A recent study has rejuvenated mice through a four-gene cocktail that allowed them to repair aging signs including loss of hair and organs malfunction. Cellular rejuvenation has been tested before, but the recent study has managed to avoid its side effects, which often includes cancer. Scientists used the Yamanaka factors for short periods and were successful in reversing aging in two mice study groups.
The study was published Thursday in the journal Cell. Scientists from the Salk Institute, including stem cell scientist Juan Carlos Izpisúa Belmonte, led author, carried the research that induced cellular reprogramming in mice successfully.
The team found that intermittent expression of genes typically found in embryos can reverse aging symptoms, including the regeneration of pancreas and muscle. The early-stage of the work provides insight into cellular drivers of aging and possible therapeutic approaches for improving human health and thus, longevity.
Salk scientists used Shinya Yamanaka induced pluripotent stem cells, also known as IPS. Yamanaka, a Japanese researcher, used four proteins -Oct4, Sox2, Klf4, and c-Myc called the Yamanaka factors- to make ordinary adult cells to behave like embryonic stem cells. The Yamanaka factors are capable of dividing indefinitely, and pluripotent means the cells can become nearly any type of cell in the body. The problem is that rapid cell division often means cancer and even death.
When cells divide in a fast speed in adults, although it is a critical process for embryos, the rapid division is one of the hallmarks of cancer. Also, having large numbers of cells reverted to their embryonic status in an adult could provoke organ failure, leading to death. The Salk study managed to use the Yamanaka factors without causing mice cancer nor death, a process easy to performed in laboratory cells but not in an entire organism.
Shinya Yamanaka won the Nobel Prize in 2012 for discovering the IPS cells.
IPS cells rejuvenated both mice with progeria syndrome and healthy ones
The research involved two groups of mice. One was made of mice that were genetically engineered to model Hutchinson-Gilford progeria syndrome, a fatal childhood disease. It causes DNA damage, heart disease, joint stiffness, hair loss and other aging-related symptoms, including a short life span. Both mice and humans with progeria die before reaching adulthood.
The second group included healthy mice aged to 12 months, considering that mice can naturally live about 18 months up to two years.
The study induced the Yamanaka factors for a short duration first in skin cells from mice with progeria and found the group of genes was successful in rejuvenating those cells. Later, Salk scientists applied the four-gene cocktail to live mice with progeria.
The infected mice were exposed for two days a week, every week, to the Yamanaka factors and showed changes in their DNA that counteract some characteristic of the Hutchinson-Gilford progeria syndrome. The IPS cells also changed epigenetic marks of aging, which are chemical groups added to or remove from the core DNA molecules that are affected by progeria. The Yamanaka factors did not modify the underlying sequence of genes in the tested mice. Instead, they improve it.
The IPS cells were produced in the mice with the condition only when they were given the antibiotic doxycycline, which created an on-off switch to control cell division. There were no signs of cancer and compared to untreated mice, the reprogrammed mice looked younger, with better organ function, improved cardiovascular performance and lived 30 percent longer.
The results showed that on a cellular level, the small animals had recovered molecular aging hallmarks that are affected by progeria and also normal aging.
Co-first author Pradeep Reddy, a Salk research associated, stated that the recent study is the first one to demonstrate that using IPS cell for a short period can maintain cell’s identity while reversing age-associated symptoms without transforming them into a stem-cell.
Healthy aged mice also experienced rejuvenation after being administered the Yamanaka factors. The induction of the cells regenerated their pancreas capacity along with muscle function. Mice with injured pancreas and muscle healed faster after receiving the IPS cells, which proves that cellular reprogramming has a definite improvement in the quality of life.
Epigenetic changes could be the answer to avoid aging
The Salk team stated that induction of epigenetic changes via chemicals or small molecules could be the most promising method to achieve rejuvenation in human beings. It could be years to start the first human trials to see if the Yamanaka factors would be the approach to fighting aging due to the complexity of the process and the human body.
Izpisua Belmonte added that reprogramming works in discrete stages. Brief exposure was the key on the mice experiments to not erase the cell’s identity, and a similar effect is hoped to be seen in human trials.
“Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person,” said Belmonte. “But this study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought.”