Do Induced Pluripotent Stem Cells Hold The Key To Aging?

The 2009 Nobel Prize in Physiology or Medicine was awarded to three scientists who solved a major problem in biology: how the chromosomes can be copied in a complete way during cell division and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes – the telomeres – and in an enzyme that forms them – telomerase.

The ability to maintain and elongate telomeres is believed to endow stem cells with the ability to endlessly replicate themselves. Researchers studying aging believe that this same ability could slow or halt natural aging, at least in human cells.

Now researchers in George Daley's, lab at Children's Hospital Boston have reported successfully reactivating the cellular enzyme telomerase, which maintains the telomeres, in patients with dyskeratosis congenita. In this rare genetic disorder, genetic mutations cause telomerase to be defective, leaving the chromosomes without protection from damage and unable to compensate for the natural shortening of telomeres that occurs when a cell divides.

As a result, a patient's cells "age" more quickly, leading to bone-marrow failure (an inability to make enough blood cells), degradation of multiple tissues, premature aging-like symptoms and a much-shortened lifespan.

The findings suggest the possibility of developing drugs to help patients with dyskeratosis congenita maintain their telomeres, prolonging their lives. But the study also has broad implications for stem-cell research, as well as research on aging and even cancer. In the cancer field, telomerase is thought to contribute to the "immortalization" and uncontrolled growth of cells that marks human cancer, and has become a target in attempts to treat cancer.

"This paper illustrates how reprogramming a patient's skin cells into stem cells can teach us surprising lessons about human disease," said Daley, who is also associate director of the Stem Cell Program at Children's.

The research team, led by Suneet Agarwal, MD, PhD, took skin cells from three patients with dyskeratosis congenita and introduced four genes into the cells to transform them into pluripotent stem cells (iPS cells), which are similar to embryonic stem cells. Their goal was to better understand the disease at the cellular level--and also to see if the process of genetic reprogramming would actually affect the disease.

And ineed it did. Once reprogrammed, the diseased cells showed increased levels of telomerase RNA component (TERC), the part of the telomerase enzyme that provides the template for adding DNA onto the telomeres. Even though the patients had a genetic defect in TERC, the telomeres were once again able to elongate, and the cells were able to replicate indefinitely - just as healthy iPS cells can.

Further studies showed that human embryonic stem (ES) cells maintain elevated TERC levels similar to those found in iPS cells derived from healthy people, and that the more TERC found in iPS cells from patients with dyskeratosis congenita, the more telomerase activity.

"This study suggests that the level of TERC isn't just static, but could possibly be manipulated," said Agarwal.  "If you give patients with dyskeratosis congenita a conventional bone marrow transplant, they tend to have higher mortality than other patients because their disease affects so many organ systems," he added. "For these patients, and for patients with other bone marrow failure syndromes, it would be ideal to give them a gentler stem cell transplant from their own cells."

Since creating iPS cells seems to promote telomere elongation, the study also suggests that people of all ages could potentially benefit from cell therapies derived from iPS cells.  Added Agarwal, "We're not saying we've found the fountain of youth, but the process of creating iPS cells recapitulates some of the biology that our species uses to rejuvenate itself in each generation." 

Adapted from the Children's Hospital Boston announcement.

Comments

[Bob Smtih]

IPS cells fit the model for the study of cancer too, where normal cells are reverted to an embryonic state by carcinogens. (E.V.Gostjeva et al)
Cancer is also caused by an embryonic stem cell that fails to mature, goes to sleep via epigenetic factors, then is reawakened later in life, again by epigenetic factors. It then goes about it's business of making the tissue or organ it was created to produce in the fetus. (Laird, USC, journal Nature Genetics) Then there are adult repair stem cells, also expected to easily be reprogrammed by carcinogens. Laird claims his work will change the way we determine which chemicals etc., are labeled as carcinogens. Our food , water, and air, the products we bring into our homes,, none have been tested for their ability to revert cells to embryonic states, none have been tested for their ability to put embryonic cells to sleep or wake them up, none have been tested for the ability to revert cells.. Now imagine what all those chemicals can do when we are exposed to them all , , at the same time! A synergy for cancer.

[Stem cell hospitals]

I would have loved to bank cord blood from both of my kids--I am a physician and I think stem cells have a lot of research potential and the blood gets thrown away otherwise. I was very disappointed that, in Arizona, there is no way to bank to a public cord blood bank. Not without a huge amount of hassle anyway. I don't agree with the expense of doing it privately in the off chance that one of my kids will develop some awful illness.