Biomarkers of Aging

What Is Cellular Senescence? – The Hallmarks Of Ageing Series

Posted on 3 June 2021

In this series of articles, we discuss the nine ‘common denominators’ of the ageing process – the hallmarks of ageing. What exactly they are, how they change during ageing, and how we might be able reverse them in the future? Hopefully, by the end of this series, you will have a wider understanding of what actually makes us age.

The Hallmarks of Aging: Cell
The hallmarks of ageing.
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What Is Cellular Senescence?

The term senescence is derived from the Latin senescere, which means “to grow old”. In common parlance, senescence is synonymous with biological ageing. With the advent of powerful microscopes and other lab techniques over the last 60 years, scientists have observed deterioration with age at the cellular level, and have repurposed the term senescence for a more specific meaning.

In 1961, gerontologist Leonard Hayflick showed that human skin cells grown under laboratory conditions could only divide about 50 times. After that, these cells entered a state in which they were no longer able to replicate – this state is known as cellular senescence. Since then, the number of times a cell will divide in culture has been shown to decrease with the age of the donor. Cells from a 30 year old divide approximately 70 times in culture, while those from an 80 year old divide about 50 times. This number, called the Hayflick limit, also varies across species. The cells of the very long-lived Galapagos tortoise have a Hayflick limit of around 110, while mouse cells become senescent within just 15 divisions. This cessation of division is the result of telomere shortening, which you can learn about in our article covering telomere attrition.

DNA testing companies offer telomere testing – but what does it tell you  about aging and disease risk?
Telomere shortening during cell division.
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While these numbers apply to cells that are fully developed and specialised, some stem cells (the cells that are still capable of dividing to give rise to multiple different cell types) may have very large or even infinite Hayflick limits. Since our tissues are supported by pools of self-renewing stem cells, it is uncertain to what extent the Hayflick limit is actually reached in living organisms. However, cells certainly do become senescent in living humans, and senescence can be triggered in multiple ways, not only in response to telomere shortening (see telomere attrition), but also in response to the build-up of excessive damage. This is a very good thing, as any genetic damage would be passed on to daughter cells during division. To prevent this from occurring, cells will either ‘commit suicide’ (a process called apoptosis) or become senescent. Senescence therefore serves to arrest the expansion of damaged, poorly functioning cells, while also acting as a safeguard against cancer by shutting down cells that are dividing too rapidly (as these cells will quickly exhaust their telomeres).

Senescent cells may have stopped dividing, but they are not inactive. Senescent cells undergo various changes, including altering their gene expression to promote the secretion of inflammatory molecules and growth factors. This is known as the senescence-associated secretory phenotype (SASP). These molecules serve as signals to the immune system to attack and remove the senescent cells, thus eliminating the ‘bad apples’ and maintaining a population of healthy and well-functioning cells. They are also thought to aid the repair of damaged tissue. In this way, the generation of senescent cells may be an important factor in wound healing.

How Is Cellular Senescence Linked To Ageing?

Unfortunately, though senescence itself is an important and necessary process, too much senescence is a bad thing. Due to changes already discussed in previous articles, ageing is accompanied by cellular damage in the form of genomic instability, telomere attrition and mitochondrial dysfunction, resulting in cells becoming senescent more frequently. Furthermore, they may not be removed as quickly due to the age-related weakening of the immune system. When the rate of accumulation of senescent cells outstrips their rate of clearance, the population of senescent cells within our tissues starts to increase.

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).
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A build-up of senescent cells is a problem for several reasons. Cellular senescence can contribute to the depletion of stem cells. Stem cells divide to give rise to one cell that will remain a stem cell, and another that will differentiate into a fully specialised cell, like a muscle cell or a white blood cell. Senescent stem cells cannot divide and are therefore unable to fulfil this function, reducing the regenerative capacity of the tissue in which they belong. This is thought to be a major cause of age-related muscle decline. Stem cell exhaustion will be covered in more detail in the next article of this series.

The signals released by senescent cells to call for their removal become problematic when senescent cells accumulate and aren’t removed. This senescence-associated secretory phenotype (SASP), which includes the release of inflammatory molecules, growth factors and enzymes that digest extracellular proteins, can result in the disruption of tissue structure and function. Inflammation is implicated in all major chronic diseases of ageing. Ironically, considering their role in preventing cancer, populations of senescent cells can promote and support the growth of tumours thanks to the factors they release, and also make cancer more likely to reoccur after the tumour is removed. This problem is actually compounded by chemotherapy, which can promote senescence in cells surrounding a tumour due to the ‘collateral damage’ that is caused. For this reason, the role of senescent cells is increasingly taken into account when it comes to developing cancer therapies.

How Can Cellular Senescence Be Measured?

Senescent cells have a unique and abnormal appearance and behaviour. They are enlarged and can be stained with dyes or labelled with fluorescent substrates that respond to the presence of an enzyme called beta-galactosidase (beta-gal), which accumulates particularly in senescent cells. Other markers for senescence also exist, such as p16 INK4A, a protein which controls cessation of cell division and is activated during senescence. Senescent cells also display structural changes in their chromatin (the complex of proteins and DNA within the nucleus) which are visible under a microscope.

Overview of Cellular Senescence and Aging | Cell Signaling Technology
Normal cells (left) and senescent cells (right) viewed following beta galactosidase staining.
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When studying diseases of ageing , it is often necessary to study not just the burden of senescent cells within tissues, but also to measure the levels of harmful signals they are producing (SASP factors). These include inflammatory mediators like IL-6 and TNF alpha, as well as enzymes for degrading the extracellular matrix like MMP-3.

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Markers of cellular senescence
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No single marker is enough to indicate senescence by itself, so scientists usually study a combination of these markers to assess whether or not cultured cells are senescent. Measuring senescence in tissue samples and in living organisms is more challenging for a variety of reasons. Even in aged organisms, the actual number of senescent cells is still very low relative to non-senescent cells. Some markers used to detect senescent cells in culture may be expressed by non-senescent cells of certain types under certain conditions, making them unsuitable for use. Different cell types may display different patterns of markers when they become senescent. Furthermore, not all cells that have stopped dividing are senescent – some stem cells are maintained in a state called quiescence, in which they do not divide but still retain the capability to do so. These cells must be properly distinguished from senescent cells.

Mice can be genetically engineered so that genes associated with senescence activate the expression of fluorescent proteins. A large number of stains and fluorescent molecules and tracers have also been developed, allowing elevated beta galactosidase to be detected in living organisms, sometimes with the use of positron emission tomography (PET).

How Might Cellular Senescence Be Fixed?

One approach to fixing cellular senescence in ageing is to simply remove senescent cells using drugs called senolytics – compounds that selectively eliminate senescent cells. Since senescent cells become a problem when they are not removed quickly enough, it is hypothesised that boosting the clearance of senescent cells may slow the development of age-related diseases. Senolytics such as dasatinib and quercetin have shown promise in slowing the progression of many age-related pathologies in animals, and there is evidence that they can reduce the burden of senescent cells in humans. Clinical trials are currently underway to investigate whether senolytics can benefit human health. Some have already published encouraging findings, but it is still too early to draw firm conclusions about possible anti-ageing effects.

Another approach would be to develop treatments to reverse the onset of senescence. Though senescence has historically been viewed as an irreversible process, recent research suggests that senescence can be reversed. Due to the role of senescence in protecting against cancer, this approach has the potential to trigger malignant transformations, but a recent study showed that inhibiting an enzyme called PDK1 could reverse senescence in skin fibroblasts without causing malignant behaviour. If it could be done safely, reversing senescence might be able to restore stem cell populations by making senescent stem cells functional again.


References

The Hallmarks of Aging: https://dx.doi.org/10.1016%2Fj.cell.2013.05.039

Senolytic drugs: from discovery to translation: https://dx.doi.org/10.1111%2Fjoim.13141

First evidence that senolytics are effective at decreasing senescent cells in humans: https://doi.org/10.1016/j.ebiom.2019.09.053

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study: https://doi.org/10.1016/j.ebiom.2018.12.052

Simulations open a new way to reverse cell aging: https://www.sciencedaily.com/releases/2020/11/201130101245.htm

Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts: https://doi.org/10.1073/pnas.1920338117

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