"Cell Senescence" verses "Cell Ageing": What is the Difference?


First published @ Senescent CELL blog


In recent times, scientific findings on cellular senescence have made headlines.  The majority of these highly publicized articles are concerned with the potential health benefits of removing senescent cells from our bodies. Destroying senescent cells in mice can reverse aspects of ageing and prevent side effects in response to chemotherapy.  

In an attempt to simplify the term "cell senescence" for public consumption, the media incorrectly use words such as "old", "aged" and "elderly" to describe such cells.  This is understandable since "senescence" means "to grow old". 

The term "senescence" regarding cells was first used over fifty years ago to describe cells that could no longer proliferate after extended time in culture. Without our current understandings, this inability to proliferate was thought to be due to processes related to cell ageing and so such cells were labelled as "senescent".  Although now inaccurate, this labeling is still in use today.

So what is the difference between cell "ageing" and cell "senescence"?

Cell ageing results from the accumulation of random damage leading to impairment in cell function with time.  Cell ageing may result from the build up of damage to cellular lipids (i.e. peroxidation), damage to proteins leading to altered protein folding and aggregation, damage to the mitochondria resulting in abnormal metabolic processes and changes (epigenetic) to DNA causing alterations in gene expression.

In contrast to cell ageing, cell senescence is a programmed change in cell state often initiated by persistent damage to DNA.  

Although the initial factors which trigger DNA damage in cells may itself be random, the accompanying cellular changes associated with cell senescence are not random.  In an orchestrated response, cells permanently stop dividing, they secrete molecules that can attract immune cells and express immune proteins on their cell surface.  As such, cell senescence can be considered as a mechanism to eliminate unwanted cells by the immune system.

Part of the reason why senescent cells stay in our bodies and promote ageing may be due to a failure in the ability of an aged immune system to kill senescent cells.  The molecules that were once beneficial in attracting immune cells now become destructive over time.



Further scientific evidence demonstrating that senescent cells are not "aged" cells but rather a programmed change in cell state, comes from studies on embryonic development.  

Two back to back publications in Cell from 2013 demonstrated that the change in cell state associated with senescent cells may be beneficial during embryonic development.  If this indeed the case, it is highly unlikely that such cells suddenly become "aged" or "old" to carry out their function.  Embryonic development is highly a regulated process.  What is more likely is that such senescent cells are indeed programmed and like programmed cell death (apoptosis), play an important role in tissue remodeling during embryonic development. 

Telomere shortening: adding further to the confusion



The vast majority of the early studies on cell senescence were focused on cells which stopped dividing after extended proliferation in culture.  This was later shown to be due to telomere shortening.

Every time a cell divides it loses a portion of DNA at the end of its chromosomes called telomeres- long repeats of non-coding DNA. Telomeres protect the ends of our DNA, but when they become too short, they can no longer perform this task. This causes the cell to recognize unprotected DNA-ends as damage. A result of this DNA damage signal is induction of cell senescence.  

Throughout our lives, cells divide and our telomeres gradually become shorter. There have been numerous studies investigating the correlation between telomere length and chronological age.  In parallel to telomere shortening, gradual random alterations associated with cell ageing will also occur.

This relationship between age, telomere length and cell senescence is likely another explanation for why senescent cells are often thought of as "aged" or "old" cells.  But even in this instance, cell senescence does not occur gradually over time like ageing cells, but suddenly in response to a very short telomere. 

There is little or no evidence suggesting that telomere shortening per se causes ageing.  Cells likely function perfectly well with progressively shorter telomeres.  Problems only arise when a telomere eventually becomes too short. As such, telomere shortening increases our risk of age-related conditions as cells are more likely to become senescent.  

Drugs which could extend the length of telomeres by activating an enzyme called telomerase (which adds lost telomeres back to DNA) could prevent cells from becoming senescent and help prevent ageing.  

In summary, cell ageing can be considered as a unprogrammed, random process leading to a gradual decline in cell function.  Cell ageing is detrimental to the function of normal biological processes.  Cell senescence can be induced randomly, but is a programmed change in cell state that can occur independent of age. Cell senescence can be both detrimental and beneficial depending on the biological context.  


Killing 'zombie' cells to improve health in old age

 Image 20170316 10913 xvyi5c


Dominick Burton, Research Fellow, Aston University

This article was originally published on The Conversation. Read the original article.


 Imagine a world where you could take just a single pill for the treatment or prevention of several age-related diseases. Although still in the realms of science fiction, accumulating scientific data now suggests that despite their biological differences a variety of these diseases share a common cause: senescent cells. This has led scientists to find drugs that can destroy these cells.

When cells become damaged, they either self-destruct (apoptosis) or they lose their ability to grow and remain stuck within the body. These are the non-growing senescent cells that no longer carry out their tasks properly. They spew out chemicals that cause damage to cells nearby, sometimes turning them into “zombies” – hence why they are sometimes referred to as “zombie cells”. Eventually, the damage builds up so much that the function of bodily organs and tissues, such as skin and muscle, becomes impaired. At this point, we identify the changes as disease.

Depending on where these senescent cells gather within the body will determine which disease will develop. Senescent cells have now been shown to be linked to several diseases, including cardiovascular disease, type 2 diabetes, osteoarthritis and cancer.

In 2011 and in 2016, researchers at the Mayo Clinic in the US showed, through the use of genetically engineered (transgenic) mice, that the removal of senescent cells reduced cancer formation, delayed ageing and protected the mice against age-related diseases. The mice also lived 25% longer, on average. A similar result in humans would mean an increase in life expectancy from 80 years to 100 years. It was proof-of-principle studies like these that laid the groundwork and inspired other researchers to build on these findings.






           
  I’ll live how much longer? Kirill Kurashov/Shutterstock.com
         

Killing a few to save the many


It is not known how many senescent cells need to be present to cause damage to the body, but the harmful effects of the chemicals they release can spread quickly. A few zombie cells may have a huge impact. Drugs for specifically killing senescent cells in order to extinguish their destructive force have recently been revealed and tested on mice. The collective term for these drugs is “senolytics”.

In 2016, two research groups independently published findings on the discovery of two new senolytic drugs which target proteins responsible for protecting senescent cells from cell death. Research lead by scientists from the University of Arkansas, US, showed that the drug ABT-263 (Navitoclax) could selectively kill senescent cells in mice, making aged tissues young again. And scientists from the Weizmann Institute of Science in Israel used the drug ABT-737 to kill senescent cells in the lungs and skin of mice.

There has also been a lot of interest in the role of senescent cells in pulmonary diseases caused by damage to the lungs. Among the risk factors, smoking is known to speed up lung ageing and disease, partly by attacking healthy cells with toxic chemicals from cigarette smoke which can result in cells becoming senescent.

In late 2016, Japanese scientists showed that the removal of senescent cells using genetically engineered mice greatly restored lung function in old mice. A more recent study, lead by scientists at the Mayo Clinic in the US, showed that idiopathic pulmonary fibrosis (scarring of the lungs) was linked to an increase in the number of senescent cells and the damaging effects of the chemicals they release. The killing of senescent cells using genetically engineered mice again greatly improved lung function. In the same study, this group also reported the possible use of a combination of drugs, dasatinib and quercetin, to destroy senescent cells.

A study published earlier this month from the University of Arkansas, extended their previous findings on the drug ABT-263 to pulmonary fibrosis. They found that ABT-263 treatment reduced the problems caused by senescent cells and reversed the disease in mice.

There’s money in senolytics


In light of these accumulating and highly promising findings, a number of start-up biotechnology companies have been created to exploit the health benefits of targeting senescent cells.  Probably the most well funded is Unity Biotechnology in the US which raised US$116m for research and development.

It will likely be several years before we see senolytic drugs being tested on humans. If you can’t wait that long, exercise may be the answer. A study published in March 2016 by the Mayo Clinic showed that exercise prevented the accumulation of senescent cells caused by a high-fat diet in mice. So if the regular health benefits of exercise were not enough to get you off the sofa, maybe the anti-ageing benefits will be.

Original Article: The Conversation
The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.