Gene Therapy

Overly Long Telomeres May Be Harmful

Posted on 6 December 2016

Credit: Salk Institute

Credit: Salk Institute

There may be a telomere sweet spot, according to research at the Salk Institute

There are few aspects of biology that are universally good; overdo something and you tend to reap the consequences by affecting another circuit of activity. One example is controlled cell death. If you’re not sensitive enough to damage you risk leaving cancerous, dysfunctional cells alive. On the other hand, if you are too quick to sentence cells to death you risk losing the ability to replenish tissue at all. Most things in life are a careful balancing act, and it appears telomere maintenance is likely the same story. 

“This work shows that the optimal length for telomeres is a carefully regulated range between two extremes. It was known that very short telomeres cause harm to a cell. But what was totally unexpected was our finding that damage also occurs when telomeres are very long”

Telomere shortening appears to be a major problem as we get older, whether it’s a cause or result of other malign cellular processes. Research on animals has therefore attempted to repair lost telomere length in a bid to extend lifespan. In mice this has a striking effect and can increase lifespan by up to 24% – perhaps most importantly increasing healthspan. However, in this rush to increase telomeres researchers have perhaps passed over potential risks that may arise along the way.  Telomere length in stem cells
Credit:  National Institutes of Health (NIH)

Credit:  National Institutes of Health (NIH)

Telomere length is perhaps most important in stem cells. These are the workhorses of the body, churning out new cells in a huge range of tissues. In order to do so, these cells express unusually high levels of telomerase (the enzyme that lengthens telomeres). Germ cells also express high levels of this enzyme to protect their DNA. Research suggests that even in stem cells however telomeres still continue to decay gradually with age, although the rate varies considerably depending on the tissue.  A team of Salk Institute scientists wanted to explore the effect of overly long telomeres on stem cell health, as while short telomeres are known to be bad news, the effect of long telomeres hasn’t been explored very much. Using laboratory-cultured lines of human embryonic stem cells (ESCs) the researchers used a number of techniques to boost telomerase activity beyond natural levels. Cells with diminished telomerase activity (predictably) died, but cells with a particularly high level of telomerase began to exhibit signs of DNA instability.  Telomere length is a dynamic process, and there are also trimming proteins called called XRCC3 and Nbs1 which appeared to kick in when long telomeres arose as a checking mechanism. Reducing expression of these prevented trimming from occurring; exacerbating lengthening. 

“In our experiments, limiting telomere length compromised pluripotency, and even resulted in stem cell death. So then we wanted to know if increasing telomere length increased pluripotent capacity. Surprisingly, we found that over-elongated telomeres are more fragile and accumulate DNA damage. We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism”

A note of caution It’s important to note that stem cells already have a high level of telomerase expression far beyond ordinary adult cells. Cells deficient in telomerase also died. This in many ways supports previous research that suggests repairing lost telomere length is still a good thing. The point to take away however is that this should not be done wildly and without caution. Understanding more precisely how telomeres are regulated is critical if we want to learn how to best repair lost telomeres without increasing risk of cancer and DNA damage.  Read more at MedicalXpress

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