introduction
From ancient times to the present, whether it is Xu Fu sent by Qin Shi Huang to find the elixir of life, or Li Shimin, Taizong of the Tang Dynasty, who has a wide history, who was poisoned to the elixir of immortality, or the unremitting research of scientists on aging, immortality or reversing aging has always been the eternal pursuit of human beings. With the development of modern medicine and biology, scientists have a very deep understanding of aging, and the role of telomeres and telomerase has gradually become prominent. Telomeres are regions located at the ends of chromosomes, protecting DNA from degradation and preventing chromosomal adhesion and recombination. When cells divide, telomeres are slightly shortened. Therefore, the length of telomeres is a limiting factor for whether cells can continue to divide, and when telomeres are too short, the cells stop dividing and enter a state of senescence. Current studies have found that abnormal shortening of telomeres is associated with a variety of geriatric-related diseases, and telomere dysfunction is closely related to cellular senescence, decline in tissue function, and aging [1-3]. In fact, organisms can also express telomerase by adding DNA to the ends of telomeres to combat the natural shortening of telomeres. However, telomerase activity is low or inactive in most somatic cells, but in stem cells, germ cells, and cancer cells, telomerase is usually more active, helping these cells maintain their ability to proliferate. Due to the importance of telomerase function, it is increasingly being seen as a key target for anti-aging research. On June 21, 2024, Ronald A. DePinho's group from the University of Texas MD Anderson Cancer Research Center published a research paper TERT activation targets DNA methylation and multiple aging hallmarks in Cell. In this study, the authors found that a compound TAC can efficiently induce the expression of telomerase reverse transcriptase TERT through large-scale small molecule drug screening, and TAC has shown important clinical value in delaying aging and improving neurodegeneration.
Telomerase is a ribonucleoprotein complex whose transcriptional activity is tightly regulated within normal somatic cells, mainly due to transcriptional inhibition of telomerase reverse transcriptase, the core catalytic subunit of telomerase (TERT). Forced expression of TERT can reverse aging by promoting telomere synthesis and regulating the expression of aging-related genes [4-6]. If a compound that induces TERT expression can be screened, then this compound is likely to be an "elixir". Based on this, the authors developed a high-throughput screening method that can screen small molecule drugs that modulate the transcriptional activity of human TERT transgenes in adult mouse ear fibroblasts at scale. By screening more than 650,000 small and medium-sized molecule compounds, the authors found that TAC (named TERT activator compound in this paper) can induce TERT expression at the highest level, and TAC treatment can rewrite the transcriptional repression state upstream of the TERT gene. More importantly, intraperitoneal injection of TAC can induce the expression of human TERT gene in multiple tissues of transgenic mice, and the induction effect of TAC has also been verified in other aging models. These results suggest that TAC is a small molecule compound that can effectively activate TERT expression, and the intraperitoneal injection and multi-tissue high efficiency indicate that TAC may be used as a specific drug for reversing aging in clinical research.
Subsequently, to uncover the mechanism by which TAC induces TERT expression, the authors first analyzed the phosphorylation profiles of kinases and their substrates using phosphorylated kinase arrays. It was found that in human primary MRC-5 cells, the phosphorylation of ERK and its downstream effector S6 kinase continued to increase after TAC treatment, and inhibition of ERK kinase activity could induce TAC. Transcriptome analysis showed that TAC treatment upregulated the expression of the FOS gene, a major component of the AP-1 transcriptional complex, and interestingly contained two AP-1 binding sites upstream of the TERT gene. TAC induction was significantly inhibited by the absence of these two AP-1 binding sites, and AP-1 inhibitors showed similar results. These data suggest that TAC specifically activates transcriptional activation of the TERT gene through the MEK/ERK/AP-1 pathway.
After clarifying the mechanism of action of TAC, the authors wanted to continue to explore whether TAC can alleviate the aging of naturally aging mice in vitro. After intraperitoneal injection of TAC, the authors analyzed its exposure levels in plasma and determined the pharmacokinetic properties of TAC. Notably, TAC is found in approximately twice the concentration of plasma in the central nervous system, indicating that it effectively penetrates the blood-brain barrier. After analyzing multiple senescence markers of TAC treated mice, it was found that the aging gene characteristics (such as cell cycle arrest and PML body) were reduced. The expression of p16INK4a, a key driver of senescence-associated secretory phenotype (SASP), was inhibited, while activating markers of growth and natural killer cell activation; The expression of DNMT3b, which is responsible for hypermethylation of the p16INK4a promoter, was significantly reduced. SASP-induced reduction in the production of pro-inflammatory factors IL-1β and IL-6, etc. These findings suggest that TAC may serve as a potential anti-aging treatment to delay aging by activating TERT and altering aging-related gene expression patterns.
Finally, the ability of TAC to penetrate the blood-brain barrier suggests that it may play an important role in the nervous system. Therefore, the authors analyzed the effects of TAC treatment on the brain in detail. They found that TAC not only improved hippocampal-dependent cognitive function by activating TERT, but also enhanced neuromuscular function, with no significant adverse consequences. These studies point to the possibility that activation of TERT by pharmacological means could be used as a potential strategy to delay neurodegeneration and cognitive decline during aging.
研究模式图（Credit: Cell）
Overall, this article discovers a small molecule compound, TAC, which can activate the expression of TERT, reveals the molecular mechanism by which TAC works, and proposes the many roles of TAC in reversing aging. These findings provide valuable insights into the development of therapeutic strategies to slow or even reverse aging.
bibliography
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