When thinking of biomedical research, you might think of studies with rats, mice or different types of human cells as you have possibly come across in previous posts. As scientists, we refer to these as ‘model organisms’ as they help us to ‘model’ or to understand human health and disease. However, this is not the entire repertoire of options we have, and sometimes it is better to go all the way back to the basics to understand complicated phenomena.
Ageing is one of the most complex phenomena we all face. It is multifactorial and occurs in different ways, at different speeds and it is the main cause of a variety of diseases. Interestingly, some animals are less vulnerable to ageing such as the naked-mole rat and the immortal jellyfish. It would be very interesting to find out what these animals have that makes them more resilient to ageing. However, to understand this we need to have a better understanding of cellular mechanisms of ageing.
A couple of years ago, scientists attempted to list the cellular and molecular hallmarks of human ageing. They proposed nine hallmarks that are generally considered to contribute to this process: 1) genomic instability, 2) telomere attribution, 3) altered intercellular communication, 4) mitochondrial dysfunction, 5) deregulated nutrient sensing, 6) cellular senescence, 7) stem cell exhaustion, 8) epigenetic alterations and 9) loss of proteostasis (López-Otín et al., 2013) (Figure 1). These all sound very complicated, but don’t worry, we will go through the most important of them slowly further in this post.
When you are drinking a beer or eating bread you might not be immediately thinking that the building blocks of these products can give us insights into the molecular process of ageing. But it is true, yeast is both the building block of beer and bread and a very useful tool in studying various cellular processes. You might not think so, but it is actually quite similar to human cells. Many of the ageing hallmarks mentioned above have also been found in yeast cells and have helped us find essential insights in the underlying mechanisms of how our cells age.
Yeast is a very versatile model organism for studying aging, since it has two different types of measuring of ageing that link to two different cellular categories of mammalian cells (Figure 2). In the human body, for example, we have brain cells that (almost) do not divide anymore. Our brain cells need to last a lifetime. You can understand other cellular processes are more important than for cells, such as ways to maintain and repair building blocks within the cells. In addition to cells that rarely divide, we also have cells that divide very often, these cells are more focused on renewal and division, than maintenance. Yeast is such a versatile model that each of these different types of cells is represented in different types of measuring ageing in yeast cells.
In yeast cells you have chronological ageing, which is the actual age of one yeast cell over time. This corresponds to the ageing of non-dividing cells, such as neurons (Rempel et al., 2020). However, yeast also has the ability to divide and create daughter cells and the number of divisions that one cell undergoes is called its replicative age. Replicative ageing is an excellent model to study ageing properties of dividing cells, such as liver cells and even some stem cells. Just like liver cells, the yeast cells divide in a very similar manner.
Another advantage is that yeast cells don’t live very long so you can follow their lifespan in about three days. Processes that would take years in human cells, only take hours in a yeast cell, so the process is sped up. Of course, the human body has many additional cells and factors relevant to ageing, but the basic principles are actually very similar. Making yeast cells a very good model to go back to the basics and trying to really understand what is going on in something so complicated as human ageing.
So why would you want to study this in yeast? What are the advantages? Additional to living short and ageing fast, yeast cells are also very easy to work with. They are very low maintenance and you can easily do experiments with them, such as adding chemical compounds or changing the temperature to create stress to the cells. Furthermore, in contrast to many human cells, yeast cells are easily genetically modified. So you can relatively easily delete a protein that might be important for ageing and see the effects. Or add color-tag to proteins so you can see them under the microscope. As for ageing research there are microfluidic devices that can trap a single yeast cell over a period of time, so you can follow one cell through its whole life.
For now, I want to zoom in on replicative ageing and the hallmarks of ageing. It turns out that yeast was very valuable for this type of ageing and that five of the nine human hallmarks were well represented in yeast cells. More importantly, for these five hallmarks the research was translatable to human ageing. For the hallmarks of loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, genomic instability and epigenetic alterations there is compelling evidence for its existence in yeast cells. I will elucidate the highlights of the first three hallmarks (and in my opinion the most interesting ones) here. For a more detailed comparison of human vs yeast ageing I recommend reading this excellent review (Janssens and Veenhoff, 2016).
Loss of proteostasis
The loss of protein homeostasis (proteostasis) means that processes that keep the amount of protein in your cells in balance are disturbed. Normally there is a balance between how much protein is produced and how much is being broken down. Additionally there are helper proteins making sure these processes occur properly and everything comes to the right location and is put in the right place. With ageing and especially in neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease this balance is broken, which leads to too much proteins in the wrong place.
In ageing especially, a reduction in these helper proteins occurs, which also happens in yeast replicative ageing. Moreover, the damaged proteins in big protein complexes are additional examples of loss of protein homeostasis that occurs similarly in yeasts and human cells.
Deregulated nutrient sensing
Nutrient pathways have been implicated with ageing in many organisms, either to extend or decrease lifespan. For example, caloric restriction has been said to extend your lifespan, whereas fatty diets could shorten it. Also in yeast, changes in the same pathways have been described to accompany ageing. Interestingly, like we usually gain some weight with the years, ageing yeast cells also increase in size when they age. This has been suggested to induce metabolic changes since the cell size to volume ratio changes. Many pathways in nutrient sensing are conserved over species, making yeast a compelling model to study changes in ageing.
Mitochondrial dysfunction
Mitochondrial dysfunction is implicated in ageing for many reasons. Mitochondria provide energy to cells, so you can see that when something is wrong with the energy suppliers, the cells will not be happy. However, what is very interesting is that in ageing yeast it seems that mitochondrial dysfunction is one of the earlier signs of ageing in the cells. Changes in the mitochondria have been observed at ages where normally still more than 98% of the population are alive. Additionally, ageing yeast cells show a change in mitochondrial appearance, production of reactive oxygen species (ROS) and the increasing damage it causes to proteins.
Hopefully after reading this blog post, you understand that yeasts are more than an ingredient in your favorite drink. They have been and are still essential in understanding basic mechanisms of complex phenomena like ageing. So next time you look a bit too deeply in your beer, you might be actually looking at a breakthrough.
References
Janssens, G., and Veenhoff, L. (2016). Evidence for the hallmarks of human aging in replicatively aging yeast. Microbial Cell 3, 263–274.
López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The Hallmarks of Aging. Cell 153, 1194–1217.
Rempel, I.L., Steen, A., and Veenhoff, L.M. (2020). Poor old pores – The challenge of making and maintaining nuclear pore complexes in aging. FEBS J.
SciFact 