Fight Aging!

Telomerase is of primary interest to the research community for its role in lengthening telomeres, the protective caps on the ends of chromosomes. This is an important function in cell dynamics: telomeres shorten with each cell division, forming a crude clock that limits the number of times cells divide in populations without significant telomerase activity. Age tends to reduce average telomere length in tissues, but this seems most likely a measure of damage and changes rather than a form of damage in and of itself - a consequence, not a cause of aging. Nonethless, using genetic engineering to boost levels of telomerase in mice leads to extension of life. In past years there has been some suggestion that telomerase might help maintain mitochondrial integrity against oxidative damage, and this could be why it can be used to extend life. But this is still an open question.

Most cancers abuse telomerase to keep their cells dividing to form tumors, and the SENS anti-cancer strategy of WILT would involve suppressing telomerase as a part of the way to strike at the root commonality shared by all cancer. But what else might telomerase do? There is no shortage of proteins in the body that have multiple important roles: evolution clearly often leads to reuse of existing components. If telomerase has other roles, this would complicate WILT. Here is a recent paper that looks into the evidence for other activities on the part of telomerase:

For more than a decade, diverse telomerase mouse models have provided us with precious opportunities for evaluating the patho-physiological significance of telomerase in genetically defined environments and at an organismal level. With an emphasis on defective telomeres, these mouse models have considerably contributed to understanding a broad spectrum of phenomena associated with cancer and ageing. Furthermore, growing evidence has indicated that defective telomerase functions are involved in distinct diseases other than human cancers including dyskeratosis congenita, atherosclerosis, and renal diseases.

Despite the evident roles in telomeres, currently emerging extra-telomeric functions of telomerase are completely changing the scope of this enzyme. Notably, the direct roles of TERT in transcriptional regulation provide good rationale for several phenotypes that cannot be explained by telomere dysfunction, and their physiological significance has been also confirmed using telomerase mouse models. As might be expected, these lines of evidence make us consider that diverse observations supporting extra-telomeric roles of telomerase should be scrutinized and validated in vivo by generating novel mouse models.

For example, in addition to the effect of short telomeres on mitochondria, mitochondrial targeting of telomerase upon certain stressful conditions, and the recently identified RNA-dependent RNA polymerase activity of TERT indicates that telomerase has direct roles in mitochondria. Furthermore, considering the important roles of telomerase in cellular homeostasis, telomerase may be a critical factor for regulating the subcellular organelle homeostasis. Undoubtedly, we believe that these extra-telomeric functions of telomerase should be intimately associated with life span regulation, and that some regions of TERT, other than the RT domain, will be required for mediating protein-protein interactions with known functions in controlling the life span of an organism.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874908/