Rolling back the years: cell competition in ageing

Time marches on, waits for no man, and even possesses the power of flight, or so the sayings go. Ageing is the natural and unavoidable result of this passage of time for living organisms. But over the years, we have been rallying against Father Time and increasing human life expectancy through better medical care, understanding of hygiene, diet and exercise. Add to this that the maximum age a person could be anticipated to reach is now around 121 years old (note that this is maximum life expectancy - few will reach this, but most of us will die trying!). 

But medical science is not only concerned with ageing in terms of life expectancy. In fact, there is another issue that comes hand in hand with slowing down the ageing process: as people live longer, they suffer from more age-related health issues, as well as the general ‘wear and tear’ that is put on our body simply caused by daily use. 100 years ago, few people had to worry about joint pain that started in their 40s, but now those bad knees may have to keep us moving through the whole second half of our lives. Furthermore, ageing in the human body cannot be looked at as a singular concept, as certain parts of our bodies, tissues, organs and even cells show signs of ageing at totally different rates and with wildly differing results.

A competitive edge

Given this increase in life expectancy, and the rise in age-related issues, scientists at Champalimaud Research’s Cell Fitness Laboratory are working on understanding the role that a biological mechanism called ‘cell competition’ plays in processes such as ageing, development, tissue regeneration and cancer. 

Mariana Marques-Reis and Eduardo Moreno, from the abovementioned Lab, recently had an overview of their field of expertise published in ‘Developmental Biology’. Their review ‘Role of cell competition in ageing’ encompasses all of the relevant literature on how ‘cell competition’ can affect ageing, and how there may be options to ‘trick’ our bodies, at the cellular level, that would result in slowing down, stopping or even reversing the ageing process. At the moment, most of the research into cell competition is based on animal models using fruit flies, zebrafish and mice, but the authors see no reason why the fundamentals of this field cannot be successfully applied to humans moving forwards, and there is early evidence that supports this.

The first question, naturally, is: what does ‘cell competition’ mean? Cell competition is a biological process in which our bodies eliminate cells that are less healthy from the tissue. It could be thought of as your body’s way of performing quality control of its own cells: as the unfit loser cells are eliminated, healthier winner cells can replace them (and yes - winner and loser cells are actually the scientific names!) In the last 50 years, cell competition has been observed and studied in a range of contexts, but it is only really in the last decade that large strides have been taken in the field - and according to the experts, we are still only scratching the surface. 

Real-life applications from head to toe

As we age, more unfit cells start to appear, but if our bodies are performing optimally, healthier cells will continue to eliminate the less-healthy. However, there are many reasons why this process sometimes fails. 

As an example specifically related to ageing, our cells succumb to something called ‘senescence’. This is when cells are not exactly unfit - in fact, they are often capable of normal function - but they are not operating for various reasons, and this happens more and more with age. In this situation, where the winner cells are cheerily eliminating their loser brethren, they won’t notice the ‘sleepy’, senescent ones. This can be dangerous, as these cells release toxins as they deteriorate and create an ‘unfavourable cell environment’. 

On the plus side, researchers have worked out how to artificially ‘fingerprint’ these cells, making them appear to be loser cells, which then allows them to be eliminated by the body’s natural defences and replaced by healthy cells. This same process of tagging unfit cells that have slipped through our natural safety net is one of the key weapons in the arsenal of the Cell Fitness Lab researchers, and may be used to treat patients with everything from cardiac problems to skin ageing.

When losing is gaining and gaining is losing

In neurological disorders such as Alzheimer’s disease, cell competition could have a role that is provoking a rethink of long-accepted dogma: that losing neurons is generally, to be blunt, not a good idea. Eduardo Moreno explained the concept using a simple metaphor: “your neural pathways are like a conversation between many people, with each person passing information to the next. If one person is spreading the wrong information, that can affect hundreds of others very quickly. In that situation, changing the message that is being sent, or blocking it somehow, may not be possible, so just removing the person with the wrong information may be the easiest course of action.” Phrased a little more formally in the review: ‘if there is a selection of the fittest neurons and elimination of the suboptimal counterparts, it is proved to ameliorate motor abilities and memory. Therefore, the elimination of neurons is proposed to be beneficial at the initial stages of the disease.’ 

But wait - before you reach for that brain-cell-killing beer, and the extra calories that come with it, you should also consider the role that your diet has on the ageing process. It is now widely accepted that a restricted, calorie controlled diet can increase life expectancy: rats, mice, worms, spiders, fish and flies all live longer with restricted diets, so it is no big jump to think that this might also be true for humans. The reason for this is fairly simple: if an organism doesn’t have too much fuel, it will focus solely on survival, rather than energy-expensive processes like reproduction. It turns out that, if an organism can put all of its available energy into maintenance, it can survive considerably longer.

What does this have to do with cell competition and ageing? From the review: ‘[Dietary Restriction] translated into an improvement of the overall epithelium fitness status. [...] By increasing the fitness status of the gut epithelia, Cell Competition is blocked, gut integrity is maintained, and the lifespan extended.’

To understand this, it is important to know that epithelial tissues are widespread throughout your body -  your guts, your kidneys, your respiratory and reproductive tracts, and many more - so anything that affects this tissue is no joke. The above excerpt suggests that a restricted diet improves the cell fitness in this tissue through cell competition, and this could result in a significant increase in longevity: ‘Competition, either by maintaining tissue integrity, or promoting the elimination of the loser cells, will ultimately lead to an increase in lifespan.’

Competition isn’t always healthy

Cancer is often seen as the final frontier in the battle for longer life because, if all other diet, lifestyle, genetic and environmental factors are equal, it is cancer that cannot be entirely avoided. Your chances of suffering from cancer increase year on year, which means that the ageing population will inevitably require more oncologic care. The role of cell competition in fighting cancer is interesting, in that it is quite different from the other previously-mentioned methods. 

So far, we have looked at how cell competition can be optimised and encouraged to help healthy cells thrive. However, cancer cells operate by ‘tricking’ the surrounding cells into identifying them as ‘super-winners’. This means that, instead of fighting the cancer cells, your own body will eliminate healthy cells in favour of the cancerous ones. Increased cell competition would only speed up the progress of the cancer more quickly, so researchers are focussing on doing the opposite - reducing the competitiveness of cells around tumours to minimise and even reverse the proliferation of cancerous cells. Researchers are at the early stages of blocking cell competition using antibodies and initial findings appear to be very promising.

Slowly advancing towards advancing more slowly

The bottom line of this review is that the applications of cell competition are still being explored, but the outlook is very promising, particularly in the area of ageing. To be clear, this research is not looking for a ‘Benjamin Button’ scenario; there will not be a pill or a vaccine that can reverse ageing and make us young again (yet!). This exciting research field instead focuses on specific functions that, in conjunction with other treatments and processes, could mitigate the effects and signs of ageing: ‘It is tempting to speculate that, if this quality control mechanism works efficiently throughout life, can it ultimately lead to a healthier ageing and extended lifespan’ the review proposes, but as the authors conclude, ‘time will tell’.

Link to full Review Article here. 

By John Lee, content developer of the Champalimaud Foundation.