Forever Young: Reprogramming the Cellular Clock

New research reported this week in the journal Regenerative Medicine points to new directions for creating therapeutic stem cells from adult cells, a technique that has many possibilities for treatment of human diseases. Applying this technique may also lead to treatments directly applying to diseases of aging.

The paper (available here [PDF]) by authors from BioTime Inc., a California research company, demonstrates a new method that helps confirm the telomere hypothesis of cell aging. The telomere hypothesis suggests that a part of the chromosome called a telomere is the "clock" that counts the cell's age.

One of the problems that has plagued research into so-called "adult" stem cells is that while it's possible to make therapeutic stem cells from adult cells, these cells "act old." Unlike embryonic stem cells, they can't replicate as many times; they die out quickly.

Chromosomes are simply collections of DNA molecules that contain the "genetic code" used to build the proteins that become the body's tissues. A chromosome is really a sequence of codons, which are like the letters in a coded message, like a teletype message. Teletype operators end each message with a sequence of repeated "K" characters, like this:

TO: READERS

THIS IS A TELETYPE MESSAGE. FOR YOUNGER READERS, A TELETYPE WAS LIKE TEXT MESSAGING EXCEPT IT PRINTED THE MESSAGES ON PAPER AND REQUIRED A KEYBOARD BIGGER THAN A BREADBOX.

KKKKK

The telomere is exactly like that series of K characters: it’s a repeated group of codons that ends the chromosome.

The telomere hypothesis says that cells keep track of the number of times they have divided by shortening the telomere a little bit for each replication. When the telomere grows too short, the "message" can't be understood any longer and the cell can't replicate. It has "grown old" and dies. There is also an enzyme involved called telomerase that helps preserve the telomeres, but this enzyme tends to disappear from older cells over time.

In the paper "Spontaneous reversal of the developmental aging of normal human cells following transcriptional reprogramming," the authors showed that they could effectively reprogram cells to act as if they were young -- they could "reset the cell's clock." By doing so, they achieved two things. First, they added to the evidence supporting the telomere hypothesis by showing that longer telomeres did in fact seem to indicate a "younger" cell.

Second, in a discovery with implications for future stem cell therapies, they demonstrated that by reprogramming cells to have longer telomeres and a higher level of the telomerase enzyme, they could make induced pluripotent stem cells -- so-called "adult stem cells," stem cells created from adult tissues — act more like embryonic stem cells.  This might lead to stem cell research without the ethical issues posed by creating embryonic stem cells from human embryos.

Therapeutically, these techniques could be applied in the future in a number of ways.  First, of course, is the possibility of the therapeutic use of stem cells: it's already known that under certain conditions, stem cells can be used to induce the body to regenerate tissues, such as nerve tissues damaged by multiple sclerosis, spinal cells damaged by spinal cord injuries, corneal cells in the eyes, and heart muscle damaged by a heart attack. So, for example, in the future a patient might be able to re-grow heart tissue following a heart attack through stem-cell therapy.

Second, better understanding of the telomere mechanism might also have implications for cancer therapy, although in the opposite direction. Cancerous cells appear to be more or less immortal; they don't "get old." This appears to be in part because of the telomerase enzyme; tumor cells keep high levels of telomerase. This discovery got Carol W. Grieder and Elizabeth H. Blackburn the 2009 Nobel Prize in Medicine.

A third exciting therapeutic possibility is that this might lead to treatments that can directly reprogram certain cells to be "younger." One example of a tissue that could benefit — exciting for anyone who is now or expects someday to be over the age of 40 — is the tissue that makes up the lens of the eye.  As a person ages, that tissue becomes stiffer, which is also associated with shorter telomeres. Treatments that "reset the clock" might lead to effective drug treatments for age-related presbyopia, the problem that leads to a need for reading classes as we age.