Further Exploration of In Vivo Reprogramming in Mice
Researchers are expanding their explorations of cellular reprogramming applied to living animals, delivering Yamanaka factors as a gene therapy. There are in principle ways to balance this sort of approach in order to minimize the conversion of somatic cells into induced pluripotent stem cells, and thus the risk of cancer, while maximizing the epigenetic rejuvenation and restoration of mitochondrial function that occurs as an early part of the reprogramming process.
Forcing cells in aged tissues to act as though they are present in youthful tissues is expected to produce meaningful benefits to health, and indeed has done so in some animal studies. It cannot fix issues related to metabolic waste that cannot be cleared effectively by even a young physiology, or issues related to stochastic DNA damage, but the hope is that the issues of aging that reprogramming can effectively address will make this a useful approach to the treatment of aging as a medical condition.
In 2016, researchers reported for the first time that they could use the Yamanaka factors to counter the signs of aging and increase life span in mice with a premature aging disease. More recently, the team found that, even in young mice, the Yamanaka factors can accelerate muscle regeneration. Following these initial observations, other scientists have used the same approach to improve the function of other tissues like the heart, brain, and optic nerve, which is involved in vision.
In the new study, researchers tested variations of the cellular rejuvenation approach in healthy animals as they aged. One group of mice received regular doses of the Yamanaka factors from the time they were 15 months old until 22 months, approximately equivalent to age 50 through 70 in humans. Another group was treated from 12 through 22 months, approximately age 35 to 70 in humans. And a third group was treated for just one month at age 25 months, similar to age 80 in humans. "What we really wanted to establish was that using this approach for a longer time span is safe. Indeed, we did not see any negative effects on the health, behavior, or body weight of these animals."
When the researchers looked at normal signs of aging in the animals that had undergone the treatment, they found that the mice, in many ways, resembled younger animals. In both the kidneys and skin, the epigenetics of treated animals more closely resembled epigenetic patterns seen in younger animals. When injured, the skin cells of treated animals had a greater ability to proliferate and were less likely to form permanent scars - older animals usually show less skin cell proliferation and more scarring. Moreover, metabolic molecules in the blood of treated animals did not show normal age-related changes.
This youthfulness was observed in the animals treated for seven or 10 months with the Yamanaka factors, but not the animals treated for just one month. What's more, when the treated animals were analyzed midway through their treatment, the effects were not yet as evident. This suggests that the treatment is not simply pausing aging, but actively turning it backwards - although more research is needed to differentiate between the two.