Asia-Pacific Biotech News

CPEB4: A Newly Identified Protein with Therapeutic Potentials for Anti-Ageing Treatments

A proteomic landscape analysis conducted in Hong Kong has revealed the role of CPEB4 proteins in regulating mitochondrial metabolism.

Ageing is inevitable. To make things worse, its associated diseases, such as cancer, dementia, and heart diseases, are the leading cause of death in the modern world. On a molecular level, ageing can be attributed to the decline in the regenerative capacity of stem cells—special cells that can divide multiple times to provide the body with fresh cells that are used to treat injuries and illnesses. Hence, a decrease in the regenerative capacity of stem cells will result in fewer healthy cells being produced, consequently resulting in an accumulation of cellular damage.   

The accumulation of cellular damage over time may then trigger a phenomenon called cellular senescence—a process in which cells stop dividing, lose their original function, and release harmful molecules. Studies have shown that stem cells enter an irreversible stage of senescence during ageing. However, the mechanism behind how stem cells enter this process is still unclear.  

Since energy is required for cells to maintain healthy functions, mitochondrial dysfunction is hypothesised to play a vital role in senescence. This is because mitochondria are responsible for providing energy for cellular activities, including cell division. Hence, the regulation of mitochondrial functions is important for cell fate determination of muscle stem cells.  

Sequencing of the skeletal muscles of ageing mice has revealed that there are systemic alterations at the gene level that may be responsible for the decline in number and function of stem cells. However, the changes in protein levels and their effects on cellular ageing were only recently investigated by a research team from Hong Kong University of Science and Technology (HKUST). In an original article published in Developmental Cell on 14 June 2023, the team, led by Professor Tom Cheung, elucidated the protein landscape of physiologically aged murine stem cells for the first time. 

The researchers first utilised low-input mass spectrometry to compare the protein levels before and after induced senescence. They found that the production of a particular protein, CPEB4, is significantly reduced in the skeletal muscles of ageing cells, and its absence impairs stem cell functions. By cross-referencing previous studies on CPEB4, the authors were able to ascertain that CPEB4 is a protein that regulates the production of mitochondrial proteins and is thus required to ensure functional mitochondrial activity. Further analysis also found that the loss of CPEB4 in the cells induces cellular senescence. Together, these observations suggest that CPEB4 governs cellular senescence by regulating mitochondrial activity.  

More importantly, the authors found that restoring CPEB4 expression improves mitochondrial functions and restores stem cell functions. Hence, there is potential for CPEB4 to be used as a drug target for anti-ageing treatments. Aside from anti-ageing treatments, its ability to rescue mitochondrial defects and reverse cellular senescence also highlights its potential as a therapeutic agent for various mitochondrial diseases, such as Leigh Syndrome.  

The authors noted that there are some limitations to their study. Most notably, their analysis could not detect all the protein changes before and after inducing cellular senescence. Hence, there may be other undetected proteins that play a major role in ageing. Despite this, their findings are still extremely relevant to the field of developmental biology and contribute significantly to our understanding of ageing. [APBN]

Source: Zeng et al. (2023). Restoration of CPEB4 prevents muscle stem cell senescence during aging. Developmental Cell, S1534580723002447. https://doi.org/10.1016/j.devcel.2023.05.012