Extension of Life Span in Normal Human Cells by Telomerase Activation: A Revolution in Cultural Senescence

Summary: Expressing the protein related to telomerase extends the telomeres and replicative lifespan of human cells.

Interestingness: 2 (but much higher back then)

Paper by Homayoun Vaziri in the Journal of Anti-Aging Medicine, Volume 1, Issue 2, Spring 1998.

(((This paper also feels old nowadays. Telomerase hype killed the excitement)))

(((I won't skip the introduction this time))) The bits at the end of the chromosomes are called telomeres. With each division of the cell, these are shortened. When they are too short, the theory goes, the cell decides to stop dividing, so that the real DNA doesn't get damaged. As evidence, tumours and other immortal cell lines maintain long telomeres somehow, and the correlation between telomere length and replicative lifespan of human fibroblasts is high. If we could activate the system that lengthens telomeres (called telomerase) the hypothesis could be tested in a causative manner.

So that's what they tried and that's what they got: activating hTERT (human telomerase reverse transcriptase) in human cells lengthens telomeres and enhances the replicative lifespan of the cell. (((That's really it for the paper. The rest is fluff because otherwise this would be too short))) It later cautions though, that this can't rule out that hTERT might be extending the replicative lifespan of the cell by a different mechanism than extension of the telomeres (ie that even though it extends telomeres, this might not be what is extending the lifespan, but some other unrelated function of hTERT is).

The rest of the paper is about how this can be used.

For research, once a cell with properties that are wanted are found or created, they can be made to express hTERT leading to an (((infinitely??))) replicative cell line. Same thing for gene therapy, introduce a cell that expresses the protein you want, add hTERT, and it will last longer. As an example of gene therapy, it gives Duchenne muscular dystrophy, even though it gives good reasons why this most likely wouldn't help (((maybe they were running trials for it at the time))). That it might help with HIV, on the hunch that the short telomeres on CD8+CD28- T-cells indicate immunosenescence, even though it might raise the likelihood of leukemia and lymphoma. Similarly for cancer, that it could prevent a hypothetical immunosenescence after chemotherapy, by extracting CD34- cells and introducing hTERT into them and reinserting the cells into the body.

It finishes by suggesting that it is p53 that acts as the detector of short telomeres that triggers senescence in the cell. (((There's a diagram of proposed gene activation in the paper that would be laborious to describe)))

Abstract follows:

Normal human cells have a limited life span in culture, exhaust their replicative potential after a fixed number of doublings, and enter a phase of cell cycle arrest termed "senescence." Senescent cells are metabolically active cells, known to up-regulate several cyclin-dependent kinase inhibitors and to be arrested primarily at the G1 phase of cell cycle. Telomere loss due to incomplete replication of the ends in normal somatic cells is thought to be the signal which initiates the senescence cascade. Lack of telomere maintenance in somatic cells may be caused by the absence or the low enzymatic activity of telomerase, the enzyme responsible for synthesis of telomeric DNA that counteracts the end-replication problem. Previous attempts to increase the life span of human cells involved inactivation of tumor suppressor genes such as p53 were not a viable method of life span extension because of significant risk of genomic instability. Extension of the life span of normal cells with minimal risk of genetic instability may be achieved by manipulation of the most upstream signals that initiate the senescence cascade. We and others have recently shown that reactivation of telomerase in normal human cells leads to restoration of the length of telomeric DNA and to a highly significant increase in cellular life span. These data provide strong evidence consistent with the telomere hypothesis and indicate that elongation of telomere length by genetic manipulation might render normal human cells virtually immortal. These findings indicate that telomere shortening and senescence act as a tumor suppressor mechanism and establish a solid genetic link between telomeres, cellular aging, and immortalization.