Senescence

Ageing And ‘Zombie Cells’ – What We Know So Far

Posted on 2 December 2022

Professor Judith Campisi is a renowned scientist responsible for ground-breaking research into the relationship between cancer, ageing, and senescent cells – ‘zombie’ cells that have lost the ability to divide, but refuse to die. She recently gave an interview for the Buck Institute to discuss everything we do and don’t know about senescence so far, and where future research is heading. Are senescent cells the key to halting the ageing process?

Understanding Senescence

What are senescent cells?

Cells can become senescent under various circumstances. Senescent cells have three defining characteristics:

  • They can no longer divide
  • They resist death in circumstances where other cells would self-destruct
  • They secrete signalling molecules that affect their neighbours

Senescent cells aren’t all bad – they can be beneficial, especially in young people. In the embryo, senescence occurs in waves that contribute to the formation of certain structures and even play a role in triggering labour. When you cut yourself, inflammation within the injured tissue causes senescence in nearby cells. These senescent cells secrete growth factors that help with the wound healing process. Senescent cells also help to protect us against cancer. Even 5 year-olds have cancer-causing mutations, but very rarely do these mutations result in a tumour, and one of the reasons for this is that most cancerous cells become senescent, leaving them unable to divide further.

As we grow older, the number of senescent cells within our tissues increases. Senescent cells are concentrated at the sites of age-related diseases including cancer, and we think they drive age-related disease through the molecules they secrete.

Scarless wound healing: From development to senescence - ScienceDirect
The effects of short term senescence are beneficial (blue), but long term accumulation of senescent cells is problematic (red).
Source

How do you detect senescent cells?

Senescent cells don’t look very different from regular cells – they look a little bit larger than normal cells, but generally aren’t easy to recognise if you haven’t been working with them for a long time. Fortunately, we have a few dozen markers for detecting them. We can use these markers to stain senescent cells so that they can be easily identified under a microscope. Unfortunately, none of these markers are truly specific – some non-senescent cells will still produce molecules indicative of senescence. For instance, some stem cells exist in a state called quiescence: they do not divide except under certain circumstances, in order to regenerate damaged tissue for example. Some of the proteins involved in blocking cell division in these cells are the same proteins blocking cell division in senescent cells.

Overview of Cellular Senescence and Aging | Cell Signaling Technology
Normal cells (left) and senescent cells (right) viewed following beta galactosidase staining, which turns senescent cells blue.
Source

What happens to cells after they become senescent?

We know that cells that become senescent in the embryo don’t stick around – it seems that the immune system removes senescent cells once they are no longer needed. However, this clearly isn’t happening quickly enough in adults. We know that the immune system declines with age, so the build-up of senescent cells may be due to an inability of the immune system to remove them as quickly as it once could. However, it is also possible that senescent cells are produced at a faster rate in older adults. This is because factors that typically trigger senescence – such as DNA damage, genetic mutations and damage to the mitochondria – become more likely with increasing age.

Cells are able to self-destruct through a process called apoptosis, yet senescent cells are resistant to apoptosis and must be removed by the immune system. We don’t really know why some cells destroy themselves, while others wait to be destroyed. It may be a kind of safety mechanism – senescent cells can serve a purpose within a tissue, so perhaps immune cells are needed to survey the overall tissue structure and ensure that the senescent cells have done their job before they are removed.

Where does our understanding of senescent cells and their behaviour come from?

Most of our knowledge of senescence comes from tissue culture, both mouse tissue and human tissue. We can cause cells in culture to become senescent, for example by exposing them to radiation. Unfortunately, we do not know for certain why senescent cells accumulate with age in living humans. Future research will focus on studying the patterns of gene expression in cells in which senescence is induced, then looking for those same patterns in human tissues. This may help us get a better understanding of what is actually driving senescence.

Is senescence different between different tissues and organs?

Cells of different types appear to undergo senescence at different rates and with different outcomes. Different cell types can also display unique markers of senescence, and these may help us distinguish senescent cells more precisely in the future. In the brain, it seems like neurons can become senescent, but it looks as though the senescence of brain-resident cells called glial cells may be more important when it comes to brain ageing. These cells are a little like the ‘gardeners’ of the brain, pruning unnecessary synapses, controlling blood flow and more.

What age-related diseases are driven by senescent cells?

Senescent cells are important drivers of cancer. This might seem counterintuitive, since senescence stops a cell from dividing and thereby prevents it from becoming cancerous. This is usually what happens in younger people. However, as more and more mutations accumulate with age, the chances of a mutation that allows a cell to escape senescence increases. Once such a cell arises, the molecular signals secreted by nearby senescent cells create a favourable environment for cancer to develop. We know that this environment plays an important role in animal models. Eliminating senescent cells from mice suppresses the development of cancer in old age, but not in youth.

Senescent cells secrete growth factors and inflammatory molecules that provide a favourable environment for cancers to grow.
Source

As already mentioned, there is evidence that senescent cells exist in the brain and play a role in brain ageing. Quite recently, it was shown that senescent astrocytes (a type of glial cell) can result in the death of neighbouring neurons. If you incubate senescent human astrocytes with healthy human neurons, they will coexist normally. However, when receiving a signal in the form of the excitatory neurotransmitter glutamate, senescent astrocytes downregulate the transport proteins that get rid of excess glutamate, and this excess glutamate can kill neighbouring neurons.

Senescent cells contribute to inflammageing – a term used to describe elevated levels of chronic inflammation throughout the body. If you give a liver biopsy to a pathologist, they can tell whether it is old or young by looking at the infiltration of certain immune cells – this is a general feature of aged tissues. Senescent cells release signalling molecules that attract immune cells and appear to be important contributors to inflammageing, though they certainly aren’t solely responsible. These immune cells cause tissue damage and can contribute to most age-related diseases.

Targeting Senescent Cells

How can we eliminate senescent cells?

Removing senescent cells in mice can be done through genetic manipulation. Professor Campisi’s lab developed mouse models in which administering an otherwise benign drug will trigger death in cells expressing senescence markers. It’s thanks to such models that we know senescence plays a role in so many age-related diseases. Eliminating senescent cells can even rejuvenate certain tissues. For example, when you eliminate senescent cells from osteoarthritic joints, cells within the joint begin to synthesise more lubricating proteins.

There are currently two main classes of drug that target senescent cells in humans:

Senolytics are drugs that are designed to kill senescent cells without harming normal cells. The most well known of these drugs generally kill senescent cells by targeting proteins that inhibit self-destruction in senescent cells. Such proteins are elevated in senescent cells but not in regular cells, which are mostly unaffected. However, this is dependant on the concentration of the drug and on the cell type. Human clinical trials of senolytics are in their very early stages.

Senomorphics are drugs that are not designed to kill senescent cells, but rather to suppress the factors they secrete. Professor Campisi is not as enthusiastic about these drugs because they don’t offer a permanent solution – if you stop taking the drug, senescent cells will resume secreting harmful molecules.

When could such drugs hit the clinic?

It’s always difficult to put a timeline on drug development, but we will probably see limited clinical applications for senolytics/senomorphics in the treatment of age-related diseases within the next decade. Drugs for treating eye conditions might be a good starting point, as drugs applied to the eye won’t enter the circulation, which minimises the risk involved with a newer class of drugs. There are also existing, widely used drugs that have been shown to target senescent cells. The diabetes drug metformin, for example, is a senomorphic that is currently under investigation to determine if it can reduce the occurrence of age-related diseases.

Can we measure someone’s senescent cell burden?

We can’t really do this at the moment, but it will hopefully be possible at some point. Ideally one could take a blood sample or even a urine sample, and look for markers of senescence that would be used to estimate what the overall burden of senescent cells might be. This will be an important step for drug development – it takes many years to prove that a drug is beneficial in terms of age-related disease, but we would at least be able to see whether it could effectively reduce senescent cell burden in a way that is practical for a large clinical trial.

What is the next big problem that needs to be solved?

One of the next hurdles for our understanding of senescence is figuring out how senescence differs in different tissues. We need to understand when senescence is helpful and when it isn’t. For example, eliminating senescent cells in mice can slow down the rate of wound healing. However, administering a molecule secreted by senescent cells, called PDGF-AA, restored their wound-healing ability. So ideally, we don’t want to eliminate all senescent cells – only those that are contributing to age related disease.


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