Can we rewire neurons to make them younger? This is how we improve the memory of elderly mice

The rise in neurological diseases associated with aging, such as dementia, has reached alarming levels worldwide. Given that effective treatments still do not exist, understanding and slowing the aging of our neurons will be key to combating these pathologies.

In this context, so-called “partial reprogramming” has recently emerged as a strategy for cell rejuvenation.

Reprogrammed cells that rejuvenate

Cell reprogramming originated in 2006 thanks to the research of Shinya Yamanaka, who received the Nobel Prize in Medicine in 2012. This Japanese researcher discovered that by using a number of factors that regulate the expression of certain genes, it is possible to transform a cell’s tissue, in particular a stem cell. That is, he was able to transfer a mature cell to a juvenile stage, capable of becoming a cell of any type. These factors are today called “Yamanaka factors”.

Overexpression of Yamanaka factors in living transgenic mice was first achieved in 2013. This was carried out by the laboratory of researcher Manuel Serrano, causing the first reprogramming of cells in a living being. However, the constant expression of these factors led to the formation of tumors that were fatal to the animal.

To avoid unwanted effects, the Izpisua-Belmonte laboratory adjusted the Yamanaka factor protocol, activating them only two days a week for several cycles. This, in addition to significantly reducing tumors, improved problems associated with aging of organs such as the pancreas and muscles. The new protocol rejuvenated the cells without turning them into stem cells: in this way they retained their identity, and the risk of tumors was limited. This approach is called “partial reprogramming.”

This protocol allowed the cell to be rejuvenated through changes at the epigenetic level, changes that occur in the way genes are expressed without changing the DNA sequence. Aging will be caused by these epigenetic changes that accumulate over time.

Epigenetic changes will ultimately lead to deterioration in cell function, even to the point of cell death. The current hypothesis suggests that these changes associated with aging can be reversed through partial reprogramming. But is this possible?

Partial reprogramming in the nervous system

The use of transgenic mice has made it possible to study partial reprogramming of living beings. However, the influence of this process at the neural level has only just begun to be studied. The first study was published only in 2020. Our laboratory then confirmed that partial reprogramming of all cells in the body improved certain cellular characteristics of the brain associated with aging. This significantly increased memory in mice.

Since partial reprogramming affected all cell types, we decided to study this process in the brain. To do this, we created a line of transgenic mice that, for the first time, expressed Yamanaka factors only in neurons present in the cerebral cortex.

This neuronal reprogramming restored markers of aging. For example, it improved brain plasticity by reorganizing the extracellular matrix that surrounds it. The activity of neurons present in hippocampal memory circuits was also increased. All these changes improved spatial and recognition memory in old mice.

In our study, published in 2024, we demonstrate in natural conditions that neurons, unlike other cells, do not lose their cellular identity, no matter how strongly they express Yamanaka factors. By not converting neurons into stem cells, tumor formation can be prevented. This could be a major advantage for future treatments based on specific partial reprogramming of neurons.

Alternative Genetic Modification Strategies

Due to the difficulty of using genetic manipulation in humans to achieve partial reprogramming, we decided to look for simpler alternatives. To do this, we investigated whether administration of certain metabolites could achieve similar effects, even managing to express Yamanaka factors.

In our studies of our transgenic mice, we found significant changes in the expression of several genes during the process of cellular reprogramming. One of them was the alpha-folate receptor. Folate is an important part of one-carbon metabolism, which is an important regulatory pathway of cellular epigenetics.

In a recent study published in collaboration with biochemist Juan Carlos Izpisua-Belmonte, we found that some molecules of one-carbon metabolism achieve results similar to those achieved through partial reprogramming. These results included improved memory in older mice and were also associated with activation of the alpha-folate receptor.

In fact, we discovered how activating this receptor in neurons using a peptide we synthesized improves the memory of old mice and induces the expression of several Yamanaka factors.

These strategies open an interesting avenue of research for the development of future treatments aimed at slowing brain aging. Its primary goal will be to prevent or mitigate the effects of neurological diseases associated with aging, such as dementia, including Alzheimer’s disease.

However, much remains to be studied and understood regarding the process of partial reprogramming at the brain level before these results can be applied to patients. Let’s hope that the combined efforts of so many laboratories will lead to promising advances as soon as possible.