Research uncovers new insights into neuronal aging and rejuvenation

As a neuron ages, it loses synaptic connections with other neurons, becomes less able to transmit nerve impulses, and its metabolism also changes. This process of neuronal aging – inevitable with the passage of time – is particularly accelerated and becomes a risk factor in neurodegenerative pathologies such as Alzheimer’s disease. But can the effects of aging be reversed in cells as specialized as neurons?

A study led by the University of Barcelona describes how brain neurons in mice can be rejuvenated through a controlled cellular reprogramming cycle that helps restore some altered neurological properties and functions. The article could open new perspectives for studying neurodegenerative diseases in patients. In an innovative approach, it focuses on the process of cellular rejuvenation in neurons and highlights the role of what is known as the Yamanaka factorskey proteins for reversing aging that have been little studied in the nervous system.

The study, published in the journal Cell Stem cellis led by experts Daniel del Toro and Albert Giralt, from the Faculty of Medicine and Health Sciences, the Institute of Neurosciences (UBneuro) and the Center for the Production and Validation of Advanced Therapies (CREATIO) of the UB, IDIBAPS and the Neurodegenerative Disease Area of ​​the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), and Rüdiger Klein, from the Max Planck Institute for Biological Intelligence (Germany). The study, whose first co-author is Sofía Zaballa (UB-IDIBAPS-CIBERNED), also includes the participation of Manuel Serrano, an expert at IRB Barcelona.

Neurons rejuvenated in the cortex of the brain with Yamanaka factors

In 2012, Japanese scientist Shinya Yamanaka and British scientist John Gurdon received the Nobel Prize in Medicine for their research into reprogramming differentiated cells to a pluripotent cell state. The Yamanaka factors – specifically Oct4, Sox2, Klf4, and c-Myc – are transcription factors that are ubiquitous in the scientific literature on cell reprogramming.

While much international research has focused on the study of factors involved in the rejuvenation and regeneration of peripheral tissues (skin, muscle, liver and heart), this study now delves into the effects these can have on the central nervous system. Specifically, the team studied the effects of controlled expression of Yamanaka factors in the brains of mice in cellular reprogramming cycles during different phases of neuronal development.

Daniel del Toro, principal investigator of the Ramón y Cajal program at the UB Department of Biomedicine, emphasizes that “when Yamanaka’s factors are introduced during the developmental phase, more neurons are generated and the brain is more voluminous (they can double in size ) This translates into better motor and social activity in the adult stages”. And he continues: “These results are explained by the fact that we have made it possible for all brain cells to express these factors, including stem cells.” “It was very surprising to discover that, if we control the expression of these factors very precisely, we can also control the process of cell proliferation and obtain brains with a larger cerebral cortex without losing the correct structure and functions,” he adds to.

The researcher notes that “we were also surprised to find that behaviorally there were no negative behavioral consequences, and that the mice even improved in motor and social interaction behavior.”

Professor Albert Giralt said that in the case of adult mice: “the expression of Yamanaka factors in mature neurons causes these cells to rejuvenate and protect against neurodegenerative diseases such as Alzheimer’s disease“In this case, we induced the expression of Yamanaka factors only in mature neurons. Because these cells do not divide, their number does not increase, but we identified many markers that indicate a process of neuronal rejuvenation. In these rejuvenated neurons we discovered that the number of synaptic connections increases, the altered metabolism is stabilized and the epigenetic profile of the cell is also normalized,” says Giralt.All these changes have a very positive effect on their functionality as neurons“, says the expert.

Cellular reprogramming to combat neurodegenerative diseases

Understanding the aging process at the cellular level opens new horizons in the fight against diseases through cellular reprogramming. However, this process also carries the risk of creating abnormal cell populations, i.e. tumors.

The experts say that “In our study, by carefully controlling specific neural populations, we were able to ensure that the factors are not only safe, but also improve neuronal synaptic plasticity, as well as higher-order cognitive functions such as the ability to socialize and form new memories. forms.They also note that, “since positive effects have also been identified when the factors are expressed at very early stages of brain development, we think it would be interesting to investigate their consequences in neurodevelopmental disorders”.

But how do these factors affect the nervous system? Everything indicates that Yamanaka’s factors act on at least three molecular scales. First, they have epigenetic effects and this would affect gene transcription (DNA methylation process, histones, etc.). It would also compromise metabolic pathways and mitochondrial function (cellular energy production and regulation). Finally, they could impact many genes and signaling pathways involved in synaptic plasticity.

The study, published in Cell Stem cellincreases understanding of the functions of the Yamanaka factors described thus far. The factors were known to enhance regeneration after injury in retinal ganglion cells (David A. Sinclair, Harvard University, 2020) and also induce epigenetic changes in neurons of the hippocampal dentate gyrus of mice (Jesús ávila, CBMSO-CSIC-UAM and Manuel Serrano, IRB Barcelona, ​​​​2020). The researchers conclude that based on the new results “to promote future research to determine which other diseases of the nervous system could benefit from cell reprogramming technology, to investigate the underlying molecular mechanisms to design new therapeutic strategies and, finally, to bring the results closer to clinical practice in the treatment of patients to bring“.