Restoring “youthful” levels of a specific telomerase enzyme slowed signs of aging in preclinical models, according to researchers at The University of Texas MD Anderson Cancer Center. These findings could have therapeutic implications for age-related diseases such as Alzheimer’s, Parkinson’s, heart disease, and cancer. The team found that telomerase reverse transcriptase (TERT) not only extends telomeres, but also affects the expression of many genes directing neurogenesis, learning and memory, cellular senescence, and inflammation.
The study was published in Cell last week. The first author is Hong Seok Shim, PhD.
Telomerase is a protein complex that extends telomeres. But its activity is reduced over time due to the epigenetic silencing of TERT, particularly at the onset of natural aging or Alzheimer’s and other age-related diseases.
These researchers used a small molecule compound that restores physiological levels of TERT when it 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.
Telomeres are the chromosomal end structures and shorten over time. When they become extremely short or modified, it triggers a continual DNA damage response that can lead to cell senescence, during which cells release inflammatory factors that can cause tissue damage, prompting aging and cancer.
The DePinho laboratory previously showed that deactivating the TERT gene in vivo led to premature aging, which could be reversed through TERT reactivation. The researchers also observed that certain cells, such as neurons and cardiac cells, were rejuvenated without undergoing the normal cell division required to synthesize telomeres.
Their observations led them to hypothesize that TERT had other functions beyond synthesizing telomeres and that overall telomerase levels were important in the aging process. Based on these findings, the researchers, led by Ronald A. DePinho and Shim aimed to develop a drug to restore TERT levels.
They used a high-throughput screen of over 650,000 compounds to find 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, treatment with TAC for six months led to new neuron formation in the hippocampus 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 in both blood and tissue samples and 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.
Further, TAC treatment in human cell lines increased telomere synthesis with reduced DNA damage signal at telomeres and extended the proliferative potential of these cells, demonstrating the activity of TAC in ex vivo human models.
“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.”
