Getting old is one thing; getting old in a healthy way is another. Many elderly people suffer from all kinds of diseases and disorders, ranging from cardiovascular problems and diabetes to Alzheimer’s and Parkinson’s disease. Wouldn’t it be nice if we could keep the body young as we grow older to prevent disease associated with old age? For instance, would it be possible to slow down or reverse the aging processes in the cells of our body?
This question has gained a lot of interest from scientists, and their research has led to the discovery of the important role that the shortening of telomeres, the protective caps on our DNA, plays in aging. While this has been described in recent posts on the LEAF blog, I would like to address another mechanism that has seen an interesting leap forward, more or less by accident: rejuvenation of tissue.
Rejuvenation is a term that has recently been used in the context of senolytics. These are newly discovered compounds that decrease the number of senescent cells in the body. For the purpose of this article, I define rejuvenation as the resetting of a genetic program within a cell or tissue, from adult back to fetal. Typically, cells develop from stem cells, which are cells that can differentiate into many different cell types. During cell differentiation, certain genetic programs in the stem cell are turned off, while others are turned on to make the formation of a specific cell type possible. During rejuvenation, this process is reversed: differentiated cells are reset to an embryonic state.
The process of rejuvenation is fairly common in certain groups in the animal kingdom, especially in flatworms, amphibians, and fish. Even in mammals, it has been observed to happen: mice can regrow the tips of their forefeet , and the fingertips of young children can regenerate after damage [2-3].
In fish and amphibians, rejuvenation occurs to repair the loss of a fin or a limb, usually due to bites from predators. Differentiated cells at the site of the injury form a mass of cells, which appear to reverse their mature differentiation and recover fetal capabilities . These animals can then regrow their fins or limbs, complete with muscles, bone and blood vessels [5-6].
The cell’s capacity to de-differentiate to a cell with properties that resemble those of embryonic stem cells depends on a network of small pieces of RNA known as microRNA. MicroRNA controls the switching on or off of genes and thus plays an important role in the cell’s rejuvenation process . What’s more, this regulatory network within the cell is the same in fish and amphibians, suggesting that this network has evolved in common ancestors of both groups during evolution .
A new study sheds light on regeneration
If the molecular machinery for regeneration and rejuvenation has been conserved throughout evolution, one could imagine that it might also be found in mammals. Until recently, however, it was believed that regeneration and rejuvenation do not occur in mammals, including humans. However, a study of the intestines of mice offers a surprising result suggesting otherwise .
The intestines of mice are often infected with a nematode, a sort of a worm, known as Heligmosomoides. The larvae from this parasite bury themselves in the gut epithelium, where they develop into adult nematodes. By doing so, they inflict wounds. As it has always been thought that adult stem cells in the intestines play a central role in wound repair, scientists were surprised to see that these adult stem cells disappeared completely from the site of infection. The fluorescent marker that should have been expressed by a gene in the adult stem cells was entirely absent. Nevertheless, the wounds healed quickly.
What could explain the efficient wound repair in the absence of adult stem cells? It turned out that at the places where the stem cells had disappeared, a different gene called Sca-1 was expressed. This gene is normally expressed in the developing guts of embryonic mice. In other words, the adult mouse gut had been reprogrammed to a more fetal state to effectively deal with the wounds inflicted by the nematode larvae.
Additional tests showed that any type of intestinal wounds, or shutting down adult stem cells with irradiation or by genetic means, rejuvenated the mouse intestines. This might be important for the survival of mice, as intestinal wounds bear a high risk of bacterial infections and disease, making it necessary to heal the wounds as fast as possible.
It is as yet unknown whether the rejuvenation of the mouse gut depends on the microRNA strands that have been discovered in fish and amphibians. We also do not know whether this same rejuvenation takes place in other organs or in humans. However, what this study shows, for the first time, is that adult mammalian tissue can be reversed to a fetal-like state that is important for the repair of damaged tissue. More research is needed to unravel all the cellular mechanisms that mediate this reversal and to determine whether similar mechanisms are at work in other organs and in humans.
If the genetic programs in fish, amphibians, and the mouse intestine could be programmed in humans, we could potentially enhance our ability to recover from injury. This is especially important for the elderly. With increasing age, wound repair slows down, increasing the risk of infection. This makes aged people more vulnerable to disease because their immune function is decreased. However, functioning rejuvenation in humans is still a long way off, and more research and hard work will be needed for us to get there.
 Borgens RB. Mice regrow the tips of their foretoes. Science 217: 747-750, 1982
 Illingworth CM. Trapped fingers and amputated finger tips in children. Journal of pediatric surgery 9: 853-858, 1974
 Douglas BS. Conservative management of guillotine amputation of the finger in children. Australian paediatric journal 8: 86-89, 1972
 Poss KD. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nature reviews genetics 11: 710-722, 2010
 Tanaka EM and Reddien PW. The cellular basis of animal regeneration. Developmental Cell 21: 172-185, 2011
 Gemberling M, Bailey TJ, Hyde JR, Poss KD. The zebrafish as a model for complex tissue regeneration. Trends in genetics 29: 611-620, 2013
 King BL and Yin VP. A conserved microRNA regulatory circuit is differentially controlled during limb/appendage regeneration. PLoS ONE 11: e0157106, 2016
 Nusse YM, Savage AK, Marangoni P, Rosendahl-Huber AKM, Landman TA, De Sauvage FJ, Locksley RM, Klein OD. Parasitic helminthes induce fetal-like reversion in the intestinal stem cell niche. Nature 559: 109-113, 2018