Researchers at The University of Texas MD Anderson Cancer Center have conducted a study demonstrating the potential benefits of restoring youthful levels of a specific subunit of the telomerase enzyme in reducing signs of aging in preclinical models. The researchers found that maintaining physiological levels of telomerase reverse transcriptase (TERT) could reduce cellular senescence, tissue inflammation, and improve memory and neuromuscular function. TERT acts not only to extend telomeres but also as a transcription factor affecting the expression of genes related to neurogenesis, learning and memory, cellular senescence, and inflammation.
The study showed that epigenetic repression of TERT contributes to cellular decline associated with aging, affecting genes involved in various functions such as muscle performance, cognition, and inflammation. Loss of TERT is linked to aging through multiple mechanisms, including the shortening of telomeres and DNA damage response triggered by the cells. Epigenetic silencing of TERT leads to reduced telomerase activity, particularly with the onset of natural aging or age-related diseases such as Alzheimer’s. The researchers hypothesized that overall telomerase levels play a critical role in the aging process.
Driven by their previous findings on TERT deactivation leading to premature aging and rejuvenation upon reactivation, the researchers aimed to develop a drug to restore TERT levels. Through high-throughput screening, they identified a small-molecule TERT activating compound (TAC) that epigenetically de-repressed the TERT gene, leading to physiological expression similar to that in young cells. Treatment with TAC in preclinical models equivalent to adults over age 75 resulted in new neuron formation in the hippocampus, improved cognitive performance, reduced inflammaging, and increased neuromuscular function, reversing sarcopenia.
The TAC treatment also reduced inflammatory markers linked with multiple diseases and repressed senescent cells by targeting the p16 gene, a key factor in cellular senescence. In human cell lines, TAC treatment increased telomere synthesis, reduced DNA damage signal at telomeres, and extended the proliferative potential of these cells, demonstrating TAC’s potential in ex vivo human models. The researchers are encouraged by these preclinical results, as TAC is easily absorbed by all tissues, including the central nervous system. Further studies are needed to assess TAC’s safety and efficacy in long-term treatment strategies.
The study was supported by various funding sources, including the National Institutes of Health and charitable foundations, and involved collaboration with experts from the Scripps Institute. The researchers believe that their deeper understanding of the molecular mechanisms driving the aging process has uncovered potential drug targets that could lead to interventions for a range of age-related chronic diseases. By exploring therapeutic strategies that target TERT and telomerase activity, there may be implications for treating conditions such as Alzheimer’s, Parkinson’s, heart disease, and cancer, offering hope for addressing the challenges of aging-related health issues.