Telomerase-restoring molecule reverses hallmarks of aging

New research finds restoring telomerase activity reduces inflammation and enhances brain and muscle function in preclinical models.

Scientists at The University of Texas MD Anderson Cancer Center have identified a molecule that may help counteract aging. This molecule works by restoring youthful levels of telomerase reverse transcriptase (TERT), a part of the telomerase enzyme that declines as we age. Their findings, published in Cell, show promising preclinical results, suggesting potential benefits for age-related diseases such as Alzheimer’s, Parkinson’s, heart disease and cancer.

Longevity.Technology: Telomeres and telomerase play crucial roles in aging. Telomeres are protective caps at the ends of chromosomes, maintaining genetic stability during cell division. Over time, these structures shorten, leading to cell senescence or death. Telomerase, an enzyme that extends telomeres, becomes less active with age, causing telomeres to shorten. This shortening is a significant factor in aging and related diseases. Restoring telomerase activity could be a key strategy in aging therapies, making TERT a critical focus of study.

The researchers identified a small molecule compound that restores physiological levels of TERT, which are typically repressed with aging. In aged lab models, maintaining TERT levels reduced cellular senescence and tissue inflammation, encouraged new neuron formation, improved memory, and enhanced muscle function, increasing strength and coordination [1].

“Epigenetic repression of TERT plays a major role in the cellular decline seen at the onset of aging by regulating genes involved in learning, memory, muscle performance and inflammation,” said corresponding author Ronald DePinho, MD, professor of Cancer Biology. “By pharmacologically restoring youthful TERT levels, we reprogrammed expression of those genes, resulting in improved cognition and muscle performance while eliminating hallmarks linked to many age-related diseases [2].”

TERT not only extends telomeres but also acts as a transcription factor, affecting the expression of many genes related to neurogenesis, learning, memory, cellular senescence and inflammation; loss of TERT is connected to aging through various mechanisms.

Aging involves epigenetic changes that affect functional and physiological decline, and one key aspect is the gradual shortening of telomeres. Free radicals can also damage telomeres, and when telomeres become very short or damaged, they trigger a continual DNA damage response, leading to cell senescence; senescent cells release inflammatory factors, causing tissue damage and promoting aging and cancer.

Telomerase synthesizes and extends telomeres, but its activity decreases over time due to the epigenetic silencing of TERT, especially during natural aging or in age-related diseases like Alzheimer’s. Previous research from the DePinho laboratory showed that turning off the TERT gene in vivo led to premature aging, which could be reversed by reactivating TERT. They also found that some cells, such as neurons and cardiac cells, were rejuvenated without undergoing normal cell division required to synthesize telomeres.

These observations led to the hypothesis that TERT has functions beyond telomere synthesis and that overall telomerase levels are important in aging. Based on these findings, researchers, led by DePinho and first author Hong Seok Shim, PhD, sought to develop a drug that could restore TERT levels.

A high-throughput screen of over 650,000 compounds identified a small-molecule TERT activating compound (TAC) that epigenetically de-represses the TERT gene and restores physiological expression found in young cells.

In preclinical models equivalent to adults over age 75, six months of TAC treatment led to new neuron formation in the hippocampus and improved cognitive test performance. Additionally, there was an increase in genes involved in learning, memory, and synaptic biology, aligning with TERT’s role in regulating diverse genes [1].

TAC treatment also significantly reduced inflammaging – an age-related increase in inflammatory markers linked with multiple diseases – in both blood and tissue samples; it also eliminated senescent cells by repressing the p16 gene, a key senescence factor.

TAC improved neuromuscular function, coordination, grip strength, and speed in these models, reversing sarcopenia—a condition where muscle mass, strength, and performance decline with age.

In human cell lines, TAC treatment increased telomere synthesis, reduced DNA damage signals at telomeres, and extended the proliferative potential of these cells, demonstrating TAC’s activity in ex vivo human models [1].

“These preclinical results are encouraging, as TAC is easily absorbed by all tissues, including the central nervous system. Yet further studies are needed to properly assess its safety and activity in long-term treatment strategies,” DePinho said. “However, our deeper understanding of the molecular mechanisms driving the aging process has uncovered viable drug targets, allowing us to explore opportunities to intercept the causes of a variety of major age-related chronic diseases [2].”

While further clinical studies are needed to confirm these results and map out potential therapeutic applications, the findings suggest that restoring TERT levels could be a promising approach to mitigating various aspects of aging and related diseases, perhaps leading to improved brain and muscle function and reduced inflammation in aging populations.

[1] https://www.cell.com/cell/abstract/S0092-8674(24)00592-0
[2] https://shorturl.at/tew4p

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