why Is Telomere Length So Important?

Telomeres are repetitive DNA sequences found at the end of linear chromosomes.¹ They protect the genome, maintain its stability, and preserve genetic information by preventing nucleolytic degradation, interchromosomal fusion, and unnecessary recombination. Telomeres shorten after each cell division due to the end replication problem, which is the inability of DNA polymerase to fully replicate the 3’ ends of linear chromosomes and exonuclease degradation of the telomeric 5′ strand; telomere length serves as a powerful biomarker of aging and age-related pathological conditions.² 

Carol Greider, Elizabeth Blackburn, and Jack Szostak won the 2009 Nobel Prize in Physiology or Medicine for discovering how telomeres and the telomere-elongating enzyme telomerase protect chromosomes.^3,4 Their research motivated scientists to study the association between telomerase, telomeres, and age-related diseases in humans.

Telomere Length Shortening and Telomerase

In normal mammalian cells, a small telomeric DNA segment is lost after each cell cycle, gradually eroding to a critical length. At this point, DNA repair systems recognize it as DNA damage and trigger a form of permanent cell cycle arrest called replicative senescence, which may lead to cell death called apoptosis.⁵ This checkpoint is important to prevent cells from replicating damaged DNA. Due to this phenomenon, scientists describe telomere length as a biological clock that indicates the lifespan of a cell and an organism.

Telomerase is a ribonucleoprotein enzyme responsible for maintaining telomere length.⁶ This enzyme comprises a telomerase RNA component (TERC) that identifies the telomeric sequence and acts as a template for telomeric DNA synthesis. It also contains telomerase reverse transcriptase (TERT), which uses TERC to synthesize and add telomeric DNA repeats to the ends of the chromosomes. In contrast to human somatic cells that are telomerase negative, telomerase activity is typically high in stem cells and germ cells to sustain telomere length and prevent premature senescence. 

When telomeres reduce to critically short lengths, they become unable to bind adequate telomere-capping proteins.⁷ This condition of exposed DNA ends triggers the DNA damage response pathway, which arrests cell proliferation. Additionally, telomeric DNA is susceptible to oxidative DNA damage. Oxidative stress can trigger accelerated telomere shortening by uncapping telomeres or inhibiting telomerase activity.

Telomere Length Measurement

Telomere length measurements provide valuable insights into diverse biological processes such as disease susceptibility, cellular aging, and overall well-being.⁸ The observed association between shorter telomeres and increased risk of cancer, cardiovascular disease, and neurodegenerative disorders emphasizes the importance of telomere length measurement. 

Scientists use various techniques to quantify telomere lengths such as terminal restriction fragment (TRF), polymerase chain reaction (PCR), next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), and single telomere length analysis (STELA).⁹ Each of these techniques has its strengths and limitations. 

A newly developed nanopore-based method, known as Telomere Profiling, facilitated telomere length measurement at nearly single-nucleotide resolution.¹⁰ “It's very exciting because it gives us an inroad into understanding new mechanisms that might be involved in telomere length regulation,” said Greider, who established this method. Shedding light on the mechanism of telomere length regulation may be further exploited for developing clinical interventions that control age-related conditions.

Telomere Length and Disease

Advanced telomere length measurement techniques not only estimate average telomere length but also highlight the potential chromatin interactions and conformation dynamics such as gene looping. Telomere shortening may influence these interactions and alter gene expression patterns through telomere position effects.¹¹ A progressive shortening of telomere length leads to important cellular changes such as apoptosis and senescence, which may significantly affect the health and lifespan of an individual. Although shorter telomeres do not always indicate a reduced lifespan, telomere shortening rates or increases in short telomeres may predict how fast a person is aging.¹²

     

Short telomere syndromes and premature aging

Scientists have linked the human short telomere phenotype with a broad spectrum of diseases that span from infancy to adulthood.¹³ A shorter telomere phenotype indicates a higher risk of bone marrow failure in children and younger adults. Dyskeratosis congenita, characterized by abnormalities in proliferative tissues such as skin, nails, and mucosa, is a disorder linked with telomerase mutations and short telomeres.¹⁴ Lung diseases such as idiopathic pulmonary fibrosis and familial pulmonary fibrosis are also manifestations of short telomere syndromes.¹⁵ Furthermore, an increased incidence of non-melanoma skin cancers, myelodysplasia, acute myeloid leukemia, and squamous cell carcinomas of the head and neck are associated with short telomere syndromes. 

Scientists have also linked telomere shortening with cognitive decline that commonly occurs in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's disease.¹⁶ Additionally, shorter telomeres may indicate an increased risk of developing cardiovascular conditions such as coronary artery disease and atherosclerosis.¹⁷ 

Long telomere syndromes

Researchers have observed that mutations in the TERT promoter elevate cancer risk through telomere lengthening.¹⁸ For example, promoter mutations that create an E-twenty-six (ETS) binding site and trigger TERT transcription can lead to an increase in telomere length. This elevates the risks of solid cancers, particularly melanoma and glioma.

Scientists have used cell and animal models to provide proof of concept for the potential efficacy of telomerase activation-based therapeutic strategies that counteract changes in telomere shortening and its consequences.¹⁹ Slowing the pace of the telomere shortening could positively alleviate many age-related degenerative conditions. Alternatively, researchers have investigated the anticancer therapeutic potential of inhibiting telomerase. 

For either strategy to be effective, it is important to understand the fundamental mechanisms associated with telomere elongation. “If you don't understand the fundamentals of how it’s regulated, then you don't have avenues to either elongate telomeres for age-related degenerative disease or shorten telomeres for cancer,” said Greider. “By understanding the fundamentals, then you can more readily potentially develop some kinds of therapies.”

FAQ:

What are telomeres and what is their function?

• Telomeres are repetitive DNA sequences found at the ends of each chromosome pair. They are responsible for maintaining chromosomal stability and preventing chromosomal degradation.

Where are telomeres located?

• Telomeres are located at the ends of linear chromosomes.

What is telomerase?

• Telomerase is an enzyme that maintains telomere length by adding guanine-rich repetitive sequences through reverse transcription.²⁰ 

How do telomeres shorten or lengthen?

• Telomeres shorten during cell division due to the inability of DNA polymerase to fully replicate the 3’ ends. They may also shorten because of oxidative damage to telomeric DNA and exonuclease degradation of the telomeric 5′ strand. Typically, telomeres lengthen through telomerase activity. In human cancer cell lines and tumors, telomeres may also lengthen through a genetic recombination mechanism called alternative lengthening of telomeres (ALT).²¹

What happens when telomeres shorten?

• Progressive telomere shortening leads to replicative senescence and apoptosis, which affects the health and lifespan of an individual.¹ 

Is it possible to repair telomeres?

• Telomerase can repair spontaneous breaks in telomeres. In some cases, DNA repair pathways activate and cause unwanted chromosomal rearrangements or fusions within damaged telomeres.²²

How do telomeres affect aging?

• When telomere length shortens, replicative senescence or cellular aging occurs.¹ Accelerated telomere shortening increases the risk of many age-related conditions such as neurodegenerative disorders and cardiovascular diseases.