Researchers from Harvard University Medical School have succeeded in rejuvenating mice in an experiment by altering their genomes. With the help of a cocktail made out of three genes, the mice regained the visual acuity of their youth.
Aging affects all cells in the human body, first, it causes dysfunction before it causes cell death. At the genome level, aging can be felt. The scientific community believes that it is due to the accumulation of epigenetic changes that alter the normal functioning of the genes.
Scientists at Harvard University Medical School proposed an attractive but still controversial solution by reversing the accumulated traces of time in the genome to reverse aging. The study, published in Nature on 2 December 2020, does not formally prove this theory but proposed a series of experiments that support it.
Using a combination of three genes, the scientists succeeded in limiting the degeneration of neurons and promoting their regeneration. Through this treatment, Mice suffering from glaucoma have regained their visual acuity.
Three anti-aging genes
The three genes chosen by the scientists, Oct4, Sox2, and Klf4 (also known as OSK) have been used in cell differentiation experiments for about ten years. This involves the transformation of a differentiated adult cell into a pluripotent stem cell, a state that can be described as juvenile. Pluripotent stem cells are able to differentiate into different cell types.
But the strategy chosen by Harvard University scientists is not to rejuvenate cells by playing with their identity or their differentiation but to modify their epigenetic markers, and more specifically the methyl groups.
The first experiment concerns the effect of the 3 genes on neuronal regeneration. The scientists focused on the cells of the retinal ganglia, which are part of the optic nerve behind the eye. Using forceps, they damaged the optic nerve in adult mice and then injected the OSK genes (the three genes). This treatment not only limited the cell death of the damaged neurons but also stimulated the growth of new neurons.
In embryonic form and after birth, neurons are able to regenerate in mice, but this ability disappears over time. In this case, the injection of the OSK genes had an anti-aging effect, restoring a neuronal capacity that is only present in young animals.
But that’s not all. Four days after the injury caused by the forceps, the methylation process in the retinal cells was accelerated. The methylation patterns then corresponded to those of a cell at the end of life. Because of their activity, the OSK genes simply reversed them throughout their DNA, but more specifically around the genes involved in light detection and synaptic transmission.
The mice regained their sight
The next experiment was about glaucoma an eye disease that appears with aging. Glaucoma is associated with a progressive increase in intraocular pressure which damages the optic nerve and leads to a progressive loss of vision. To mimic this condition in mice, scientists have artificially increased eye pressure by injecting beads into the anterior chamber of the eye. OSK genes were injected after 21 days. The treated eyes had then a higher density of functional axons than the untreated diseased eyes. The mice also underwent a vision test which showed that the treated mice regained 50% of the vision, they had lost.
In a final experiment, the scientists injected the genes into the eyes of one-year-old mice. At this age, their vision is already weakened compared to younger mice. It is about 15% weaker than in five-month-old mice. After four weeks of treatment, the older mice started to see as well as the younger ones.
These three experiments show that the cells respond to the OSK genes by adapting the epigenetic changes they carry to those observed in younger individuals. The success of the injections also depends on the presence and activity of demethylases (TET1 and TET2), the enzymes that remove methyl groups from the DNA. In mice with lower levels of demethylases, the results were less impressive.
It seems tempting to try at all costs to rejuvenate our cells to avoid the ravages of time and the diseases it causes. But this type of cell modulation is not without risks, as cell rejuvenation can lead to cancer. All the mechanisms involved are not yet understood, and the experiments must be repeated before this approach is considered as a possible treatment for the effects of old age, especially in degenerative eye diseases.