Telomerase
Telomerase is a reverse transcriptase composed of RNA and protein that maintains telomere length. Telomerase uses its own RNA as a template to synthesize telomere DNA, thereby enabling cells to proliferate indefinitely. It is mainly composed of three parts: human telomerase RNA (hTERC), human telomerase-associated protein (hTEP1) and human telomerase reverse transcriptase (hTERT). hTERT is considered to be the key component of telomerase activity expression, and the mRNA level encoded by hTERT is consistent with the overall activity of telomerase. Therefore, the hTERT subunit mRNA level gene expression can be used to measure the telomerase activity. The catalytic activity of hTERT and hTERC is necessary for telomere maintenance and elongation. DKC1 is an important part of the telomerase complex and belongs to one of the cooperative proteins. It plays an important role in the maintenance of normal telomere function, the processing of precursor rRNA, the normal ribosome biosynthesis, and the post-transcriptional modification of genes.
In normal human cells, the activity of telomerase is tightly regulated, and active telomerase can only be detected in hematopoietic cells, stem cells, and germ cells, which must constantly divide. When the cells are differentiated and mature, the activity of telomerase will gradually disappear. However, telomerase was reactivated in tumors, suggesting that telomerase may be involved in malignant transformation.
Fig. 1 Human telomere structure and telomerase recruitment (Sandin S.; Rhodes D. 2014).
Telomere Shortening is Considered A Sign of Aging
Telomeres represent essential structures located at the ends of eukaryotic cell chromosomes. They play a critical role in safeguarding DNA during cell replication by preventing interchromosomal end recombination, fusion, and chromosomal degradation, functioning similarly to protective caps. As cell division proceeds, telomeres naturally undergo a gradual reduction in length. However, when telomeres reach a certain critical point, they are no longer able to sustain chromosome stability, leading to cell dysfunction and potential demise. Consequently, telomere shortening is regarded as a marker of aging, highlighting the significance of telomerase in preventing this phenomenon.
The Potential Role of Telomerase in Cell Therapy in Aging
The elucidation of the various roles of telomeres and telomerase in the mechanisms of aging and disease has shed light on their potential as targets for interventions aimed at mitigating age-related pathologies. However, despite significant progress in this field, numerous knowledge gaps persist, particularly regarding the mechanisms governing the regulation of telomerase expression and activity. Thus, researchers continue to dedicate their efforts to addressing these gaps in our understanding.
A promising therapeutic approach that has emerged involves transient induction of telomerase, which allows for the restoration of telomere reserves and repair of telomere damage, all while mitigating the potential risks associated with constitutive telomerase activation and its potential to promote cancer. Preclinical studies utilizing a mouse model with long telomeres have demonstrated that overexpression of telomerase reverse transcriptase (TERT) can extend lifespan by as much as 40%.
Furthermore, as our comprehension of the intricate molecular network controlled by telomerase deepens, there has been a growing interest in exploring anti-aging drugs that can activate TERT expression, ultimately promoting rejuvenation. Although the precise mechanisms by which these drugs function remain largely elusive, certain small molecules, such as TA-65 (cycloastragenol) and histone deacetylase inhibitors, have shown potential in activating TERT.
References
- Hornsby P.J. Telomerase and the aging process. Experimental Gerontology. 2007, 42(7): 575-81.
- Sandin S.; Rhodes D. Telomerase structure. Current Opinion in Structural Biology. 2014, 25: 104-10.
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