Sierra Sciences working towards antiaging via Controlling Telomere Length

Sierra Sciences is is a company devoted to finding ways to extend our healthspans and lifespans beyond the theoretical maximum of 125 years. They believe aging can be controlled
by controlling telomere length. Relengthening telomeres may possibly rejuvenate cell function to a healthy pre-senescent state.

Telomere Length Therapy

So what about us? Can we insert the telomerase gene into all of our cells and extend our lifespan?

Inserting the gene directly into our DNA, through the use of viral vectors, is not a viable option. The main problem with this approach is that inserting genes into cells often causes cancer. That’s because the gene gets inserted into our chromosomes at random sites, and if the wrong site is chosen, the gene can interrupt and disable cancer suppressor genes or turn on cancer-inducing genes. And you only need one out of the hundred trillion cells in your body to become cancerous in order to kill you.

Fortunately, the telomerase gene already exists in all our cells. That’s because the DNA in every one of our cells is identical: a skin cell, muscle cell, and liver cell all contain exactly the same genetic information. Thus, if the cells that create our sperm and egg cells contain the code for telomerase, every other cell must contain that code as well.

The reason that most of our cells don’t express telomerase is that the gene is repressed in them. There are one or more regions of DNA neighboring the telomerase gene that serve as binding sites for a protein, and, if that protein is bound to them, telomerase will not be created by the cell.

However, it is possible to coax that repressor protein off its binding site with the use of a small-molecule, drug-like compound that binds to the repressor and prevents it from attaching to the DNA. If we find the appropriate compound, we can turn telomerase on in every cell in the human body.

Compounds such as these have very recently been discovered. One such compound is TA-65, a nutraceutical discovered by Geron Corporation and licensed to TA Sciences. Additionally, Sierra Sciences, using a robotically-driven high-throughput drug screening effort, has discovered over two hundred compounds in twenty-nine distinct drug families that induce the expression of telomerase in normal cells. However, the perfect drug hasn’t been found yet. None of the compounds induce telomerase in large enough quantities that are likely to stop or reverse aging; even the strongest known compound, a synthetic chemical patented by Sierra Sciences but not approved for human use, induces only 16% of the telomerase expression found in some immortal cell lines. Also, many of these compounds (with the notable exception of TA-65) are somewhat toxic to cell cultures and probably unsafe for human consumption.

Finding a more powerful drug will require more screening and more research, and the speed of that progress is dependent almost entirely on the level of funding that the project can achieve.

In November 2008, scientists published a paper describing how they had created cloned mice from mouse cells containing the inserted telomerase gene, which continually produced the telomerase enzyme. These mice were shown to live 50% longer than cloned mice created from cells that didn’t contain the inserted telomerase gene.

It’s becoming increasingly clear that prevention of telomere shortening might be the best way to extend human lifespan beyond the theoretical 125-year maximum lifespan. How long this can extend the human lifespan is anyone’s guess, but living a healthy, youthful life to 250, 500, or even 1,000 years is not outside the realm of possibility.

Although telomerase is necessary for cancers to extend their lifespan, telomerase does not cause cancer. This has been repeatedly demonstrated: at least seven assays for cancer have been performed on telomerase-positive human cells: the soft agar assay, the contact inhibition assay, the mouse xenograft assay, the karyotype assay, the serum inhibition assay, the gene expression assay, and the checkpoint analysis assay. All reported negative results.

As a general rule, bad things happen when telomeres get short. As cells approach senescence, the short telomeres may stimulate chromosome instability.9 This chromosome instability can cause the mutations normally associated with cancer: tumor suppressor genes can be shut off and cancer-causing genes can be turned on. If a mutation that causes telomerase to be turned on also occurs, the result is a very dangerous cancer.

Paradoxically, even though cells require telomerase to become dangerous cancers, turning on telomerase may actually prevent cancer. This is not just because the risk of chromosome rearrangements is reduced, but also because telomerase can extend the lifespan of our immune cells, improving their ability to seek out and destroy cancer cells.

It’s fairly obvious that long telomeres in human beings are not correlated with cancer. If that were true, young people would get cancer more often than the elderly. Instead, we usually see cancers occurring in people at the same time they begin to show signs of cellular senescence – that is, at the same time their immune system begins to age and lose its ability to respond to threats. Extending the lifespan of our immune cells could help our bodies fight cancer for much longer than they presently can.

Popular Science – the Man who would stop time.

Nature – Telomere dysfunction induces metabolic and mitochondrial compromise

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

If you liked this article, please give it a quick review on ycombinator or StumbleUpon. Thanks