Teaching Old Cells New Tricks


The laboratory of Helen Blau at Stanford University has devised a technique to lengthen the sequences that cap the ends of chromosomes in skin cells. This treatment enlivens the cells and makes them behave as though they were younger.

In order to properly protect linear chromosomes from loosing DNA at their ends, chromosomes have a special set of sequences called “telomeres” at their ends. Telomeres consists of short sequences that are repeated many times. A special enzyme called the telomerase replicates the telomeres and maintains them. As we age, telomerase activity wanes and the telomeres shorten. This threatens the genetic integrity of the chromosomes, since a loss of genes from the ends of chromosomes can be deleterious for cells. In young humans, the telomeres may be 8,000 to 10,000 bases long. When the telomeres shorten to a particular length, growth stops and the cells become quiescent.

Human telomeres

Embryonic stem cells have long telomeres at the ends of their chromosomes and they also have robust telomerase activity. Adult stem cells have varied telomerase activity and telomere length, but it seems that the length of the telomeres and the activity of the telomerase correlates with the vitality of the stem cell population and its capacity to heal (see H. Saeed and M. Iqtedar (2013). J. Biosci. 38, 641–649). As we age our stem cell quality decreases as their telomeres shorten.

Blau and her colleagues used a modified type of RNA to lengthen the telomeres of large numbers of cells. According to Blau: “Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life. This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

In these experiments, Blau and her coworkers used chemically modified messenger RNA molecules that code for TERT, which is the protein component of the telomerase. The expression of these messenger RNAs in human cells greatly increased the levels of telomerase activity.

This technique devised by Blau and her team have distinct advantages of previously described protocols. First, this technique boosts telomerase activity temporarily. The modified messenger RNA sticks around for several hours and is translated into TERT protein, but this protein only lasts for about 48 hours, after which its activity dissipates. After the telomerase have lengthened the telomeres, they will shorten again after each cell division as before.

“This new approach paves the way toward preventing or treating diseases of aging,” said Blau. “There are also highly debilitating genetic diseases associated with telomere shortening that could benefit from such a potential treatment.”

Blau and her team are testing their technique in other cell types besides skin cells.

Restoring Muscle Strength in Aging Muscle


Unfortunately, muscle tone and strength decrease as we age. You can work out at the gym all you want. Eventually the relentless march and deterioration of age catches up with even the most avid athlete. However, a Stanford University group believes that they might have discovered why this happens and new cell targets to help reverse it.

According to Helen Blau (the doyen of muscle research), over time, stem cells that help repair damaged muscle cells after injury are less able to do so. This explains why regaining strength and recovering from a muscle injury gets more difficult with age. Blau and her team published their results in the journal Nature Medicine.

Fortunately, Blau’s study also suggests a way to make older muscle stem cells function more like younger ones. The caveat is that research in mice often doesn’t translate to humans. Therefore more work is necessary in order to determine if this technique could ever be used in people.

“In the past, it’s been thought that muscle stem cells themselves don’t change with age, and that any loss of function is primarily due to external factors in the cells’ environment,” study senior author Helen Blau, director of Stanford’s Baxter Laboratory for Stem Cell Biology, said in a university news release.

“However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age,” said Blau, a professor of microbiology and immunology at the university. “Two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.”

The research also revealed, however, that there is a defect specific to old muscle stem cells that can be corrected, which allowed scientists to rejuvenate these stem cells.

“Most exciting is that we also discovered a way to overcome the defect,” Blau said. “As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage.”

The muscle stem cells in 2-year-old mice are the equivalent of those found in 80-years-old humans. In the course of their study, Blau and her team found that many muscle stem cells from these mice had increased activity in a certain biological pathway (p38α and p38β mitogen-activated kinase pathways, for those who are interested) that inhibits the production of the stem cells.

Drugs that block this pathway in old stem cells, however, allowed the aged stem cells to make a larger number of new cells that could effectively repair muscle damage.

According to Blau: “In mice, we can take cells from an old animal, treat them for seven days — during which time their numbers expand as much as 60-fold — and then return them to injured muscles in old animals to facilitate their repair.”

Once the mice received their rejuvenated muscle stem cells, the researchers tested their muscle strength with assistance from co-author Scott Delp, a professor in the School of Engineering, who has developed a way to measure muscle strength in animals that underwent stem cell therapy for muscle injuries.

Study lead author Benjamin Cosgrove, a postdoctoral scholar at the university, said: “We were able to show that transplantation of the old, treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice. Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all.”

The study’s authors said they plan to continue their research to determine if people could benefit from this technique.

“If we could isolate the stem cells from an elderly person, expose them in culture to the proper conditions to rejuvenate them and transfer them back into a site of muscle injury, we may be able to use the person’s own cells to aid recovery from trauma or to prevent localized muscle atrophy and weakness due to broken bones,” Blau said.

“This really opens a whole new avenue to enhance the repair of specific muscles in the elderly, especially after an injury,” she said. “Our data pave the way for such a stem cell therapy.”