NANOG the Rejuvenator
A Protein that Can Restore Aging Muscle Cell Precursors
Background
When your myogenic progenitors (the cells that divide to give rise to new muscle cells) grow old, they exhibit a variety of distinctive changes. Their size increases, their biochemical processes become impaired, their DNA mutation repair mechanisms become less effective, their mitochondria become unhealthy, and they divide slower and less frequently. Essentially, these cells become fat, sluggish, and inefficient as they age, impairing regeneration of skeletal muscle. This makes it challenging for old muscles to grow, heal, and maintain a healthy size, causing weakness and chronic injuries in the elderly.
What if there was a way to undo the effects of aging on myogenic progenitors, enabling them to produce new muscle cells with the same vigor that they had in their youth? New research suggests that this may eventually be possible, thanks to a protein called NANOG. When this protein is expressed in old myogenic progenitors, it has been shown to have a multitude of anti-aging effects that restore a youthful phenotype to the cell.
Summary
A team of researchers at SUNY recently carried out a study that determined the effects of NANOG on myogenic progenitors both in vitro (using isolated cells) and in vivo (using a whole organism).
The in vitro portion of the study used human myoblasts (a type of myogenic progenitor found primarily in the developing embryo) that had been engineered to produce NANOG when treated with doxycycline. To create these special myoblasts, researchers isolated the gene that codes for NANOG and attached it to a promoter sequence designed to switch the gene on only when doxycycline was present. This DNA was then placed in a lentivirus, which subsequently infected the myoblasts, incorporating the NANOG gene and doxycycline-sensitive promoter into the myoblast genome.
To create cells with characteristics of old age, the myoblasts were grown without doxycycline until they began to divide slowly and infrequently. Once the cells were in this state, the researchers added doxycycline, causing the NANOG promoter to be turned on and the protein to be made in the cells. After the myoblasts began to express NANOG, the researchers noted the following dramatic changes in their phenotype:
1) The cells began to divide faster and more frequently.
2) Biochemical pathways that had been damaged by aging were repaired.
3) The nucleus was restored to its prior size and shape, and levels of heterochromatin (highly condensed DNA) were restored to previous levels.
4) DNA repair pathways that had been damaged by aging were restored, preventing further mutations associated with aging.
5) The cells were reduced to a smaller, healthier size.
6) Protein-folding and proteolysis (healthy destruction of unnecessary proteins) increased, correcting the problem of protein accumulation in aging cells.
7) The cells showed increased activation of AMPK, an enzyme that promotes autophagy (healthy destruction of old organelles), increases mitochondrial health, and increases ATP concentration in the cell.
These changes remained, reverting the cells to their former morphology and productivity levels for as long as the myoblasts were provided with doxycycline.
The in vivo portion of the study used mice that were genetically engineered to make NANOG when given doxycycline. To create an old-age phenotype, the researchers also gave the mice a gene that causes progeria (a disease that causes rapid aging). When samples of myoblasts were removed from the mouse muscles and treated with doxycycline, the researchers noted many of the same changes observed in vitro, as well as an increase in the number of myoblasts.
To observe the effects of NANOG on the entire muscle, the researchers injected doxycycline into the tibialis anterior muscles of live mice. They allowed NANOG to be expressed in the muscles for 3–5 weeks, then euthanized the mice with carbon dioxide and removed the muscle. Under the microscope, the researchers noted many new muscle fibers, another result of NANOG expression in the cells.
The results of this study are exciting because of the multitude of profound phenotypic changes induced by NANOG. Whenever it was expressed in myogenic progenitors, NANOG was able to restore their normal functional capacity. While this protein is far from being a miracle cure for old age, its anti-aging effects may in the future be used to create new therapies that reduce the effects of age on muscles.
