Small Molecule Upregulation of TERT Expression Improves Function in Aged Mice

Increased telomerase expression achieved via gene therapy is well demonstrated to improve health and extend life span in mice. The end of every chromosome is capped with telomeres, repeated sequences of DNA that act as part of a system to limit cell replication, the Hayflick limit. A little of the length of a telomere is lost with each replication, and a cell becomes senescent or enters programmed cell death when telomeres become too short. The cells of the body are divided between the vast majority of somatic cells that are limited in this way, and the tiny minority of privileged stem cells that are capable of using telomerase to extend their telomeres, and thus replicate indefinitely. The role of stem cells is to produce new somatic cells to replace those lost to the Hayflick limit. This complicated system most likely evolved because it keeps the risk arising from cancerous mutations and other pathological forms of cell damage to a low enough level for a species to compete effectively.

When looking at telomere length in cell populations, the average is some reflection of pace of somatic cell division versus the pace at which stem cells deliver replacement somatic cells with long telomeres. With advancing age, stem cell function declines, and thus average telomere length decreases. This correlation isn't very strong, and only shows up in large data sets; there isn't much predictive power to measuring an individual's average telomere length in isolation. Nonetheless, forcing greater telomerase expression is beneficial in mice, improving tissue function across the board. Will this be true in larger mammals such as humans, species with quite different telomere dynamics? Mice express more telomerase more widely in their cell populations than is the case in primates, so that remains an open question.

This complicated business of telomere length is just one of the ways in which telomerase influences cell and tissue function, as today's research materials make clear. Telomerase expression declines with age, and when restored to youthful levels it initiates a broad cascade of changes in gene expression and improvements in cell function. Unlike past research, the scientists here made use of a newly discovered small molecule that can increase telomerase expression. Long-term use improves outcomes in aged mice in similar ways to one-time telomerase gene therapy, though the effect size will likely be smaller once enough work has been conducted to robustly calibrate the results. This is usually the case when moving from gene therapies to small molecule therapies that target the same mechanisms. Given that mice express telomerase to at least some degree most of their cells, while humans do not, one might wonder whether a small molecule approach to increase expression that works well in mice will be anywhere near as useful in our species - it may not work at all in somatic cells that do not express telomerase. The researchers tested in human cell lines, but these cell lines are by definition immortalized, expressing telomerase to maintain lengthy telomeres.

Activating molecular target reverses multiple hallmarks of aging

Researchers have identified a small molecule compound that restores physiological levels of telomerase reverse transcriptase (TERT), which normally is repressed with the onset of aging. Maintenance of TERT levels in aged lab models reduced cellular senescence and tissue inflammation, spurred new neuron formation with improved memory, and enhanced neuromuscular function, which increased strength and coordination. "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. 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."

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 present in young cells. In preclinical models equivalent to adults over age 75, TAC treatment for six months led to new neuron formation in the hippocampus (memory center) and improved performance in cognitive tests. Additionally, there was an increase in genes involved in learning, memory, and synaptic biology, consistent with TERT's ability to interact with and control the activity of transcription factor complexes regulating diverse genes. TAC treatment also significantly reduced inflammaging - an age-related increase in inflammatory markers linked with multiple diseases - in both blood and tissue samples and 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 under which muscle mass, strength and performance naturally worsen with advancing age.

TERT activation targets DNA methylation and multiple aging hallmarks

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

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