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The Goldilocks effect in aging

Scientists at Salk Institute have found they can balance telomere elongation in stem cells by trimming them. Just like Goldilocks — not too short, not too long, but just right!


Telomeres are repetitive stretches of DNA located at the ends of each chromosome. They shorten with each cell division, making dividing chromosomes more vulnerable to damage. Their loss eventually leads to cell death. However, telomere length can be increased using an enzyme called telomerase made up of protein and RNA, which elongates chromosomes by adding TTAGGG sequences at their tips. Telomerase can be found in fetal tissues, adult germ cells (our sperm and egg cells), and even in tumor cells.

Telomerase allows stem cells to continue to divide and differentiate into virtually any cell type — a quality known as pluripotency — and makes it a promising tool for regenerative therapy to combat age-related cell damage and disease. Reporting in the December 5, 2016, issue of Nature Structural & Molecular Biology, researchers are deepening our understanding of stem cell mechanics, thus advancing development of stem cell therapies related to aging and regenerative medicine.


Ever since research figured out shortened telomeres are connected to aging and disease, a race has been on to determine how to control telomere length.
Image Credit: PLOS One


Jan Karlseder, Teresa Rivera and colleagues began investigating telomere maintenance growing human embryonic stem cells (ESCs) in their lab. Their team varied the activity of telomerase by manipulating it's molecular structure. Not surprisingly, cells with too little telomerase had very short telomeres and in time died. But, at the opposite end of that scale, cells with higher levels of telomerase grew very long telomeres, which then became unstable, broke down and also died. Instead of thriving with increased telomorase, these cells died just as the cells with very short telomeres.


"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.

"We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to an initiation of cancer
. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism."

Jan Karlseder PhD, Professor, Molecular and Cell Biology Laboratory, holder of the Donald and Darlene Shiley Chair and senior author of the work, the Salk Institute for Biological Studies, La Jolla, California, USA.


Next, the team looked at induced pluripotent stem cells (iPSCs), cells which have differentiated (already committed to, in this case, being skin cells) that can be reprogrammed back to a stem-cell state.


The team found that very long telomeres activated a trimming mechanism controlled by two proteins called XRCC3 and Nbs1.

Experiments confirmed that reducing these 2 proteins in ESCs prevented telomere trimming.


Because iPSC cells can be genetically matched to donors and are easy to create, they are common and crucial in developing potential stem cell therapies.

Salk researchers also discovered iPSCs contain markers indicating what amount of trimming has occurred on their telomeres, which makes them useful for gaging how well a cell has been reprogrammed.


"Stem cell reprogramming is a major scientific breakthrough, but still needs perfecting. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine."

Teresa Rivera PhD, Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, La Jolla, California, USA.


Abstract
Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively. We found that reprogramming of differentiated cells induces T-circle and single-stranded C-rich telomeric DNA accumulation, indicating the activation of telomere trimming pathways that compensate telomerase-dependent telomere elongation in hiPSCs. Excessive telomere elongation compromises telomere stability and promotes the formation of partially single-stranded telomeric DNA circles (C-circles) in hESCs, suggesting heightened sensitivity of stem cells to replication stress at overly long telomeres. Thus, tight control of telomere length homeostasis is essential to maintain telomere stability in hESCs.

Subject terms: Induced pluripotent stem cells Telomeres

Other authors included Candy Haggblom of the Salk Institute and Sandro Cosconati of the Second University of Naples.

The work was funded by the California Institute for Regenerative Medicine training grant TG2-01158, the Salk Institute Cancer Center Core Grant (P30CA014195), the National Institutes of Health (R01GM087476, R01CA174942), the Highland Street Foundation, the Fritz B. Burns Foundation, the Emerald Foundation and the Glenn Center for Research on Aging.

About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

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Dec 26, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Immunofluorescence scan shows off  how the pluripotent markers Nanog (RED) and
TRA-1-60 (GREEN) appear in human iPSC stem cells made from skin. DNA appears BLUE.

Image Credit: Salk Institute

 


 


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