New Drug Restores Telomerase, Improves Cognition in Mice (2024)

Scientists have identified a small molecule that upregulates telomerase reverse transcriptase (TERT) in multiple tissues, improving health and cognition in old mice.

Telomere attrition and health

The enzyme telomerase can prevent telomere attrition from happening by extending the length of telomeres. However, in most multicellular organisms, including humans, telomerase expression is switched off, except in germ cells, some types of stem cells, and certain white blood cells. While this might play a role in preventing cancer, as most cancerous cells must switch telomerase expression back on via mutations to enable runaway replication, numerous studies have shown that increasing telomerase through TERT delays aging and increases longevity of model organisms [1].

The small molecule that could

In the lab, this is usually done by introducing genetic vectors carrying a working copy of the gene that codes TERT. It’s this gene that is switched off in somatic cells. However, gene therapies are complex and expensive, and they are just entering the medical mainstream. What if we could do the same using a small molecule?

In a new paper, scientists from the University of Texas MD Anderson Cancer Center report that they have found such a molecule: TERT activator compound (TAC). The researchers started by screening more than 600 thousand molecules and found about 100 that could increase the activity of the human TERT gene. One of them particularly shined.

TAC worked narrowly and precisely, significantly upregulating only TERT and the two genes needed for its derepression.

Excited by these results, the researchers moved to experiments in vivo. TAC was shown to reach numerous tissues and organs, including, importantly, the central nervous system, and to be cleared from the organism in about three hours.

This, according to the researchers, was enough to improve multiple hallmarks of aging. Peripheral mononuclear blood cells (PBMCs), taken from the treated 12-month-old mice, had markedly lower expression levels of p16, an important marker of cellular senescence, as well as several other senescence-associated and pro-inflammatory molecules. Conversely, expression signatures of organism growth and of natural killer cell activation were upregulated.

In genetically modified mice lacking TERT, those changes did not happen, proving that TAC works specifically by upregulating TERT rather than via some other pathway. Interestingly, however, the treatment did not affect the levels of another popular marker of senescence, p21.

Cognitive improvements and more

Chronic TAC administration had a marked effect on the brain health and cognitive abilities in mice, in line with previous research on genetic reactivation of TERT [2]. The treatment increased the creation of new neurons (neurogenesis) and upregulated numerous genes associated with brain function. It also significantly diminished the number of activated microglia, the resident immune cells of the brain. Activated microglia are the primary drivers of neuroinflammation, which, in turn, is a major factor in age-related neurodegeneration. Accordingly, levels of several pro-inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α), were significantly downregulated in the hippocampi of the treated mice.

All of this translated into cognitive improvements. Treated old (26-27 months) mice scored better in hippocampus-related cognitive tests compared to controls. Interestingly, the mice also showed improved rotarod performance and grip strength. Unfortunately, the researchers did not investigate possible lifespan extension.

“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 Ronald DePinho, professor of Cancer Biology and the corresponding author on the paper. “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.”

This study highlights the significant regenerative capacity of aging organ systems as well as the ability to pharmacologically modulate aging hallmarks during natural aging. We report the discovery of a novel small-molecule telomerase activator that induces the physiological expression of TERT in both human and mouse somatic tissues. Our findings reinforce the view that TERT exerts anti-aging activity not only by preserving telomere integrity but also by modulating gene expression and cellular signaling pathways governing cellular survival, senescence, neurogenesis, and stress resistance, among other processes.

Literature

[1] Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO molecular medicine, 4(8), 691-704.

[2] Shim, H. S., Horner, J. W., Wu, C. J., Li, J., Lan, Z. D., Jiang, S., … & DePinho, R. A. (2021). Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models. Nature aging, 1(12), 1162-1174.