Research uncovers new insights into neuronal aging and rejuvenation

When a neuron ages, it loses synaptic connections with other neurons, it is less able to transmit nerve impulses, and its metabolism is also altered. This process of neuronal aging — inevitable with the passing 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 research study led by the University of Barcelona describes how brain neurons in mice can be rejuvenated through a controlled cellular reprogramming cycle that helps to recover some altered neurological properties and functions. The paper could open up new perspectives for studying neurodegenerative diseases in patients. In an innovative approach, it addresses the process of cellular rejuvenation in neurons and emphasizes the role of what are known as the Yamanaka factors, key proteins for reversing aging that have been little studied in the nervous system.

The study, published in the journal Cell Stem Cell, is led by experts Daniel del Toro and Albert Giralt, from the Faculty of Medicine and Health Sciences, the Institute of Neurosciences (UBneuro) and the Centre for the Production and Validation of Advanced Therapies (CREATIO) of the UB, IDIBAPS and the Neurodegenerative Diseases 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 were awarded the Nobel Prize in Medicine for their research into reprogramming differentiated cells back to a pluripotent cell state. The Yamanaka factors — specifically Oct4, Sox2, Klf4 and c-Myc — are transcription factors found throughout the scientific literature on cell reprogramming.

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

Daniel del Toro, principal investigator of the Ramón y Cajal program at the UB's Department of Biomedicine, stresses that, "when Yamanaka's factors are introduced during the developmental phase, more neurons are generated and the brain is more voluminous (it 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 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.

The researcher notes that "we were also surprised to find that, behaviourally, there were no negative behavioral consequences, and the mice even improved in motor and social interaction behaviors".

Professor Albert Giralt said that, in the case of adult mice, "the expression of Yamanaka factors in adult neurons causes these cells to rejuvenate and show protection against neurodegenerative diseases such as Alzheimer's". "In this case, we induced the expression of Yamanaka factors only in mature neurons. As 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 detected 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 fight neurodegenerative diseases

Understanding the aging process at the cellular level opens new horizons in the fight against disease through cellular reprogramming. However, this process also carries the risk of generating the growth of aberrant populations of cells, i.e. tumors.

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

But how do these factors act on the nervous system? All indications are that Yamanaka's factors act on at least three molecular scales. Firstly, they have epigenetic effects and this would influence 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 signalling pathways involved in synaptic plasticity.

The study, published in Cell Stem Cell, extends the understanding of the functions of the Yamanaka factors described to date. The factors were known to enhance regeneration after injury in retinal ganglion cells (David A. Sinclair, Harvard University, 2020) and also to cause 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, they want 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".