We continue discussing cellular reprogramming on Science to Save the World, our general science show. In Part 2, we discuss a mouse experiment that used the OSKM reprogramming factors.
Could we “reprogram” old cells to make them young again inside living animals?
In part 1, we covered the origins of using four genes referred to as Yamanaka factors to reprogram old cells to an early state.
Relatively speaking, it was easy for the scientists to isolate cells in a dish, take them back to developmental state, then guide them to become whatever cell type they wanted using Yamanaka factors. But this was obviously not practical in a living animal, as cells cannot have their memory erased while reverting to a pluripotent state. Imagine if a heart cell forgot it was a heart cell while it was supposed to be helping pump blood around the body.
There was also the concern that the expression of Yamanaka factors was known to induce cancer in animals. Some researchers believed that it might be possible to avoid cancer and reverse aging in old cells without completely reverting them to pluripotency. In other words, they thought there was a way for us to have our cake and eat it.
But no one had successfully managed to achieve this in living animals. This was all about to change in December 2016. Professor Juan Carlos Izpisua Belmonte and his team of researchers at the Salk Institute reported the conclusion of their study, which showed for the first time that the cells and organs of a living animal could be rejuvenated.
For the study, the researchers used a specially engineered progeric mouse designed to age more rapidly than normal as well as an engineered normally aging mouse strain. Both types of mice were engineered to express the Yamanaka factors when they came into contact with doxycycline, a common antibiotic used in veterinary practice, which was given to them via their drinking water. They allowed the Yamanaka factors to be transiently expressed by including doxycycline in the water for two days then removed it so that the OSKM genes were silenced again. The mice then had a five-day rest period before another two days of exposure to doxycycline. This cycle was repeated for the duration of the study.
After just six weeks of this treatment, which steadily reprogrammed the cells of the mice the researchers noticed improvements in their appearance, including reduced age-related spinal curvature. Some of the mice from both experiment and control groups were also euthanized at this point so that their skin, kidneys, stomachs, and spleens could be examined. The control mice showed a range of age-related changes compared to the treated mice, which had a number of aging signs halted or even reversed, including some epigenetic alterations. The treated mice also experienced a 50% increase in their mean survival time in comparison to untreated progeric control mice.
It should be noted that not all aging signs were affected by partial cellular reprogramming, and if treatment was halted, the aging signs returned.
Not only did the transient expression of Yamanaka factors at least partially rejuvenate cells and organs in progeric mice, but it also appeared to improve tissue regeneration in the engineered 12-month-old normally aging mouse group. The researchers observed that the partial reprogramming improved these mice’s ability to regenerate tissue in the pancreas, resulting in an increased proliferation of beta cells. Additionally, there was an increase of satellite cells in skeletal muscle. Both of these types of cells typically decline during aging. Then, in October 2020, another study took us a step closer to partial cellular reprogramming reaching the clinic when researchers showed that the technique improved memory in old mice.
As the previous studies showed, partial cellular reprogramming is a balancing act between epigenetically rejuvenating cells and resetting their aging clocks, without completely resetting their cell identity where they would forget what kind of cell they are. As before, the mice in this study had their cells engineered to react to doxycycline in order to express the OSKM reprogramming factors. The researchers found that giving the mice just enough exposure improved their cognitive function without an increase in mortality during a four-month period.
Could this technique even be used to restore lost vision in an older organism? Stay tuned for our next episode to find out!