How Telomerase Fights Aging

Abstract：Telomerase, an enzyme that extends the protective telomeres at the ends of chromosomes, plays a critical role in cellular aging and longevity. As cells divide, telomeres shorten, eventually triggering cellular senescence or apoptosis. Telomerase can counteract this process by replenishing telomeres, theoretically extending cellular lifespan and delaying aging. However, excessive telomerase activity is also associated with cancer, as it allows uncontrolled cell division.

Recent studies suggest telomerase might have broader benefits beyond telomere extension, including gene regulation and cellular health improvement. Short-term telomerase activation in animal models has shown promise in reversing age-related decline without increasing cancer risk. Notably, the discovery of a small-molecule compound, TAC, capable of safely activating telomerase, has reignited hopes for anti-aging therapies. However, precise control remains essential to balance the enzyme's rejuvenating potential against its oncogenic risks.

Telomeres and telomerase are often mentioned in discussions of aging and longevity. Telomeres are specialized DNA structures located at the ends of chromosomes, acting like protective caps that prevent genetic material from degrading during cell division. Human cells carry 23 pairs of chromosomes, each with long telomere sequences composed of the repetitive nucleotide sequence TTAGGG, repeated 500 to 3000 times.

Telomeres play a crucial protective role, similar to the plastic tips on shoelaces that prevent fraying. However, with each round of cell division, telomeres naturally shorten by 50-200 base pairs due to the inherent limitations of DNA replication. Once telomeres become critically short, cells lose their protective buffer and can no longer divide, entering a state of cellular senescence or programmed cell death, known as apoptosis. This phenomenon, termed the Hayflick limit, restricts human cells to about 40-60 divisions before aging sets in. As a result, telomere length has become a widely studied biomarker for cellular and organismal aging.

Could Extending Telomeres Reverse Aging?

The idea seems intuitive: if telomere shortening drives aging, could artificially extending them reverse it? The enzyme telomerase offers a possible answer.

Telomerase was discovered in the 1980s and functions by extending telomeres. It consists of two main components: an RNA template (with a CCCUAA sequence complementary to telomere repeats) and a reverse transcriptase enzyme that synthesizes new telomeric DNA. Together, they elongate telomeres by adding TTAGGG repeats to the chromosome ends.

In theory, activating telomerase should counteract telomere shortening, preventing cellular aging. Indeed, studies have shown that deactivating telomerase leads to premature aging, while reactivating it can extend cellular lifespan. Some individuals with genetic mutations impairing telomerase function experience early-onset aging disorders, while increasing telomerase activity in cells can delay cellular senescence.

However, this promising mechanism comes with significant risks.

The Double-Edged Sword of Telomerase

While telomerase can extend cellular lifespan, it also poses serious cancer risks. In most adult human tissues, telomerase activity is suppressed, as mature cells do not need to divide frequently. However, telomerase is highly active in most cancer cells, where it helps maintain indefinite replication by bypassing the Hayflick limit.

Cancer cells often reactivate telomerase to sustain uncontrolled growth. Approximately 85-90% of human tumors show abnormal telomerase activity, and mutations that upregulate telomerase are found in roughly 20% of cancers. Therefore, while telomerase can extend cellular life, its activation can also promote cancer by enabling unchecked cellular division.

This dual role has led to conflicting findings: mice genetically engineered to overexpress telomerase from birth often develop cancer, while in elderly mice, careful reactivation of telomerase can delay aging without triggering tumor formation.

Can Telomerase Be Used Safely?

Despite the risks, researchers continue exploring ways to harness telomerase for anti-aging purposes. One promising approach involves short-term activation in older organisms.

In a 2012 study, scientists used gene therapy to introduce telomerase genes into 1- and 2-year-old mice using viral vectors. The treatment extended lifespan by 24% in the younger group and 13% in the older group, without significantly increasing cancer incidence. The treated mice also exhibited improved metabolism, muscle function, and cognitive performance.

The key appears to be careful, temporary activation of telomerase, as excessive activation can still lead to tumorigenesis. Interestingly, telomerase also seems to have cellular benefits beyond telomere extension.

Telomerase Beyond Telomeres

Recent findings suggest telomerase might play additional roles unrelated to telomere maintenance. In non-dividing cells like neurons, increased telomerase activity has been linked to improved cellular health and cognitive function.

Studies have shown that introducing telomerase into aging neurons can reverse certain aging markers and enhance cognitive performance in mice models of Alzheimer's disease. Notably, these improvements occurred even when the enzyme's reverse transcriptase activity was disabled, suggesting a separate gene-regulating function.

Telomerase can bind to promoter regions of specific genes, modulating their expression and improving cellular health independently of telomere length.

New Drug Discoveries and Clinical Trials

A major breakthrough came in July 2024, when researchers published a study in Cell detailing the discovery of a small-molecule drug capable of activating telomerase safely.

Scientists screened 650,000 compounds and identified a molecule named TAC (TERT-Activating Compound), which directly stimulated telomerase expression by activating the AP-1 transcription factor. When administered to aging mice, TAC treatment extended telomeres, improved gene expression patterns linked to youth, and reduced inflammatory markers associated with aging.

Crucially, short-term TAC administration reversed age-related cognitive decline in mice, improving hippocampal neurogenesis and synaptic function while reducing chronic inflammation. These benefits persisted without the emergence of tumors, likely due to the temporary nature of the intervention.

However, the study also highlighted practical challenges: TAC requires frequent injections due to its short half-life and might not be a suitable long-term solution without further modifications.

A Parallel with Yamanaka Factors

The telomerase approach has parallels with another anti-aging strategy involving Yamanaka factors—a set of genes (Oct4, Sox2, Klf4, and c-Myc) capable of reprogramming mature cells to a youthful stem-cell-like state.

In 2016, a study showed that brief activation of Yamanaka factors in mice reversed cellular aging and improved organ function without causing cancer. However, prolonged activation led to tumorigenesis, much like telomerase.

Conclusion: Balancing Benefits and Risks

Telomerase remains a promising yet complex tool in the quest to combat aging. While its potential to extend cellular lifespan and reverse age-related decline is well-supported, the risks of unchecked cellular proliferation and cancer cannot be ignored.

The key to harnessing telomerase lies in precise control—short-term activation, carefully measured dosages, and targeted delivery. As research advances, the hope is that telomerase-based therapies can be developed to safely extend healthy lifespan, offering a powerful tool in the fight against age-related decline.