Picture this: You’re made up of trillions of microscopic cells. Our body replaces 330 billion of these cells each day1. Why, you may ask? Well, simply put, it maintains the body's regular function by replacing dead or damaged cells2. But, some cells rebel. Some refuse to die. These cells are known as senescent ‘zombie’ cells.
So, what makes these senescent cells so different to normal cells? Why do they ‘refuse to die’?
Cellular senescence refers to ‘an irreversible arrest of cell proliferation with maintenance of cell functions’. This is because of genes present in normal cells, that are missing in senescent cells3; often occurring in response to triggers such as DNA damage, possibly by mutation4. These missing genes, such as Cyclin A, rapidly increase the production of Thymidine Kinase, the cell’s nuclear antigen, and DNA Polymerase are regulated by E2F, a transcription factor. In senescent cells, the production of the components of E2F and certain genes is inhibited, triggering the inability of the cell to carry out DNA synthesis3. Therefore, the damaged cells can no longer replicate and act as ‘zombie’ cells because they continue to act as a metabolic burden without contributing to the organism’s life processes.
So, why are they called ‘zombie’ cells? That’s because they metaphorically and physically ‘refuse’ to die. Senescent cells display resistance to apoptosis, programmed cell death3. Apoptosis is a cellular process mediated by proteolytic enzyme ‘caspases’, which trigger the cell's ‘programmed death’ through the cleavage of the cytoplasmic and nuclear proteins. Caspases exist in all cells, though, in an inactive form as procaspases and are activated by intra or extracellular death signals which cause the aggregation of adaptor molecules within the cell which activate the procaspases5. Caspase activation is regulated by the Bcl-2 group. Senescent cells present high levels of Bcl-2 along with Bcl-xL and Mcl-1 which halt the ability of the cells to follow a programmed cell death6. Thereby, preventing cellular death.
A Zombie Heart?
Senescent cells secrete senescence-associated secretory phenotypes containing soluble signalling factors, proteases and insoluble proteins. Senescent cardiac cells secrete different senescence-associated secretory phenotypes leading to the production of mediator cells during paracrine signalling and exacerbation of the senescent phenotype. Some consequences of these include cardiac hypertrophy and inflammation6.
Hypertrophic Cardiomyopathy refers to the enlargement of the cardiac muscle cells, leading to an overall thickening of the cardiac wall. Over time, the heart is unable to take in or pump out sufficient blood each heartbeat to sustain the body7.
Among other mediator cells, produced during paracrine signalling, inflammatory mediators are also produced to maintain and propagate the senescence process in neighbouring cells and ‘recruit’ white cells to clear out senescent cells8. This causes inflammation of the cardiac tissue, which, in-turn can lead to a range of serious health problems such as arrhythmia, heart failure or cardiovascular disease.
Ageing is the ‘progressive loss of tissue and organ function over time’. Senescence, especially as you age, causes a loss of tissue-repair capacity because of cell cycle arrest in progenitor cells and produces SASP. Due to this, senescence is a major factor in ageing, accentuating its tell-tale signs such as wrinkles and fine due to an accumulation of cells in the skin, reducing collagen and elastin causing a loss of elasticity9. Hair changes such as greying are caused by senescence in melanocytes reducing melanin production, so more hairs will be white10.
References
1 - Crowley, R. (2024, September 25). Cells by the numbers – Biomedical Beat Blog – National Institute of General Medical Sciences. NIGMS Biomedical Beat Blog. https://biobeat.nigms.nih.gov/2024/09/cells-by-the-numbers-2/
2 - How do normal cells and tissues grow? (2024, December 5). Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/what-is-cancer/how-cancer-starts/how-cells-and-tissues-grow
3 - Raffetto, J. D., Leverkus, M., Park, H., & Menzoian, J. O. (2001). Synopsis on cellular senescence and apoptosis. Journal of Vascular Surgery, 34(1), 173–177. https://doi.org/10.1067/mva.2001.115964
4 - Di Micco, R., Krizhanovsky, V., Baker, D., & Di Fagagna, F. D. (2020). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology, 22(2), 75–95. https://doi.org/10.1038/s41580-020-00314-w
5 - Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Programmed cell death (Apoptosis). Molecular Biology of the Cell - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK26873/
6 - Barriuso, D., Alvarez-Frutos, L., Gonzalez-Gutierrez, L., Motiño, O., Kroemer, G., Palacios-Ramirez, R., & Senovilla, L. (2023). Involvement of BCL-2 family proteins in Tetraploidization-Related senescence. International Journal of Molecular Sciences, 24(7), 6374. https://doi.org/10.3390/ijms24076374
7 - Hypertrophic cardiomyopathy - Symptoms and causes. (n.d.). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/hypertrophic-cardiomyopathy/symptoms-causes/syc-20350198 : Also source of the image
8 - Lasry, A., & Ben-Neriah, Y. (2015). Senescence-associated inflammatory responses: aging and cancer perspectives. Trends in Immunology, 36(4), 217–228. https://doi.org/10.1016/j.it.2015.02.009
9 - Farage, M. A., Miller, K. W., Elsner, P., & Maibach, H. I. (2008). Intrinsic and extrinsic factors in skin ageing: a review. International Journal of Cosmetic Science, 30(2), 87–95. https://doi.org/10.1111/j.1468-2494.2007.00415.x
10 - Nishimura, E. K., Granter, S. R., & Fisher, D. E. (2004). Mechanisms of hair graying: Incomplete melanocyte stem cell maintenance in the niche. Science, 307(5710), 720–724. https://doi.org/10.1126/science.1099593