Restoring TERT levels reduces senescence/inflammation and improves neurogenesis/cognition

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This post is about a new article about the means to rejuvenate organisms, which indeed has important implications for neurodegenerative diseases.

Telomerase restores short bits of DNA known as telomeres, which are otherwise shortened after repeated division of a cell via mitosis. In normal circumstances, where telomerase is absent, a cell can't divide in daughters indefinitely. When it reaches the Hayflick limit the cells become senescent and cell division stops. Telomerase allows each daughter cell to replace the lost bit of DNA, allowing the cell line to divide without ever reaching the limit. This same unbounded growth is a feature of cancerous growth. enter image description here Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a subunit of the enzyme telomerase. TERT inhibition has been linked directly or indirectly to all hallmarks of aging, but TERT expression is linked to the development of many cancers. Unfortunately, TERT gene is epigenetically repressed with the onset of aging markers in all tissues.

Researchers at the University of Texas MD Anderson Cancer Center have shown they can therapeutically restore "youthful" levels of TERT and this can significantly reduce the signs and symptoms of aging in preclinical models (primary human cells and naturally aged mice).

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.

In the brain, scientists report that a new therapy (TAC) alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. This is probably too beautiful to be entirely true. Enhancing TERT expression notoriously promotes cancer and some cancer drugs downregulate TERT transcription, inhibiting telomerase activity and TERT expression.

To find a suitable compound, the authors used a high-throughput screen of over 650,000 compounds. TAC restores TERT levels to promote telomere maintenance and reprogram gene expression.

The usual suspects enhance TERT levels: Physical activity, good diet, and resveratrol.

It can also be done with a genetic therapy: Scientists insert a specific DNA sequence into a safe and predictable location on the genome to insert new genes. The new DNA fragment includes, for example, a "loxP-flanked stop cassette." This cassette acts like a switch that can be turned on or off. Under the control of an enzyme, for example, the "Cre recombinase" the "loxP" sites in the inserted DNA remove the stop cassette, allowing the TERT gene to be expressed in the targeted cells.

If these findings are confirmed in clinical studies, there may be major therapeutic implications for age-related diseases such as Alzheimer's, Parkinson's, heart disease and cancer.

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