Telomeres are repetitive stretches of DNA at the ends of each
chromosome whose length can be increased by an enzyme called telomerase.
Our cellular machinery results in a little bit of the telomere becoming
lopped off each time cells replicate their DNA and divide.
shorten over time, the chromosomes themselves become vulnerable to
damage. Eventually the cells die.
‘It was believed that increasing telomeres could lengthen an organism's life. Now, it has been observed that forcing cells to generate long telomeres caused telomeric fragility, which can lead to cancer.’
The exception is stem cells, which use
telomerase to rebuild their telomeres, allowing them to retain their
ability to divide, and to develop ("differentiate") into virtually any
cell type for the specific tissue or organ, be it skin, heart, liver or
muscle - a quality known as pluripotency. These qualities make stem cells
promising tools for regenerative therapies to combat age-related
cellular damage and disease.
Ever since researchers connected the shortening of telomeres - the
protective structures on the ends of chromosomes - to aging and disease,
the race has been on to understand the factors that govern telomere
length. Now, scientists at the Salk Institute have found that a balance
of elongation and trimming in stem cells results in telomeres that are,
as Goldilocks would say, not too short and not too long, but just right.
The finding, which appears in the Nature Structural & Molecular Biology
deepens our understanding of stem cell biology and could help advance
stem cell-based therapies, especially related to aging and regenerative
"This work shows that the optimal length for telomeres is a
carefully regulated range between two extremes," says Jan Karlseder, a
professor in Salk's Molecular and Cell Biology Laboratory and senior
author of the work. "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."
"In our experiments, limiting telomere length compromised
pluripotency, and even resulted in stem cell death," says Teresa Rivera,
a Salk research associate and first author of the paper. "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."
Karlseder, Rivera and colleagues began by investigating telomere
maintenance in laboratory-cultured lines of human embryonic stem cells
(ESCs). Using molecular techniques, they varied telomerase activity.
Perhaps not surprisingly, cells with too little telomerase had very
short telomeres and eventually the cells died. Conversely, cells with
augmented levels of telomerase had very long telomeres. But instead of
these cells thriving, their telomeres developed instabilities.
"We were surprised to find that forcing cells to generate really
long telomeres caused telomeric fragility, which can lead to initiation
of cancer," says Karlseder, who also holds the Donald and Darlene Shiley
Chair. "These experiments question the generally accepted notion that
artificially increasing telomeres could lengthen life or improve the
health of an organism."
The team observed that very long telomeres activated trimming
mechanisms controlled by a pair of proteins called XRCC3 and Nbs1. The
lab's experiments show that reduced expression of these proteins in ESCs
prevented telomere trimming, confirming that XRCC3 and Nbs1 are indeed
responsible for that task.
Next, the team looked at induced pluripotent stem cells (iPSCs),
which are differentiated cells (e.g., skin cells) that are reprogrammed
back to a stem cell-like state. iPSCs - because they can be genetically
matched to donors and are easily obtainable - are common and crucial
tools for potential stem cell therapies. The researchers discovered that
iPSCs contain markers of telomere trimming, making their presence a
useful gauge of how successfully a cell has been reprogrammed.
"Stem cell reprogramming is a major scientific breakthrough, but the
methods are still being perfected. Understanding how telomere length is
regulated is an important step toward realizing the promise of stem
cell therapies and regenerative medicine," says Rivera.