Zombie cells and the diseases of aging

Credit: Dr. Raowf Guirguis. National Cancer Institute

So called ‘zombie cells ’are cells that have lost the ability to divide, with the cell cycle going into arrest permanently, yet remain alive. Also termed senescent cells, they were discovered in 1961 when Leonard Hayflick showed that normal human fetal cells will only divide between 40 and 60 times, before they become senescent (unable to divide). He aptly named this the ‘Hayflick limit’.

The Hayflick limit is a response to shortening telomeres at the end of a DNA molecule. Telomeres are long, repeat sequences of DNA at the end of our genome that protect useful DNA from being damaged and stop chromosomes from accidentally fusing together. At every cell division they wear down slightly. Eventually, cell division starts eating away at normal coding DNA and the cell triggers a DNA damage mechanism, stopping the cell cycle and releasing inflammatory SASPs (senescence-associated secretory phenotypes). This allows the immune system to identify and destroy the senescent cell. Reaching the Hayflick limit isn’t the only way to stop the cell dividing though, any DNA damage or enough cellular stress is sufficient. If the cell continues to replicate after DNA damage, mutations and dysfunctional genes could readily cause cancer and other diseases, so suppressing its ability to divide stops the damaged DNA from causing the body harm.
Unfortunately, this isn’t entirely the case. Zombie cells have already been shown to accumulate in areas involved in diseases of aging, including osteoarthritis, atherosclerosis, Alzheimer’s and Parkinson’s. While the immune system should be able to clear out senescent cells, growing old can often come with a weakening of the immune system which allows senescent cells to build up unchecked.

Previous studies undertaken at the Mayo Clinic in Minnesota have shown that removing senescent cells from mice allowed them to live healthier for longer, and their treatment once diseases have become established helped to slow its progression. Conversely,  transplanting senescent cells into healthy mice cause them to experience physical dysfunction and frailty.

In an attempt to gain a better understanding of the zombie cells, Dr. Darren Baker’s lab at the Mayo Clinic studied senescent cells in a model mouse that is known to accumulate sticky tau proteins in its brain. These lead to loss of cognitive function, and are involved in the progression of Alzheimer’s and other neurodegenerative diseases.

It was found that when senescent cells were removed from the brain, the mice retained the ability to form memories, did not show signs of inflammation in the brain, and did not accumulate clumps of tau proteins (one of the main symptoms of Alzheimer’s, called neurofibrillary tangles). They were also able to identify the two specific types of cells in the brain that readily become zombie cells, astrocyte cells and microglial cells. When these cells function normally, astrocyte cells provide nutrients to nervous tissue and microglial cells protect the brain from pathogens.

What does this new research mean for the treatment of ageing diseases? Senescent cells are still human cells, which means that targeting them without accidentally damaging healthy cells is not easy, and even when successful they express pathways that make destroying the cell more difficult. However, in the earlier Mayo Clinic study, Navitoclax (an experimental anti-cancer drug) was trialled with success; specifically targeting senescent cells and leaving healthy cells untouched. Of course, this is far from a one-size-fits-all miracle cure for ageing and its associated diseases, but it could be a step forward in the long road to finding novel treatments and improving quality of life for the elderly.

This article was written by Magnus Gwynne and edited by James Hitchen. 

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